Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)(=[O:37])=[O:36].FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:44][CH:41]4[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NC2CCN(S(C)(=O)=O)CC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 43 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, triethylamine (0.1 mL, 0.818 mmol), and 1-(methylsulfonyl)-4-piperidinamine as the trifluoroacetic acid salt (171 mg, 0.589 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[-(methylsulfonyl)-4-piperidinyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 43% yield), as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.33 (d, J=7.6 Hz, 1 H), 8.58 (s, 1 H), 7.41 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-7.00 (m, 2 H), 4.14-4.09 (m, 3 H), 3.75-3.69 (m, 2 H), 3.58 (s, 3 H), 2.97 (m, 2 H), 2.82 (s, 3 H), 2.14 (m, 2 H), 1.76 (m, 2 H); HRMS m/z calcd for C23H26FN4O5S: 489.1602. Found: 489.1609.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[NH2:1][C:2]1[C:11](/[CH:19]=[CH:18]/[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(N)c(Br)cc2c1CCCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(N)c(/C=C/C(=O)OC(C)(C)C)cc2c1CCCC2
Temperature: 200 °C
Yield: 30.2 %

Procedure:
A mixture of Example 476A (0.327 g, 1.2 mmol), tert-butyl acrylate (0.203 mL, 1.40 mmol), acetonitrile (1.5 mL), tri(ortho-tolyl)phosphine (0.035 g, 0.12 mmol), palladium diacetate (0.013 g, 0.06 mmol), and triethylamine (0.32 mL, 2.3 mmol) was sealed and heated in a microwave reactor for 10 minutes at 200° C. The reaction mixture was concentrated and purified by flash chromatography (15% ethyl acetate/hexanes) to provide the desired product (0.12 g, 32%); MS (DCI) m/e 332 (M+H)+.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)ccc1-n1cccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-fluoro-2-(1H-pyrazol-1-yl)benzoic acid (CAS number 1152964-04-9; 75 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH:25][NH2:26])[CH2:23][CH3:24]>CO>[C:1]1([CH:7]2[N:25]([CH2:22][CH2:23][CH3:24])[N:26]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10][CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: CCCNN
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1
Yield: 57.5 %

Procedure:
A mixture of 5.84g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one and 1.48g of n-propyl hydrazine in 100ml of methanol is heated at reflux temperature for 3 hours. Upon cooling, solids are collected and washed with methanol. Recrystallization from methanol gives 4.0g of material, melting point 111°-120°C. Two recrystallizations from acetonitrile yield 2.0g of the title compound, melting point 119.5°-122°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5]2.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5]3)=[CH:20][CH:21]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)c1cc2cc(Br)ccc2nc1C
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc2cc(-c3ccc(C)cc3)ccc2nc1C
Temperature: 25 °C
Yield: 100.6 %

Procedure:
Under argon atmosphere, a solution of methyl 6-bromo-2-methylquinoline-3-carboxylate (1.22 g), 4-methylphenyl borate (0.65 g) and potassium carbonate (1.18 g) in toluene-ethanol-water (40-4-4 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakis-triphenylphosphinepalladium (0.15 g), and the mixture was refluxed for 18 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:1) to give methyl 6-(4-methylphenyl)-2-methylquinoline-3-carboxylate (1.27 g) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].O>CC(CC(C)C)=O>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][S:21][C:19](=[O:22])[CH3:20])[CH2:5][CH2:6]1
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(=O)SCC1CCOCC1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 95.4 %

Procedure:
To a solution of 224 g (0.83 mol) of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70° C. for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through Celite® (20 g), activated charcoal (20 g) and Na2SO4 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester as a yellow-orange oil (CAUTION: Stench!). Yield: 96%; ES-MS: m/z 175 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.40 (2 H, m), 1.59-1.78 (3 H, m), 2.33 (3 H, d, J=4.16 Hz), 2.82 (2 H, dd, J=6.24, 3.79 Hz), 3.27-3.39 (2 H, m), 3.88-4.02 (2 H, m)
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]=[CH2:19])=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>C1(C)C=CC=CC=1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:19][CH:25]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8]2[CH3:20])=[CH:4][CH:3]=1
Reactant: C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CCCCCCCC(=O)O
Product: CCOC(=O)C1CC1c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C

