Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][N:6]=1.P([O-])(O)(O)=O.[K+]>C(#N)C>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][N:6]=1)[C:11]#[N:12]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C#N)ccn1
Temperature: 0 °C
Reaction time: 23 h
Yield: 70.5 %

Procedure:
A stirred suspension of 17.86 g NaOMe (330.7 mmol, 1.22 eq) in 95 mL acetonitrile was cooled to 0° C. and a solution of 37.56 g 2-chloro-4-cyano pyridine (8, 271.1 mmol) in 225 mL acetonitrile was added over 45 min. Stirring was continued at room temperature for 23 h until less than 4% (area) starting material were detected by HPLC. 11.1 g potassium dihydrogen phosphate (81.56 mmol, 0.30 eq) were added at 0° C. and stirring was continued for 3 h at room temperature. The reaction mixture was then evaporated to dryness in a rotary evaporator (40° C./10 mbar) yielding the crude product (64.94 g, 179% by weight) as a brown solid. 64.94 g crude product were extracted with 900 mL toluene for 18 h at reflux temperature using a soxhlet extraction apparatus yielding the title product (25.65 g, 71% by weight) as an orange solid.
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)[CH2:6][CH2:7][NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Reactant: CN(CCN)c1nccn1C
Agent: N=C=N
Solvent: ClCCl
Product: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1nccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
2.3 g (≅2.8 mmol) PS carbodiimide was added to a solution of 215 mg (1.4 mmol) N1-methyl-N1-(1-methyl-1H-imidazol-2-yl)ethane-1,2-diamine and 378 mg (2.1 mmol) 3-(3-chloro-phenyl)propiolic acid in DCM (30 ml) and the reaction solution was shaken for 16 h at RT. The resin was subsequently filtered off, washed with DCM and ethanol and the filtrate concentrated in a vacuum. CC (DCE/EtOH 5:1) was performed with the residue, whereby 241 mg (0.8 mmol, 54%) 3-(3-chlorophenyl)-N-(2-(methyl(1-methyl-1H-imidazol-2-yl)amino)ethyl)-propiolamide was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].[CH3:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[N:5]([CH2:17][CH2:16][O:15][CH3:14])[N:4]=1)[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOC)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (prepared as in WO 98/49166) (1.7 g, 8.8 mmol), 2-bromoethyl methyl ether (0.85 mL, 8.85 mmol) and cesium carbonate (2.9 g, 9.0 mmol) in dimethylformamide (20 mL) was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (125 mL) and brine (100 mL). The phases were separated, and the organic layer was dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate:methanol (97:3) as eluant to afford 3-ethyl-1-(2-methoxyethyl)-4-nitro-pyrazole-5-carboxamide (831 mg, 39%).
Reaction SMILES: [N:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:6]2[C:7]([N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:2]=[N-:3].S(Cl)([Cl:25])=O>CN(C)C=O>[N:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:6]2[C:7]([N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:25])=[O:18])[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)O)C2=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)Cl)C2=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
15.0 g (0.05 mol) of the 6-(3-azidophthalimidyl)-caproic acid obtained according to Example 8 are dissolved in 327 g (2.75 mols) of thionyl chloride, and the solution is warmed to 80° C., the operations being carried out under yellow light. At 80° C., 0.5 ml of N,N-dimethylformamide is added to the clear solution obtained. The reaction mixture is stirred for 15 minutes at 80° C. and is then cooled to room temperature. This produces a beige-coloured suspension, which is filtered with suction, under N2. The crude product is recrystallised from 250 ml of dry ligroin. 12.5 g (75.4% of theory) of 6-(3-azidophthalimidyl)-caproyl chloride are obtained; melting point 68°-69° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16]C(O)C1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:16][CH:17]([CH3:19])[CH2:18][CH:13]([CH2:12][CH2:11][C:10]([O:9][CH3:8])([CH3:22])[CH3:21])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: COC(C)(C)CCC1CC(C)CC(O)C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(C)(C)CCC1CC(C)CC(OC(C)=O)C1

