Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:31])[CH2:24]2.Cl>C1COCC1.CCCCCC.C(O)C>[Cl:16][C:17]1[C:22]([C:25]2([OH:31])[CH:26]3[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]3)[CH2:24]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2nccnc2Cl)CN2CCC1CC2
Temperature: -77 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
A solution of 7.2 ml 2,2,6,6-tetramethylpiperidine (0.034 mol) in 300 ml of dry THF was cooled to -8° C. as 25 ml of 1.6 M butyllithium (0.04 mol) in hexane was added dropwise. The reaction was stirred 20 min then cooled to -77° C. A solution of 2.9 ml of 2-chloropyrazine (0.031 mol) in 5 ml of THF was added to the reaction dropwise. After 15 min, 4.4 g of 3-quinuclidinone (0.0352 mol) in 5 ml of THF was added dropwise and the reaction stirred another 1.5 h. A solution of 8 ml of concentrated HCl and 4 ml of ethanol was added and the cooling was removed. When the temperature reached -5° C., 20 ml of 5 N NaOH was added and the volatile organics were evaporated. The residue was suspended in 50 ml of ice-water and the mixture filtered. The aqueous filtrate was extracted 3× with 50 ml of CHCl3. The extracts were combined with the solid collected from the filtration and the volume of the mixture adjusted to 450 ml with additional CHCl3. The mixture was heated on a steam bath until most of the solid had dissolved. The mixture was dried, filtered, and the solvent evaporated to give a dark brown solid that was recrystallized from isopropanol to give 6.3 g of (7), mp 215°-216° C. NMR ppm (CDCl3) 1.25(1H, m), 1.5 (2H, m), 2.2 (1H, m), 2.65-3.1 (6H, m), 3.6 (1H, bs), 4.05 (1H, d), 8.3 (1H, d), 8.5 (1H, d). Anal. C11H14ClN3O requires C: 55.12; H: 5.89; N: 17.53%. Found C: 55.21; H: 5.99; N: 17.30%.
Reaction SMILES: [CH3:1][I:2].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=1>CC(C)=O>[I-:2].[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][C:6]=1[CH:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][CH2:13][N+:14]1([CH3:1])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Cc1ccc(O)c(C(CCN2CCCC2)c2ccccc2)c1
Reactant: CI
Solvent: CC(C)=O
Product: Cc1ccc(O)c(C(CC[N+]2(C)CCCC2)c2ccccc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (10 equivalents) was added to a solution of the free base 4-methyl-2-(1-phenyl-3-pyrrolidin-1-ylpropyl)phenol of Example 30 (0.3 g, 1.02 mmol) in acetone (4 mL). The reaction mixture is stirred overnight at room temperature. The solution is concentrated to initiate the precipitation of the resulting quaternary ammonium salt. The white precipitate is filtered, washed with diethyl ether and dried under vacuum to give a quaternized salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 68.1 %

Procedure:
Using 5-bromo-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1N.Br.N([O-])=O.[Na+].[C:17](#[N:20])[CH:18]=[CH2:19]>O.C1CCCCC1.CC(C)=O>[Br:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1/[CH:19]=[CH:18]/[C:17]#[N:20]
Reactant: Cc1cc(C)c(N)c(Br)c1
Reactant: C=CC#N
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(/C=C/C#N)c(Br)c1
Temperature: 15 °C

Procedure:
A 5 1, 3-necked round-bottom flask, equipped with an overhead stirrer, thermometer and addition funnel was charged with 2-bromo-4,6-dimethylaniline hydrobromide (713 g, 2.54 mol) and acetone (1.9 1). The slurry was cooled to 15° C. and 48% aqueous hydrobromic acid (450 ml, 4.0 mol), was added. The mixture was cooled to -4° C. then a solution of sodium nitrite (219 g, 3.17 mol) in 400 ml of water was slowly added with vigorous stirring while maintaining an internal temperature of 0° C. Acrylonitrile (550 ml) was charged and the reaction mixture was degassed under vacuum then purged with nitrogen. Cuprous bromide (3.0 g, 0.021 mol) was charged and the mixture stirred with gradual warming to ambient temperature over 6 hours. The mixture was aged with stirring, for 6 additional hours. The mixture was concentrated under vacuum, collecting 3 1 of solvent. The residue was diluted with toluene (3 1), the organic extract was washed with 3×500 ml of water, dried over sodium sulfate, filtered, and concentrated to a volume of 1 1. The dark concentrate was charged with triethylamine (1.2 1) and heated at 80°-90° C. under nitrogen for 6.5 hours. The mixture was concentrated under vacuum to a thick slurry then diluted with toluene (2.5 1). The organic phase was extracted 2×500 ml with 3 N aqueous hydrochloric acid, 2×500 ml with water, then dried over sodium sulfate. After filtration the toluene extract was treated with activated charcoal (10 g) at ambient temperature then filtered through super-cel. Removal of the solvent in vacuo yielded a yellow oil which solidified on standing. The crude nitrile was dissolved in a solution of cyclohexane (525 ml) and hexanes (840 ml) with heating. The mixture was gradually cooled to 3° C., filtered, washed with 500 ml of cold hexane and dried in vacuo to yield the Compound 2a as a light yellow solid (mp 95°-96° C.). The crystallization mother liquors contained an additional product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[NH:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].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>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:17]1[C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:14][Si:15]([CH3:19])([CH3:18])[CH2:16]1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: C[Si]1(C)CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Yield: 66.1 %

