Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:16])=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CNS(=O)(=O)c1cc(C(=O)c2c(C)[nH]c3ccccc23)ccc1Cl

Procedure:
is obtained as described in Example 10 a) from 2.68 g 4-chloro-3-methylsulfamoylbenzoyl chloride and 1.3 g 2-methylindole in the presence of 2.7 g aluminum chloride in dichloroethane. Colorless crystals, m.p. 246° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[O:19][N:18]=3)=[CH:10][C:7]=2[S:8][CH:9]=1.[OH-].[K+].OP(O)(O)=O>O1CCCC1>[CH3:14][C:12]1[C:11]([O:15][CH2:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:19][N:18]=2)=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[C:6]=2[CH:13]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)c(C)cc12
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2c(CC(=O)O)csc2cc1OCc1cc(-c2ccc(Cl)cc2)on1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Compound 79A (0.03 g, 0.07 mmol) from the preceding step was dissolved in 2-3 mL of tetrahydrofuran, an equal volume of 2N KOH was added, and the mixture stirred at room temp. After 18 hours 75 mL of icewater was added and the mixture was acidified with H3PO4. After 30 min the precipitate was filtered off, rinsed 3× with water, and dried. The product was triturated in 4N HCl, allowed to stand for an hour, then filtered off, rinsed with water then ethanol, and dried to afford 0.01 g (99%) of the title compound as a white powder; mp 198-200° C. (dec). MS m/z 413 (M). Synthesis of {6-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethoxy]-benzofuran-3-yl}-acetic acid (Compound 80) Step 1. Preparation of {6-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethoxy]-benzofuran-3-yl}-acetic acid methyl ester (Compound 80A)
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:21][C:22]([C:24]1[N:25]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=[CH:27][CH:28]=1)=O)C=C.[O-]CC.[Na+].C(O)C>ClCCl.CO.CN(C)C=O>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:29]2[C:13](=[O:14])[C:12]([C:7]3[NH:6][C:5]4[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)=[C:22]([OH:21])[C:24]3=[CH:28][CH:27]=[CH:26][N:25]23)=[CH:36][CH:35]=1
Reactant: C=CCOC(=O)c1cccn1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64 %

Procedure:
N,N-Dicyclohexylcarbodiimide (4.33 mL of a 1.0 M solution in dichloromethane, 4.33 mmol) was added to a solution of (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (Example 4b, 1.58 g, 4.32 mmol) and 1-(4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 9a, 1.08 g, 3.94 mmol) in a 4:1 mixture of dichloromethane and N,N-dimethylformamide (25 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2.5 h then was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (20 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (8.0 mL, 24.6 mmol) was added and the reaction mixture was heated at 80° C. for 8 h. After cooling to 25° C., the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a dark solid. Trituration of this material with methanol afforded a grey solid that was collected by vacuum filtration to afford the desired product, 1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (1.42 g, 2.52 mmol, 64% yield). 1HNMR (400 MHz, DMSO-d6) δ: 5.64 (2H, s), 6.58-6.60 (1H, m), 7.01-7.02 (1H, m), 7.14-7.18 (2H, m), 7.42-7.46 (2H, m), 7.70-7.70 (1H, m), 8.02-8.04 (1H, m), 8.12-8.12 (1H, m), 13.70 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1>CO.[Pd].CCCCCC>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reaction time: 18 h

Procedure:
To a solution of 11.3 gm (50 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 250 mL methanol were added 3.0 gm 5% palladium on carbon. The mixture was hydrogenated at room temperature under an initial hydrogen pressure of 60 p.s.i. for 18 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a dark gum which was slurried in hexane to give the title compound as a brown solid.
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[C:15]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]=O>C(O)C.[Pd]>[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[C:15]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2c(N3CCNCC3)cccc12
Reactant: C=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1

Procedure:
A solution of 3-benzenesulfonyl-7-piperazin-1-yl-1H-indole (101) (500 mg, 1.46 mmol) and 1 mL of 37% aqueous formaldehyde in 25 mL of ethanol was hydrogenated at atmospheric pressure in the presence of 250 mg of 10% Pd-C for 30 min. The mixture was filtered, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, dried, and evaporated to yield the crude free base of 3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole. The hydrochloride salt was crystallized from ethanol-ether to afford 290 mg of (501), m.p. 160-162° C.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2cccnc2)CCN(C)C1
Temperature: 95 °C
Yield: 25.3 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 3-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K3PO4 (235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-3-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 8.35 (bs, 1H), 8.10 (bs, 1H), 7.95 (s, 1H), 7.8 (s, 1H), 7.45 (bs, 1H), 7.3-7.2 (m, 2H), 6.95 (d, 1H), 6.9 (d, 1H), 4.5 (bs, 2H), 3.6-3.45 (m, 2H), 3.15-3.05 (m, 1H), 3.0 (s, 3H), 2.65-2.59 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C([BH3-])#N.C(O)(=O)C.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH:28]=O>CO.C(Cl)Cl.O>[C:11]1([C@@H:3]([N:2]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: O=CCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CCCCC1
Reaction time: 0.5 h