Procedure:
Acetic anhydride (1.4 mL, 0.014 mol), 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-ol (2.0 g, 0.0093 mol), toluene (3.0 mL) and sodium acetate (0.05 g) were combined and heated at reflux for 16 hours. Workup provided 1-acetoxy-3(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexane, bp0.5 175-177~C. (1.61 g) as a mixture of diastereoisomers (ratio 92.3:3.2:4.5); NMR(CDCl3)δ 0.6(q,1H), 0.9(d,3H), 1.0-1.3(m,3H), 1.2(s,6H), 1.4-1.6(m,4H), 1.6-2.0(m,4H), 2.1(s,3H), 3.2(s,3H), 5.1(m,1H); IR(neat) 2960, 2925, 1740, 1460, 1380, 1250, 1085, 1015 cm-1 ; MS(m/e) 43, 73, 93, 108, 149, 164, 181, 241, 242.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:22]([O:24]CC)=O)=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C(O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:24])[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[NH:16][C:14]2=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 118.0 g of ethyl 2-chloro-5-[3-(2-ethoxycarbonyl-1-cyclopenten-1-yl)ureido]-benzoate in 800 ml of absolute 1,2-dimethoxyethane is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 7.7 g of sodium hydride in 800 ml of absolute 1,2-dimethoxyethane. The reaction mixture is subsequently stirred for 1 hour. treated with 20 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 2 l of methylene chloride and washed twice with 1 l of water. The organic phase is dried over anhydrous sodium sulphate and evaporated until crystallization occurs. The residue is treated with 1 l of n-hexane and the crystals are filtered off under suction and rinsed with n-hexane. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 178°-180° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13]([C:34]#[N:35])[CH:12]=1)=[O:10])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.CCOC(C)=O>[C:34]([C:13]1[CH:12]=[C:11]([C:9]([OH:10])=[O:8])[C:19]([CH3:20])=[C:18]2[C:14]=1[C:15]1[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=1[NH:17]2)#[N:35]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(C#N)c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)O)cc(C#N)c21
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A 500 mL Parr flask was charged with 5-cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (14.24 g, 0.030 mol), 1:1 MeOH/EtOAc (180 mL), and Pd(OH)2 (20% on C, 3.02 g). The flask was shaken on a Parr shaker at 5 psi above ambient pressure for 30 minutes. The reaction mixture was filtered through a pad of Celite, washed with methanol and concentrated. Trituration with hexanes yielded 11.11 g (96.4%) of an off-white powder. 1H NMR (CDCl3) δ 10.21 (br s, 1H), 8.22 (s, 1H), 4.22 (m, 2H), 4.00 (m, 2H), 3.09 (m, 4H), 2.89 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.90 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CC[O:38]CC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][CH:17]=[O:38]
Reactant: CCOCC
Reactant: COc1ccc(OC)c(C2CCCC2CC#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(C2CCCC2CC=O)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Dissolve [2-(2,5-dimethoxy-phenyl)-cyclopentyl]-acetonitrile (3.9 g, 16 mmol) in ether (85 ml), cool to −10° C., add diisobutylaluminum hydride 1.5M in toluene (19 ml, 29 mmol), and stir at −10° C. for 1 hour. Quench with 1N hydrochloric acid, and add ethyl acetate. Separate layers, wash organic with brine, dry, and concentrate to give the title compound (3 g, 76%): 1H NMR (CDCl3) δ 9.50-9.49 (m, 1H), 6.77-6.69 (m, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.58-3.54 (m, 1H), 2.88-2.83 (m, 1H), 2.08-1.87 (m, 5H), 1.74-1.65 (m, 2H), 1.44-1.39 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:13][N:12]([C:14]2[C:15]3[N:16]([N:25]=[N:26][N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:11]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:11][N:12]([C:14]2[C:15]3[N:16]([N:25]=[N:26][N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.3 %

Procedure:
