Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O>[CH3:5][O:4][C:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)=[O:3]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl chloroformate (12.90 g, 0.137 mol) was added dropwise, over 10 minutes, to a stirred, cooled (5° C.) solution of compound 3 (10.00 g, 0.047 mol) in sodium hydroxide (5.44 g, 0.136 mol) and water (150 ml). During the addition a white precipitate was formed and this stirred mixture was allowed to warm to room temperature overnight. The resultant mixture was carefully acidified (pH 5) with dilute hydrochloric acid and the resultant voluminous white solid was filtered off, washed with water until acid-free and dried (phosphorus pentoxide) in vacuo.
Reaction SMILES: O(C(C)(C)C)[Na].Cl[C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1.[O:15]([CH2:22][CH2:23][OH:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:14][C:13]1[C:8]([O:24][CH2:23][CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: OCCOc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: CC(C)(C)O[Na]
Solvent: C1COCCO1
Product: Clc1nccnc1OCCOc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
NaO-t-Bu (2.91-8, 30.29 mmol) was added to a mixture of 2,3-dichloropyrazine (4.75 g, 31.9 mmol) and 2-phenoxyethanol (4.18 g, 30.3 mmol) in dioxane (25 mL). The reaction mixture was stirred at ambient temperature for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure and the crystalline residue obtained was dried in a vacuum oven affording 4.4 g (62%) of the title compound as white waxy crystals: mp 55-54° C. Anal. (C12H11ClN2O2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([C:20]#[C:21][CH2:22][OH:23])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1>CO.C1COCC1.[Pd]>[F:1][C:2]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(C#CCO)cc2F)cc1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc(CCCO)cc2F)cc1=O
Yield: 90 %

Procedure:
4-[2-Fluoro-4-(3-hydroxy-1-propynyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a crystalline cream solid (90%), m.p. (EtOAc/MeOH) 214-216° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.15 (s, 1H), 8.32 (s, 1H), 7.85 (br s, 1H), 7.43 (br s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.17 (dd, J=11.8, 1.7 Hz, 1H), 7.07 (dd, J=8.2, 1.6 Hz, 1H), 5.40 (s, 1H), 4.50 (t, J=5.1 Hz, 1H), 3.41 (q, J=6.0 Hz, 2H), 3.36 (s, 3H), 2.63 (t, J=7.7 Hz, 2H), 1.76-1.69 (m, 2H). Anal. Calcd for C16H18FN3O3: C, 60.2; H, 5.7; N, 13.2. Found: C, 60.5; H, 5.8; N, 13.3.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH:4]=[N:5][NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].Cl>CN1C(=O)CCC1.O>[I:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[N:5]=[CH:4]2
Reactant: O=C(O)c1ccc(NN=Cc2cc(I)ccc2F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Yield: 94.1 %

Procedure:
4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (141d, 3.42 g, 8.9 mmol) and potassium tert-butoxide (2.29 g, 20.5 mmol) was stirred under argon atmosphere in NMP (45 mL) at 150° C. for 15 min. The mixture was then cooled, diluted with water and acidified with aqueous HCl (1.7 M). The precipitate that formed was collected by filtration and dried in vacuo to give crude 4-(5-iodo-1H-indazol-1-yl)benzoic acid (3.05 g, 94%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20][C:19]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc2cnccc21
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Yield: 67.6 %

Procedure:
Palladium black (1.1 g, 10.3 mmol) is added to a solution of 2-(4-benzyloxycarbonyl-2-oxo-piperazin-1-ylmethyl)pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester (1.7 g, 3.7 mmol) in HCO2H/MeOH (45 mL, 4.4% solution). After 40 minutes the catalyst is filtered through Celite and washed with MeOH. The filtrate is concentrated in vacuo to remove methanol then the resulting solution is diluted with methylene chloride and washed with saturated sodium bicarbonate, and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The resulting solid is purified by column chromatography eluting with a gradient of 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to give the product (0.8 g, 2.5 mmol) as a pale yellow foamy solid. 1H NMR (CDCl3, 300 MHz) δ8.78 (s, 1H), 8.40 (d, 1H), 7.9 (d, 1H), 6.48 (s, 1H), 4.98 (s, 2H), 3.7 (s, 2H), 3.51 (t, 2H), 3.40 (t, 2H), 1.91 (bs, 1H), 1.70 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:19])[C@@H:6]([CH3:20])[N:5]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:4]=2[N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:37])[CH:31]=[C:32]2[C:36]=1[NH:35][N:34]=[CH:33]2.C(O)C(F)(F)F.FC(F)(F)C(O)=O>>[CH:21]1([N:5]2[C:4]3[N:3]=[C:2]([NH:37][C:30]4[CH:31]=[C:32]5[C:36](=[C:28]([F:27])[CH:29]=4)[NH:35][N:34]=[CH:33]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:19])[C@H:6]2[CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Cl)nc2N1C1CCCCC1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Nc3cc(F)c4[nH]ncc4c3)nc2N1C1CCCCC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one (30.4 mg, 0.081 mmol) and 7-fluoro-1H-indazol-5-amine (37.2 mg, 0.25 mmol) in trifluoroethanol (2.0 mL, 27 mmol) in a microwave reactor vial was added trifluoroacetic acid (42 mg, 0.37 mmol). The vial was then sealed, and the mixture was stirred at 100° C. (oil bath). More 7-fluoro-1H-indazol-5-amine (29.5 mg, 0.195 mmol) and trifluoroacetic acid (0.025 mL, 0.32 mmol) was added after 15 h, and heating at 100° C. was continued for additional 24 h. The reaction mixture was cooled to rt and quenched with saturated aq. NaHCO3 solution (5 mL). The resulting mixture was extracted with 5% MeOH in dichloromethane (15 mL×4). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue, which was then purified by silica gel column chromatography (eluent: 8% methanol in dichloromethane) to give the desired product (24%).
Reaction SMILES: S([CH2:5][CH2:6][OH:7])([O-])(=O)=O.[Na+:8].N1CCNCC1.S(CCO)(O)(=O)=O.[N:22]1([CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Na+].C1OC1>O>[OH:7][CH2:6][CH2:5][N:25]1[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][S:30]([O-:33])(=[O:31])=[O:32])[CH2:23][CH2:24]1.[Na+:8]
Reactant: O=S(=O)([O-])CCN1CCNCC1
Reactant: O=S(=O)([O-])CCO
Agent: C1CNCCN1
Agent: O=S(=O)(O)CCO
Agent: [Na+]
Solvent: O
Solvent: C1CO1
Product: O=S(=O)([O-])CCN1CCN(CCO)CC1
Temperature: 93.33333333333333 °C
Reaction time: 4 h

