Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].O.O.[Sn](Cl)Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of 5-(4-chloro-3-(trifluoromethyl)phenoxy)-2-nitropyridine (8 g, 25.1 mmol) in ethanol (100 mL) was added tin (II) chloride dihydrate (56.7 g, 251 mmol). The reaction mixture was stirred at 80° C. for 2 hr. and poured into 500 mL of H2O and adjusted to basic with 10% NaHCO3. Then, the reaction mixture was extracted with 500 mL of EtOAc. The organic layer was separated, and then dried over Na2SO4, and concentrated under reduced pressure to give 5-(4-chloro-3-(trifluoromethyl)-phenoxy)pyridin-2-amine (6 g, 72.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[ClH:35].F[C:37]1[NH:38][CH:39]=[CH:40][N:41]=1>CN(C)C=O>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH:33][C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reactant: Fc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](Nc1ncc[nH]1)c1nc(C)no1
Reaction time: 6 h
Yield: 34.1 %

Procedure:
A solution of 985 mg of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl -methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl) -silanyloxy]-5-methoxy-6-methyl-benzoic acid methyl ester and 237 mg of 2-fluoroimidazole hydrochloride in 5 ml of N,N-dimethylformamide were stirred under argon at 50° C. for 3 h. A second portion of 117 mg of 2-fluoroimidazole hydrochloride was added and stirring was continued for 6 h. The reaction mixture was cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using methanol/dichloromethane (1:20, v/v) as eluent to yield 310 mg of (R)-3-hydroxy-2-[2-(imidazol-2-ylamino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-5-methoxy-6-methyl-benzoic acid methyl ester hydrochloride as yellow solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[N:6]1[CH:7]=[CH:8][C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Nc2ccncc2)cc1
Temperature: 140 °C

Procedure:
A stirred mixture of 4-chloropyridine hydrochloride (2 g) and 4-methoxyaniline (4.9 g) was heated at 140° C. for 5 hours. After cooling the residue was dissolved in dichloromethane (250 ml), the solution extracted with water (2×100 ml). The aqueous extracts were treated with sodium hydroxide solution and then extracted with ethyl acetate (4×100 ml). The combined organic extracts were washed with water, and saturated sodium chloride solution, then dried and the solvent evaporated. Purification by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane gave 4-(4-pyridylamino)-methoxybenzene, 2 g, as a fawn solid: m.p. 159°-160° C.; NMR (d6DMSO) δ 8.47 (1H, s), 8.09 (2H, d), 7.10 (2H, d), 6.92 (2H, d), 6.70 (2H, dd), 3.73 (3H, s); m/e 201 (M+H)+ ; calculated for C12H12N2O3 : C, 72.0; H, 6.0; N, 14.0. found: C, 71.4; H, 6.1; N, 13.8%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:26]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:34][CH:35]=1)[CH3:25]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][C:11]3[N:12]([C:13](=O)[NH:14][C:15]=3[C:16]#[C:17]C(O)(C)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:24].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[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
Reactant: [OH-]
Reactant: CN1Cc2c(Cl)cccc2-n2c(c(C#CC(C)(C)O)[nH]c2=O)C1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
660 mg (2 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one was heated to boiling under reflux overnight with 80 mg of sodium hydroxide in 10 ml of toluene. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed twice with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 200°-201°.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][OH:12])[N:5]=1)([O-])=O>O1CCCC1.NN.[Ni]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][OH:12])[N:5]=1
Reactant: O=[N+]([O-])c1ccn(CCCO)n1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: Nc1ccn(CCCO)n1
Reaction time: 0.08 h

Procedure:
To a solution containing 3-(3-nitro-pyrazol-1-yl)-propan-1-ol (72 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 3-(3-amino-pyrazol-1-yl)-propan-1-ol as a yellow oil, which was then immediately used in the next step with no further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[NH:21][C:22]2=[O:23])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C1NC2CCCCC2N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
In this reference example, a solution of 631 mg of 1-benzyl-4-(2-amino-cylohexylamino)-piperidine in a free form obtained in Reference Example 17 and 550 mg of 1,1'-carbonyldiimidazole in 10 ml of acetonitrile is stirred at room temperature for 12 hours. The deposited crystals are separated by filtration, washed with acetonitrile and then dried to obtain 383 mg of crude crystals. The crude crystals are recrystallized from 34 ml of isopropanol to obtain 300 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Yield: 94.3 %

