Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][N:10]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[N:11]=1.[N-:20]=[N+:21]=[N-:22].[Na+].Cl.C(OCC)(=O)C>O.[Br-].[Zn+2].[Br-]>[N:16]1[NH:20][N:21]=[N:22][C:15]=1[C:14]1[CH:13]=[C:12]([N:10]2[N:9]=[N:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:11]2)[CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(-c2nnn(-c3cccc(-c4nn[nH]n4)c3)n2)nc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
3-(5-Pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (300 mg, 1.21 mmol), sodium azide (86.5 mg, 1.33 mmol) and zinc bromide (272 mg, 1.21 mmol) were suspended in water (3 mL). The reaction was capped with a reflux condenser and stirred at 90° C. for 24 h, after which time it was cooled to rt and HCl 3N (1.5 mL) and ethyl acetate (20 mL) were added and the mixture stirred vigorously until no solid was left. The organic layer was isolated and aqueous layer extracted with ethyl acetate (2×20 mL). The combined organic layers were evaporated, 10 mL of 0.25N NaOH was added, the mixture was stirred for 30min, until the original precipitate was dissolved and a suspension of zinc hydroxide was formed. The suspension was filtered, and the solid washed with 10 ml 1 N NaOH. To the filtrate was added 2 mL of 3N HCl with stirring causing the tetrazole to precipitate. The tetrazole was filtered and washed with 5 mL of 3N HCl and dried in vacuo to afford white powder. 1H NMR (CD3OD, 500 MHz) δ 8.91 (s, 1H), 8.83 (d, 1H), 8.41 (d, 1H), 8.32-8.25 (m, 2H), 8.09 (t, 1H), 7.95 (t, 1H), 7.64 (t, 1H). MS 292.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[Si]([N:11]=[C:12]=[O:13])(C)C>C(O)(C)C>[N:1]1([C:12]([NH2:11])=[O:13])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=O
Reactant: C1CSCCN1
Solvent: CC(C)O
Product: NC(=O)N1CCSCC1
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a stirred solution of thiomorpholine (1.0 g, 9.7 mmol) in isopropanol (25 mL) at rt was added trimethylsilylisocyanate (1.9 mL, 13.45 mmol) and the resulting solution stirred overnight. The resulting suspension was filtered and the filtrate concentrated in vacuo to give thiomorpholine-4-carboxylic acid amide (1.18 g, 89%); 1H-NMR (300 MHz, d6-DMSO) 6.00 (2H, s), 3.53-3.57 (4H, m), 2.46-2.51 (4H, m, obscured by solvent).
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][N:35]=1)#[N:33].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:38]([C:37]5[CH:41]=[CH:42][C:34]([C:32]#[N:33])=[N:35][CH:36]=5)=[O:39])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(C#N)nc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 17 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added 6-cyano-nicotinoyl chloride (Preparation 46, 17 mg, 96 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 72 hours and then saturated aqueous sodium hydrogen carbonate solution (5 mL) was added. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by reverse phase chromatography (Method C) to afford 6.9 mg of the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[NH2:20])[CH2:14][CH2:13][CH2:12][CH:11]=1>C1C=CC=CC=1>[C:10]1([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[NH:20][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1nn(C)c(N)c1C1=CCCC1
Solvent: c1ccccc1
Product: Cc1nn(C)c(NC(=O)Nc2ccccc2)c1C1=CCCC1
Temperature: 25 °C

