Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=1[CH2:6][NH:7][CH2:8][CH2:9][OH:10])([O-:3])=[O:2].[N:19]#[C:20]Br>O1CCCC1>[N+:1]([C:4]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:5]=1[CH2:6][N:7]1[CH2:8][CH2:9][O:10][C:20]1=[NH:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CNCCO
Reactant: N#CBr
Solvent: C1CCOC1
Product: N=C1OCCN1Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 56 h

Procedure:
In a sealed tube, added 2-(2-nitro-4-(trifluoromethyl)benzylamino)ethanol (Step 1, 1.10 g, 4.16 mmol), cyanogen bromide (1.32 g, 12.4 mmol), and tetrahydrofuran (4.2 mL). Stirred at room temperature for 56 hours. Concentrated down to yield 3-(2-nitro-4-(trifluoromethyl)benzyl)oxazolidin-2-imine. MS (M+H)+=290; Calc'd 289.22 for C11H10F3N3O3.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[F:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([CH2:13][CH2:14][CH2:15][N+:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=3)=[CH:18][CH:17]=2)=[O:12])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[F:6][C:7]1[CH:32]=[CH:31][C:10]([CH:11]([OH:12])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH:18]=[C:19]([C:22]3[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[O:24][N:23]=3)[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: O=C(CCC[n+]1ccc(-c2cc(C(F)(F)F)on2)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: OC(CCCN1CC=C(c2cc(C(F)(F)F)on2)CC1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a 1.0 g. portion of 1-(3-p-fluorobenzoylpropyl)-4-[5-(trifluoromethyl)-3-isoxazolyl]pyridinium perchlorate, prepared as described in Example 8, in 40 ml. of methanol, is added portionwise with stirring 1.0 g. of sodium borohydride. The mixture is stirred for 2 hours and poured into ice-water causing the formation of a white solid which is collected and recrystallized from methanol, m.p. 120.5°-121.5°C.
Reaction SMILES: [C:1]([N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](Cl)=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)(=[O:3])[CH3:2].[NH3:35]>CCOC(C)=O>[C:1]([N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:22]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH2:35])=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Reactant: N
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(N)=O)c2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
A mixture of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (0.1 mmol, 50.0 mg) and ammonia (1.0 mmol, 1.0 mL, 1M in MeOH) was refluxed at 70° C. for 6 h with vigorous stirring. The solvent was removed in vacuo and the crude product was purified by crystallization using EtOAc. The product was obtained as a white solid; Rf 0.1 (EtOAc); MS (ES+): 508 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2[S:17][C:18]([CH3:21])([CH3:20])[CH3:19].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:26]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-methoxy-3-(t-butylthio)indole-2-carboxylate from step 1 in DMF (50 ml) at 0° C. was added sodium hydride (60% suspension in mineral oil 460 mg, 11.5 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and p-chlorobenzyl chloride (1.93 g, 12.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 14 hours and was then poured into H2O (200 ml) and extracted with ethyl acetate. The organic phase was washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (8:1 hexane/ethyl acetate) to provide 4.1 g of ethyl 1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindole-2-carboxylate.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.C([NH2:28])C1C=CC=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:28][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](N)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 174.6 %

Procedure:
To a room temperature solution of ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (4 g, 14.1 mmol), benzylamine (1.71 g, 15.9 mmol), and acetic acid (1.27 g, 21.2 mmol) in 1,2-dichloroethane (20 ml), sodium triacetoxyborohydride (5 g, 23.3 mmol) was added. The mixture was stirred under an atmosphere of nitrogen for 15 hours at room temperature. The reaction was quenched by adding aqueous saturated sodium bicarbonate, and extracted with dichloromethane three times. The organic layer was dried over sodium sulfate and evaporated to give 7 g of the title compound. The crude material was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[Cl:16])([CH3:6])[CH3:5].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]OS(C)(=O)=O)=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:17])[C:4]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]([F:18])([F:37])[F:38])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[Cl:16])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C(C)(C)Oc1cc(Cl)c(O)cc1Cl
Solvent: CC#N
Product: COC(=O)C(C)(C)Oc1cc(Cl)c(OCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1Cl

Procedure:
In analogy to the procedure described in. example 20A], 2-(2,5-dichloro-4-hydroxy-phenoxy)-2-methyl-propionic acid methyl ester was treated with methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) in acetonitrile at the reflux temperature of the solvent for 3 h to give the title compound as colorless oil.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([NH:16][C:17]([CH2:18][OH:19])([CH3:21])[CH3:20])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C

Procedure:
In a methylene chloride solution containing 0.30 g of Boc-Thz-OH, 0.12 ml of 2-amino-2-methyl-1-propanol and 0.29 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process 3) to give 190 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Clc1nc2ccccc2n2ccnc12
Product: c1ccc2c(c1)nc(N1CCOCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with morpholine, according to a procedure that is similar to that followed in example 3, there is obtained 4-(4-morpholinyl)imidazo[1,2-a]quinoxaline. m.p. (DSC)=142.8° C. (onset); IR (KBr): 3016, 2962, 1517 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,s), 7.8÷7.5 (3H,m), 7.5÷7.2 (2H,m), 4.4 (4H,t), 3.9 (4H,t); UV (EtOH): λmax =230, 248, 292, 304, 330 nm. Elementary analysis for C14H13N4O (m.w. 254.29): calcd. C 66.13, H 5.55, N 22.03%; found C 65.43, H 5.47, N 22.25%.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Yield: 47.4 %

