Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate (0.13 g) in ethyl acetate (1 mL) and methanol (1 mL), 10% palladium-carbon (63 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.081 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:29])[CH:5]=[C:6]3[C@:26]([CH3:27])([C@@H:2]12)[C@@H:25]1[C@H:9]([C@H:10]2[C@:22]([CH3:28])([CH2:23][CH2:24]1)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.[Li].[Cl-].[NH4+]>N.O1CCCC1>[OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:29])[CH2:3]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Barton et al, J.A.C.S. 95:8, 2748 (1973) describe reduction of 1α,2α-epoxycholesta-4,6-dien-3-one with large excesses of each of lithium metal and ammonium chloride in ammonia/tetrahydrofuran at reflux to obtain 1α,3β-dihydroxycholest-5-ene which is a precursor of 1α-hydroxyvitamin D3.
Reaction SMILES: [C:1]([CH:7]([OH:26])[C@H:8]1[O:12][C@@H:11]([N:13]2[CH:24]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[OH:25])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>N1C=CC=CC=1>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([C@@:9]2([OH:25])[C@@H:8]([CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[OH:26])[O:12][C@@H:11]([N:13]3[CH:24]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH2:10]2)=[O:35])[CH:30]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@]1(O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.1 %

Procedure:
To a stirring solution of 450 mg of 5'-pivaloyltrifluorothymidine in 10 mL of pyridine was added 1.0 g of nicotinoyl chloride hydrochloride under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, then was poured into 100 mL of ice water and extracted with 100 mL of ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and then evaporated in vacuo to give an oil. Crystallization from n-hexane afforded 500 mg (87%) of colorless needles melting at 175°-177° C. The product had the structure ##STR133## as further confirmed by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][NH:6][CH:7]=1.[O:15]1CCC[CH2:16]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:15][CH2:16][N:6]1[CH:7]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5]1
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Reactant: C1CCOC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn(CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
207 mg of 4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole, 5 ml of tetrahydrofuran and 5 ml of formaldehyde 36% in water were mixed. 0.2 ml of tetrabutylammonium hydroxide 10% in water was added to the mixture at room temperature, followed by stirring at room temperature for 10 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product of 1-hydroxymethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[CH2:23]([S:30][C:31]1([CH2:37][NH2:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>C(#N)C.O1CCCC1>[CH2:23]([S:30][C:31]1([CH2:37][NH:38][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])=[O:14])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC1(SCc2ccccc2)CCOCC1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCOCC3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.50 g), 1-[4-(benzylthio)tetrahydro-2H-pyran-4-yl]methanamine (0.39 g), 1H-1,2,3-benzotriazol-1-ol (0.20 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.34 g), tetrahydrofuran (10 ml) and acetonitrile (3 ml) was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (NaSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (764 mg, yield 92%) as colorless crystals from a fraction eluted with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(C(F)(F)F)c(-c2ccccc2)s1
Product: O=C(Nc1nc(C(F)(F)F)c(-c2ccccc2)s1)c1cc(Br)ccc1O
Yield: 33.2 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2C=CC(O)=CC=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1>C(Cl)Cl>[C:10]([C:7]1[CH:6]=[CH:5][C:4]([OH:3])=[CH:9][CH:8]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O)cc1

Procedure:
To this polymer liquid, a methylene chloride solution of p-t-butyl phenol (PTBP) (one obtained by dissolving 140 g of PTBP in 2.0 L of methylene chloride) and an aqueous sodium hydroxide solution of bisphenol A (BPA) (one obtained by dissolving 1012 g of BPA in an aqueous solution prepared by dissolving 577 g of NaOH and 2.0 g of sodium dithionite in 8.4 L of water) were added, and a polymerization reaction was conducted for 50 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[C:7]([C:6]1[CH:9]=[C:2]([N:28]2[C@H:27]([CH3:26])[CH2:31][O:30][C:29]2=[O:32])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3C#N)CC2)c(C)c1
Yield: 77.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 193 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (326 mg) was obtained.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][C:35]1([CH3:39])[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][C:35]([NH2:34])([CH3:39])[CH2:36]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CC1(N)CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
