Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28]CCCCC.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: CCCCCC
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane washed 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Brown semi-solid. Yield: 150 mg (36%); 407 (M+H); 1H NMR: δ 7.91(1H, m), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 3.77(3H,s), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)[C:3]([NH2:5])=[O:4].[ClH:12]>O>[ClH:12].[ClH:12].[NH2:1][CH:2]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)C(N)c1cncnc1
Agent: Cl
Solvent: O
Product: NC(=O)C(N)C1CN=CNC1
Yield: 92.5 %

Procedure:
Amino(pyrimidin-5-yl)acetamide (950 mg, 6.7 mmol) is suspended in a mixture of 50 ml water and concentrated hydrochloric acid (13.3 mmol). The mixture is hydrogenated at 26 psig over 300 mg Pd-on-carbon 10% in a Parr hydrogenator for 3 h. Then the suspension is filtered and the filter rinsed twice with hot water (20 ml). The filtrate can be evaorated in vacuo to give 1.41 g yellow oil (92%). The oil is crystallized from anhydrous methanol/THF to give 1.33 g (87%) white crystals, identified by 300 MHz nmr.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39]>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4(3-chloropropoxy)-3-methoxyphenyl]-ethanone (5.3 g, 22 mmol), and dimethylfonnamide (60 ml) was heated at 90° C for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:24]1(=[O:39])(=[O:38])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:29][CH2:30][S:24]3(=[O:39])=[O:38])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CC(C)(C)OC(=O)N1CCNS(=O)(=O)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.188 g, 0.50 mmol), tert-butyl 1,2,5-thiadiazepane-5-carboxylate 1,1-dioxide (0.12 g, 0.45 mmol) and Cu2O (0.071 g, 0.50 mmol) in pyridine (3 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH2:12][C@H:13]([NH:17][C@@H:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]([F:22])([F:21])[F:20])[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:30][C:31]1([C:37]#[N:38])[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:37]([C:31]1([NH:30][C:14](=[O:16])[C@@H:13]([NH:17][C@@H:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]([F:20])([F:21])[F:22])[CH2:12][S:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:11])[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1)#[N:38]
Reactant: N#CC1(N)CCSCC1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccc(F)cc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccc(F)cc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CCSCC1
Reaction time: 1 h
Yield: 16 %

Procedure:
3-(4-Fluorophenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid (146 mg) and 4-aminotetrahydrothiopyran-4-carbonitrile (104 mg) were weighed into a 4 mL vial fitted with a stir bar and cap and DMF (2 mL) was added to give a dark amber solution. Diisopropylamine (0.23 mL) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (271 mg) were added and the vial was flushed the vial with nitrogen and sealed with the cap. After 1 h, the reaction mixture was diluted with a 9:1 mixture of CH2Cl2:EtOAc (40 mL)) and washed with 1.0M aqueous KHSO4, water, a 1:1 H2O: saturated aqueous NaHCO3, and brine and dried over anhydrous MgSO4. After concentration, the residue was purified by flash chromatography on 20 cm3 silica gel using 9:1 CHCl3: EtOAc eluent to give the N-(4-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide (30 mg) as a beige solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[NH2:10][C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O.C(Cl)(Cl)Cl>[N:10]([C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N=C=S)sc(C)c1C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a mixture of thiophosgene (5.10 mL, 7.64 mmol) and calcium carbonate (1.05 g, 10.54 mmol) in CHCl3/H2O (½ by volume, 6 mL) was added dropwise a solution of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (1.05 g, 5.27 mmol) in CHCl3 (7 mL) at 0° C. over a period of 1 h. The reaction mixture was the stirred for 2.5 h at 0° C., washed with water (3×). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (1.21 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ1.32 (t, 3H, J=7.1 Hz), 2.19 (s, 3H), 2.30 (s, 3H), 4.28 (q, 2H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][NH:15][C:14](=O)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.P(Cl)([Cl:34])(OC1C=CC=CC=1)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:34][C:14]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:18]=2[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][N:15]=1
Reactant: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12

Procedure:
Ethyl 1-{[4-(methyloxy)phenyl]methyl}-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (2.90 g) and phenyl dichlorophosphate (18 ml) were heated at 180° C. under argon for 30 minutes. The reaction mixture was allowed to cool, poured onto iced water, and neutralised to pH7 using solid sodium bicarbonate. To the reaction mixture was added ethyl acetate and the insoluble material was filtered off. The aqueous was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a clear oil (2.0 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 65 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 65% of theory, C31H35N7O7S (649.7) Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1) ##EQU74##
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7](O)[CH2:8][CH3:9])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:12].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8](=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCC(O)c1ccc(C)s1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)Cc1ccc(C)s1

Procedure:
A solution of 1-(5-methylthien-2-yl)propanol from above (20 mmol) and pyridinium dichromate (9.03 g, 24 mmol) in 100 mL CH2Cl2 was stirred for 18 h. The reaction was then filtered through Celite and the filtrate was concentrated. The resulting residue was purified by chromatography (silica gel, etherhexanes, 1:9) to afford 1.86 g (60% over the two steps) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:23]#[CH:24])([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl>CO.O.[Fe]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])([C:23]#[CH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)OCC)CC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a stirred solution of 22.3 g of 1-ethoxycarbonyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine in 535 ml of methanol was added 37 ml of concentrated hydrochloric acid in 150 ml of water. To the stirred mixture was added 78.6 g of iron (reduced, electrolytic) in aliquots. The reaction temperature rose to 45°. The reaction mixture cooled to ambient temperature over 1.5 hr. The mixture was poured into water/ice/sodium carbonate solution, extracted with dichloromethane, washed with water and saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided 20.2 g of an oil. An aliquot of 10.0 g of the oil was dissolved in ether and filtered through 200 g of alumina and the filtrate was evaporated. The residue was dissolved in 10% methanol/dichloromethane, filtered through 200 g of silica gel, and the filtrate was evaporated to provide 8.6 g (84.7%) of product, as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.[H-].[Na+].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].O>C1COCC1>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:4]2[N:3]=[C:2]3[NH:1][C:30](=[O:31])[NH:10][C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)=[N:12]1
Reactant: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1
Reaction time: 0.42 h

