Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH:35]=[O:36])=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH2:35][OH:36])=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(C=O)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CO)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 331 (8.5 g, 14.1 mmol) in methanol (150 mL) and tetrahydrofuran (80 mL) was added sodium borohydride (530 mg, 14.1 mmol) at about 0° C. The mixture was stirred for about 3 hours while being allowed to warm to room temperature and was then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide the desired product. MS (ESI): m/z 607 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]([C@H:46]([OH:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].[NH:56]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C@H:57]([C:60](O)=[O:61])[CH2:58][OH:59]>CN(C=O)C>[C:66]([O:65][C:63]([NH:56][C@@H:57]([CH2:60][OH:61])[C:58]([NH:34][C@@H:35]([C@H:46]([OH:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:59])=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: COc1ccc([C@@H](O)[C@H](N)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Sequentially HATU (645 mg, 1.70 mmol) and DIEA (0.99 mL, 5.7 mmol) were added to a 0° C. solution of (2S,3R)-benzyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 477 mg, 1.41 mmol) and Boc-Ser-OH (290 mg, 1.41 mmol) in DMF (8 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1) twice to afford (2S,3R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (646 mg, 93% yield) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:36])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([F:31])[F:30])[CH:23]=4)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:36][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Yield: 28.4 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30, by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide (Intermediate-35, 0.050 g, 0.09 mmol), cyclopropylcarbonyl chloride (0.016 g, 0.14 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.67 (s, 4H), 1.59 (m, 1H), 3.92 (s, 3H), 3.32 (d, J=4.8 Hz, 2H), 7.03-7.33 (m, 1H), 7.35-7.47 (m, 3H), 7.62-7.68 (m, 2H), 7.76-7.84 (m, 2H), 8.09 (m, 2H), 8.70 (m, 1H), 10.28 (s, 1H), 12.69 (brs, 1H); MS (m/z): 586.12 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([NH:10][NH:11][C:12](OC(C)(C)C)=O)[CH2:3]1.[C:20](O)(=[O:27])/[C:21](=[C:23](\C=O)/[Cl:24])/[Cl:22]>Cl.O>[Cl:22][C:21]1[C:20](=[O:27])[N:10]([CH:4]2[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([CH3:1])([CH3:19])[CH2:3]2)[N:11]=[CH:12][C:23]=1[Cl:24]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: CC1(C)CC(NNC(=O)OC(C)(C)C)CC(C)(C)C1
Agent: Cl
Solvent: O
Product: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
t-Butyl N′-(3,3,5,5-Tetramethylcyclohexyl)hydrazine carboxylate (5.0 g, 0.0194 moles) was suspended in 6M hydrochloric acid (375 mL) and mucochloric acid (3.28 g, 0.0194 moles) was added. Heated to reflux with stirring overnight and allowed to cool. Diluted with water and filtered off the product as a grey solid. Dried in a desiccator over phosphorus pentoxide. (4.89 g, 83%). 1H NMR (300 MHz CDCl3) 7.8 (s, 1H), 5.25 (m, 1H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11](O)=[O:12]>C1C=CC=CC=1>[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([Cl:3])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
15 ml of thionyl chloride were added to a solution of 5.22 g (0.0216 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XII), R1 --OCHF2, R3' =H, X=X'=F] (prepared as described in Preparation 1, 2 or 3) in 300 ml of benzene, and the mixture was heated under reflux for 3 hours. At the end of this time, benzene and excess thionyl chloride were removed by distillation under reduced pressure, to give 3-difluoromethoxy-2,4,5-trifluorobenzoyl chloride [(XIII), R1 =--OCHF2, R3' =H, X=X'=F].
