Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[NH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][CH:36]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[S:47]1[CH:51]=[CH:50][C:49]([CH:52]=O)=[CH:48]1>C1(C)C=CC=CC=1>[S:47]1[CH:51]=[CH:50][C:49](/[CH:52]=[CH:14]\[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[C:5]([C:3]([NH2:2])=[O:4])[CH:36]=[CH:35][CH:34]=2)=[CH:48]1
Reactant: NC(=O)c1cccc(OCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(OCCCCC/C=C\c2ccsc2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a stirred suspension of 6-[3-(aminocarbonyl)phenoxy]hexyl(triphenyl)phosphonium bromide (2.0 g, 3.55 mmol, 1.2 equiv.) in anhydrous toluene (28 ml) was added a solution of potassium bis(trimethylsilyl)amide (0.5M; 7.1 ml, 3.55 mmol, 1.2 equiv.) in toluene, slowly, dropwise over a period of 15 min at 0° C., under N2. The dark orange solution was stirred for another 20 min at 0° C. and cool—d to −78° C., when thiophene-3-carboxaldehyde was instantly added, and the temperature was left to rise—from −78° C. to r.t. The light yellow mixture was stirred at r.t. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 ml) and the solvent was evaporated under reduced pressure. The residue was taken-up in CH2Cl2 and H2O, the organic phase was separated, washed with brine and dried (Na2SO4). The solved was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-50% gradient) to give the desired compound as an off-white solid (300 mg, 35%), mp 71-73° C. By 1H NMR analysis it consisted of a mixture of Z:E (90:10). HPLC-MS (method 1): m/z 316 [M+H]+, Rt=4.62 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O-:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.[Na+].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:18]([C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[O:20])=[CH:25][CH:24]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C([O-])c1cccc2c1CCN(Cc1ccncc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Sodium 2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (80 mg, 0.276 mmol) was dissolved in N,N-dimethylformamide (1 mL) then added 4-chloroaniline (42 mg, 0.331 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (133 mg, 0.414 mmol), and N,N-diisopropylethylamine (56 mg, 0.552 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The remaining orange oil was purified by silica gel chromatography (1% to 3% 7N ammonia in methanol/dichloromethane) to afford N-(4-chlorophenyl)-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (89 mg) as a light yellow solid. MS (ESI, pos. ion) m/z: 378.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:48][CH2:47]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methanesulfonyl-ethyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C35H43N4O5SCl2 [(M+H)+] 701.2326, observed 701.2325.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=2[F:27])[CH2:12][CH2:11]1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([O:16][C:17]3[C:18]([F:27])=[C:19]([F:26])[C:20]([F:25])=[C:21]([F:24])[C:22]=3[F:23])[CH2:14][CH2:15]2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCl)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1ccnc1)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
A stirring solution of 7.11 g of imidazole in 100 ml of dimethylformamide was treated with a solution of 7.22 g of 1-(2-chloroacetyl)-4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of dimethylformamide and then stirred at 75° C. for five hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Recrystallization of the resulting solid from ethyl acetate/hexane (10:1) afforded 3.70 g (47.0%) of 1-[(2-imidazol-1-yl)acetyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 95°-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=O)[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2N=C3c4ccncc4CCC3CC2=O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CCC3CCc4cnccc4C3=N2)cc1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
4,4a,5,6-Tetrahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnolin-3(2H)-one (0.14 g; from Example 1 above) was placed in a flask under nitrogen. Borane tetrahydofuran complex (1M, 2.4 ml) was added and the solution warmed to room temperature for 3.5 hours. Methanol (5 ml) was added. Water was added and the aqueous solution extracted thrice with ethyl acetate. The organics were washed with sodium hydrogen carbonate (saturated solution), and brine then dried, filtered and concentrated to give a yellow solid. The solid was adsorbed onto silica then chromatographed eluting with first 7:3 dichloromethane:ethyl acetate, then ethyl acetate to give a yellow solid. Recrystallisation from ethyl acetate/hexane gave the title compound (30 mg)
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)[CH2:42][NH2:43]>>[CH3:48][O:47][C:45]1[CH:44]=[C:41]([CH:40]=[C:39]([O:38][CH3:37])[CH:46]=1)[CH2:42][NH:43][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: COc1cc(CN)cc(OC)c1
Product: COc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc(OC)c1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3,5-dimethoxybenzylamine, m.p. 183-184° C. MS [(+)ESI, m/z]: 584 [M+H]+
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[OH:20])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].O>C1COCC1>[CH3:30][C:26]1([CH3:29])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:20][C:33](=[O:34])[N:17]([CH2:16][CH2:15][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:18]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2O1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Reaction time: 21.5 h
Yield: 72.7 %