A 2 L round bottom flask was charged with tert-butyl methyl(1-(5-(thiophen-2-yl)tetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)carbamate (50 g, 0.13 mol) and dichloromethane (500 mL). To the solution was added trifluoroacetic acid (100 mL). The resulting slurry was stirred at room temperature for 2.5 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was suspended in water (500 L) and treated with solid Na2CO3 (pH 10-11, there was un-dissolved Na2CO3 remaining). The solid was collected by filtration, re-suspended in water (500 mL×2) with stirring to remove Na2CO3. It was further washed with EtOH (500 mL), and dried to afford 27 g (73%) of the product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.19 (s, 1H), 7.96 (dd, J=4.0, 0.8 Hz, 1H), 7.76 (dd, J=4.8, 0.8 Hz, 1H), 7.27 (dd, J=4.8, 4.0 Hz, 1H), 4.60 (br, 2H), 4.18 (br, 2H), 3.73 (m, 1H), 2.43 (br, 1H), 2.29 (s, 3H). MS m/z: 288 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[C:31]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:30][S:29][C:28]=1[C:38](Cl)=[O:39]>C1COCC1>[Cl:26][C:27]1[C:31]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])=[CH:30][S:29][C:28]=1[C:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: CC(C)S(=O)(=O)c1csc(C(=O)Cl)c1Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3scc(S(=O)(=O)C(C)C)c3Cl)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-chloro-4-(isopropylsulfonyl)-2-thiophenecarbonyl chloride: ESMS m/e: 596.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[NH:7][C:4]1[NH:3][C:2]([CH3:1])=[N:6][N:5]=1
Reactant: COC1CCCCC1=O
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC1CCCCC1Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and 2-methoxycyclohexanone (3.9 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.8 g, 51%).
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.O[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[CH:40][CH:41]=[N:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:66]>C1COCC1>[ClH:66].[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:37]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:38]=3[N:39]=[CH:40][CH:41]=[N:42]4)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: Oc1cccc2nccnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)c2nccnc2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
TMAD (0.55 g, 3.20 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 5-hydroxyquinoxaline* (0.45 g, 3.08 mmol) and PPh3 (0.85 g, 3.24 mmol) in THF (20 mL). The reaction was stirred at room temperature for 1.5 h and at 65° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica using toluene/EtOAc (1:1) as eluent. The resulting solid was crystallized twice from diethyl ether/petroleum ether to remove PPh3O. The recrystallized material (0.50 g) was dissolved in MeOH (15 mL) and 1 M HCl (3.5 mL) was added. The resulting mixture was stirred at room temperature for 4 h (only 10% N-Boc-deprotection had occurred according to HPLC/MS). The mixture was concentrated and the residue was treated with CH2Cl2/TFA/H2O (50:45:5; 20 mL) for 1 h. After concentration in vacuo, the residue was dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was lyophilized to give a yellow oil that was dissolved in 1 M HCl. The solution was concentrated and MeOH and diethyl ether was added. The precipitate formed was collected and dried in vacuum to give 0.32 g (76%) of the title product. Pos-EI-MS shows M+ and 8 ions supporting the stated structure. HRMS m/z calcd for C18H20N6O2 (M)+ 352.1648, found 352.1662.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O-:13])=O)=[N:3]1.[CH3:14][NH2:15]>CO>[CH3:14][NH:15][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:13]
Reactant: Cn1nc(C(=O)[O-])c2ccccc21
Reactant: CN
Solvent: CO