Procedure:
Phenylisocyanate (0.176 mol) is added to 4-(1-cyclopenten-1-yl)-1,3-dimethyl-1H-pyrazol-5-amine (0.16 mol) in benzene (800 ml). The reaction mixture is stirred at room temperature and then at a temperature between 50° and 70° C. After distillation under vacuum, the product of the title is recovered by usual procedures. M.p. 204° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][C:11]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]3[O:32][CH2:31][O:30][C:16]=3[CH:17]=2)[N:12]=1.[Na+].[I-]>CN(C=O)C.CCCCCC>[N:3]1([CH2:9][CH2:10][C:11]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:18]3[C:13](=[CH:14][C:15]4[O:32][CH2:31][O:30][C:16]=4[CH:17]=3)[N:12]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: ClCCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: c1cn(CCc2nc(-c3ccc4c(c3)OCO4)c3cc4c(cc3n2)OCO4)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To a suspension of hexane washed NaH (60% in oil, 84 mg, 2.1 mmol) in dry DMF (5 mL) was added imidazole (142 mg, 2.1 mmol). The mixture was stirred at rt for 15 min and was treated with 2-chloroethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline (232 mg, 0.7 mmol), and then with NaI (105 mg, 0.7 mmol). The mixture was stirred at rt for 15 h and it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and air dried. The yellow solid was then crystallized from EtOAc to give the title compound as pale yellow needles (101 mg); mp 160-163° C.; 1H NMR (CDCl3) 7.5 (s, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 7.15-7.20 (m, 2H), 6.91-7.05 (m, 3H), 6.15 (s, 2H), 6.08 (s, 2H), 4.60 (m, 2H), 3.53 (m, 2H). Anal. calcd. for C21H16N4O4: C, 64.94; H, 4.15; N, 14.43. Found: C, 64.52; H, 4.11; N, 14.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CCCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-hept-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-chloro-2-heptyl-1H-indole.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:21])[CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1/[CH:40]=[CH:41]/C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1/[CH:40]=[CH:41]/[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10](=[O:21])[CH2:9]1)=[O:7]
Reactant: O=C(O)/C=C/c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCN(CCN2CCCC2)C(=O)C1
Reaction time: 1 h

Procedure:
3-Oxo-4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 6; 0.03 g, 0.1 mmol) was treated with a hydrogen chloride solution (4 M in 1,4-dioxane, 1 ml) for 15 minutes after which time the solvent was evaporated. The crude salt was dissolved in N,N-dimethylformamide (0.8 ml) with triethylamine (0.06 ml, 0.4 mmol) and (E)-3-naphthalen-2-yl-acrylic acid (0.02 g, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) were added. The mixture was shaken for 1 h after which time it was directly purified by preparative HPLC. MS (ISP)=378.6 (M+H)+.
Reaction SMILES: C([NH:11][C:12](=[NH:41])[NH:13][C:14]1[CH:40]=[CH:39][C:17]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.O.C(O)(=O)C>CO.[Pd]>[NH:13]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:25]2)=[O:19])=[CH:39][CH:40]=1)[C:12]([NH2:41])=[NH:11]
Reactant: N=C(NC(=O)OCc1ccccc1)Nc1ccc(C(=O)N2CCN(CCCC(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)Nc1ccc(C(=O)N2CCN(CCCC(=O)O)CC2)cc1

Procedure:
A solution of 1 g of benzyl 4-(4-(4-(3-CBZ-guanidino)benzoyl)piperazin-1-yl)butyrate (FAB 558; obtainable by condensing 4-(3-CBZ-guanidino)benzoic acid with benzyl 4-(piperazin-1-yl)butyrate) in a mixture of 38 ml of methanol, 6 ml of water and 6 ml of acetic acid is hydrogenated on 0.6 g of 5% Pd/C at 20° and 1 bar until the uptake of H2 has ceased. It is filtered, the filtrate is evaporated and the residue is recrystallized from ethyl acetate to give 4-(4-(4-guanidinobenzoyl)piperazin-1-yl)butyric acid, FAB 334.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]([OH:19])[C@H:9]([N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.CC(C[AlH]CC(C)C)C>[Cl-].[Na+].O.C1(C)C=CC=CC=1.O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@H:9]([N:20]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.8 %

