Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]4[S:31][N:30]=[CH:29][N:28]=4)(=[O:24])=[O:25])=[CH:20][CH:21]=3)[N:16]([CH3:43])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: Cn1cc(-c2ccc(F)c(C#N)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3-cyano-4-fluorophenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(3-cyano-4-fluorophenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 7.54-7.60 (m, 2 H) 7.91-8.07 (m, 5 H) 8.13 (dd, J=6.13, 2.35 Hz, 1H). m/z (ESI) 413.0 (M+H)+.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][CH3:17])[C@H:13]([NH:18]C(OC(C)(C)C)=O)[CH2:12]1)=O)C1C=CC=CC=1.F[C:27]1[C:36](C)=[C:35]2[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:29][CH:28]=1.C(N(CC)CC)C>[C].[Pd].CO>[NH2:18][C@H:13]1[C@@H:14]([CH2:16][CH3:17])[CH2:15][N:11]([C:9]2[C:36]([CH3:27])=[C:35]3[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]3[C@@H:38]3[CH2:40][C@@H:39]3[F:41])=[CH:29][CH:28]=2)[CH2:12]1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2ccc3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@H]1N
Temperature: 65 °C
Reaction time: 192 h
Yield: 50.1 %

Procedure:
A 10% palladium carbon catalyst (27 mg) was added to a solution of (3S,4S)-1-(benzyloxycarbonyl)-3-(tert-butoxycarbonylamino)-4-ethylpyrrolidine (270 mg, 775 μmol) in methanol (7.75 mL), and the resultant mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (3 mL), and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (216 mg, 775 μmol) and triethylamine (130 μL, 930 μmol) were added to the solution, followed by stirring in an oil bath at 65° C. for 8 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed sequentially with a 10% aqueous citric acid solution (30 mL), water (30 mL×2), and saturated brine (30 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Subsequently, concentrated hydrochloric acid (2 mL) was added to the obtained residue at room temperature, and the resultant mixture was transferred to a separatory funnel with water (20 mL), followed by washing by chloroform (30 mL×2). The pH of the obtained aqueous layer was adjusted to 12.0 with a 10 mol/L aqueous sodium hydroxide solution under cooling with ice. The pH was adjusted again to 7.4, and the resultant mixture was extracted with chloroform (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from hot ethanol, and dried under reduced pressure, to thereby yield the title compound as pale yellow crystals (145 mg, 50.1%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17]>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: Cc1noc(NS(=O)(=O)c2ccccc2F)c1Br
Yield: 44 %

Procedure:
2-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-fluorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a white solid, m.p. 87-89° C., yield 44%.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][N:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:44]1=[O:55]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:42][C@H:43]1[CH2:48][CH2:47][CH2:46][N:45]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:44]1=[O:55])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCN(c2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-phenylpiperidin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (10 mg, 0.018 mmol) and Intermediate 32 (3.4 mg, 0.018 mmol) to give a white solid (5.0 mg, 36% yield). Anal. Calcd. for C42H50N4O6S m/z 738.4. found: 739.4 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 7.46-7.35 (m, 2H), 7.32-7.25 (m, 3H), 7.23-7.08 (m, 10H), 5.49 (dd, J=6.32, 3.02 Hz, 1H), 5.08-5.02 (m, 1H), 4.98-4.91 (m, 1H), 4.17 (dd, J=11.00, 6.05 Hz, 1H), 3.97 (s, 1H), 3.73 (d, J=7.15 Hz, 1H), 3.64 (s, 3H), 3.09 (s, 1H), 2.89-2.76 (m, 2H), 2.76-2.65 (m, 3H), 2.65-2.51 (m, 2H), 2.31 (br. s., 1H), 2.11-1.91 (m, 5H), 1.90-1.80 (m, 1H), 1.77-1.55 (m, 7H), 1.57-1.46 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([OH:18])=O)=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:50][C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:16]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][C:51]([F:50])=[CH:52][CH:53]=2)=[O:18])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1nc(Br)ccc1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 3-(benzyloxy)-6-bromopicolinic acid (1.90 g, 6.2 mmol), HATU (4.69 g, 12.4 mmol) and Et3N (0.5 mL) in DMF (20 mL) was added 4-fluorobenzylamine (2.30 g, 18.5 mmol) dropwise. The mixture was stirred at room temperature overnight. Then it was concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (PE:EtOAc=2:1) to afford the product of 3-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)picolinamide (2 g, yield: 77.8%). 1H-NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.42˜7.45 (m, 3H), 7.23˜7.37 (m, 6H), 6.97 (t, J=8.8 Hz, 2H), 5.21 (s, 2H), 4.57 (d, J=6.0 Hz, 2H). MS (M+H)+: 415/417.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[CH:5]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+]>CN(C)C=O>[CH3:15][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[C:4]([CH2:3][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:5]1
Reactant: CS(=O)[O-]
Reactant: Cn1cc(CCl)c(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 16 h

