Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22](Cl)[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21].[CH3:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[NH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH:22]([C:4]3[C:5]4[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=4[C:19]([C:20]#[N:21])=[C:2]([Cl:1])[CH:3]=3)[CH3:23])[N:27]=[C:26]([CH3:25])[C:34]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CC(Cl)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Temperature: 90 °C

Procedure:
The crude tert-butyl 7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.090 g, 0.26 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.076 g, 0.51 mmol) and cesium carbonate (0.17 g, 0.51 mmol) were added. The reaction was heated to 90° C. for 18 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and then decanted from the solids. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give tert-butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an oil. LCMS calculated for C23H27ClN7O3 (M+H)+: m/z=484.1; found: 484.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.O>[ClH:15].[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A slurry of 6-hydroxy-naphthalene-1-carboxylic acid (0.100 g, 0.531 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.143 g, 0.638 mmol) and Cs2CO3 (0.519 g, 1.59 mmol) in 2.66 mL of DMSO under argon was stirred for 15 min at RT. The mixture was heated to 140° C. in a microwave. After 1 h, the reaction was diluted with ca. 2.7 mL of water. 6N HCl was added dropwise until the solution was at pH 3-4. The resulting precipitate was filtered and washed with acetone to afford the titled compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13]1[N:18]=[N:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][N:18]3[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc3ccc(Cl)cc3c(=O)n2n1
Yield: 54.3 %

Procedure:
A mixture of 5-chloroanthranilic acid (5.4 g, 31.6 mmol) and 6-chloropyridazine-3-carboxylic acid (5.0 g, 31.6 mmol) is heated at reflux in acetic acid (50 ml) for 80 hrs. The mixture is cooled and the precipitate which formes is collected to give 4.73 g of crude product, m.p. 253°-300° C. (dec.). Recrystallization of this material from pyridine gives the analytical material, m.p. 260°-262° C.
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]1([N:7]2[CH2:11][CH2:12][O:13][C:22](=[O:24])[O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCN(CCO)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCCN(c2ccccc2)CCO1
Yield: 55.3 %

Procedure:
The procedure of Example 1 was followed using N-phenyldiethanolamine (15.2 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a clear oil containing a mixture of products. The product was purified using a column chromatography EtOAc:Hexanes (3:1) yielding 3.3 g (19%) of a clear oil which turned brown over time.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].CS(O[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:12]=1)(=O)=O.[C:28](OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:3][CH2:28][C:11]1[N:12]=[C:13]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCOC(C)=O
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
Ethyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.23 g, 24%) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([Cl:17])[CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C(C)(C)C)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (77 mg, 84%), MS (ISP) m/z=367.5 [(M+H)+], mp 252° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]=2[CH:4]=1.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O>C(OCC)C>[C:37]1([PH+:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]=2[CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCC1c2cc(CBr)ccc2-c2ccc(CBr)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1

