Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(NS(=O)(=O)C(F)(F)F)sc2-c2ccc(OC)cc2)cc1
Yield: 26.7 %

Procedure:
13.5 g of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 5.0 g of 2-amino-4,5-bis(4-methoxyphenyl)thiazole and 5.0 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 2 hours. Then the reaction mixture was successively washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using chloroform/ethyl acetate as a developer. The crystals thus obtained were recrystallized from isopropyl ether/ethyl acetate to give 1.9 g of 2-trifluoromethanesulfonylamino-4,5-bis(4-methoxy-phenyl)thiazole. The melting point of this product was from 240° to 242° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C:7](=[CH:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([O:19][C:12]1[CH:13]=[CH:14][C:15]2[C@@H:16]3[C:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[CH:3]=[CH:4][CH2:5]4)=[CH:8][CH2:9][C:10]=2[CH:11]=1)(=[O:28])[CH3:27]
Reactant: C[C@@]12C=CC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra-1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 mL, 32 mmol) and acetic anhydride (0.36 mL, 3.8 mmol) was stirred 6 h, after which 30 mL of ethyl acetate were added. The mixture was washed with three 10 mL portions of 1N hydrochloric acid+10 mL of saturated sodium bicarbonate+10 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24. (NA-1994A-286A)
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[C:19]([C:21]([NH:23][CH:24]([CH:29]([CH3:31])[CH3:30])[C:25]([O:27]C)=[O:26])=[O:22])[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:20]=[C:19]([C:21]([NH:23][CH:24]([CH:29]([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])=[O:22])[O:18][N:17]=4)=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(Oc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1cc(-c2ccc(Oc3nc4ccc(F)cc4s3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.8 %

Procedure:
To Methyl 2-(3-(4-(6-fluorobenzo[d]thiazol-2-yloxy)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (160 mg) in THF (4 ml), 1 M aqueous solution of Lithium hydroxide monohydrate (0.68 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to yield 82 mg (52%) of the title compound as white solid. MS (ES+): m/z 456 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 12.9 (bs, 1H), 9.04 (d, 1H), 8.08 (d, 2H), 7.93 (dd, 1H), 7.81 (s, 1H), 7.75 (dd, 1H), 7.67 (d, 2H), 7.3 (m, 1H), 4.29 (m, 1H), 2.23 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](=O)[CH:12]([CH3:14])[CH3:13]>>[CH:12]([CH:14]1[NH:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:10]1)([CH3:13])[CH3:11]
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)C=O
Product: CC(C)C1NCC(c2ccccc2)O1

Procedure:
2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2-hydroxyethylamine. The ethanolamine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:8]([NH:10][C:11]1([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:29])=[O:9].C(O)C>O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:8]([NH:10][C:11]1([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:29])=[O:9]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.8 %

Procedure:
1.5 ml of 4N sodium hydroxide and 5 ml of water were added to a mixed solution of 1.20 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-(3-phenylpropyl)-1H-indol-3-yl]propionate, 20 ml of ethanol and 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, then made acidic with 10% hydrochloric acid and extracted with ethyl acetate. After the extract was dried, the solvent was removed by evaporation. The residue was recrystallized from ethanol-ethyl acetate to afford 1.09 g of 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-(3-phenylpropyl)-1H-indol-3-yl]propionic acid as colorless needles. Melting point: 242° to 243° C., IR (Nujol) (cm-1): 3285, 1715, 1690, 1675, 1615, FAB-MS (m/z): 513 & 511 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1
Reactant: CCCCCI
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In DMF (166 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (19.5 g). To the mixture was added under ice-cooling 65% sodium hydride (5.3 g), and the mixture was stirred at room temperature for 1.5 hours. To the mixture was added dropwise iodopentane (17.7 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-(2-pentyloxyethoxy)benzene (12.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[N:18]3[C@@H:13]([CH:14]=[CH:15][CH2:16][C:17]3=[O:19])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[N:18]3[C@H:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:19])[CH2:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C1CC=C[C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Yield: 99.8 %

