Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([Cl:12])[CH:6]=1)C.[NH4+:14].[OH-]>>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:14])=[O:3])=[CH:6][C:7]=1[Cl:12]
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Agent: [OH-]
Product: NC(=O)c1ccc(N)c(Cl)c1
Temperature: 50 °C
Yield: 62.3 %

Procedure:
A 18 ml vial was loaded with 4-Amino-3-chloro-benzoic acid ethyl ester (350 mg, 1.88 mmole) and 5 ml of 30% NH4OH. The vial was sealed and the mixture was heated at 50° C. for 3 days. The mixture was cooled down and concentrated to half. The suspension was filtered off, solid was washed with water and dried to give 200 mg product, 62.3% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:27])=[C:19]([CH2:21][C:22](OCC)=[O:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:27])=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCO
Yield: 91.7 %

Procedure:
Starting ester, the compound of Step B 4.43 g (11.88 mmole), was dissolved in 83 ml tetrahydrofuran with stirring, under nitrogen. Solid lithium aluminum hydride (LAH), 450 mg (11.88 mmole), was cautiously added. There was much bubbling. The mixture was stirred 30 minutes and another 225 mg (5.94 mmole) lithium aluminum hydride was added and the reaction stirred under nitrogen overnight. Water (0.675 ml) was cautiously added followed by 0.675 ml 15% sodium hydroxide, followed by 2.0 ml water. The inorganics were filtered off and the filtrate was stripped, dissolved in ethyl acetate, washed once with 1 N hydrochloric acid, twice with brine, and stripped to give 3.61 g (92%) of product which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2S,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.1 g) and TFA (20 mL) in DCM (30 mL) was stirred at rt for 2 hours. The reaction was concentrated to give (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C)[CH:12]=[O:13].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:12]=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
N-Butyl lithium (50 mL, 2.5M in hexane) was added drop wise to a solution of 5-Bromo-2-methoxy-pyridine (22.4 g, 119.1 mMol) in dry tetrahydrofuran (240 mL) at −78 degrees. After complete addition the solution was stirred at −78 for an additional ninety minutes at which time dimethylformamide (18.5 mL, 238.3 mMol) was added drop wise and the solution stirred for ninety more minutes at −78 and then allowed to warm to room temperature. The mixture was then poured into saturated sodium bicarbonate solution (1000 mL) and extracted with diethyl ether (3×250mL). The combined organics were dried with magnesium sulfate, filtered, and concentrated to dryness to yield 15.4 g (94% yield) of 6-Methoxy-pyridine-3-carbaldehyde as a pale yellow solid. 1H NMR (DMSO-d6): δ=9.97 (s,1H), 8.77 (m, 1H), 8.12 (dd, 1H, J=8.6, 2.3 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.97 (s, 3H). LC/MS (Method A), rt=0.25 mins., purity=92.8%, calculated mass=137, [M+H]+=138. HPLC (Method C): rt=4.9 mins., purity=95.9% @ 210-370 nm and 98.7% @ 256 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:13][CH:12]([CH3:14])[CH2:11][CH:10]([C:15]2[NH:20][C:19]3=[CH:21][CH:22]=[N:23][C:18]3=[CH:17][N:16]=2)[CH2:9]1.CC[O:26]C(C)=O.[ClH:30]>CO>[OH2:26].[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:13][CH:12]([CH3:14])[CH2:11][CH:10]([C:15]2[NH:20][C:19]3=[CH:21][CH:22]=[N:23][C:18]3=[CH:17][N:16]=2)[CH2:9]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2F)N1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing [1-(2-fluorophenyl)vinyl]pyrrolidine (freshly prepared before use) (1.02 g, 5.34 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.10 g, 5.34 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (1.3 mL, 7.73 mmol), piperidine (Aldrich Chemical Company) (0.9 mL, 5.34 mmol), NEt3 (Aldrich Chemical Company) (1.0 mL) and SnCl2 (Aldrich Chemical Company) (16 mL of a 2M solution in DMF). The residue was purified by flash. chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 142 mg (9%) of the free base as a cream colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.65 (br s, 6), 2.43 (s, 3), 3.73 (br s, 4), 6.63 (s, 1), 7.33 (br s, 3), 7.44 (br s, 1), 7.87 (s, 1), 11.04 (s, 1). MS m/z: 311 (M+1). To a hot solution of 6-(2-fluorophenyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine (0.14 g, 0.46 mmol) in 5:1 EtOAc:MeOH (30 mL) was added 1N etheral HCl (Aldrich Chemical Company) (460 mL, 0.46 mmol). Crystallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (3×10 mL) and dried under vacuum to give 140 mg (88%) of the title compound as white colored long needles. Mp: 287-289° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (br s, 6), 2.58 (s, 3), 4.05 (br s, 4), 6.80 (d, 1, J=1.6), 7.39-7.46 (m, 2), 7.57 (q, 1, J=7.1), 7.89 (t, 1, J=7.7), 12.13 (s, 1), 14.37 (s, 1). MS m/z: 311 (M+1). Anal. Calcd for C18H19FN4.HCl.H2O: C, 59.28; H, 6.08; N, 15.37; Cl, 9.72. Found C, 59.28; H, 6.02; N, 15.39; Cl, 9.77.