Procedure:
To a room temperature solution of the indole from Step 1 (3.91 g, 11.0 mmol) in 20 mL toluene was added rhodium (II) octanoate dimer (109 mg, 0.14 mmol), and the solution was cooled to 0° C. A solution of ethyl diazoacetate (3.0 mL, 28.5 mmol) in 13 mL toluene was then added via syringe pump at 1.2 mL/hr. Fresh catalyst was then added along with an additional 1 mL ethyl diazoacetate in toluene over 2.5 h. The crude reaction mixture was applied directly to a silica gel column and eluted with 1% to 2.5% ethyl acetate/toluene. 1.1 g of the trans isomer of the title compound was thus obtained, followed by 1.2 g of the cis isomer of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH:12]1([C:15]2[CH:16]=[C:17]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=3)[CH:18]=[CH:19][C:20]=2[CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:14][CH2:13]1.CC(O)=O>CO>[CH:12]1([C:15]2[CH:16]=[C:17]([NH:29][C:30](=[O:39])[C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[C:35]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:36]=3)[CH:18]=[CH:19][C:20]=2[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[CH2:14][CH2:13]1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 14 (nitro reduction performed in a manner similar to that described for Example 17; 0.25M in MeOH/10%AcOH). The product was obtained as a solid: 505 m/z (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.Cl.[C:22]12([NH2:27])[CH2:26][CH:24]([CH2:25]1)[CH2:23]2.O>CS(C)=O>[C:22]12([NH:27][C:2]3[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=3)[CH2:26][CH:24]([CH2:25]1)[CH2:23]2
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: NC12CC(C1)C2
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(NC23CC(C2)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a stirred solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (3.0 g, 16 mmol) in DMSO (20 mL) was added DIEA (6.2 g, 48 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (1.9 g, 16 mmol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)). The resulting mixture was stirred at 60° C. for 2 h and then poured into water. The mixture was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product (3.5 g, 14.9 mmol, 93% yield). MS (ESI) m/z=233.2 [M+1]+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH3:11][C:12]1[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=1[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][C:12]1[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=1[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: Cc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.288 g (1.2 mmol) of 4-(2-methylbenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:32]3[CH2:33][CH2:34][CH:29]([C:20]4[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])[CH2:30][CH2:31]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1cccc(C(F)(F)F)c1C1CCNCC1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (72 mg, 0.27 mmol) in THF (2.2 mL) was added a solution of LiOH monohydrate (12 mg, 0.29 mmol) in H2O (1.5 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (2.8 mL) under an atmosphere of N2. To this mixture was added 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine hydrochloride (23, 75 mg, 0.27 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (236 mg, 0.53 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (30 mL) and concentrated under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a light orange film (80 mg, 64%): 1H NMR (300 MHz, DMSO-d6) δ 9.12-9.10 (m, 1H), 8.00-7.95 (m, 1H), 7.74-7.68 (m, 1H), 7.65-7.50 (m, 3H), 5.29-5.15 (m, 1H), 4.82-4.68 (m, 1H), 3.41-3.19 (m, 2H, overlaps with H2O), 3.07-2.97 (m, 1H), 2.34-2.19 (m, 1H), 2.15-2.02 (m, 1H), 1.93-1.75 (m, 2H); ESI MS m/z 472 [M+H]+.]
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1>C1COCC1>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=2)[CH:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc(C#N)cn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In an atmosphere of nitrogen, sodium hydride was added under ice-cooling to a THF solution of (2′,6′-dimethylbiphenyl-3-yl)methanol, followed by stirring at that temperature for 15 minutes. Thereafter, 6-chloronicotinonitrile was added to the reaction mixture under ice-cooling, followed by warming up to room temperature and stirring for 3 hours to obtain 6-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]nicotinonitrile.
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:7]([O:6][C:5](=[O:14])[NH:4][CH2:3][C:2]1([CH3:1])[CH2:15][O:24]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CNC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CNC(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
Benzyl N-(2-methyl-2-propenyl)carbamate (3.90 g, 19.0 mmol) prepared in Reference Example 173 was dissolved in methylene chloride (80 ml), to which m-chloroperbenzoic acid (5.15 g, 20.9 mmol) was added, and the mixture was stirred at room temperature overnight. Sodium thiosulfate aqueous solution and saturated sodium hydrogencarbonate aqueous solution were added to the reaction mixture, which was stirred for a while. The organic layer was separated, washed with saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford benzyl(2-methyl-2-oxiranylmethyl)carbamate (4.31 g, quantitative) as a colorless oil.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([C:58]#[C:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:41])[CH3:40].[H][H]>C(O)C.[Rh]>[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([C:58]#[C:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[C:45]([OH:6])=[O:46])([CH3:42])([CH3:40])[CH3:41].[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: [H][H]
Reactant: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Rh]
Solvent: CCO
Product: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(CCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
Preparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)acetic acid (37A): (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)acetic acid (4.9 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethanol instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 7.95 (m, 1 H), 7.90 (s, 1 H), 7.7-7.6 (m, 6 H), 7.50 (m, 3 H), 7.37 (d, J=8.8 Hz, 1 H), 5.23 (s, 1 H), 2.72 (s, 3 H), 0.99 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C30H27ClNO3: 484.2. Found: 484.2. Preparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)ethanol: The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethanol (6 mg) and rhodium on alumina (2 mg) in ethanol (1.5 mL) was stirred under 1 atm of hydrogen for 3 hours. Celite was added, and the mixture was filtered and washed with ethyl acetate. Concentration of the mother liquor under reduced pressure gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)ethanol (6.5 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33ClNO2: 474.2. Found: 474.3.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][CH:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>ClCCl.CN(C=O)C.CCOC(C)=O>[Cl:18][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)nc1C1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(CCl)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
To a stirring solution of (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)methanol (890 mg, 4.1 mmol) in dichloromethane (10 mL) at room temperature under argon was added thionyl chloride (730 mg, 6.1 mmol) followed by 3 drops of DMF. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was then concentrated under vacuum to obtain a light brown oil. This oil was diluted with EtOAc (20 mL) and washed with 10% aqueous Na2CO3 solution (20 mL). The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to obtain 900 mg of the title compound as a light brown oil. HPLC/MS: retention time=3.66 min, [M+H]+=236.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C:11]1([CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C.CCOCC>O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][NH:3][C:11]1([CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:12]1
Reactant: CN(C(=O)OC(C)(C)C)C1(CCc2cccnc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC1(CCc2cccnc2)CC1
Reaction time: 4 h