Reaction SMILES: [CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8]Cl)(=[O:5])=[O:4].[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC#N.O>[CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8][N:12]([CH3:13])[CH3:11])(=[O:5])=[O:4]
Reactant: CNC
Reactant: CN(C)S(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)CCCS(=O)(=O)N(C)C
Temperature: 65 °C
Yield: 68.6 %

Procedure:
A solution of 3-chloro-propane-1-sulfonic acid dimethylamide (0.55 g, 3.00 mmol) in MeCN (5 mL) was treated with dimethylamine (2 M in THF; 10 mL, 20 mmol), potassium carbonate (455 mg, 3.30 mmol) and a catalytic amount of potassium iodide (50 mg, 0.03 mmol). This mixture was heated in a sealed tube at 65° C. for 18 hours, then cooled and diluted with water and extracted into EtOAc. The organic extract was washed with brine then dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a pale brown oil (0.40 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][CH2:2][C:3]2[CH:18]=[CH:17][C:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[CH:5][CH:4]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
4-(4-Aminomethylbenzyl)-nitrobenzene (500 mg) was dissolved in dichloromethane (7 mL) and heated with 4-methoxybenzenesulfonyl chloride (426 mg) and triethylamine (0.3 mL). The mixture was stirred at room temperature for 15 hours, poured into dilute aqueous hydrochloric acid, and extracted with dichloromethane (3×). The solvent was evaporated to give 4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene as a yellow solid (851 mg, ˜100%), and was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]2[C:14](=O)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:4]2=[C:3]1[C:22]#[N:23].[OH-].[K+].CC(C)([OH:29])C.C(O)(=O)C>O>[C:8]1([C:6]2[NH:7][CH2:2][C:3]([C:22]([NH2:23])=[O:29])=[C:4]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH2:14][C:5]=23)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1c2c(c(-c3ccccc3)[nH]c1=O)C(=O)c1ccccc1-2
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)C1=C2C(=C(c3ccccc3)NC1)Cc1ccccc12

Procedure:
A mixture of 1 part of 3,9-dihydro-3,9-dioxo-1-phenyl-2H-indeno[2,1-c]pyridine-4-carbonitrile, 5 parts of potassium hydroxide, and 39 parts of 1,1-dimethylethanol is heated at the boiling point under reflux for 16 hours. The resultant mixture is diluted with 1000 parts of water, followed by sufficient acetic acid to neutralize the base present. The precipitate which forms is filtered off; consecutively washed with water, methanol, and 1,1'-oxybisethane; and dried in vacuo. The resultant yellow solid is crystallized from aqueous N,N-dimethylformamide to afford 3,9-dihydro-1-phenyl-2H-indeno[2,1-c]pyridine-4-carboxamide melting above 300°. The product has the formula ##STR19##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:21]([N:25]=[C:26]=[S:27])([O:23][CH3:24])=[O:22]>C(OCC)C>[C:21]([NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O:23][CH3:24])=[O:22]
Reactant: COC(=O)N=C=S
Reactant: CCCCNc1ccc(C(=O)c2ccccc2)cc1N
Solvent: CCOCC
Product: CCCCNc1ccc(C(=O)c2ccccc2)cc1NC(=S)NC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
To a solution of 3-amino-4-n-butylaminobenzophenone (2.38 g.) in diethyl ether (200 ml.) is added carbomethoxy isothiocyanate (1.4 g.). The reaction mixture is stirred at room temperature for 3 hours. The product is collected by filtration and dried to afford 0.2 g. of product, m.p. 160°-162° C., dec. The filtrate is allowed to stand overnight at room temperature and a second crop is collected amounting to 0.15 g., m.p. 162° C., dec. The total amount of 3-(3-carbomethoxythioureido)-4-n-butylamino-benzophenone obtained is 0.35 g. (10.2% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1.Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(O)(C)C.C(=O)(O)[O-].[Na+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(Oc2nccnc2C2CCCOC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4C4CCCOC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.082 g, 0.30 mmol) and 2-chlorobenzothiazole (0.039 mL, 0.30 mmol) were mixed in isopropyl alcohol (0.50 mL) in a microwave tube. The tube was sealed, and the reaction mixture was refluxed for 2.5 h. The reaction mixture was cooled to room temperature, diluted with sat. sodium bicarbonate, and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 405.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[CH2:23][CH:24](C(OCC)=O)[C:25]([O:27]CC)=[O:26].[OH-].[K+].O1CCCC1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(Cc1cccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(CCC(=O)O)c2)c1
Yield: 76.6 %

Procedure:
A mixture of diethyl 2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzyl]malonate (0.70 g), a 4N aqueous potassium hydroxide solution (10 mL), tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated and water was added to the residue. The mixture was neutralized with 2N hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in pyridine (40 mL) and this mixture was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, 2N hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.44 g, yield 77%) of 3-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C.C(=O)([O-])O.[Na+].CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of methyl 2-[(2,4-dichlorophenyl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference Example 103; 72.0 g, 0.183 mol) in tetrahydrofuran (800 mL) and triethylamine (127 mL) was added methanesulfonyl chloride (42.5 mL, 0.731 mol) at 0° C. The mixture was stirred at 0° C. for 2 hr, and diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The mixture of the residue, potassium carbonate (75.9 g, 0.549 mol) in N,N-dimethylformamide (800 mL) was stirred at 70° C. for 3 h. The mixture was diluted with water, and the precipitate was collected by filtration, washed with water, washed with diisopropyl ether to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (50.2 g, 0.133 mol, 73% in 2 steps).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:21])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>O1CCOCC1.C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([Cl:23])[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc[nH]2)c2ccc(Cl)cc21