To 350 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-3-methylazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 40 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol to obtain 64 mg of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].CC(C)=O.CCN(CC)CC.Cl[CH2:46][O:47][C:48](=[O:61])[C@@H:49]([NH:53]C(OC(C)(C)C)=O)[CH:50]([CH3:52])[CH3:51].CC#N.Cl.O1CCOCC1>>[C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@H:29]([C:30]([OH:32])=[O:31])[OH:33])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[N:7]([CH2:46][O:47][C:48](=[O:61])[C@@H:49]([NH2:53])[CH:50]([CH3:52])[CH3:51])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)n(COC(=O)[C@@H](N)C(C)C)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 74.5 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (95.5 mg, 0.2 mmol) was dissolved in acetone (886 μL, 12.1 mmol). Et3N (70 μL, 503 μmol) and (S)-2-t-butoxycarbonylamino-3-methyl-butyric acid chloromethyl ester (56.1 mg, 211 μmol) were added, and the resulting mixture was stirred at 60° C. for 6 hours. The solvent was removed in vacuo and the residue was purified using flashy chromatography (normal phase; MeOH:EtOAc=0:50). The pure fractions were collected, concentrated, then dissolved in MeCN (630 μL, 12.1 mmol). A solution of 4.0 M HCl in 1,4-dioxane (503 μL, 2.0 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to yield the title compound (90 mg).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.N(OCCC(C)C)=O.Cl>C1COCC1.[Cu](Cl)Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([CH:10]4[CH2:15][CH2:14][CH2:13][CH2:12][O:11]4)[C:7]([C:8]#[N:9])=[CH:2][N:3]=3)[N:21]=2)=[CH:30][CH:29]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.21 mmol) of the compound from Example 14 are initially charged in 5 ml of dry THF, and 167 mg (1.42 mmol) of isopentyl nitrite and 3 mg (0.02 mmol) of copper(II) chloride are added. The reaction mixture is stirred at RT for 8 h. Another 3 mg (0.02 mmol) of copper(II)-chloride are added, and the reaction mixture is stirred at RT for another 12 h. 6 ml of 1 N hydrochloric acid are then added to the mixture. The aqueous phase is extracted twice with in each case 10 ml ethyl acetate. The combined organic phases are washed once with 5 ml of saturated aqueous sodium bicarbonate solution and once with 5 ml of saturated aqueous sodium chloride solution. The mixture is then dried over magnesium sulfate. After removal of the solvent the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH2:11][CH2:10]2)(=[O:6])=[O:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[C:34]([N:12]3[C:13]4[C:9](=[CH:8][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=4)[CH2:10][CH2:11]3)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a suspension of sodium hydride (0.25 g, 2 eq) in 10 mL of DMF, was added 5-methanesulfonyl-2,3-dihydro-1H-indole (0.63 g, 1 eq). The mixture was stirred at room temperature for 10 minutes then 3a (1 g, 3.19 mmol) was added. The resulting mixture was heated up to 80° C. for 18 h. The reaction mixture was then allowed to cool down to room temperature and brine (200 mL) was added. The solution was extracted with DCM twice (200 mL then 50 mL). The combined extracts were washed with brine (2×50 mL), dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography (elution with 10-100% ethyl acetate and 0.1% TEA in hexanes) to give 0.61 g of 4a (40% yield), LCMS 475.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:22]([CH:25]=1)[CH:23]=O.[Na]>ClC(Cl)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][CH2:23][C:22]2[CH:25]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=2[O:26][CH2:27][CH2:28][O:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH:7]=1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Reactant: COc1ccc(OCCOS(C)(=O)=O)c(C=O)c1
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc(OCCOS(C)(=O)=O)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Yield: 62 %

Procedure:
To stirred solution of 9.1 g (45 mmol) 1b, 12.3 g (45 mmol) 4a and one drop of glacial acid in 60 ml dichloroethane (pH=5) were added 14.8 g (70 mmol) sodium tris-acetoxy hydro borane. The reaction mixture was stirred over night and diluted with 5 ml water. The pH value was adjusted with aqueous sodium hydroxyd solution to pH=8-9. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and were dried with magnesium sulfate. The desired crude product 4b was obtained in 62% yield (12.9 g, 27.9 mmol) as yellow oil. The crude product 4b was used without further purification.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22](Cl)=[O:23])[C:10]=2[CH3:25])=[CH:5][CH:4]=1>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([NH2:1])=[O:23])[C:10]=2[CH3:25])=[CH:5][CH:4]=1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: N
Solvent: ClCCl