Procedure:
20 ml of 4N hydrochloric acid in dioxane are added to a mixture containing 4.4 g of the product obtained in Step 2 in 20 ml of dioxane. Stirring is carried out for 4 hours at 20° C. and then 20 ml of ether are added. Crystallisation is observed. The crystals are filtered off, washed with ether and dried at 50° C. and 0.5 torr, allowing the expected product to be obtained.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:10]=3[CH2:9][O:8]2)[CH2:4][CH2:3]1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:38]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:38].[CH3:21][S:18]([NH:17][C:15]1[CH:14]=[CH:13][C:11]2[CH2:12][C:5]3([O:8][CH2:9][C:10]=2[CH:16]=1)[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]3)(=[O:19])=[O:20]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCC2(CC1)Cc1ccc(NS(C)(=O)=O)cc1CO2
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)COC1(CCNCC1)C2
Product: Cl

Procedure:
To a solution of 1,4-dihydro-1'-methyl-7-methanesulfonamido-spiro[(3H)-2-benzopyran-3,4'-piperidine] (0.575 g) and N,N,N',N'-tetramethyl-1,8-napthalenediamine (proton sponge) (0.6 g) in dichloroethane under nitrogen at 0° C. was added 1-chloroethyl chloroformate (0.613 ml). The mixture was stirred at reflux for 2 hours, cooled filtered through silca gel (20 g) and the product eluted with ethyl acetate. The eluate was concentrated and the residue dissolved in methanol (20 ml) and refluxed for 18 hours. The reaction was concentrated to a foam and crystallized from ethanol/hexanes yielding 0.548 g of product.