Procedure:
(2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol) was dissolved in the mixed solvent (3.8 ml, toluene/tetrahydrofuran=1/1). Triphenyl phosphine (268 mg, 0.99 mmol) and 4-nitrobenzoic acid (149 mg, 0.87 mmol) were added to the solution at 0° C. Thereafter, diethyl azocarboxylte (156 μl, 0.99 mmol) was slowly added to the reaction through syringe. The reaction mixture was stirred for 3 days at the room temperature. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by short silica gel column chromatoghaphy to semi-product. Further purification was not accomplished. The crude product was dissolved in dichloromethane. DIBAL-H (1 M in hexane, 1.36 mmol) was slowly added to the solution dropwise at −20° C. The reaction mixture was stirred for 20 min. To terminate the reaction, the saturated brine solution was added to the reaction mixture. The organic layer was separated. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (18 mg, yield: 19%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[N:19]=1.[B-](F)(F)(F)[CH:21]=[CH2:22].[K+].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:21]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[N:19]=1)=[CH2:22]
Reactant: CC(C)(C)OC(=O)N1CCCCc2ccc(Cl)nc21
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCCC2

Procedure:
A degassed mixture of tert-butyl 2-chloro-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate (690 mg, 2.44 mmol), potassium trifluoro(vinyl)borate (344 mg, 2.44 mmol), PdCl2(dppf). CH2Cl2 (199 mg, 0.244 mmol) and Cs2CO3 (2.00 g, 6.1 mmol) in THF (50 ml) and H2O (10 ml) was heated at 80° C. for 3.5 h. The reaction mixture was diluted with H2O and extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 120 g RediSep® silica column and purified by normal phase chromatography, eluting with 1:3 EtOAc/heptanes. Product-containing fractions were combined and evaporated to give the title compound as an off-white solid. (UPLC-MS 6) tR 1.18; ESI-MS 275.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]=12.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccn2ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccn2ccnc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 95 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-7-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 95% of theory; LC (method 4): tR=1.59 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28]>N1C=CC=CC=1>[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH:28][C:4]([C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[NH2:1])=[O:6]
Reactant: COC(=O)CN
Reactant: Nc1cnccc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: COC(=O)CNC(=O)c1ccncc1N
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of 100 mg of 3-amino-isonicotinic acid in pyridine (2.5 mL) is added 117 mg of 1,1′-carbonyldiimidazole and the mixture is stirred for 20 min at 55° C. Then the mixture is cooled to room temperature and 91 mg of glycine methylester hydrochloride is added and the resulting mixture is stirred for 30 min at 55° C. and 1 h at room temperature. Then the solvent is removed under vacuum and the residue is purified by flash chromatography on silica gel to give 100 mg (66%) of [(3-amino-pyridine-4-carbonyl)-amino]-acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:23][CH3:24])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][NH:27][CH3:28]>CCO>[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:10]2[C:9]([S:23][CH3:24])=[N:8][N:7]3[C:2]([N:27]([CH3:28])[CH3:26])=[CH:3][C:4]([CH3:25])=[N:5][C:6]=23)(=[O:12])=[O:13])=[CH:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C(C)C)cc1
Reactant: CNC
Solvent: CCO
Product: CSc1nn2c(N(C)C)cc(C)nc2c1S(=O)(=O)c1ccc(C(C)C)cc1

Procedure:
In an analogous manner to that described in Example 5, from 7-chloro-3-(4-isopropyl-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and dimethyl-amine in EtOH there was obtained [3-(4-isopropyl-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl]-dimethyl-amine as colorless crystals, m.p. 222-224°.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14]>>[CH3:9][O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH3:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COC(=O)C=C(C)C
Product: COC(=O)CC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was reacted with methyl-3,3-dimethylacrylate to provide the title compound: 1H NMR (400 MHz, CDCl3) 1.74 (s, 6H), 2.81 (s, 2H), 3.57 (s, 3H), 7.57 (d, 1H, J=1.3 Hz), 7.90 (d, 1H, J=1.6 Hz); MS m/z 228.2 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCCCCO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCCCCO
Temperature: 60 °C
Yield: 94.4 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.6 g of 5-amino-1-pentanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.9 g of 5-(4-nitro-2-methylphenylamino)pentan-1-ol (19) were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1C(=O)c1ccc(F)cc1