Procedure:
A mixture of (R)-5-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine (350 mg, 0.92 mmol, Preparation 9), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (170 mg, 0.97 mmol), HATU (400 mg, 1.05 mmol), and DIPEA (700 mg, 5.4 mmol), in DCM (50 mL) was stirred at RT overnight. The reaction mixture was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (20% EtOAc in petroleum ether) to give the title intermediate (300 mg, 66% yield) as a straw yellow solid. (m/z): [M+H]+ calcd for C21H29BrN4O3Si, 493.12 found 493.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].FC1C=CC(N[C@H](CC)C(O)=O)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC[C@H](N)C(=O)O
Agent: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Product: CC[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O

Procedure:
4-Bromo-2-fluoronitrobenzene was treated with (S)-2-aminobutyric acid according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield (2S)-2-[(5-bromo-2-nitrophenyl)amino]butanoic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2cncc(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of 2-{6-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (40 mg, 0.09 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd(OH)2 (10 mg, 20%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 3 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford {6-[2-(4-fluoro-phenyl)-ethyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (24 mg, 60%). 1H NMR (400 MHz, CD2Cl2) δ 9.15 (s, 1H), 8.36 (s, 1H), 7.28-7.37 (m, 5H), 7.13-7.17 (m, 2H), 6.92-6.96 (m, 2H), 6.25 (bs, 1H), 4.60 (d, J=4.0 Hz, 2H), 3.07-3.16 (m, 4H), 2.73 (s, 3H); HRMS (M+H)+=433.15.
Reaction SMILES: C([Cl:4])(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])O)=[CH:8][CH:7]=1>ClCCl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[Cl:4])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccc(F)cc2)c2ccccc2F)cc1
Reaction time: 12 h

Procedure:
A 20% solution of acetyl chloride in dichloromethane (60 mL) was added to the crude bis(4-fluorophenyl)-2-fluorophenylmethanol at rt. The resulting solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (100 mL) was added to the residue and was then evaporated to afford crude bis(4-fluorophenyl)-2-fluorophenylchloromethane which was used without purification in the next step.
Reaction SMILES: [C:1](=[O:18])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]3[CH:42]=[C:41]4[C:36]([CH2:37][CH2:38][NH:39][CH2:40]4)=[CH:35][CH:34]=3)[N:30]=[C:29]([NH2:43])[N:28]=2)[CH2:23][CH2:22]1>>[NH2:43][C:29]1[N:30]=[C:31]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][N:39]([C:1]([O:2][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:18])[CH2:40]3)=[CH:35][CH:34]=2)[CH:32]=[C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]2)[N:28]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from cyclopentyl 4-nitrophenyl carbonate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=437.4.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:24][P:25](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].O>ClCCl>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][P:25]([CH3:24])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CP(=O)(Cl)c1ccccc1
Reactant: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CP(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)c1ccccc1
Reaction time: 1 h
Yield: 28.7 %

Procedure:
A solution of 20 mg of 3-styryl-1H-indazol-5-ol, 5.76 mg of imidazole and 20.7 mg of methylphenylphosphinic chloride in 5 ml of dichloromethane is stirred at ambient temperature. After stirring for approximately one hour, 5.76 mg of imidazole and 20.7 mg of methylphenylphosphinic chloride are added. The suspension is stirred at ambient temperature for approximately 18 hours. 10 mg of imidazole and 70 mg of methylphenylphosphinic chloride are added. After 30 hours at ambient temperature, the reaction medium is treated with 10 ml of distilled water. The aqueous phase is extracted with 2×10 ml of dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure in a rotary evaporator. The reaction crude is purified by preparative LC/MS to obtain 9.1 mg of methylphenylphosphinic acid 3-((E)-styryl)-1H-indazol-5-yl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11](Cl)(Cl)[CH:12]([OH:14])O.NO.S(=O)(=O)(O)[OH:20]>>[F:9][C:8]1[CH:7]=[C:6]2[C:4](=[CH:3][C:2]=1[F:1])[NH:5][C:11](=[O:20])[C:12]2=[O:14]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=S(=O)(O)O
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: NO
Product: O=C1Nc2cc(F)c(F)cc2C1=O

