Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH2:6])=[NH:5].[C:7](OC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.[OH-].[Na+].Cl>CCOCC>[Cl:2][CH2:3][C:4]1[N:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[N:5]=1
Reactant: COC(=O)CC(C)=O
Reactant: N=C(N)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cc(O)nc(CCl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetamidine hydrochloride (6.45 g, 0.05 mole), methyl acetoacetate (6.38 g, 0.055 mole) and 2 N aqueous sodium hydroxide solution (50 ml) were mixed and stirred for 1 hour at room temperature. The reaction solution was acidified (pH 4-5) with 6 N hydrochloric acid, followed by extraction with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown crystal. The crystal was stirred in ether and then filtered to obtain 5.1 g (64% of the theoretical yield) of 2-(chloromethyl)-4-hydroxy-6-methylpyrimidine as colorless plate-like crystals (m.p. 157°-159° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH3:20])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH3:20])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24]
Reactant: CNCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNCC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC)c(C)n(C)c5c4)c3s2)C1
Yield: 54.6 %

Procedure:
This material was prepared by the reaction of N-({1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl)-N-methylamine 46a (0.115 g, 0.41 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.090 g, 0.41 mmole) and Cs2CO3 (0.147 g, 0.41 mmole) in a manner as previously described for example 1 to give an off-white solid (0.110 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (1H, s), 8.01 (1H, s), 7.83 (1H, m), 7.54 (2H, m), 7.02 (1H, s), 6.64 (1H, d, J=5.46 Hz), 3.93 (2H, m), 3.68 (3H, s), 3.54 (2H, m), 3.16 (2H, m), 2.99 (1H, m), 2.80 (3H, s), 2.79 (3H, s), 1.98 (2H, m), 1.65 (1H, m); HRMS (MH+): Calcd: 492.2064. Found: 492.2048.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[O:23][N:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COCc1ncc(C(=O)OC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ncc(C(=O)OC)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg 2-Methoxymethyl-3H-imidazole-4-carboxylic acid methyl ester in 1 ml DMF, 95 mg caesium carbonate and 82 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 72 mg.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.[OH:21]O>C(O)(=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11](=[O:21])[C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1
Reactant: OO
Reactant: c1ccc2c(c1)CCc1ccc(-c3nnn[nH]3)cc1S2
Solvent: CC(=O)O
Product: O=S1c2ccccc2CCc2ccc(-c3nnn[nH]3)cc21

Procedure:
A mixture of 600 mg. of 10,11-dihydro-3-(5-tetrazolyl)dibenzo[b,f]thiepin, 25 cc. acetic acid and 5 cc. 30% hydrogen peroxide is stirred for 6 hours. The suspended solid is filtered, washed with acetic acid, then water and dried to yield 575 mg. of pure material, m.p. 278° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[CH2:12][CH2:13][N:14](CC4C=CC=CC=4)[CH2:15][C@H:6]3[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[CH2:12][CH2:13][NH:14][CH2:15][C@H:6]3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)[C@@H]1CN(Cc3ccccc3)CC[C@H]1N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)[C@@H]1CNCC[C@H]1N2
Yield: 77.8 %

Procedure:
A mixture of intermediate 8 (11.3 g) in methanol (250 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE (30 ml). The precipitate was filtered off and dried, yielding 6.1 g (78%) of (±)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-1H-pyrido[4,3-b]indole (intermediate 10).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH2:25][CH3:26])=[C:14]([CH2:23]O)[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]2[CH:9]=[N:8]1)[CH3:6]>>[Cl:3][CH2:23][C:14]1[C:13]([CH2:25][CH3:26])=[N:12][C:11]2[N:7]([CH2:5][CH3:6])[N:8]=[CH:9][C:10]=2[C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of thionyl chloride (1.46 mL, 20.0 mmol) was added [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (0.609 g, 2.0 mmol) slowly. The mixture was stirred at room temperature for 30 min and then was concentrated on rotavap under vacuum. The residue was twice taken up in DCM (5 mL) and concentrated on rotavap to afford the title compound 0.386 g (60%). LC-MS m/z 319 (M+H)+ [molecular ion of the compound with methoxy from LC-MS solvent methanol where OMe substituted chloro group of the original product].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]([CH3:17])([CH3:21])[CH2:19][CH3:20])=[CH:23][CH:24]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 1.16 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.56 (t, 3H, J=7.2 Hz), 1.18 (s, 6H), 1.54 (q, 2H, J=7.2 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.40 (m, 4H), 7.45 (dd, 1H, J=8.8 Hz, 2.0 Hz), 7.56-7.62 (m, 3H, 7.78 (d, 1H, J=8.8 Hz), 9.95 (s, 1H). MS: m/z 442.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:29][O:30][C:31]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=2[CH:33]=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:29][O:30][C:31]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=2/[CH:33]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CCCCC1
Yield: 47.1 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (350 mg, 1.072 mmol) with 2-cyclohexylmethoxy-3-methoxybenzaldehyde (372 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 281 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.03-1.10 (m, 2H), 1.18-1.25 (m, 3H), 1.68-1.79 (m, 6H), 3.60-3.68 (m, 2H), 3.77 (s, 3H), 6.81-6.88 (m, 2H), 6.91-6.96 (m, 3H), 7.40-7.46 (m, 5H), 7.98 (d, J=6.3 Hz, 1H), 8.14 (d, J=15.0 Hz, 1H); ESI-MS (m/z) 557.44 (M+H)+.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=[O:7])C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH2:23][CH2:22][CH2:21]2.[OH-].[Na+].C>O>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:25]3[N:24]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=1
Reactant: COc1ccc2c(c1)CCCN2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c3c(c1)c(=O)c(C(=O)O)cn3CCC2
Temperature: 220 °C