Product: CNC(=O)c1nn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A suspension of methyl (1-methyl-1H-indazolecarboxylate (3.88 g, 20.4 mmole) in 40% aqueous CH3NH2 (100 mL) and MeOH (5 mL) was stirred at RT for 4 hr. During that time the suspension became a solution. The mixture was concentrated to approximately ⅓ by volume at which time the product precipitated as a pale yellow solid. The solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (3.42 g, 89%) which was sufficiently pure for use in the next step: 1H NMR (300 MHz, CDCl3) δ 8.24 (m, 1 H), 7.47 (m, 2 H), 7.34 (m, 1 H), 6.95 (bs, 1 H), 4.19 (s, 3 H), 3.05 (d, J=12.0 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([C:27]2[C:28]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1>>[F:11][C:12]1[CH:13]=[C:14]([C:27]2[C:28]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:34])=[O:35])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3S(=O)(=O)NCCO)cc2F)OC1(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Product: O=S(=O)(NCCO)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine and 3′-fluoro-N-(2-hydroxyethyl)-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C21H18FN3O3S, 411.11; m/z found, 412.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.44-8.41 (m, 1H), 8.24-8.21 (m, 1H), 8.14-8.05 (dd, J=8.0, 1.3, 1H), 7.71-7.64 (m, 1H), 7.63-7.55 (m, 2H), 7.46-7.44 (d, J=3.5, 1H), 7.44-7.41 (dd, J=7.6, 1.2, 1H), 7.36-7.34 (dd, J=3.8, 1.7, 1H), 7.34-7.31 (dd, J=7.3, 1.4, 1H), 6.59-6.55 (d, J=3.5, 1H), 3.52-3.47 (t, J=5.9, 2H), 2.92-2.87 (t, J=5.9, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([N:25]=[N+:26]=[N-:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:9]([N:25]1[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:27]=[N:26]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCN=[N+]=[N-]
Reactant: C#CCOC(=O)C=C
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cn(CCCCCCCCCCCCCCCC)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Propargyl acrylate (1.10 g, 10 mmoles), hexadecyl azide (2.37 g, 10 mmoles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (74 mg, 0.2 mmoles) are dissolved in DMF (20 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured into water wherefrom the product precipitated as a white crystalline solid (2.95 g; yield 85%; mp 72-73° C.). 1H NMR (CDCl3, δ ppm) 7.61 (s, 1H), 6.44 (d, 1H), 6.14 (dd, 1H), 5.85 (d, 1H), 5.31 (s, 2H), 4.34 (t, 2H), 1.92 (q, 2H), 1.26 (m, 28H), 0.88 (t, 3H). 13C NMR (CDCl3, δ ppm) 166.00, 142.73, 131.39, 128.04, 123.64, 57.75, 50.43, 31.89, 30.22, 29.66, 29.65, 29.64, 29.62, 29.61, 29.56, 29.47, 29.33, 29.32, 28.95, 26.46, 22.66, 14.08. MS for C12H39N3O2 calculated 377.58; found 377.20.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[C:18]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH:9]2[NH:8][C:6]1[CH:7]=[C:2]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:3]=[CH:4][C:5]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C1CNCCN1
Reactant: COc1ccc(OC)c2c1CCCC2Nc1cc(F)ccc1S(C)(=O)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c2c1CCCC2Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 71.6 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalen-1-amine (1.234 g, 3.26 mmol), piperazine (5.63 g, 65.1 mmol) and N,N-diisopropylethylamine (5.7 mL, 32.6 mmol) in acetonitrile (20 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 610 mg (42%) of 1,2,3,4-tetrahydro-5,8-dimethoxy-N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)naphthalen-1-amine: 1H NMR (400 MHz, CD3OD): δ 7.49 (d, 1H), 6.81 (d, 1H), 6.76 (d, 1H), 6.38-6.36 (m, 2H), 5.98 (d, 1H), 4.80 (br s, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.37-3.32 (m, 4H), 2.98-2.92 (m, 1H), 2.88-2.82 (m, 7H), 2.44-2.36 (m, 1H), 2.20 (br d, 1H), 1.86-1.58 (m, 3H). MS (ESI) m/z: Calculated: 445.20; Observed: 446.2 (M++1).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (119 mg, 94 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (122 mg, 99%) which was obtained as a white solid. MS: m/e=410.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.Cl.[NH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][N:2]=1
Reactant: O=Cc1ccnnc1
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
In a 25 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, pyridazine-4-carbaldehyde x66 (0.93 g, 8.6 mmol) and ethyl 4-aminobutanoate hydrochloride x67 (1.58 g, 9.5 mmol) are dissolved in CHCl3 (15 ml). Triethylamine (1.3 ml, 9.5 mmol) and MgSO4 (2 g) are added and the mixture is stirred at room temperature for 4 h. The mixture is filtered, washed with water, dried over MgSO4 and concentrated to give 1.92 g (100%) of crude ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoate x68, which is used in the next step without further purification.