Procedure:
A solution of (1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (4.803 g) in THF (100 ml) under nitrogen was treated with 1,1′carbonyldimidazole (1.702 g) and the mixture was stirred at 20° for 21.5 h. Water (125 ml) was added, the mixture was stirred for 10 min and then extracted with Et2O. The extract was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in THF (60 ml) and was treated with a solution of tetrabutyl ammonium fluoride in THF (1.0 M, 15.95 ml). The mixture was stirred at 20° for 100 min, water (30 ml) was added and the mixture was extracted with Et2O. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by chromatography on a Biotage cartridge (90 g). Elution with EtOAc-petroleum ether (2:3) gave the title compound (2.82 g). LCMS RT=3.01 min ES+ve 370 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Nc1cccnc1)Oc1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 6 using 3-aminopyridine and phenyl chloroformate. Yield 7 g, 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccn1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-pyridyl)acetate hydrochloride (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=123-125° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[OH-].[Na+].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:11]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CSCN1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 108.2 %

Procedure:
1 liter of acetone was added to a solution of 266.2 g of (4R)-thiazolidine-4-carboxylic acid in 1 liter of a 2N aqueous solution of sodium hydroxide. The solution was cooled at a temperature between 2° and 5° C., and then a solution of 280 g of benzoyl chloride in 0.8 liter of acetone was added dropwise, while maintaining the pH value of the reaction mixture at 7.5-8.0 by the addition of 1 liter of a 2N aqueous solution of sodium hydroxide. When the addition was complete, the reaction mixture was stirred at a temperature between 0° and 5° C. for 1 hour, after which it was concentrated by evaporation under reduced pressure to a volume of about 2.5 liters. The concentrate was washed with 2 liters of ethyl acetate, the aqueous phase was adjusted to a pH value of 2.0 by the addition of concentrated hydrochloric acid, maintaining the temperature at between 0° and 5° C., and the mixture was extracted twice, each time with 2 liters of ethyl acetate. The ethyl acetate phase was washed with a 10% w/v aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 511.2 g of (4R)-3-benzoylthiazolidine-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:18][NH2:19])[NH:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.CCN(C(C)C)C(C)C>[O:23]=[C:21]1[N:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:18][NH:19]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C1(CN)CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C12CNCCN1C(=O)NC2
Reaction time: 0.5 h

Procedure:
3-Aminomethyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Compound AA) from Step 3 was dissolved in 4 mL of dichloromethane and 1 mL of DIPEA, then triphosgene (108 mg, 0.36 mmol) was added at room temperature. After the reaction mixture was stirred for 30 minutes, the solvent was removed in vacuo. The residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. The reaction mixture was stirred for 1 hour at room temperature, and the solvent was removed in vacuo to give the crude Compound X which was used directly without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:26][OH:27].C(N(CC)CC)C>CO>[F:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH:10]([O:11][CH3:12])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:26][OH:27])=[CH:24][CH:23]=1)=[O:22]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)NO)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.4 %