Procedure:
3-Chloromethyl-1-methyl-4-quinolone hydrochloride (2.0 g.) was added portionwise during 1 minute to a stirred suspension of sodium methanesulphinate (5.0 g.) in anhydrous dimethylformamide (70 ml.) at room temperature. The mixture was stirred at this temperature for 16 hours, then evaporated to dryness. The residue was triturated with water (50 ml.), filtered, the filtrate basified with aqueous sodium hydroxide and then extracted with dichloromethane (2×50 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give the novel 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 201°-204° (from acetone).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([N:25]([CH2:36][CH3:37])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:24]>O1CCCC1>[CH2:36]([N:25]([CH2:23][CH3:24])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:4](=[O:5])[C:3]([OH:7])([CH3:8])[C:2]([F:10])([F:9])[F:1])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:37]
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a solution of α-trifluoromethyl lactic acid (0.37 g) in dry tetrahydrofuran (10 ml) at 22° C. was added carbonyldiimidazole (0.38 g) in one portion. The mixture was stirred for 30 minutes, then treated with 4-(N,N-diethylaminosulfonyl)aniline (0.53 g) and stirred at 22° C. for 1 hour followed by heating at reflux for 18 hours. After cooling to 22° C., the mixture was concentrated to an oil which was purified by chromatography (9:1 CH2Cl2 : diethyl ether) and crystallization from hexane to produce the title compound as a colourless crystalline solid (0.15 g); mp 115°-130° C.; MS: m/z=341(M+1); NMR (250 MHz, CDCl3): 1.12 (t,6), 1.78 (s,3), 3.22 (s,4), 3.73 (s,1), 7.67-7.79 (m,4), 8.62(broad s,1). Analysis for C14H19F3N2O4S: Calculated: C, 45.64; H, 5.19; N, 7.61; Found: C, 45.74; H, 5.22; N, 7.66.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C@H:11]([CH:30]([CH3:32])[CH3:31])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[CH2:13][N:12]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[C@H:11]([CH:30]([CH3:32])[CH3:31])[CH2:10]1
Reactant: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
N-{2-[(2S,4R)-4-Benzyloxy-2-isopropylpyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (0.630 g, 1.40 mmol) was dissolved in methanol (60 mL) and then palladium hydroxide (90 mg) was added to the solution. The flask was purged with hydrogen and then stirred under an atmosphere of hydrogen using a balloon. After three hours, TLC indicated complete consumption of starting material. The reaction was then flushed with nitrogen and filtered through Celite on a glass frit and washed with methanol. The filtrate was concentrated to give the desired alcohol as a white solid, 0.52 g (100%).
Reaction SMILES: [F:1][C:2]1[N:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13]([CH3:15])C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1CN)[CH3:23]>C1COCC1>[F:1][C:2]1[N:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:15][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[CH2:22][CH3:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCN1CCC[C@H]1CN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(I)c(F)nc1F
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNC[C@@H]1CCCN1CC)C(=O)c1cc(I)c(F)nc1F
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 66.3 %