Procedure:
The method described in Part E of Examples 431–436 was used to treat 7-bromo-4-chloro-3-nitroquinoline (12.43 g, 43.45 mmol) with C-(tetrahydropyran-4-yl)methylamine (10 g, 87 mmol) to provide 15.0 g of (7-bromo-3-nitroquinolin-4-yl)(tetrahydropyran-4-ylmethyl)amine as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH2:30])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of (1S,2R,3S,5S)—N2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)bicyclo[3.1.0]hexane-2,3-diamine (42 mg, 0.094 mmol) in dichloromethane (1.9 mL) at 0° C. was added DIEA (0.025 mL, 0.14 mmol) and acryloyl chloride (0.009 mL, 0.11 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R,3S,5S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)bicyclo[3.1.0]hexan-3-yl)acrylamide (36 mg, 76%) as a pale yellow solid. MS (ES+) C25H24Cl2N4O3 requires: 498, found: 499
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(NS(=O)(=O)[O:33][CH2:34][C@@H:35]1[C@@H:42]2[C@@H:38]([O:39][C:40]([CH3:44])([CH3:43])[O:41]2)[C@H:37]([N:45]2[CH:53]=[N:52][C:51]3[C:46]2=[N:47][CH:48]=[N:49][C:50]=3Cl)[O:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(O)C>[C@@H:3]1([N:2]([CH3:1])[C:50]2[N:49]=[CH:48][N:47]=[C:46]3[C:51]=2[N:52]=[CH:53][N:45]3[C@H:37]2[C@@H:38]3[O:39][C:40]([CH3:44])([CH3:43])[O:41][C@@H:42]3[C@@H:35]([CH2:34][OH:33])[O:36]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: CN[C@H]1CCc2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21)[C@H]1CCc2ccccc21
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of (1S)-N-methylindan-1-amine (67.8 mg, 0.461 mmol), [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl tritylsulfamate (200 mg, 0.309 mmol) and DIPEA (0.160 mL, 0.919 mmol) in ethanol (3.0 mL) was heated at 150° C. for 600 s using microwave irradiation. The residue was purified via flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound as a brown oil (74.3 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:11]3[NH:12][CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=3)[CH2:15]2)[N:24]=[C:23]([NH2:28])[N:22]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)cc1
Yield: 72.5 %

Procedure:
A solution of 2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}morpholine (1.9 g, 6.42 mmol), 4,6-dichloro-2-pyrimidinamine (1.053 g, 6.42 mmol) and Hunig's base (2.8 mL, 16.1 mmol) in ethanol (80 mL) was heated overnight at 85° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography using as eluent 40% EtOAc in CH2Cl2 to afford the title compound (1.8 g) as a white solid. LC-MS (ES) m/z=387 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NCCN1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1.7 h

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 (0.25 mole) of K2CO3, 20.0 g (0.12 mole) of KI and 58.5 g (0.25 mole) of 4-benzyloxybenzyl chloride. The reaction mixture was heated to 105° over 0.5 hours, held at 105°-110° for 1.7 hours, poured with stirring into 1.5 l of H2O, stirred for 0.3 hours and filtered. The green-yellow solid was washed with 300 ml of H2O, air dried overnight, and dried to a constant weight at 60°, m.p. 110°-122°. Yield: 62 g (87%). Recrystallization from 1:1 methane: water gave an analytical sample, m.p. 156°-157°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C:33]1[CH:65]=[CH:64][C:36]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[N:40]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]2=[O:63])=[CH:35][CH:34]=1.[C:66]([O:70][C:71]([NH:73][C@H:74]([CH3:77])[CH2:75]O)=[O:72])([CH3:69])([CH3:68])[CH3:67]>C1C=CC=CC=1>[C:66]([O:70][C:71]([NH:73][C@H:74]([CH3:77])[CH2:75][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[N:40]([C:44]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:39]2=[O:63])=[CH:64][CH:65]=1)=[O:72])([CH3:69])([CH3:68])[CH3:67]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
13.2 g of diethyl azodicarboxylate were added dropwise to a solution of 20.7 g of triphenylphosphine in 300 ml of benzene, whilst ice-cooling. The mixture was then stirred at room temperature for 30 minutes, after which 35.0 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 11] were added. The mixture was then stirred at room temperature for one hour, after which 13.2 g of (R)-2-t-butoxycarbonylamino-1-propanol were added to the mixture and the mixture was allowed to stand overnight at the same temperature. 40.9 g of triphenylphosphine, 23.68 ml of diethyl azodicarboxylate and 33 g of (R)-2-t-butoxycarbonylamino-1-propanol were then added, in turn and in 3 or 4 portions, to the mixture, and the mixture was stirred for 2 days. At the end of this time, the reaction mixture was freed from benzene by distillation under reduced pressure. The residue was then purified by column chromatography through silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 30.0 g of 5-{4-[2(R)-t-butoxycarbonylamino-1-propoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione, melting at between 153° C. and 157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C@@H:28]1[CH2:30][C@H:29]1[C:31]([NH:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:32]>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31]([C@@H:29]2[CH2:30][C@H:28]2[CH3:27])=[O:32])=[CH:41][CH:40]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CN)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 79 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.94 g, 2.2 mmol) with a solution of (±)-trans-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamine (0.899 g, 4.403 mmol) in anhydrous toluene (22 mL) and anhydrous dioxane (5.8 mL). Purify by chromatography on silica gel to afford (±)-trans-7-chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.834 g, 79%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:42])[C@@H:29]([NH2:41])[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH3:26][O:27][C:28](=[O:42])[C@@H:29]([NH:41][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid was coupled with (S)-2-amino-3-naphthalen-2-yl-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:47])[C:32]4[CH:37]=[C:36]([NH:38][C:39]([C:41]5[S:42][CH:43]=[CH:44][CH:45]=5)=[O:40])[CH:35]=[CH:34][C:33]=4[Cl:46])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[Cl:46][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39]([C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=[O:40])=[CH:37][C:32]=1[C:31](=[O:47])[NH:30][C:27]1[CH:28]=[N:29][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:25][CH:26]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccs5)ccc4Cl)cn3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cccs1
Reaction time: 3 h