Procedure:
In ethanol (15 mL) were suspended ethyl 4-chloro-3-nitrobenzoate (1.10 g, 4.79 mmol), 4-chlorothiophenol (0.72 g, 4.98 mmol) and potassium carbonate (0.95 g, 6.78 mmol), and the suspension was heated under refluxing for 3 hours. The mixture was then placed under reduced pressure to distill the solvent off. After addition of water (100 mL), the mixture was subjected to extraction with ethyl acetate (100 mL×2) and dried over anhydrous sodium sulfate. The dry extract was placed under reduced pressure to distill the solvent off. The residue was purified-by silica gel column chromatography (ethyl acetate/hexane), to obtain 767 mg (yield 47%) of the titled compound as a yellow crystalline product.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:13]([O:20][N:21]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2C1=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a suspension of 5.0 g of isatin in 200 ml of ethanol was added a solution of 9.75 g of O-benzylhydroxylamine hydrochloride and 4.18 g of sodium acetate in 50 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from ethanol gave 6.06 g (71%) of 3-(benzyloxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:12][CH3:17])=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(C(C)(C)C)cc(Br)cc1C(C)(C)C
Yield: 107.1 %

Procedure:
Under argon atmosphere, to a solution of 4-bromo-2,6-di-tert-butylphenol (50 g, 0.175 mol) and potassium carbonate (96.7 g, 4.0 equivalents) in acetone (750 mL) was added dimethyl sulfate (38.6 g, 1.75 equivalents) at 22° C. The mixture was stirred under reflux for 13 hours. Insoluble substances were filtered off and the solvent was distilled off under reduced pressure. By adding ethyl acetate (150 mL) and water (100 mL) to the residue, the reaction mixture was allowed to separate into layers. An organic layer was washed successively with water (100 mL), a 5% NaHCO3 aqueous solution (100 mL) and a 5% NaCl aqueous solution (100 mL), dried over anhydrous magnesium sulfate and then naturally filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (56.1 g, brown oil). Yield 95.2%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH2:33].Cl>C(O)(C)C>[ClH:1].[ClH:22].[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc2c(Cl)cccc12
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4c(Cl)cccc34)ncnc2c1
Temperature: 25 °C
Yield: 159.7 %

Procedure:
A mixture of 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.08 g), 5-chloro-1-naphthylamine (0.055 g), 6.2M hydrogen chloride in isopropanol (0.044 ml) and isopropanol (3 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.129 g), a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 1.9-2.1 (m, 4H), 2.22 (s, 3H), 2.25-2.4 (m, 2H), 2.6-2.7 (m, 2H), 3.94 (s, 3H), 4.7 (br s, 1H), 6.6 (s, 1H), 6.9 (s, 1H), 7.4 (m, 1H), 7.62 (d, 1H), 7.7 (m, 1H), 8.0 (m, 2H), 8.25 (d, 1H), 8.46 (s, 1H), 9.9 (br s, 1H); Mass Spectrum: M+H+ 449 and 451.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:5]=1[Cl:22]>CO.ClCCl>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:5]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(C=O)cc2)cc(N)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(CO)cc2)cc(N)c1Cl
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
Sodium borohydride (112 mg, 3 mmol) was slowly added to a solution of methyl 4-amino-3-chloro-6-(4-formylphenyl)pyridine-2-carboxylate (2.87 g, 9.87 mmol) in methanol/dichloromethane (1:1, 100 mL) cooled by an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 15 minutes and then concentrated. The residue was dissolved in ethyl acetate/water and the organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography over silica gel (40% ethyl acetate/hexane) to yield methyl 4-amino-3-chloro-6-(4-hydroxymethylphenyl)pyridine-2-carboxylate (2.5 g 8.54 mmol), mp 138-139° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(O)(C(F)(F)F)=O.O[CH2:18][N:19]1[CH2:23][CH:22]([CH2:24][CH2:25][CH3:26])[CH2:21][C:20]1=[O:27]>>[CH2:24]([CH:22]1[CH2:23][N:19]([CH2:18][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[C:20](=[O:27])[CH2:21]1)[CH2:25][CH3:26]
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: c1cnc2[nH]ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2c[nH]c3ncccc23)C1
Temperature: 70 °C
Yield: 13 %