Procedure:
Forty-four grams of ethylene oxide (1 mole) is bled into a reaction vessel containing 104 grams of sodium bisulfite in water (45 percent by weight). The mixture is agitated at ambient temperature and 100 psi pressure during the addition of the bisulfite. The reactants interact to form an aqueous isethionic acid salt comprising 54 percent by weight sodium isethionate. A quantity of 86 grams of piperazine (1 mole) is admixed with the solution and the admixture is heated to a temperature of about 200° F. at atmospheric pressure. The reaction vessel has a cold finger trap attached thereto in communication with the contents of the reaction vessel. As the reaction progresses, water is produced as a by-product of the reaction which vaporizes as it is formed together with the other water present and which is collected as ice crystals upon the cold finger trap. The heating is continued for approximately 4 hours after which approximately 38 percent by weight of the reactants (about 127 grams) in the reaction vessel have collected upon the cold finger trap as ice crystals. The remaining liquid reaction product is analyzed and found to comprise sodium N-piperazineethanesulfonate. Further reaction with 44 grams of ethylene oxide (1 mole) at ambient conditions results in the formation of sodium N'-hydroxyethyl-N-piperazineethanesulfonate.
Reaction SMILES: [C:1]1(=[O:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[C:3](=[O:9])[O:2]1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:35][OH:36]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:35][O:36][C:3]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[C:1]([OH:10])=[O:2])=[O:9]
Reactant: O=C1OC(=O)C2CCCC12
Reactant: CO
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)O
Temperature: -55 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
(1S,2R)-2-(Methoxycarbonyl)cyclopentanecarboxylic acid was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. Tetrahydro-cyclopenta[c]furan-1,3-dione (5.0 g, 35.7 mmol) was dissolved in a 1:1 mixture of toluene and carbon tetrachloride (720 mL). The mixture was cooled to −55° C. under a nitrogen atmosphere, and then quinine (12.7 g, 39.3 mmol) was added. A solution of methanol (4.33 mL, 107 mmol) in toluene-carbon tetrachloride (1:1, 30 mL) was slowly added via an addition funnel. The suspension was stirred at −55° C. for 36 h, and then allowed to warm to 25° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (400 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×400 mL) and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R)-2-(methoxycarbonyl)cyclopentanecarboxylic acid (6.2 g, 35.7 mmol, quantitative), as a clear oil. 1H NMR (400 MHz, CD3OD) δ: 1.67 (1H, m), 1.84 (1H, m), 1.99 (4H, m), 3.08 (2H, m), 3.63 (3H, s).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 48.1 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 35 mg (0.2 mmol) of 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of dry pyridine under nitrogen in the presence of 30.4 mg (0.2 mmol) of DBU under reflux conditions. The solvent was removed under reduced pressure and to the orange viscous oil water was added and the solid was collected which was further purified from methanol to yield 20 mg of the desired product, m.p. 228°-230° C. 1H NMR (TFA) δ: 9.28 (s, 1H), 8.68 (s, 1H), 8.57 (d, 1.4Hz, 1H), 5.9-5.75 (m, 4.14 (m, 5H), 3.1-2.72 (m, 5H), 1.7-1.2 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(Cl)c3)c2)CC1
Yield: 82.7 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-chlorobenzoyl chloride (120 mg, 0.687 mmol), 67.6 mg (83%) of the title compound were recovered.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][O:24][CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][O:24][CH3:23])[CH:30]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[K].Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH:19][C:13]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Product: O=C1Nc2cc(Cl)ccc2Oc2ccccc21