Procedure:
To a slurry of (R)-tert-butyl 2-amino-2-phenylacetate HCL (Chem-Impex, 0.200 g, 0.821 mmol), MP-cyanoborohydride (2.44 mmol/g; 500 mg) and acetic acid (0.141 mL, 2.462 mmol) in MeOH (2.00 mL) and CH2Cl2 (2 mL) at rt was added glutaraldehyde (0.155 mL, 0.821 mmol) as a 50% solution in water. The reaction was stirred for 30 min., the reaction filtered, washed with MeOH and concentrated. The residue was taken up in CH2Cl2, washed with saturated NaHCO3, dried (Na2SO4) and concentrated to give the title compound. MS (DCI; M+H) m/z=276.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][OH:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:27](=O)(O)[O-:28].[Na+].CI>O.[Ru](Cl)(Cl)Cl.O.C(#N)C.C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][C:24]([O:28][CH3:27])=[O:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)CC1=O
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: COC(=O)CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
Carbon tetrachloride (550 mL), acetonitrile (550 mL), and water (550 mL) were dissolved in (3S)-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (38.2 g, 0.110 mol), and ruthenium (III) chloride hydrate (456 mg, 2.20 mmol) and sodium periodide (94.1 g, 0.440 mol) were sequentially added. The mixture was stirred in a water bath with a thermostatic circulator at 15° C. for 2.5 hours while maintaining the internal temperature at 20 to 25° C. The reaction solution was cooled in an ice bath and a 1N hydrochloric acid solution (2.2 L) was added at an internal temperature of 10° C. or less, followed by extraction with 2 L of chloroform. The aqueous layer was extracted with chloroform (1 L×3). Then, the organic layers were combined, washed with brine (2 L×2), and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting crude was dissolved in N,N-dimethylformamide (370 mL). Sodium bicarbonate (37.9 g, 0.451 mol) and methyl iodide (70.7 g, 0.498 mol) were added with stirring at room temperature, and the mixture was stirred for three days. The reaction solution was poured into ice water (1.8 L), followed by extraction with ethyl acetate (1.8 L, 0.5 L). The organic layers were combined, washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1), and the fraction containing the target substance was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate, washed with a 10% sodium thiosulfate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting solid was dried to give 35.0 g of the title compound as a pale yellow brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:16]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:29][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNC(c1ccccc1)c1ccccc1)Nc1ccc(Cl)cc1C(=O)O
Yield: 49 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid obtained in Example 72-(i), 2.94 g (16.0 mmol) of benzhydrylamine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 3 mL of DMF solution at 80° C. for 1 hour. Thereafter, the mixture was diluted with ethyl acetate, and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the condensed residue, and solids were collected by filtration, followed by drying, thereby giving 744 mg of the target 5-chloro-2-{[N-(diphenylmethyl)glycyl]amino}benzoic acid (yield: 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([CH:29]=O)=[CH:25][CH:26]=[CH:27][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1-c1ccccc1C=O
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1-c1ccccc1CN1CCN(c2ccccc2OC)CC1

Procedure:
382 mg of the target compound (0.98 mmol, 59.6%) was obtained using 1-(2-methoxyphenyl)piperazine (634 mg, 3.30 mmol), 2′-methoxybiphenyl-2-carbaldehyde (350 mg, 1.65 mmol) and NaBH(OAc)3 (1.1 g, 4.95 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][C:9](=S)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CCCCCC.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][O:28][C:29]([CH2:30][C:9]1[S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:32]
Reactant: S=C1N=C(c2ccccc2)C(c2ccccc2)S1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
The starting material can be produced, for example, in the following manner: 6 g of 4,5-bis-phenylthiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (0.89 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is stirred for 30 minutes at room temperature, 3.57 g of bromoacetic acid methyl ester are slowly added dropwise, the mixture is then stirred for 1 hour at room temperature, poured into 500 ml of ice-water, extracted by shaking twice with 300 ml of ethyl acetate each time, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. The remaining oil is dissolved in toluene and purified by chromatography over 50 g of silica gel. The eluate with toluene/ethyl acetate (95:5) is concentrated by evaporation under reduced pressure. 2-Methoxycarbonylmethyl-4,5-bis-phenylthiazole having a melting point of 65°-67° is obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[N:6][CH:7]=[CH:8][CH:9]=1.Cl.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl>CN(C)C=O>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][N:10]([C:5]1[C:4]([NH2:3])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CN(C)CCCCl
Reactant: Nc1cccnc1Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1N