Procedure:
Diethyl ethoxymethylenemalonate (43.2 g., 0.20 mole) and 6-methoxytetrahydroquinoline (32.6 g., 0.20 mole) are mixed and heated at 125°-130° C. for three hours. Polyphosphoric acid (200 g.) is added, and the mixture is heated gradually to 220° C. then maintained at 220° C. for one hour. The mixture containing the product ester of Formula III is poured into about 600 ml. of water, then made basic with 40 percent sodium hydroxide solution and heated on a steam bath for two hours. The solution is treated with decolorizing charcoal, filtered and acidified. The solid product is isolated by filtration, washed with water and ethanol, then recrystallized from N,N-dimethylformamide to give 6,7-dihydro-9-methoxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 253°-257° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1C
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.56 g, 0.008 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (4.90 g, 0.038 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (2.40 g, 0.008 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (910 mg, 29%) as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17](N)[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>>[CH3:23][N:24]([CH3:29])[S:25]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(S(=O)(=O)N(C)C)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and dimethyl sulfamoyl chloride, the title compound is prepared as in example 15. 0.16 g (29%). LC-MS m/z 402.1 (M++1).
Reaction SMILES: CI.[C:3]1([S:9][C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[CH3:22][N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:10]([S:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:11]1[C:19]([NH2:21])=[O:20]
Reactant: NC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CI
Product: Cn1c(C(N)=O)c(Sc2ccccc2)c2ncccc21
Yield: 38.8 %

Procedure:
Add methyl iodide (20 mg, 0.14 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid amide (Ia-1, 27 mg, 0.1 mmol), Cs2CO3 (43 mg, 0.13 mmol) in pyridine (0.5 ml). Heat the reaction at 80° C. in a sealed vessel for 15 minutes. Cool the mixture cooled and extract into ethyl acetate from water. Separate the organic solution and evaporate. Purify the residue (33 mg) by flash chromatography (silica gel, 3 gm, elute with MeOH 0-4% in dichloromethane) to provide the title compound (11 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=283) are consistent for the title compound structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(O)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
To a stirred solution of 3-bromo-5-hydroxybenzoic acid (2 g, 9.22 mmol) in dimethyl formamide (50 mL), was added potassium carbonate (1.27 g, 9.21 mmol), and the mixture was stirred at 0° C. for 20 minutes. Benzyl bromide (1.1 mL, 9.25 mmol) was added, and the reaction mixture allowed to warm to room temperature over 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered, and concentrated under reduced pressure to afford the title compound (2.85 g, quantitative yield).
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C@@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1.CCN(C(C)C)C(C)C>C(O)C>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:4]1[CH2:3][CH2:2][N:9]([CH2:10][C@@H:11]([OH:12])[C:13]2[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][CH2:16]3)[CH2:6][CH2:5]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@H](O)CN2CCN(CC(O)c3ccc4c(c3)C[C@@H](C)OC4=O)CC2)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (150 mg, 0.54 mmol) in ethanol (2 mL) was added (3R)-3-Methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 23) (110 mg, 0.54 mmol) and Hunig's base (95 uL, 0.54 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield (3R)-6-(1-hydroxy-2-(4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)-3-methylisochroman-1-one as a diastereomeric mixture.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](OCC)=[O:12])[CH:6]=[CH:7][CH:8]=1.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:19][NH2:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: CCOC(=O)CCc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1cccc(C(F)(F)F)c1
Yield: 80.9 %