Procedure:
(RS)-N-(4-Cyano-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide (example 15.2, 251 mg) was dissolved in methanol (7 ml). Hydroxylamine hydrochloride (212 mg) and triethylamine (618 mg) were added. The mixture was stirred for 19 h at rt. The solvent was evaporated. The residue was dissolved in methylene chloride, washed with water, dried and filtered. The solvent was evaporated to give (RS)-2-(2-fluoro-4-methoxy-phenyl)-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-methoxy-acetamide (269 mg) as an off-white foam. MS 362.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i97 (0.55 g, 1 eq, 1.94 mmol) and lithium hydroxide monohydrate (0.16 g, 2 eq, 3.89 mmol) in tetrahydrofurane/water (28 ml 1:0.1, v/v) is stirred at room temperature for 1 h 30. The mixture is diluted with water and extracted with ethyl acetate. The aqueous layer is then acidified to pH 2 with 2 N hydrochloric acid. The precipitate that forms is filtered and washed with water to give 0.48 g of 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylic acid i98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][C:14]([CH:16]=[N:17][OH:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:19][N:20]([CH:22]=[O:23])C.CN=C=O>O>[CH3:19][NH:20][C:22]([O:18][N:17]=[CH:16][C:14]1[O:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: COc1ccc(-c2ccc(C=NO)o2)cc1OC
Reactant: CN(C)C=O
Agent: CN=C=O
Solvent: O
Product: CNC(=O)ON=Cc1ccc(-c2ccc(OC)c(OC)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
5-(3,4-Dimethoxyphenyl)furylformaldoxime (9.5 g, 0.038 mole) and DMF (500 ml) was treated with methyl isocyanate (16 ml, 0.27 mole). The solution was stirred at room temperature for 4 hours and at steam bath temperature for 1 hour. The reaction solution was poured into 3 liters of water. The tan precipitate was collected to give 6 g (51%) of product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[S:27](N)([NH2:30])(=[O:29])=[O:28]>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: NS(N)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(N)(=O)=O)CC2)nc1N

Procedure:
[4-Amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (308 mg, 0.848 mmol, Example 107) in dioxane (3 mL) and sulfamide (814 mg, 8.48 mmol, Aldrich) refluxed overnight. The mixture was diluted with water and sodium bicarbonate and extracted with dichloromethane. The organic solution was washed with water, dried (MgSO4), filtered and evaporated. Chromatography on silica gel (methanol/triethylamine/ethyl acetate 5:2:95) gave, after crystallization from ethanol/ethyl ether, 255 mg of colorless solid, MP 217–218° C. MS(ES) MH+ 443
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:27]([C:35]([O:37]C(C)C)=[O:36])=[N:28][C:29]([O:31]C(C)C)=[O:30].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O.O>[C:21]1([P:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[N:27]([C:35]([O-:37])=[O:36])=[N:28][C:29]([O-:31])=[O:30]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: O=C([O-])N=NC(=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The substrate phenol or carboxylic acid is dissolved in THF (0.05-0.5 M) and chilled to 0° C. Triphenylphosphine (1-4 eq), alcohol (1-4 eq) and diisopropyl azodicaroxylate (DIAD) or diethyl azodicarboxylate (DEAD) (1-4 eq) were added, in turn. The reaction was stirred overnight with gradual warming to rt. The reaction mixture is diluted with EtOAc/water and the layers were separated. The aqueous layer is further extracted with EtOAc. The organic layers were combined and washed with water and brine and dried over Na2SO4. The mixture is concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel to afford the coupling product.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([CH3:14])=[CH:5][C:4]=3[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:14][C:6]1[CH:7]=[C:8]2[C:13]3=[C:4]([N:3]=[C:2]([N:19]4[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]4)[N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c3c(c1)nc(Cl)n3CCC2
Product: Cc1cc2c3c(c1)nc(N1CCN(C)CC1)n3CCC2
Yield: 76 %

Procedure:
A solution of 2-chloro-5,6-dihydro-8-methyl-4H-imidazo[4,5,1-ij]quinoline (3.50 g) in N-methylpiperazine (20 ml) was stirred, under nitrogen, under reflux for 1.5 hrs. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica; 9:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 3.48 g (76%) of product, mp 164°-165° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[H-].[Na+].Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>O1CCCC1.C(O)C.O>[N:1]([CH2:4][CH2:5][O:6][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was then partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature and treated with methyl 2-(2-chlorobenzylidene)acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°.