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O.O[NH:38][C:39]([C:41]1[C:42]2[CH:43]=[CH:44][NH:45][C:46](=[O:51])[C:47]=2[CH:48]=[CH:49][CH:50]=1)=[NH:40]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:40]=[C:39]([C:41]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:42]=3[CH:43]=[CH:44][NH:45][C:46]4=[O:51])[N:38]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1cccc2c(=O)[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(=O)[nH]ccc34)no2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 5.2 g) and hydroxybenzotriazole (HOBt; 3.6 g) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3; 2.9 g) in DMF (200 ml) at room temperature, and the resulting solution was stirred for 30 minutes. N-hydroxy-1-oxo-1,2-dihydro-5-isoquinolinecarboximidamide (D37, 2.75 g) was added and the suspension was stirred at room temperature for 2 hours. The reaction mixture was heated to 140° C. and stirred for 1 hour. The solvent was evaporated and the residue was washed with water, followed by ethyl acetate to give the title compound (2.6 g).
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][N:21]([CH2:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:14]=1.Cl.[CH2:43]([NH2:45])[CH3:44].[OH-].[Na+].C(OC(=O)C)C.Cl>C(OCC)(=O)C.C(N(CC)CC)C.CN(C=O)C>[ClH:1].[ClH:1].[ClH:1].[CH2:43]([NH:45][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH2:35][C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)=[CH:34][CH:33]=1)[CH3:44]
Reactant: CCN
Reactant: O=C(O)c1ccc(OCCCN(CCc2cccnc2)Cc2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(OCCCN(CCc2cccnc2)Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (95 mg), and 1-hydroxy benzotriazole(HOBt) (66 mg) were added to a DMF solution(4 ml) of 4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}benzoic acid(149 mg), ethyl amine hydrochloride(38 mg), and triethylamine (0.08 ml). The mixture was stirred at room temperature overnight. The reaction mixture was added to ice water. A 1N-sodium hydroxide aqueous solution was added thereto, followed by extraction using ethyl acetate. The organic layer was washed with water and then was dried with anhydrous sodium sulfate, followed by condensation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(0.16 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound(80 mg) as a white powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:22][C:23]([NH2:25])=[NH:24])=[N:5][CH:4]=1.Cl.N[C:28](N)=N.O>CS(C)=O>[CH3:28][O:20][C:19](=[O:21])[C@@H:17]([CH3:18])[NH:16][S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:11][CH:10]=1)(=[O:14])=[O:15]
Reactant: C[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Reactant: N=C(N)N
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 4.9 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine hydrochloride ##STR33## NaH (35 mg, 80% dispersion by wt in mineral oil, 1.17 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (179 mg, 1.87 mmol) in DMSO (5 mL) and the mixture was heated at 60° C. under N2 for 45 min. 1-{[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]amino}-D-alanine methyl ester (170 mg, 0.47 mmol) was added and the mixture heated at 90° C. for 4 h. The cooled mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4) and the solvents evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (66:33 to 0:100) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine methyl ester (22 mg, 0.057 mmol) as a yellow foam/oil.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:21])[CH:12]=[C:13]([C:16](OCC)=[O:17])[O:14][CH:15]=2)=[CH:6][CH:5]=1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:21])[CH:12]=[C:13]([C:16]([NH2:1])=[O:17])[O:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc(=O)c(-c2ccc(OC)cc2)co1
Reactant: N
Solvent: CCO
Product: COc1ccc(-c2coc(C(N)=O)cc2=O)cc1
Reaction time: 0.5 h