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc[nH]2)c2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 4.5 g of 1-acetyl-6-chloro-3-[1-hydroxy-1-(2-pyrrolyl)methylene]-2-indolinone and 3.4 g of phosphorus pentachloride in 50 ml of dioxane and 50 ml of toluene is stirred for 3 hours at 90° C. Then the solvent is distilled off and the residue is purified by chromatography on silica gel (eluant: toluene).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.O>C(O)(=O)C.Br>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCCCCCc1ccc(-c2cnc(-c3ccc(OC)c(F)c3)nc2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(-c2cnc(-c3ccc(O)c(F)c3)nc2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
2.5 g of the 2-(3-fluoro-4-methoxyphenyl)-5-(4-heptylpheny)pyrimidine obtained in Example 1 was dissolved in a mixture of 200 ml of acetic acid and 100 ml of 47% hydrobromic acid. The obtained solution was heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and 500 ml of water was added thereto. The crystals thus precipitated were filtered. The product thus obtained was purified by column chromatography (developing solvent: hexane: ethyl acetate=5:1) to thereby give 2.1 g of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-heptylphenyl)pyrimidine. Yield: 87%.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1)[NH2:22].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:18]([NH:22][NH:21][C:23]2[N:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[CH:25][N:24]=2)=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cyclopentanecarboxylic acid (0.10 g, 0.36 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.10 g, 0.43 mmol), NMM (0.11 g, 1.08 mmol) and HOAt (0.059 g, 0.43 mmol) in DMF (2 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.085 g, 0.43 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.085 g, 57%). MH+438.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.CC[N:19]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([NH2:19])=[O:16]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C)c(CC(N)=O)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
A reaction mixture containing Compound 1 (880 mg, 4.02 mmol), EDCl (1.16 g,6.04 mmol), HOBt (816 mg,6.04 mmol), DIPEA (2.8 mL, 16.08 mmol), ammonium chloride (430 mg, 8.04 mmol) in anhydrous DMF 16 mL (4 mL DMF/1 mmol) was stirred at rt for 5 hours. The reaction was diluted with water and extracted with EtOAc (3×10 mL). The combined EtOAc extracts were washed with saturated NaHCO3 (2×10 mL), water, dried (MgSO4), filtered, and the solvent concentrated in vacuo till a minimum volume of EtOAc remained. Upon cooling, the desired primary amide crystallized out as a white crystalline solid, in 64% yield. mp=146-148° C. t is noted that Shaw, “The Synthesis of Tryptamines Related to Seratonin”, Vol. 77, J. Amer. Chem. Soc., pp. 4319-4324 (1955) reported the mp=147-150° C. 1H NMR (DMSO-d6) δ 10.56 (s, 1 H, NH), 7.34 (bs, 1 H, CONH), 6.96-7.22 (m, 1 H, ArH), 6.81 (s, 1 H, ArH), 6.74 (bs, 1 H, CONH), 6.58-6.62 (m, 1 H, ArH), 3.78 (s, 3 H, CH3), 3.34 (s, 2 H, CH2), 2.29 (s, 3 H, CH3). ESI-CID 219 (MH+), m/z 187, 174, 148.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>C(Cl)Cl>[Si:10]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 3-bromobenzyl alcohol (5.00 g, 26.7 mmol) in freshly drieddimethylformamide (10 mL) was added t-butyldimethylsilyl chloride (5.13 g, 33 mmol) and imidazole (4.56 g, 67 mmol). The resulting solution was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted (3x, 50 mL 1:1 ether:hexanes). The combined organic layers were washed (2x, brine), dried over MgSO4, filtered, and concentrated in vacuo to give a colorless oil which was passed througha short silica gel plug using 10% methylene chloride:hexanes to give pure 3-(t-butyldimethylsilyloxymethyl)bromobenzene (7.9 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.47 (1H, br s), 7.37 (1H, dt, J =7, 1 Hz), 7.16-7.25 (2H, m), 4.24 (2H, s), 0.94 (9H, s), 0.11 (6H, s). MS m/e 318/320(M+NH4)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:44])[CH:15]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[CH:19][C:18]=2[CH2:32][CH2:33][CH3:34])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C1COC(COCCO)C1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:44])[CH:15]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=2[CH2:32][CH2:33][CH3:34])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OCCOCC1CCCO1
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(CO)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 26.2 %

Procedure:
To a solution of 3.20 g (5.01 mmol) of the product of Step D dissolved in 5.0 mL of anhydrous THF was added 5.06 mL (5.06 mmol) of a 1.0M solution of tetrabutylammonium fluoride in ThF and the reaction mixture was stirred at room temperature under a nitrogen atmosphere. After 2.5 hours 1.0 mL additional tetrabutylammonium fluoride in THFP was added and the reaction mixture was stirred for an additional 14 hours. The reaction mixture was then concentrated in vacuo and applied to a silica gel flash chromatography column and eluted with 60% EtOAc-hexane. Combination of the purified fractions and drying in vacuo afforded 0.691 g (26%) of the title compound as an amorphous powder.