Procedure:
Ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 37, 0.500 g, 1.10 mmol) was taken up THF (40 mL) and cooled to 0° C. for 10 min and then (S)-(1-ethylpyrrolidin-2-yl)methanamine (0.153 mL, 1.10 mmol) was added and stirred at room temperature for 2 min. The reaction mixture was quenched with sat NH4Cl diluted with EtOAc and separated, dried, and solvent removed. The residue was purified by a 0-5% gradient on the ISCO of DCM/Methanol to give (S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-((1-ethylpyrrolidin-2-yl)methylamino)acrylate (0.360 g, 67%) as a red oil.
Reaction SMILES: C(O)C.C([O:7][CH:8](OC(=O)C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:24][C:25](=[O:27])[CH3:26])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(=O)C.S(=O)(=O)(O)O>O>[C:25]([O:24][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:8]=[O:7])=[CH:14][CH:13]=1)([C:16]([F:19])([F:18])[F:17])[C:20]([F:21])([F:23])[F:22])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(=O)OC(c1ccc(C=O)cc1)(C(F)(F)F)C(F)(F)F
Yield: 89.1 %

Procedure:
To 130 ml of ethanol are added 60 g (0.15 mole) of α,α-bis-acetyloxy-4-[1-(acetyloxy)-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]toluene and 13.5 ml of concentrated sulfuric acid in 135 ml of water. The resulting solution is stirred and heated at reflux for thirty minutes. The solution is then cooled and extracted with 1 liter of ether to obtain an ether solution which is washed with water and a saturated sodium bicarbonate solution until the washes were basic. The ether solution is dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give 42 g of 4-[1-(acetyloxy)-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzaldehyde. This compound was not further purified but was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8].CCOCC>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.8 %

Procedure:
To a solution of Intermediate 1A (8.0 g, 36.7 mmol) in THF (35 mL) was added LAH (40.4 mL, 2 M in THF, 81 mmol) dropwise for 40 min at 0° C. under Ar. The colorless solution turned yellowish brown, and a precipitate formed after stirring at rt for 30 min. The suspension was stirred at rt for 6 h. The reaction mixture was cooled to 0° C. and quenched by careful addition of H2O (3 mL), 15% NaOH (3 mL) and then H2O (9 mL). Et2O (ca. 100 mL) was added. The mixture was stirred at rt for 20 min then filtered through Celite® and rinsed with Et2O (ca. 150 mL). The filtrate was concentrated. The residue was dissolved in Et2O (100 mL) and CH2Cl2 (10 mL), dried over Na2SO4, filtered and concentrated to give a light tan oil after drying under vacuum. 3-(3,4-Dichlorophenyl)propan-1-amine was taken to the next step without further purification. LC-MS: 203.9 (M+H), RT=2.76 min (Method A). TEA (8.36 mL, 60.0 mmol) was added to 3-(3,4-dichlorophenyl)propan-1-amine (6.8 g, 33.3 mmol) in THF (100 mL) followed by the addition of di-tert-butyl dicarbonate (8.22 g, 37.6 mmol) and the reaction mixture was stirred at rt overnight. The solvent was removed under vacuum and Et2O was added. The organic solution was washed with H2O and then brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography using Hexanes/EtOAc to give the product tert-butyl 3-(3,4-dichlorophenyl)propylcarbamate (6.9 g, 23 mmol, 68% yield) as a colorless oil. LC-MS (ESI) 248.0 (M−tBu+H), RT=3.85 min (Method A). tert-Butyl 3-(3,4-dichlorophenyl)propylcarbamate (3.48 g, 11.44 mmol) was stirred in 4N HCl in dioxane (20 mL) at rt for 2 h. The volume of the mixture was reduced under reduced pressure, and Et2O was added. The reaction mixture was stirred at rt for 30 min. The resulting precipitate was filtered and rinsed with Et2O to give Intermediate 1 (1.95 g, 8.11 mmol, 70.9% yield). LCMS=203.9 [M+1], RT=1.51 min (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccc(F)cc1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and 4-fluorobenzyl bromide (230 μL, 1.85 mmol) in dimethylformamide (3 mL) was heated at 80° C. overnight. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 50-60% ethyl acetate/petroleum ether, and dried under high vacuum for 2 days to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-1-(4-fluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (103 mg, 51%) as a light brown solid. APCI(+)-MS (M+H) 429.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:14]([O:16][CH:17]([O:27][CH2:28][CH3:29])[CH2:18]OS(C(F)(F)F)(=O)=O)[CH3:15].C(N(C(C)C)CC)(C)C.FC(F)(F)S([O-])(=O)=O>ClCCl.CCN(C(C)C)C(C)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH2:18][CH:17]([O:27][CH2:28][CH3:29])[O:16][CH2:14][CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(S)ccc21
Reactant: CCOC(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CSc1ccc2c(c1)CCN2C(C)=O)OCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76.5 %