Procedure:
In a 1 L three-neck flask equipped with a stirrer, a thermometer and a reflux condenser, 43.6 g (0.1 mol) of 2,7-bis(bromomethyl)-9-normal-hexylfluorene, 78.7 g (0.3 mol) of triphenylphosphine, and 500 ml of dimethylformamide were introduced and reacted for 12 hours at reflux temperature. When the temperature was decreased to room temperature after reaction, and the reaction solution was dropped down slowly into a 3 L ethylether solvent being thoroughly stirred, to obtain a white solid. After filtering, this solid was washed several times with ethylether, and then dried sufficiently in a vacuum oven at a temperature of 40° C. As a result, 92.2 g (yield: 96%) of a white solid was obtained. [1H-NMR (CDCl3), δ 0.25(br, 3H, CH3), 1.60-1.24(m, 10H, CH2), 2.83(t, 1H, CH), 5.66-5.76(d, 4H, CH2Br), 6.76-7.11(m, 6H, aromatic fluorenyl), 7.49-7.81(m, 30H, aromatic)].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:2]2[N:7]=[N:6][C:5]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])=[N:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1cccc(F)c1-c1ncc(Cl)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1cccc(F)c1-c1ncc(NCc2ccc(Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.9 g of 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine is placed in 10 ml of methylene chloride, and 0.57 g of 4-chlorobenzylamine and 0.81 g of triethylamine are added. After being stirred at room temperature for 2 h, the reaction mixture is poured into water and extracted with methylene chloride; the organic phase is concentrated and the residue is purified by means of column chromatography over silica gel. In this way the title compound having a melting point of 200-205° C. is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:19]=[O:20]>C(O)C.Cl.C(OCC)(=O)C.O>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: COCCCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COCCCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Potassium carbonate (14.7 g, 106 mmol) and benzyl chloride (12.2 mL, 106 mmol) were added to a solution of 3-hydroxy-4-(3-methoxypropoxy)benzaldehyde described in Production Example 32-1 (17.2 g, 81.7 mmol) in ethanol (200 mL) under nitrogen atmosphere at room temperature, and the mixture was stirred under a thermal condition of 90° C. for 2 hours. The reaction liquid was cooled to 0° C., and the mixture was diluted with 2 M hydrochloric acid, ethyl acetate, and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-3:7) to obtain the title compound (19.8 g, 81%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 96.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (28 mg) was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]([O:36]CC)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:13]=2[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]([OH:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:13]=2[CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nc2ccc(NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1nc2ccc(NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
1.30 g (2.5 mmol) of ethyl 4'-[(6-benzylamino-2-n-butylbenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate are dissolved in 20 ml of ethanol, treated with 20 ml of 2N sodium hydroxide and heated at reflux for 2 hours. After cooling to ambient temperature, the solution is diluted to 500 ml using water and acidified to pH 5 using glacial acetic acid. The precipitate thus obtained is filtered off under suction, suspended in acetone, filtered off once again under suction and dried at 90° C. in vacuum.
Reaction SMILES: O[C:2]1[CH:3]=C2C(=C[CH:11]=1)N=CC=C2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1CCN1CCC(N3C4C(=CC=C(C(N)=O)C=4)C=C3)CC1)[N:20](C)[CH2:19][CH2:18][CH2:17]2.C(N1C2C(=CC(OC)=C(CCN3CCC(N4C5C(=CC=C(C(N)=O)C=5)C=C4)CC3)C=2)CCC1)(=O)C>>[CH2:3]([C:15]1[C:14]([O:13][CH3:12])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH:2]=[CH2:11]
Reactant: Oc1ccc2ncccc2c1
Reactant: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C)CCC2
Agent: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C(C)=O)CCC2
Product: C=CCc1c(OC)ccc2ncccc12

Procedure:
The subject compound was synthesized from 6-hydroxyquinoline according to the methods described in Example 22, (1), (2), and (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:40][CH3:41])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:39])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:40][CH3:41])[C:9]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][C:32]([CH3:37])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:27][CH:28]=3)=[O:22])[CH:13]([CH3:39])[CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)OC)cc2)c2ccccc21)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN(C(=O)C1CC(C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)O)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of (±)-trans-methyl 5-(4-{[4-{[(4-chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoate (500 mg, 0.87 mmol) in 1:1 THF/methanol (5.0 mL) was added a solution of sodium hydroxide (69.5 mg, 1.74 mmol) in water (1.0 mL). The resulting mixture was heated at 60° C. for 18-20 hours and concentrated. The resulting residue was dissolved in water (˜50 mL), cooled to 0° C., and the solution acidified using 3N hydrochloric acid. The resulting precipitated material was collected via suction filtration, washed with 1N hydrochloric acid (3×25 mL), and dried to afford crude 5-(4-{[4-{[(4-Chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoic acid as a mixture of cis and trans isomers. Purification via HPLC yielded (±)-trans-5-(4-{[4-{[(4-Chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoic acid (23%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]1.C(N(CC)CC)C.O>C1COCC1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:8][CH:7]2[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(N)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Methanesulfonyl chloride (34 mg) was added to a solution of tert-butyl (6SR,7SR)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (90 mg) and triethylamine (33 mg) in THF (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (90 mg).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH2:2][C:3]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:6][C:7](=[O:16])[NH:8][CH2:9]2)=[O:4]
Reactant: O=C1NCc2ccccc2N1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1NCc2cc(C(=O)CBr)ccc2N1