Procedure:
Reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine followed cyclization with sulfuric acid, in a manner analogous to Parts A and B of Preparation 6, gave 5,6-difluoroisatin, which was reacted with hydrazine hydrate followed by sodium methoxide in ethanol, in a manner analogous to Preparation 4, to give the title compound, m.p. 187°-190° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:8]([CH:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]([CH3:37])=[CH:6]2.[Br:38]C1C=CC=CC=1CC(=O)C.COC1C=C(CC(=O)C)C=CC=1>>[Br:38][C:4]1[CH:3]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:37])[C:8]([CH:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:9]2[O:13][S:14]([C:17]([F:18])([F:20])[F:19])(=[O:15])=[O:16]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2cc(OC)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)Cc1ccccc1Br
Agent: COc1cccc(CC(C)=O)c1
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(Br)cccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
Ethyl 2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl oxy)acetate (35) was prepared similarly to ethyl 2-(6-methoxy-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 32, using 1-(2-bromophenyl)propan-2-one as the starting material instead of 1-(3-methoxyphenyl)propan-2-one. 1H-NMR: 400 MHz, (CDCl3) δ: 8.11 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.81 (d, J=7.6 Hz, 2H), 5.61 (s, 1H), 4.62 (q, J=11.2 Hz, 2H), 4.26-4.15 (m, 2H), 3.75 (s, 3H), 2.62 (s, 3H), 1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C@H:11]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH2:10]1)C1C=CC=CC=1.C(Cl)(Cl)Cl.N.[C:38]([OH:47])(=[O:46])[C@H:39]([C@@H:41]([C:43]([OH:45])=[O:44])[OH:42])[OH:40]>CO.O>[C:38]([OH:47])(=[O:46])[C@H:39]([C@@H:41]([C:43]([OH:45])=[O:44])[OH:42])[OH:40].[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:12]2[CH2:13][CH2:14][NH:9][CH2:10][C@H:11]2[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2COc2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: N
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Reaction time: 2.5 h
Yield: 33.4 %

Procedure:
A suspension containing 9.1 g (0.02 mol) of (±)-trans-1-benzyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride in the mixture of 100 ml of chloroform and 50 ml of water is alkalinized to pH 9 by adding concentrated aqueous ammonia solution. After separation of the phases, the aqueous layer is extracted with 20 ml of chloroform. The combined organic phase is dried over magnesium sulfate and, after filtering the drying agent the solution is evaporated to solvent-free. The evaporation residue is dissolved in 120 ml of ethanol and hydrogenated in an autoclave in the presence of 0.8 g of 10% palladium-on-carbon catalyst at 40° C., under 5×105 Pa pressure for 2 to 3 hours. After taking up the hydrogen, the catalyst is filtered and the filtrate is evaporated to solvent-free. The evaporation residue (weighing 6.6 g) is dissolved in 80 ml of methanol, a solution of 3 g (0.02 mol) of (+)-D-tartaric acid in 20 ml of methanol is added at room temperature and the mixture is stirred for 5 hours. The precipitated crystalline product is filtered to yield 3.2 g (66%) of (−)-trans-4-(4-flurophenyl)-3-(3,4-metylenedioxyphenoxymethyl)piperidine (+)-D-tartarate, m.p.: 178-180° C.; [α]D20−50.5° (c=1, dimethylformamide).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([N:16]=C=O)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.[OH-].[Na+].C(O)CO.Cl>C(OCC)C.O>[NH2:16][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1
Reactant: O=C=NC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: O
Product: NC1(c2ccccc2)CCC(=O)CC1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
A reaction mixture consisting of 21.9 gm. (0.085 mole) 4-isocyanato-4-phenylcyclohexanone ethylene ketal (prepared as in Example 17, Part G), 10.9 gm. sodium hydroxide, and 210 ml. ethylene glycol is heated at the reflux temperature for sixty-six (66) hours. A solution results which is cooled in an ice-water bath. A small amount of ice is added to the solution followed by 23 ml. of concentrated hydrochloric acid which is added dropwise with stirring. After five minutes, the acidified solution is made strongly basic by adding 50% aqueous sodium hydroxide. The basic solution is diluted with 800 ml. water. The strongly basic, dilute aqueous solution is then extracted four times with 200 ml. portions of diethyl ether. The extracts are combined and washed with water and with brine, before removing the ether by evaporation under reduced pressure. The residue thus obtained is dissolved in 50 ml. of diethyl ether and the oily solution is treated with an equivalent of 3 N hydrogen chloride in diethyl ether. A precipitate forms which is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 15.2 gm. (52% yield) of 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride which has a melting point at 226° to 228° C. (with decomposition). A second crop of crystals weighs 1.60 gm. and has a melting range from 222° to 226° C. An analytical sample has a melting point at 248° to 249° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7](O)(=O)[CH2:8]C([CH2:14][C:15]([OH:17])=[O:16])(C(O)=O)O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH2:2][O:17][C:15]([CH3:14])=[O:16].[CH3:7][CH2:8][CH2:1][CH:2]([CH3:5])[CH3:3]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCC(C)C
Product: CCOC(C)=O
Reaction time: 4 h
Yield: 20 %