Procedure:
A mixture of thiol (D3, 3.38 g, 17.5 mmol), acetal trifluoromethanesulphonate (D4, 5.05 g, 19 mmol) and diisopropylethylamine (3.2 ml, 19 mmol) in dry dichloromethane (80 ml) was stirred for 4.5 h at room temperature. Further small portions of trifluoromethane sulphonate and of DIPEA (2 drops each) were added and stirring was continued for another 1 h before the mixture was washed sequentially with dilute hydrochloric acid, dilute sodium hydroxide, and water. The organic phase was dried and evaporated, and the residue was chromatographed on silica (300 g) eluted with ethyl acetate to give the title compound (4.14 g, 76.6%), as a waxy solid, mp <52° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25]2)[N:3]=1.C[O-].[Na+]>CO.C(O)(CC)C.CO>[N:32]1([C:30]([CH:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:4]3[N:3]=[C:2]4[NH:1][C:9]([C@@H:11]5[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]5)=[N:8][C:7]4=[CH:6][CH:5]=3)[CH2:25]2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2N)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc3ccc(N4CCCC(C(=O)N5CCCC5)C4)nc3[nH]2)C1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-((2-amino-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate in methanol/sec-butanol (1:2, 15 mL) was added a solution of 25% sodium methoxide in methanol (9.0 mL). The reaction mixture was stirred at 90° C. for 16 h. The solvent was removed under reduced pressure and a solution of methanol/dichloromethane (1:9, 50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL) were added to the residue, and the layers were separated. The aqueous layer was extracted again with methanol/dichloromethane (1:9, 25 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via column chromatography to afford (R)-tert-butyl 3-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-yl)piperidine-1-carboxylate.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:40]([OH:44])[CH:41]([CH3:43])[CH3:42]>>[CH2:40]([O:44][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)CO
Agent: [Li]CCCC
Product: CC(C)COc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (65 mg, 0.12 mmol) was reacted with 2 equivalents each of n-butyl lithium and isobutyl alcohol by the procedure described in Reference Example 6 and 7 to yield the title compound: HPLC/MS: m/e=535 (M++1); Rt=5.28 min. 1H-NMR 400 MHz (CDCl3): 0.97 (d, J=7 Hz, 6H), 2.07 (m, 1H), 4.01 (d, J=7 Hz, 2H), 6.90-6.94 (m, 1H), 7.05-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][Ti:20](Cl)([Cl:31])[C:21]1([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]1[CH3:29]>C1(C)C=CC=CC=1>[Cl:19][Ti:20]([Cl:31])([C:21]1([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]([CH3:27])=[C:25]1[CH3:26])[O:16][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(-c2ccccc2)c1O
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(-c3ccccc3)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 67 %

Procedure:
700 mg (3.28 mmol) of 2-isopropyl-6-phenylphenol and 236 mg (9.84 mmol) of sodium hydride were dissolved in 10 ml of toluene, and then refluxed for 4 hours. The refluxed solution was cooled to room temperature, and then a solution of 930 mg (3.21 mmol) of trichloro(pentamethylcyclopentadienyl)titanium (IV) was slowly added dropwise thereto, and the mixture was refluxed for 24 hours. After completion of the reflux reaction, volatile components were removed from the reaction solution, and the residue was washed with purified hexane, recrystallized from a mixed solvent of toluene/hexane −35° C., filtered, and then dried in a vacuum, thus obtaining 1.0 g of a red solid.