Procedure:
To a stirred suspension of sodium hydride (in mineral oil) in anhydrous dimethylformamide, under nitrogen atmosphere was added, portionwise, [2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanone. To the mixture was added 3-dimethylaminopropyl chloride hydrochloride to give a solution containing some of the title compound as indicated by chemical ionization mass spectrascopy analysis. With time, this cyclized spontaneously to the corresponding pyrido[2,3-b][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[C:5]([N:12]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=2)[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1cccc(C(F)(F)F)c1)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (275.3 mg) and potassium carbonate (108.3 mg) in N,N-dimethylformamide (5 ml) was added 3-trifluoromethylbenzyl bromide (0.180 ml). After the mixture was stirred at room temperature for 1 hour, 1N hydrochloric acid (ca. 30 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (35 g, hexane:ethyl acetate=20:1) to give the title compound (345.3 mg, 82%).
Reaction SMILES: [C@H:1]1([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=3)=[C:15]([NH:34][C:35]3[C:36]4[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH:14]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(OC(=O)NC1C=CC(SC2C=CC(C(=O)N[C@H](C3C=CC=CC=3)C)=CC=2NC2C3C=CC(C(C)C)=NC=3N=CN=2)=CC=1)(C)(C)C>>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[O:12])=[CH:14][C:15]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H]4CCc5ccccc54)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H]4CCc5ccccc54)ccc3Sc3ccc(N)cc3)ncnc2n1
Yield: 89 %

Procedure:
The title compound was prepared (yield 89%) by the procedure in Example 385G substituting the product of Example 446A for the product of Example 385F. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (d, J=7.0 Hz, 6H), 1.86-2.04 (m, 1H), 2.33-2.53 (m, 1H), 2.74-3.03 (m, 2H), 3.22 (septet, J=7.0 Hz, 1H), 5.48-5.62 (m, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.1 Hz, 1H), 7.11-7.28 (m, 4H), 7.13 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.1, 1.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 8.56 (s, 1H), 8.73 (d, J=8.1 Hz, 1H), 8.86 (d, J=8.5 Hz, 1H), 10.11 (s, 1H) MS ESI+ m/z: 547 (M+H), ESI− m/z: 545 (M−H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>C(OCC)C>[C:16]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:18])[CH3:17]
Reactant: Oc1ccc(Br)cn1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A suspension of 0.5 g (2.87 mmol) of 5-bromo-2-pyridinol in 10 ml of ethyl ether is prepared and 1 ml (7.1 mmol) of triethylamine and then 1 ml (14 mmol) of acetyl chloride are added at ambient temperature. The mixture is stirred at ambient temperature for 24 hours and then the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel, elution being carried out using a toluene/2-propanol mixture (9/1; v/v). The expected product is obtained in the form of a pale yellow powder with a yield of 52%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[C:7]([Cl:12])[CH:6]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1Cl
Yield: 86.2 %

Procedure:
A mixture of 45 g of product from Example 62, 62.2 g of 1-bromotetradecane, 58.9 g of powdered potassium carbonate and 500 ml of acetone is heated at reflux temperature for 51 hours. The cooled solution is filtered and concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2% sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:5% ethyl acetate) and recrystallized from hexane to give 76.8 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C@H:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.C(N(CC)CC)C.[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C.O>C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C@H:4]2[C@H:3]([CH2:2][NH:1][C:37](=[O:38])[CH2:36][O:35][CH3:32])[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NC[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (140 mg) and triethylamine (0.156 mL) in THF (3.0 mL) was added acetoxyacetyl chloride (81 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (168 mg).
Reaction SMILES: C([O:3]C1C=CC=CC=1)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:3]
Reactant: COc1ccc(C)cc1
Reactant: CCOc1ccccc1
Product: COc1ccc(C)cc1O
Yield: 46.9 %

Procedure:
The reaction was carried out in the same manner as in Example 6 except that ethoxybenzene was replaced by 150 g. (1229.5 m.moles) of p-methoxytoluene and 4.11 g. (29.8 m.moles) of 2-methoxy-5-methylphenol was obtained in a yield of 46.9 %.