Procedure:
Bromoacetyl chloride (6.2 g) is added dropwise to a stirring mixture of 3,4-dihydro-2(1H)-quinazolinone (2.6 g) and anhydrous aluminum chloride (6.3 g) in carbon disulfide (60 ml). The reaction mixture is stirred under reflux for 4.5 hours, the carbon disulfide decanted, and the residue treated with HCl (6N). The resulting solid is poured into ice water, filtered, the filtered solid washed with water and dried in vacuo, affording the desired product, which is used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[N:5]=[CH:4][CH:3]=1.[I-].[Na+].Cl[Si](C)(C)C.O>CC#N.CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][NH:5][C:6](=[O:10])[C:7]=1[CH:8]=[O:9]
Reactant: COc1nccc(I)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c(I)cc[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A mixture of 4-iodo-2-methoxynicotinaldehyde (25 g, 83 mmol) and sodium iodide (37.0 g, 249 mmol) in MeCN (500 mL) was treated drop-wise with chlorotrimethylsilane (31.4 mL, 249 mmol) over 15 minutes. The reaction mixture was stirred at RT for 2 h, then to dryness. The residue was suspended in EtOAc, water, and satd. NaHCO3, the solid collected via filtration, triturated with MeCN and dried to afford 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (12 g, 51%) as a yellow solid. MS (ESI) m/z: 250.0 (M+H+).
Reaction SMILES: S1C2C=CC=CC=2N=C1C(C1CCN([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)CC1)=O.ClCCCOC1C=CC(C(OC)=O)=CC=1.[I-:47].[Na+]>CC(C)=O.C(OCC)C>[I:47][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OCCCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Reactant: [I-]
Agent: COC(=O)c1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCI)cc1

Procedure:
4-[3-[4-[(2-Benzothiazolyl)carbonyl]-1-piperidinyl]propoxy]benzoic acid, methyl ester ##STR22## Dissolve 4-(3-chloropropoxy)benzoic acid, methyl ester (6.97 g, 30.5 mmol) in anhydrous acetone (100 mL) and add powdered sodium iodide (16.0 g, 107 mmol). Heat at reflux under an argon atmosphere for 38 hours. Dilute with ethyl ether (100 mL) and filter through Celite® filter aid. Wash the filtrate with water and brine, then dry (MgSO4). Evaporate the solvent in vacuo to give 4-(3-iodopropoxy)benzoic acid, methyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:41][CH:42]=3)(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 186-188° C.; MS m/e 559 (M−H)+;
Reaction SMILES: OS(O)(=O)=O.C(=O)=O.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:9]([C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccccc1N
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Concentrated H2SO4 (1 L) was cooled to −10° C. with a dry ice IpOH bath in a 2 L 3-neck round bottom flask fitted with a mechanical stirrer and temperature probe. 2-t-Butylaniline (109 g, 730 mmol) was added, giving a clumpy solid. Once the temperature of the mixture was stabilized at −10° C., KNO3 (101 g, 1001 mmol) was added portion-wise, as the solid, over 4 h, maintaining the temperature between −20 and −5° C. Once all of the KNO3 was added, the reaction was stirred overnight with gradual warming to RT. The reaction was quenched by diluting with H2O and extracting 3× with EtOAc. The EtOAc extracts were washed multiple times with saturated NaHCO3(aq), until gas evolution ceased, then with brine. The EtOAc extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving a black oil. The oil was eluted through a 36×7 cm column of silica gel with a 5%; 10%; 15%; 25%; and 50% EtOAc:Hexanes step gradient (2 L each step) giving 2-tert-butyl-5-nitro-phenylamine as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][CH2:27]1)[C:6](=[O:11])[C:5]12[O:12][CH2:13][CH2:14][O:15]1
Reactant: Cc1ccc2c(c1)C1(OCCO1)C(=O)N2
Reactant: ClCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(OCCO1)C(=O)N2CCC1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
5'-Methyl-spiro[1,3-dioxolane-2,3'-[3H]indol]-2'(1'H)-one (1 equivalent) in dry DMF (5 ml) was added dropwise to sodium hydride (3 equivalents) in dry DMF (2 ml) at 0° C. After 20 minutes, a solution of 4-(2-chloroethyl)-1-(phenylmethyl)piperidine hydrochloride (1.5 equivalents) in dry DMF (15 ml) was slowly added. The mixture was heated to 80° C., stirred at this temperature for 3 hours, and then left at RT overnight. The mixture was evaporated to dryness under reduced pressure and the residue purified by flash chromatography to yield the title compound (53%).