Procedure:
A mixture of (syn)-5-chloro-N-(2-oxobicyclo[2.2.1]hept-7-yl)thiophene-2-sulfonamide (0.100 g, 0.313 mmol), methyl(triphenylphosphonium) bromide (0.125 g, 0.35 mmol) and potassium tert-butoxide (1M in THF, 1.0 mL) in dry toluene (2 mL) was reluxed under N2 for 4 h. The mixture was cooled, diluted with 1M citric acid (15 mL) and extracted with EtOAc (2×15 mL). The extracts were dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with 10% then 20% EtOAc-isohexane, gave the title compound as a pale yellow solid (0.027 g, 28%). 1H NMR (CDCl3, 360 MHz) δ 1.30-1.34 (2 H, m), 1.69-1.73 (2 H, m), 1.96 (1 H, d, J 15), 2.26-2.35 (2 H, m), 2.41 (1 H, d, J 3), 3.42 (1 H, d, J 6), 4.55 (1 H, d, J 6), 4.83 (1 H, s), 4.95 (1 H, s), 6.92 (1 H, d, J 4), 7.39 (1 H, d, J 4); m/z 306 and 304 (M+H+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.Br.[NH2:12][C:13]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:16]=2[O:15][C:14]=1[Br:36].C(N(CC)CC)C>C(Cl)Cl>[Br:36][C:14]1[O:15][C:16]2[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:20][C:17]=2[C:18](=[O:19])[C:13]=1[NH:12][CH:1]=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(N)c(=O)c2cc1Oc1ccccc1
Agent: Br
Solvent: O=CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
3.06 g of acetic anhydride and 2.76 g of formic acid were mixed and stirred for 1.5 hours at 40°-45° C. to prepare a mixed acid anhydride. Separately, 5.06 g of 3-amino-2-bromo-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one hydrobromide was suspended in 100 ml of methylene chloride. To the suspension being ice-cooled was added 1.06 g of triethylamine, and the mixture was stirred for 30 minutes at the same temperature. Thereto was added the above mixed acid anhydride, and the resulting mixture was stirred for 1 hour at 20°-25° C. The solvent was removed by distillation under reduced pressure. The residue was mixed with 200 ml of water. The resulting crystal was collected by filtration and recrystallized from ethyl acetate-diisopropyl ether to obtain 4.15 g (yield: 97.6%) of 2-bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 237°-238° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=[O:42].[O:43]1[CH2:47]CCC1>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][O:12][C:9]1[C:8]2[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4][C:3]=2[C:2]([C:47]([OH:43])=[O:42])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: [C]=O
Reactant: COc1ccc(Br)c2ccc(C)nc12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2ccc(C)nc12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixtures of 5-bromo-8-methoxy-2-methylquinoline (2.0 g), triethylamine (11 ml), triphenylphosphine (0.79 g), and bis(tripbenylphosphine)palladium (II) chloride (1.56 g) in tetrahydrofuran (200 ml) and water (90 ml) was stirred in a pressurised reaction vessel and charged with carbon monoxide to a pressure of 160 psi. The vessel was heated to 80° C. and stirred for 72 hours. The reaction was allowed to cool and depressurised. The mixture was filtered ant the organic solvent was removed in vacuo. The aqueous residue was basified with 1M sodium hydroxide and washed with ethyl acetate (300ml). The aqueous solution was acidified to pH 5 with glacial acetic acid and extracted with ethyl acetate (2×400 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to yield the title product (1.0 g) as an off-white solid.