Procedure:
Platinum oxide (100 mg) was added to a solution of (3S,8aR)-3-(3,4,5-trifluorophenyl)-2,3,6,8a-tetrahydro-1H-indolizin-5-one (680 mg) in methanol (20 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm at room temperature for 2.5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 684 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24]>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)=[O:7]
Reactant: CC1(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (C49) (30 g, 300 mmol) in dichloromethane (500 mL) was added 1,1′-carbonyldiimidazole (51 g, 315 mmol) portion-wise, not allowing the temperature to exceed 25° C. The mixture was stirred at room temperature for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (34.8 g, 357 mmol) was added in one portion and stirred at room temperature for 12 hours. The mixture was washed with water (2×200 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate and concentrated to give crude product as a colorless oil, which was directly used in the next step. Yield: 49 g, 342 mmol, 114%. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.20 (s, 3H), 1.34 (s, 3H), 1.01 (dd, J=6.4, 4.4 Hz, 2H), 0.53 (dd, J=6.4, 4.4 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[CH2:12][N:11]([CH3:20])[C:10](=[O:21])[C:9]=2[CH:22]=1.C[O-].[Na+].[Na]>CO>[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18](=[N:2][OH:3])[NH2:19])=[C:13]3[CH2:12][N:11]([CH3:20])[C:10](=[O:21])[C:9]=2[CH:22]=1
Reactant: NO
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)cc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
6.2 g (89.2 mmol) of hydroxylamine hydrochloride and 16.3 g (63.6 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile were added in succession at room temperature under argon to a sodium methylate solution which had been prepared in the usual manner from 2.0 g (86.9 mmol) of sodium and 85 ml of methanol. The reaction mixture was stirred at room temperature for 24 hrs. and then cooled in an ice bath. The separated crystals were filtered off and triturated in 35 ml of water. The white crystals were filtered off and dried at 60° in a vacuum. There were obtained 12.4 g (67%) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime as white crystals of m.p. 249°-250° (dec.).
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[Cl:23][CH2:24][C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)=[O:26].CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:23][CH2:24][C@H:25]([C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)[OH:26]
Reactant: O=C(CCl)C1CCc2cc(F)ccc2O1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O[C@H](CCl)[C@H]1CCc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of (−)-B-chlorodiisopinocampheylborane [(−)-DIP-Chloride™] (2.10 g, 6.55 mmoles) in toluene (7 ml) is cooled to 0° C. under nitrogen atmosphere. On the magnetically stirred solution is added in 3 hours a solution of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanone (1.0 g, 4.373 mmoles) in toluene (3 ml). At the end of the addition, the mixture is stirred at 0° C. for further 20 hours. On the reaction mixture is added acetone (0.5 g), followed by a 10% w/w (5 ml) aqueous solution of sodium carbonate, and then demi water (5 ml). The reactive mixture is heated to 20° C. at the end of the additions and transferred in a separator funnel. The mixture is diluted with demi water (5 ml) and toluene (5 ml) and phases are separated. The organic layer is then washed with additional demi water (15 ml) and concentrated and anhydrified under vacuum to obtain crude (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol (98% de via GC). The product is purified by chromatography on silica using a toluene:ethyl acetate 9.5:0.5 eluting mixture. After separation, the product (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol is isolated as a colorless oil (0.31 g, 31%).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].C([Li])(CC)C.[B:25](OC)([O:28]C)[O:26]C.Cl>C(OCC)(=O)C.C1COCC1.C1CCCCC1.CCCCCC>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([B:25]([OH:28])[OH:26])=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: COB(OC)OC
Reactant: CCCCOC1CC=C(c2cccc(F)c2F)CC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCCOC1CC=C(c2ccc(B(O)O)c(F)c2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
4-Butoxy-(2,3-difluorophenyl)cyclohexene (48) (11.0 g) and THF (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 50.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. Subsequently, trimethyl borate (5.2 g) in a THF solution (50 ml) was added dropwise thereto in the temperature range of −74° C. to −65° C., and the mixture was stirred for 8 hours while allowing the temperature to come to 25° C. The reaction mixture obtained was added into a vessel containing an aqueous 1N—HCl solution (100 ml) and ice-water (500 ml), and mixed. Then, ethyl acetate (300 ml) was added thereto and the mixture was allowed to be separated into organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 10.7 g of 4-(4-butoxycyclohexenyl)-2,3-difluorophenyl boronic acid (49). The yield based on the compound (48) was 83.6%.
Reaction SMILES: [Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH2:7][CH:8]3[CH2:9][C@@H:10]3[C:15]2=[CH:14][C@H:13]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1.ClOC(C)(C)C>C(N(CC)CC)C>[Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C:15]2=[CH:14][C@H:13]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3C(CN4)C[C@H]2N(C)C1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
This compound is prepared analogously to Example 9 by reacting 3-(12-bromo-9,10-didehydro-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea with tert-butyl hypochlorite in the presence of triethylamine.
Reaction SMILES: [CH3:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CC(C)=O.O>[CH3:16][C:2](=[CH2:1])[CH2:3][N:4]([CH2:10][CH:11]=[O:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=C(C)CN(CC(OC)OC)C(=O)OCC
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)CN(CC=O)C(=O)OCC