Procedure:
A stirred suspension of intermediate 26 (Example 37) (0.10 g, 0.143 mmol) in DCM (8 mL) was treated with TFA (0.200 mL) and stirred for 3 h. Solvents were then removed yielding desired product as TFA salt (0.075 g, 87%). 1H NMR (DMSO-d6): δ 1.61-1.70 (m, 2H), 2.01-2.04 (m, 2H), 2.80-2.90 (m, 2H), 7.23-7.27 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.86-7.91 (m, 2H), 8.04-8.05 (m, 4H), 8.21-8.25 (m, 1H), 8.65-8.69 (m, 1H), 8.9 (s, 2H), 10.37 (s, 1H), 10.53 (s, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([C@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy (2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (225.3 mg) in dichloromethane (20 ml), 3-chloroperbenzoic acid (70%, 113 mg) was added at 0° C., and the mixture was stirred at room temperature for 20 hours. To the reaction solution, sodium thiosulfate solution was added, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give, as pale yellow crystals 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 77) (125.5 mg).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[N:14][C:15]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C(Cl)(Cl)Cl>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:14][C:13]=2[N:24]([CH:25]2[CH2:27][CH2:26]2)[C:28]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(N2CCCC2)nc1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(C2CC2)c(=O)n1OCc1ccccc1
Yield: 74.5 %

Procedure:
A solution of N-benzyloxy-2-cyclopropylamino-5-fluoro-6-pyrrolidinyl-3-pyridinecarboxamide (Example I-2, 155 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (CDI) (142 mg, 0.88 mmol) in chloroform (2 mL) was refluxed overnight. The mixture was concentrated and purified by flash chromatography on a silica gel column with dichloromethane as eluent giving 130 mg of the title compound as a solid, mp 184-186° C.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[C:14]2[C:10](=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1.O>CS(C)=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:11]1[O:12][N:13]=[C:14]2[C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=[CH:9][C:10]=12
Reactant: Clc1ccc(-c2onc3c(CBr)cccc23)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3Cl)onc12
Reaction time: 8 h
Yield: 33 %

Procedure:
To a slurry of 1.8 g (0.028 mole) of potassium cyanide in 80 ml of dimethylsulfoxide at 60° C. was added 9.7 g (0.027 mole) of 7-(bromomethyl)-3-(2,4-dichlorophenyl)-2,1-benzisoxazole. The mixture was heated at 50°-60° C. for 3 hr, poured into 1 liter of water and let stand overnight. The resulting solid was collected by filtration, washed with water and dried to give 7.6 g of crude tan solid. The solid was chromatographed on 160 g of silica gel to give 2.7 g of solid. The solid was recrystallized from carbon tetrachloride (charcoal) and then from acetonitrile to yield 0.7 g (8%) of crystals, m.p. 147°-148° C.