Procedure:
70 mg (0.19 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carb oxamide (example 104A) were initially charged in 7 ml of THF and, while cooling with ice, 30.8 mg (0.77 mmol) of sodium hydride (60% in mineral oil) were added over a period of 5 min. The mixture was stirred for 25 min, then 46.9 mg (0.29 mmol) of 1,1′-carbonyldiimidazole were added with ice cooling over 5 min. Conversion was effected at room temperature for 1 h and at reflux temperature for 90 min. After cooling, the mixture was hydrolyzed with 2 ml of water. The precipitate formed was filtered off and then stirred in 7 ml of methanol/water (5/2). The remaining precipitate was filtered off and dried under high vacuum. Thus, 26 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][C:12]=1F.C(N(CC)C(C)C)(C)C>>[F:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][C:12]=1[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CSCN1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCSC2)c(F)c1
Yield: 23.9 %

Procedure:
Using the same general procedure as step 1, of Example 1, 4.092 g (45.90 mmol) thiazolidine was treated with 4.1 mL (37.03 mmol) 3,4-difluoronitrobenzene and 10.0 mL (57.41 mmol) N,N diisopropylethyl amine to provide 2.020 g (24%) of the title compound as an orange solid. Recystallization from methylene chloride/hexane provided an analytical sample with a melting point of 94°-95° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N+:3]=1[O-].[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OCc1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc(COC(C)=O)nc1

Procedure:
2-Methyl-5-acetoxymethylpyridine-N-oxide (0.05 mole) is refluxed in 50 ml. of acetic anhydride for two hours and then evaporated to dryness. The residue is fractionally distilled under high vacuum to obtain 2,5-di(acetoxymethyl)pyridine.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][N:17]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[S:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:41](=[NH:46])(OCC)[CH3:42].C(N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:41]([N:36]1[CH2:37][CH2:38][CH2:39][N:33]([C:30]2[CH:31]=[CH:32][C:27]([N:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[S:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])=[O:19])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[NH:46])[CH3:42]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.4 %

Procedure:
590 mg of ethyl [N-[(7-amidino-2-naphthyl)methyl]-N-[4-(hexahydro-1H-1,4-diazepin-1-yl)phenyl]sulfamoyl]-acetate dihydrochloride obtained in Example 6 was dissolved in 22 ml of ethanol, to which were added 680 mg of ethyl acetimidate hydrochloride and 555 mg of triethylamine, and stirred at room temperature for 15 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS column chromatography using an eluent solvent of ethanol/water (10/90). A small amount of 1 N hydrochloric acid was added to this, which was then freeze-dried to obtain 118 mg of ethyl [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]-sulfamoyl]acetate dihydrochloride.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[NH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(#N)C>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][CH2:26][C:25]([NH:24][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:3]=2[CH3:23])([CH3:36])[CH3:37])=[CH:35][CH:34]=1)#[N:33]
Reactant: CC(C)(N)CNc1ccc(C#N)cc1
Reactant: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(NC(C)(C)CNc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 23.1 %

Procedure:
In a bomb tube of stainless steel (Parr) fitted with an internal cylindrical glass vessel and magnetic stirrer, methyl 6-iodo-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM1, 1447 mg, 3.3 mmol), 4-(2-amino-2-methylpropylamino)benzonitrile (750 mg, 4.0 mmol), triethylamine (3.2 mL, 23 mmol) and acetonitrile (35 mL) were mixed. The mixture was purged with argon for 10 minutes. After adding bis(tributylphosphine)palladium (120 mg, 0.23 mmol), the bomb tube was sealed, evacuated and back-filled with carbon monoxide five consecutive times. The contents of the bomb tube were stirred under carbon monoxide (6.5 bar) at 50° C. for 9 h. LC-MS indicated about 50% conversion to desired product and unreacted SM. The dark red-brown solution was concentrated to dryness, dissolved in ethyl acetate (200 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated with silica to dryness. Flash chromatography on silica with ethyl acetate/n-heptane (1:3 and 1:1) as eluents gave methyl 6-(1-(4-cyanophenylamino)-2-methylpropan-2-ylamino)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (0.38 g, 22%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH:26][NH2:27])([CH3:25])[CH3:24]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Reactant: CC(C)NN
Product: CCc1nn(C(C)C)c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
4-(3-Benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1-isopropyl-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione and isopropylhydrazine in analogy to Example 55 b): colourless solid; MS (ISP): 337.3 ((M+H)+.).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.COC(OC)(C)C>C1(C)C=CC=CC=1>[CH3:10][C:9]1([CH3:14])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
Prepared according to WO patent: 2013004290A1. To a stirred suspension of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (Sigma Aldrich Chemical Company, St. Louis, Mo., 5.36 g, 46.5 mmol) and p-toluenesulfonic acid (44 mg, 0.233 mmol) in toluene (100 mL), 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 1.5 h. The reaction was equipped with a Dean-Stark apparatus then additional 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 36 h. The solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one as an orange waxy solid. MS (ESI) 156.1 [M+H]+. The crude material was taken to the next step without further purification.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1>CN(C=O)C>[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Reactant: Fc1cnc(Cl)c([C@H]2CCCN2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL), then dried (Na2SO4) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68% yield). MS (apci) m/z=390.0 (M+H).