Procedure:
11.5 g (50 mmol) of N-(2-methylprop-2-enyl)-N-(2,2-dimethoxyethyl)-urethane and 1.25 g (5 mmol) of pyridinium p-toluenesulphate in 100 ml of acetone and 10 ml of water are heated under reflux for two days. The mixture is concentrated and the residue is distilled.
Reaction SMILES: I[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>CN(C=O)C.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.[Cu]I>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: N#Cc1ccncc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccncc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 3-iodo-isonicotinonitrile (911 mg, 3.96 mmol) in DMF (10 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (139 mg, 0.20 mmol), copper(I) iodide (22.6 mg, 0.12 mmol), triethylamine (1.10 ml, 7.9 mmol) and 1-bromo-4-ethynyl-benzene (716 mg, 3.96 mmol). The mixture is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 18 hours. The reaction mixture is allowed to cool to room temperature and partitioned between dichloromethane and 1 N HCl. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-bromo-phenylethynyl)-isonicotinonitrile as beige solid; HPLC/MS 2.13 min (A), [M+H] 283/285.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].ClS([N:43]=[C:44]=[O:45])(=O)=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:44]([NH2:43])=[O:45]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[3,5-Bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (40.3 mg, 0.073 mmol) (Example 20) was dissolved in CH2Cl2 (3 mL) and the solution was cooled to −78° C. Chlorosulfonyl isocyanate (32 μL, 0.367 mmol) was added dropwise by syringe. The reaction was stirred at −78° C. for 15 minutes, and then at 0° C. for 20 minutes. The reaction was then poured into H2O (15 mL) and saturated NaHCO3 (15 mL) was added. The mixture was extracted with CH2Cl2 (2×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 50% EtOAc/hexanes afforded N-[3,5-bis(trifluoromethyl)benzyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}urea. Rf=0.24 (40% EtOAc/hexanes). LCMS=593.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.75 (s, 1H), 7.66 (s, 2H), 7.60 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.5, 2.3 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.80 (d, J=15.8 Hz, 1H), 4.53 (s, 2H), 4.48 (d, J=15.8 Hz, 1H), 4.45 (d, J=17.8 Hz, 1H), 4.07 (d, J=17.8 Hz, 1H), 3.69 (s, 3H), 2.87 (m, 1H), 1.20-1.22 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:20]1)[OH:18].Cl.[OH-].[Na+]>C(O)(C)C.O.C1(C)C=CC=CC=1.CO>[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:17]([CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:24]1)[OH:18]
Reactant: COc1cccc([C@@H](O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: 50 °C
Yield: 24.3 %

Procedure:
A portion of the resolution methanol mother liquors from Scheme B, step b, is concentrated to a solid (185.6 g of salt). The residue was dissolved in methanol to a concentration of 0.67 g/mL. The methanol solution was then added dropwise to an agitated suspension of toluene (464 g), water (280 g) and potassium carbonate (40.86 g, 0.3 mol). The phases were agitated for a half hour at 50° C. and then allowed to separate. The bottom aqueous phases were extracted a second time with toluene (250 mL). The two organic phases were combined and concentrated on the rotary evaporation to a solid. The solid (82 g, 0.22 mol of (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3c) by assay) was then dissolved in isopropanol (382 mL) and water (127 mL). To the solution, 37% HCl (138 g, 1.4 mol) was added. The solution was heated to reflux for a total of 17 hours. The solution was cooled to room temperature and neutralized with 50% NaOH (112.8 g, 1.41 mol). The addition was done slowly to control exotherm. The phases were agitated for 10 minutes before removing the isopropanol on the rotary evaporator. Toluene (500 mL) was added to the residue. The phases were agitated for 10 minutes before being separated. The bottom aqueous phase was extracted a second time with toluene (200 mL). The organic phases were then combined and concentrated on the rotary evaporation until an approximately 30 wt % of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5) was reached. The slurry was heated to reflux and then slowly cooled to 40° C. where it was seeded. The solution crystallized and was cooled to room, temperature. The slurry was chilled in an ice bath for a half an hour before being suction filtered through a coarse sintered glass funnel. The wet cake was washed with 50 mL of chilled isopropanol and then dried to a constant weight. Isolation of the slurry gave 19.96 g of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5) (23.6% yield, 95% assay). The mother liquor contained 3.3% (4.22 g) α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:9].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH2:26].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:26][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(NS(=O)(=O)c2cnccc2Cl)cc1OC
Reactant: NCc1c(F)cccc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NS(=O)(=O)c2cnccc2NCc2c(F)cccc2Cl)cc1OC
Yield: 6 %

Procedure:
A solution of 4-Chloro-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (IntD1) (0.5 g, 1.50 mmol), 2-chloro-6-fluoro-benzylamine (0.26 g, 1.67 mmol) and K2CO3 (0.41 g, 3.0 mmol) in DMF (10 mL) was heated at 130° C. for 4 h. The mixture was added to saturated aqueous NaHCO3 (50 mL), extracted with EtOAc (3×25 mL) and the combined organic phases dried over Na2SO4 and concentrated in vacuo. Purification by gradient column chromatography eluting with 0-45% EtOAc in hexane yielded the title compound (40 mg, 0.09 mmol).