Procedure:
Cold concentrated ammonia solution (30%, 80 ml) was added to a stirred suspension of ethyl 5-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (12.4 g) in ethanol (120 ml) at 5°-10° C. The mixture was stirred for a further 30 minutes at 0°-5° C. then the solid title product was washed with water and dried (mp 262°-263° C. with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH:15][CH3:16])=[O:14].CO.Cl.[O:26]([NH2:28])[CH3:27]>O>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:28][O:26][CH3:27])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COc1cc(C)ccc1C
Yield: 95.3 %

Procedure:
To 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-N-methyl-2-oxoacetamide (0.27 g, 0.9 mmol), added were methanol (2.0 ml) and methoxylamine hydrochloride (0.15 g, 1.8 mmol), and the reaction mixture was heated under reflux for 4 hours. After completion of the reaction, water (100 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methyl-acetamide (0.28 g; yield, 98.9%) as a mixture of E-form and Z-form.
Reaction SMILES: [C:1]([CH:3]([CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl[CH:18]([CH2:24][CH2:25][Cl:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(C(C(C1C=CC=CC=1)C)C(OC)=O)#N.BrC(CCBr)C(OC)=O>>[C:11]1([CH:9]([C:3]([C:1]#[N:2])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:24][CH2:25][Cl:26])[CH3:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C#N)C(C)c1ccccc1
Reactant: CCOC(=O)C(Cl)CCCl
Agent: COC(=O)C(Br)CCBr
Agent: COC(=O)C(C#N)C(C)c1ccccc1
Product: CCOC(=O)C(CCCl)C(C#N)(C(=O)OCC)C(C)c1ccccc1

Procedure:
Ethyl 2-cyano-3-phenylbutyrate and ethyl 2,4-dichlorbutyrate can be used in place of methyl 2-cyano-3-phenylbutyrate and methyl 2,4-dibromobutyrate, respectively, in the alkylation reaction of Example 3 to produce the corresponding diethyl 2-phenyl-3-cyano-6-chlorohexane-3,4-dicarboxylate. The latter product can then be reacted with the tricarboxylate of Example 4 and the dicarboxylate of Example 7 to give the corresponding pentaester and tetraester products.
Reaction SMILES: C1([C@@H]([N:9]2[CH2:13][CH:12]([C:14]3([NH:18]C(OC(C)(C)C)=O)[CH2:17][CH2:16][CH2:15]3)[CH:11]([F:26])[CH2:10]2)C)C=CC=CC=1.[NH2:27][C:28]1[C:37]([F:38])=[C:36](F)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:27][C:28]1[C:37]([F:38])=[C:36]([N:9]2[CH2:13][C@H:12]([C:14]3([NH2:18])[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: C[C@@H](c1ccccc1)N1CC(F)C(C2(NC(=O)OC(C)(C)C)CCC2)C1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(N)CCC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
Cis 1-[(1-(S)-phenylethyl]-4-(1-tert-butoxycarbonylaminocyclobutyl)-3-fluoropyrrolidine (optical isomer B; 1.13 g, 3.12 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 10% palladium-carbon catalyst (water content, 55.6%; 1.0 g) and stirred at 50° C. for 18 hours under a hydrogen atmosphere. The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (10 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (1.18 g, 3.78 mmol) and triethylamine (5 ml) and stirred at 140° C. for 4 days under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (50 ml) and washed with a 10% citric acid aqueous solution (50 ml) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with an eluant of chloroform:methanol 9:1. The eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 30 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative TLC (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1) to obtain a crude title compound, and this was recrystallized from a mixture of ethanol and ether to obtain 157 mg (17%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: O=Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: Nc1ccc(-c2ccc(O)cc2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(-c3ccc(O)cc3)cc2)c(Cl)c1
Temperature: 70 °C
Yield: 81.6 %