Procedure:
To a solution of commercially available 1H-pyrrolo[2,3-b]pyridine x7 (20.31 mmol, 1.2 eq, 3.19 g) dissolved TFA (25 ml) is added 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (16.93 mmol, 1 eq, 2 g). The mixture is heated at 70° C. overnight. The solvent is then evaporated under reduce pressure. CH2Cl2 (600 ml) is then added to the residue, and the resulting organic solution is washed with a saturated aqueous solution of sodium carbonate (200 ml). The organic phase is then dried over MgSO4 and the volatiles are removed under reduced pressure. The product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 97/3/0.3 (v/v/v)) and recristallized in acetonitrile. 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231 is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[I:22]I>CO.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][I:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1Cc2c(C#CI)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.72 g (10 mmol) of 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 30 ml of methanol and cooled to 10°. There were then added simultaneously thereto in portions within about 10 minutes 5 ml of 28% sodium hydroxide solution and 3 g of iodine. After stirring at room temperature for 1 hour the suspension was diluted with about 30 ml of water, suction filtered and the suction filter cake was dried. By two recrystallizations from methylene chloride and ethyl acetate and from dioxane there was obtained 7-chloro-4,5-dihydro-3-(2-iodoethynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 215°-216°.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[O:25]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[CH:28]([C:20](=[O:22])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[C:26](=[O:27])[O:25]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: -5 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
DMAP (106 g, 0.86 mol) was added to a solution of Boc-L-4-nitro-Phenylalanine (1800 g, 0.58 mol) and Meldrum's acid (92 g, 0.64 mol) in dichloromethane (1.5 L). The resulting solution was cooled at −5° C. under N2 atmosphere, followed by addition of DCC (240 g, 1.16 mol) in dichloromethane (1 L) over 1 h. The mixture was stirred overnight at 0˜5° C. Then the precipitated N, N′-dicyclohexylurea was removed by filtration and the filtrate was washed with 5% aqueous HCl (1 L×3), and brine (1 L×1), and was dried over MgSO4. After removal of MgSO4 by filtration, the organic phase was concentrated to dryness. The residue was triturated with EtOAc/hexane (1:1, 500 mL), and was dried to afford tert-butyl (S)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(4-nitrophenyl)-1-oxopropan-2-yl)carbamate (130.0 g, 51% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])(CC)C.CN(C)[CH:27]=[O:28]>O1CCCC1.C(OCC)(=O)C>[F:19][C:14]1[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCC#Cc1ccccc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene in tetrahydrofuran (60 ml) at -78° C. was added slowly sec-butyllithium (1.3 M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30 min, and dimethylformamide (2.8 ml) was added dropwise. The mixture was stirred for 5 min at -78° C. and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel (eluted with ethyl acetate/heptane/1:10). The appropriate fractions were collected and evaporated. The residue was chromatographed a second time over silica gel (eluted with dichloromethane) to afford 7.10 g (91%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(OC([NH:18][CH2:19][CH2:20][NH:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)[C:23](O)=[O:24])=O)(C)(C)C>>[NH2:18][CH2:19][CH2:20][NH:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)=[O:24]
Reactant: COc1cccc(C(NCCNC(=O)OC(C)(C)C)C(=O)O)c1
Reactant: Nc1ccc2[nH]ncc2c1
Product: COc1cccc(C(NCCN)C(=O)Nc2ccc3[nH]ncc3c2)c1

Procedure:
5-Aminoindazole was coupled with (2-tert-butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid according to the method described in Example 1. The BOC protecting group was then removed according to the method described in Example 8 to afford compound I-1017. 1H NMR (400 MHz, DMSO-d6) δ 3.02–3.14 (4H, m), 3.80 (3H,s), 4–5 (1H, vbr s), 5.11 (1H, brs), 7.05 (1H,d), 7.20 (2H,m), 7.40 (2H,m), 7.52 (1H,d), 7.5–8 (2H, brs), 8.05 (1H,s), 8.07 (1H,s), 8.2–10.1 (1H, brs), 10.68 (1H,brs), 13.15 (1H,brs); MS (ES+): m/e=340.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[N:24][CH:25]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COc1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-methoxy-nicotinamide was prepared starting from intermediate D and 6-methoxy-nicotinic acid. MS calcd. for C23H18ClN3O3 [(M+H)+] 419.1, obsd. 420 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[F:1][C:2]1[CH:8]=[C:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1F
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)cc1F
Temperature: 190 °C
Reaction time: 0.25 h

Procedure:
2-Fluoroaniline (40 g, 0.36 mol) was added dropwise to a stirred solution of concentrated sulphuric acid (60 ml) and the mixture heated to 190° C. for 15 h. The reaction mixture was then cooled to room temperature and poured slowly onto a stirred solution of ice-water. After stirring for 15 mins the mixture was filtered to yield a solid, 2-fluoro-4-sulphoaniline (41 g). NMR: 7.05 (t, 1H), 7.20-7.30 (m, 2H), 8.1 (br s, 3H); MS: 190 (M−H)−. The 2-fluoro-4-sulphoaniline (41 g) was dissolved in acetic anhydride (70 ml) and stirred in an ice bath. Triethylamine (22 g, 0.22 mol) was added very slowly with vigorous stirring (and concomittant release of heat). The reaction mixture was left to stir for 14 h, at which point a solid formed; this was filtered to yield the title compound (39 g, 0.12 mol). MS: 232.