Procedure:
Thionyl chloride (1.6 ml) was added to a solution of 2-(4-fluorobenzoyl)benzoic acid (3.6 g) and pyridine (0.03 ml) in benzene (40 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluorobenzoyl) benzoyl chloride (IRνmaxNujol : 1790 cm-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22](F)(F)F)N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36][S:37](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:39])=[O:38].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:22]=[C:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:21]=1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of methyl 2-(4-(2-fluorophenyl)pyridin-3-ylamino)acetate (272 mg, 1.05 mmol; example 196, intermediate) in CH2Cl2 (3 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (280 mg, 1.05 mmol, example 114, intermediate a) and 2-bromo-1-ethylpyridinium tetrafluoroborate (343 mg, 1.25 mmol) and N,N-diisopropylethylamine (270 mg, 365 μL, 2.09 mmol). The reaction mixture was stirred at room temperature for 22 hours and then concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (323 mg, 61%). MS (ESI): m/z=511.094 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]=O)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:18])[C:16]#[CH:17].CO.[BH4-].[Na+]>O1CCCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[C:1]([O:5][C:6]([N:8]([CH:9]([CH3:11])[CH3:10])[CH2:12][CH2:13][NH:18][CH2:15][C:16]#[CH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN
Reactant: CC(C)N(CC=O)C(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#CCNCCN(C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.9 %

Procedure:
3.9 mL (13 mmol) of titanium isopropoxide and 2 g (10 mmol) of (tert-butoxycarbonyl-isopropyl-amino)-acetaldehyde (prepared according to the method described by Kato, Shiro et al., J. Chem. Soc. Perkin Trans. 1, 1997, 21, 3219-26) are added to a solution of 1.65 g (30 mmol) of propargylamine in 50 mL of anhydrous tetrahydrofuran. The solution is stirred for 5 hours at room temperature then 5 mL of anhydrous methanol and 317 mg (8.4 mmol) of sodium borohydride are added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2) to give 1.2 g (50%) of N-tert-butoxycarbonyl-N-isopropyl-N′-prop-2-ynyl-ethane-1,2-diamine in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:25][CH2:24][C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCc1cccnc1
Product: CO[C@@H]1C[C@@H](C(=O)NCc2cccnc2)N(C(=O)OC(C)(C)C)C1

Procedure:
The title compound is prepared analogously as described in example 14 step B using (2S,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester instead of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and 3-picolylamine instead of 4-methoxyphenethylamine.
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.[CH3:19][S:20](Cl)=[O:21]>C(OCC)C>[CH3:19][S:20]([N:11]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:21]
Reactant: C1CCC2CCCC(C1)N2
Reactant: CS(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)N1C2CCCCC1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of 10-azabicyclo[4.3.1]decane hydrochloride (10 mg, 0.057 mmol) in anhydrous diethyl ether (1 mL) was cooled in an ice bath. The reaction mixture was treated with triethylamine (0.1 mL, 0.72 mmol) and methanesulfinyl chloride (10 mg, 0.1 mmol). The reaction vial was sealed and placed in a −40° C. freezer overnight. The reaction mixture was warmed to room temp, diluted with ether (2 mL), washed with water (2×1 mL), sat. aq. KCl (1×2 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as an oil (8.1 mg, 71%): 1H NMR (CDCl3, 600 MHz, δ) 4.02 (br quin, 1H, J=4 Hz, C1- or C9-H), 3.84 (br quin, 1H, J=4 Hz, C1- or C9-H), 2.55 (s, 3H, C1′H), 1.88-1.72 (m, 5H), 1.65-1.48 (m, 9H); ESIMS m/z 224.1 (89, MNa+), 202.1 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).