Procedure:
A solution of ethyl 3-[3-(trifluoromethyl)phenyl]propionate (9.85 g, 40.0 mmol) and hydrazine monohydrate (9.70 mL, 200 mmol) in ethanol (50 mL) was heated under reflux overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (7.51 g, yield 81%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:5](=[O:7])[C:4]2[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[C@H:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1C
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 3,5-dichlorobenzoic acid (2.6 g), (3R)-1-benzyl-3-(3,4-dimethylbenzyl)piperazine dihydrochloride (5.0 g) and triethylamine (8.54 ml) in dichloromethane (80 ml) was added 2-chloro-1-methylpyridinium iodide (3.83 g) under ice-cooling, and then the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved into ethyl acetate. The ethyl acetate solution was filtrated and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using hexane-ethyl acetate (10:1) as eluent to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine (5.58 g).
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[CH3:31][O:32]C1C=CC=CC=1C=O>>[CH3:31][O:32][C:29]1[CH:30]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1CNCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-methoxybenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, br. s.) 10.27 (1H, s) 8.04 (1H, t, J=5.56 Hz) 7.99 (1H, d, J=5.47 Hz) 7.75 (1H, d, J=5.47 Hz) 7.45 (1H, d, J=5.27 Hz) 7.23-7.32 (2H, m) 7.13-7.21 (1H, m) 6.91 (1H, d, J=8.00 Hz) 6.81-6.87 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.40 (1H, dd, J=3.51, 1.76 Hz) 3.72 (3H, s) 3.67 (2H, s) 3.34 (2H, q, J=6.31 Hz) 2.65 (2H, t, J=6.35 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:16](=[O:18])[CH3:17])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Commercially available 2-amino-4-chloropyridine (50 g, 389 mmol) was dissolved in acetic anhydride (500 mL), triethylamine (271 mL, 1.94 mol) was added at 20° C., and the mixture was stirred at 60° C. for 12 hours. The mixture was cooled to 25° C. and then the solvent was evaporated. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1) and then the target fraction was concentrated under vacuum to obtain the title compound (66 g, 99%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28]3)=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 7-hydroxy-2-phenyl-chromen-4-one via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow solid.
Reaction SMILES: C(=O)=O.C(Cl)(Cl)(Cl)Cl.[CH:9]1[C:17]2[C:16]3[C:18]([C:26]4[C:27]([F:34])=[C:28]([OH:33])[C:29]([F:32])=[CH:30][CH:31]=4)=[C:19]4[C:24](=[CH:25][C:15]=3[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH:23]=[CH:22][CH:21]=[CH:20]4.[Br:35]Br>C(Cl)Cl>[Br:35][C:25]1[C:15]2[S:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:17]=3[C:16]=2[C:18]([C:26]2[C:27]([F:34])=[C:28]([OH:33])[C:29]([F:32])=[CH:30][CH:31]=2)=[C:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: BrBr
Reactant: Oc1c(F)ccc(-c2c3ccccc3cc3sc4ccccc4c23)c1F
Agent: O=C=O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reaction time: 0.47 h

Procedure:
To a cold (-23° C. dry ice/carbon tetrachloride bath) stirred solution of 3-(benzo [b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (1.38 g, 3.81 mmol) in methylene chloride (35 mL) was added a solution of bromine (0.22 mL, 4.19 mmol) in methylene chloride (7 mL) dropwise, very slowly, over a period of 28 minutes. After stirring an additional 1.5 h the reaction was quenched with dilute sodium bisulfite and the organics were extracted with ether. The extract was concentrated to give a yellow solid (1.64 g, 98% crude yield). A small portion was taken up in methylene chloride and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (85/15 petroleum ether/ethyl acetate) to give the title compound as an off white solid: mp 180-182° C.; NMR (400 MHz, DMSO-d6); δ10.64 (s, 1 H), 8.30 (d, J=9 Hz, 1 H), 8.09 (d, J=9 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.64-7.51 (m, 3 H), 7.42-7.37 (m, 1 H), 7.33-7.29 (m, 1 H), 6.96-6.91 (m, 1 H), 6.81-6.78 (m, 1 H); MS (FAB): (M-H): one bromine pattern observed; 439/441 (8%); Anal. Calc. for C22H11BrF2OS: C, 59.88, H, 2.51, N, 0.00%. Found: C, 59.82, H, 2.59, N, 0.06.