Product: Cc1c(C(N)=O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Thionyl chloride (1.3 ml, 22.0 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2.09 g, 5.5 mmol) in toluene (50 ml) maintained at room temperature. The mixture was refluxed at 110° C. for 2 hours and then cooled to room temperature. The resulting solution was evaporated and dried under a vacuum to produce crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride, which are not further purified. 27% aqueous ammonia (2 ml) was added to the solution of crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride in methylene chloride (10 ml) at 0° C. After stirring 3 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride which was extracted twice with 50 ml portions of ethyl acetate. After concentrating the extract by evaporation, the crude residue was purified using a silica gel column (hexane/ethyl acetate=1/1), to obtain the title compound (2.07 g, 99%) as white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[S:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1.Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([CH:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:9]1)(=[O:3])[CH3:2]
Reactant: C1=Cc2ccccc2SC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C1C=Cc2ccccc2S1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Under a dry nitrogen atmosphere, 7.18 g (0.0914 mole) of acetyl chloride was added to a cold (5° C.), stirred mixture of 11.9 g (0.0893 mole) of aluminum chloride in 100 ml of carbon tetrachloride. To this mixture was added a solution of 10.6 g (0.079 mole) of thianaphthalene in 25 ml of carbon tetrachloride. The reaction mixture was allowed to warm to room temperature and was stirred for two hours. The mixture was heated at reflux for 45 minutes and was cooled. The resultant mixture was poured into ice water, and 100 ml of concentrated hydrochloric acid was added. This mixture was stirred until the ice melted. The organic phase was removed and saved. The aqueous phase was extracted with methylene chloride. The organic phases were combined and dried over anhydrous sodium sulfate. This mixture was filtered, and the filtrate was treated with silica gel and decolorizing charcoal. The resulting mixture was filtered through a pad of silica gel. The filtrate was evaporated under reduced pressure to yield 11.3 g of 2 -acetylthianaphthalene as an oil.
Reaction SMILES: [F:1][C:2]([F:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][C@@H:14]([C:16]2[CH:27]=[CH:26][C:19]3[O:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23][C:18]=3[CH:17]=2)[O:13]C1=O.C[Si](C)(C)[O-].[K+].[Cl-].[NH4+]>O1CCCC1>[F:35][C:2]([F:1])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:15][C@@H:14]([C:16]1[CH:27]=[CH:26][C:19]2[O:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23][C:18]=2[CH:17]=1)[OH:13]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCC(F)(F)c4ccccc4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCC(F)(F)c3ccccc3)ccc2O1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 35 (1.5 g, 3.0 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.54 g, 12 mmol). The mixture was stirred at 70° C. under inert atmosphere for 2 hours. To the cooled reaction mixture was added saturated solution of ammonium chloride (60 mL). The suspension was extracted with methylene chloride (2×30 mL). The organic layer was washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and methylene chloride/ethanol/ammonium hydroxide (100:8:1) as eluent. The title compound was obtained (900 mg, 65%) as oil.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:12]2[CH2:13][CH2:14][CH:9]([C:2]([OH:15])([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][CH2:11]2)=[CH:21][CH:22]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CC(O)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(c1ccccc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
The mixture of 2 g of α-methyl-α-(4-piperidyl)-benzyl alcohol, 1.95 g of 4'-fluoro-4-chlorobutyrophenone, 2 g of sodium carbonate (anhydrous), a crystal of sodium iodide and 150 ml of 4-methyl-2-pentanone are stirred and refluxed for 72 hours. The reaction mixture is filtered to remove the inorganic salts and the filtrate evaporated under reduced pressure. Diethyl ether is added to the residue and the resulting solution extracted with 5% aqueous hydrochloric acid. The aqueous solution is made basic with ammonia and extracted with diethyl ether. The extract is then dried and evaporated under reduced pressure to afford the 4'-fluoro-4-[4-(α-hydroxy-α-methylbenzyl)-piperidino]- butyrophenone of the formula ##STR5## Recrystallization from isopropanol yields the above compound melting at 55°-57° and isolated as a solvate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH2:18][CH2:19][C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:18][CH2:19][C:20](=[O:21])[N:22]([O:24][CH3:25])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCN1CCN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a cooled (0° C.) solution of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester 5.9 g (28 mmol) and 4-bromo-N-methoxy-N-methyl-butyramide 5.4 g (28 mmol) in DMF (220 ml) was added NaH 1.3 g (30 mmol, 55% dispersion in oil), the mixture allowed to reach RT and the mixture stirred for a further 2 h. The reaction was then concentrated, the residue redissolved in EtOAc and washed with 10% aq. KHSO4 solution, brine, dried (MgSO4) and concentrated affording the title compound 9.1 g (quant) as white foam. MS: 330.3 (MH+).