Procedure:
A suspension of 0.840 g of 2-chloro-4-nitro-1-nitrosobenzene in 20 ml of glacial acetic acid was heated to 70° C. and treated while stirring with a solution, heated to 110° C., of 0.926 g of 4-amino-4'-hydroxybiphenyl [prepared according to Chem. Berichte 27 (1894) 2627] in 43 ml of glacial acetic acid. The dark solution was stirred at 70° C. for a further 2.25 hours, then cooled to room temperature and extracted with methylene chloride. The extracts were washed with water, 10% sodium hydrogen carbonate solution and again with water, dried over sodium sulphate and concentrated in vacuo. Thus yielding 1.3 g of crude 2-chloro-4-nitro-4'-(4-hydroxyphenyl)azobenzene as brown crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[N:12]1[C:17]2[NH:18][C:19]3[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>CCCCCC>[F:35][C:32]([F:33])([F:34])[C:26]1[CH:27]=[C:28]([N:7]2[CH:8]=[CH:9][C:5]([C:4]([F:11])([F:10])[F:3])=[N:6]2)[CH:29]=[CH:30][C:25]=1[C:23]([N:21]1[C:20]2[CH:36]=[CH:37][CH:38]=[CH:39][C:19]=2[NH:18][C:17]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:22]1)=[O:24]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Yield: 58.4 %

Procedure:
Sodium hydride (60% suspension in oil, 0.17 g, 4.25 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). 3-trifluoromethyl pyrazole (0.34 g, 2.5 mmol) was added in one portion. After the gas evolution subsided stirring was continued at room temperature. The (6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-methanone of Example 4, Step B (0.75 g, 1.94 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) overnight. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was crystallized from ethanol to yield the title compound (0.57 g) as an off-white solid, m.p. 127-129° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:11]=1.[C:27](=O)([O:30]C)[O:28][CH3:29]>>[CH3:29][O:28][C:27](=[O:30])[CH2:16][C:14]1[CH:13]=[C:12]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[N:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 3.0 mL, 5.4 mmol) was added slowly to a stirred solution of 2-Chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (545 g, 2.0 mmol) under N2 at −78° C. After 30 minutes dimethyl carbonate (400 μL, 4.0 mmol) was added. After stirring at −78° C. for an additional 30 minutes, the solution was allowed to warm up slowly and stirred at 0° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (4 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (40-80% CH2Cl2 in heptane) to give the product as an off white solid (520 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.29 Hz, 2H), 7.72 (d, J=8.29 Hz, 2H), 7.62 (s, 1H), 7.28 (s, 1H), 3.76 (s, 3H), 3.71 (s, 2H). MS m/e 330.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].O.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 5 L flange flask was charged 1-benzyloxycarbonylpiperidine-4-carboxylic acid 20 (200 g, 759.6 mmol) in DCM (500.0 mL) followed by additional DCM (2.000 L), t-butanol (140.8 g, 181.7 mL, 1.899 mol) and DMAP (46.40 g, 379.8 mmol). The mixture was cooled on ice/salt/water bath (internal −3.4° C.). 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (Hydrochloric Acid (1)) (145.6 g, 759.6 mmol) was added portionwise over 15 mins, with addition funnel rinsed with DCM (500.0 mL). Mixture was stirred on ice bath for approx. 2 h. Ice bath was then removed (internal 3° C.) and allowed to warm to room temperature overnight. Mixture was washed with 5% citric acid (2×500 mL), then saturated NaHCO3 (500 mL), water (500 mL), and organics dried over MgSO4, which was then filtered and concentrated in vacuo to leave product 21 as a viscous light yellow oil which turned to a white solid on standing. (246.1 g, 101%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.31 (m, 5H), 5.08 (s, 2H), 3.90 (dt, 2H), 2.93 (br s, 2H), 2.43 (tt, 1H), 1.80-1.76 (m, 2H) and 1.45-1.37 (m, 11H).