Procedure:
The title compound was prepared according to the procedures reported in Coyne et al (J. Med. Chem., 1967, 10:541). Briefly, this entailed coupling potassium salicylaldehyde with 2, 5-dichloronitrobenzene, followed by oxidation to the carboxylic acid, reduction of nitro, and finally ring closure, to yield the desired 8-chloro starting material.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][CH:22]=1)[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2.O>CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[N:26]=[C:25]([C:27](=[N:2][OH:3])[NH2:28])[CH:24]=[CH:23][CH:22]=1)[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2
Reactant: NO
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(N)=NO)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a suspension of hydroxylamine hydrochloride (233 mg) in dimethylsulfoxide (1.7 mL) was added sodium hydrogen carbonate (338 mg), and this mixture was stirred at 50° C. for 1 hour. Subsequently, 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carbonitrile (114 mg) was added thereto, followed by stirring at 80° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (124 mg). 1H-NMR (DMSO-d6) δ ppm: 3.76 (3H, s), 5.51 (2H, s), 5.65 (2H, br s), 6.59 (1H, s), 6.70-6.85 (2H, m), 7.11 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=8.9 Hz), 7.35-7.70 (7H, m), 9.92 (1H, s).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:16]=1
Reactant: c1ccc(COc2ccc(-c3cccnc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 92.9 %

Procedure:
3-(4-Benzyloxy-phenyl)-pyridine 1.15 g, 4.4 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.5 g) over period of 48 h at rt under H 2 balloon, Reaction mixture was filtered through Celite and concentrated to obtain the product (700 mg, 93%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[CH2:16][CH2:15][C:14]2=[O:48])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:56](OC(=O)C)(=[O:58])[CH3:57]>ClCCl.CN(C)C1C=CN=CC=1>[C:56]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[CH2:16][CH2:15][C:14]2=[O:48])=[O:11])[CH2:6][CH2:5]1)(=[O:58])[CH3:57]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCN(CCO)CC4)c4ccccc43)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN1CCN(C(=O)CN2C(=O)CCN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc(C)cc4)cc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.1 %

Procedure:
To a solution of 1-[[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl}-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (178 mg) and triethylamine (31 mg) in dichloromethane (4 ml) was added acetic anhydride (31 mg) and the mixture was stirred at ambient temperature for 1.5 hours. To the mixture was added 4-dimethylaminopyridine (10 mg) and acetic anhydride (10 mg), and then the mixture was stirred at ambient temperature for 15 minutes. The resulting mixture was diluted with dichloromethane and the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was triturated with a mixture of diethyl ether and n-hexane (1:1) to give 1-{[4-(2-acetoxyethyl)-1-piperazinyl]-carbonylmethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]-benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (205 mg) as a slightly-yellow powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I>C1COCC1>[F:13][C:14]1[C:19]([I:24])=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]=1
Reactant: II
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1nc(C(F)(F)F)ccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of N,N-diisopropylamine (1.4 mL, 10.0 mmol) in anhydrous THF (15 mL) is cooled under N2 to −78° C. and nBuLi (2.5 M in hexanes, 4.0 mL, 10.0 mmol) is added dropwise at a rate to maintain the temperature below −65° C. A solution of 2-fluoro-6-(trifluoromethyl)pyridine (1.65 g, 10.0 mmol) in anhydrous THF (15 mL) is added dropwise over 10 min and the resulting orange solution is stirred for 2 h at −78° C. Iodine (2.54 g, 10.0 mmol) in anhydrous THF (12.5 mL) is then added dropwise over 15 min (keeping the temperature under −65° C.), causing the colour of the solution to change to red-brown and a precipitate to form. After 30 min the mixture is allowed to warm to 10° C. and the solvent is evaporated under reduced pressure. The residue is diluted with diethyl ether (25 mL) and washed with Na2S2O3 (2 M aq., 10 mL), HCl (2 M aq., 2×12.5 mL), NaHCO3 (sat. aq., 12.5 mL) and brine (12.5 mL). The organic solvents are dried over Na2SO4 and evaporated under reduced pressure to afford a yellow oil. The product is purified by silica chromatography, eluting with cyclohexane, to afford the title compound as a white solid (1.36 g). Alternatively, this compound may be used directly in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 88.8 %

Procedure:
A solution 58.0 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester, 45.0 g of (1,1-dimethylethyl)dimethylsilylchloride, 69 ml of triethylamine, 1.50 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride is stirred at room temperature for 18 hours. The resulting solution is washed with water, 2N hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The organic layer is dried and concentrated in vacuo. The residue, dissolved in methylene chloride, is filtered through a silica gel pad and concentrated in vacuo to give 76.5 g of the desired product as a colorless oil.
Reaction SMILES: N[C@H:2]([C:7](O)=[O:8])[CH2:3]C(C)C.[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15]NC(=N)N>>[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:3]=[CH:2][C:7]([OH:8])=[CH:15][CH:14]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N=C(N)NCCCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
0.98 Leu: 1.00 Har: 0.97 Pro: 0.96