Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[CH2:11][C@@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42]=1[O:56][CH2:57][CH3:58])O)C1C=CC=CC=1>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH2:57]([O:56][C:42]1[CH:43]=[CH:44][C:45]([CH2:47][C:48]2[CH:49]=[CH:50][C:51]([CH2:54][CH3:55])=[CH:52][CH:53]=2)=[CH:46][C:41]=1[C@@H:10]1[CH2:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8])[CH3:58]
Reactant: CCOc1ccc(Cc2ccc(CC)cc2)cc1[C@@]1(O)C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2ccc(CC)cc2)cc1[C@@H]1C[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 19 h
Yield: 20.3 %

Procedure:
To a solution of the (1S,2R,3S,4R,5R)-2,3,4-tris-benzyloxy-5-benzyloxymethyl-1-[2-ethoxy-5-(4-ethylbenzyl)-phenyl]cyclohexanol (402 mg, 0.517 mmol) in THF (4 ml) and methanol (2 mL) as obtained in Example 67, a 20% palladium hydroxide catalyst (78 mg) was added and the mixture solution was stirred under a hydrogen atmosphere for 19 hours. After filtering the catalyst, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (10:1)] to obtain the title compound (42 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:19]/[C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:17][CH:16]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: O=Cc1ccc(F)cc1
Product: Cc1ccc2c(c1)O/C(=C\c1ccc(F)cc1)C(=O)/C(=C/c1ccc(F)cc1)O2

Procedure:
Calone is reacted with 4-fluorobenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-fluorophenyl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: C(O[C:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[C:11]([C:5]1([NH:16][CH2:15][CH2:13][OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)#[CH:12]
Reactant: C#CC1(OC(C)=O)CCCCC1
Reactant: NCCO
Product: C#CC1(NCCO)CCCCC1

Procedure:
This was synthesized in the same manner as in Production Example 18 except that 1-acetoxy-1-ethynylcyclohexane (Production Example 17) and ethanolamine were used.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:2]=1>N.CO.[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[C:9]([CH2:10][NH2:11])=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:2]=1
Reactant: N#Cc1cccnc1Oc1cccnc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccnc1Oc1cccnc1
Reaction time: 6 h
Yield: 87.7 %

Procedure:
To a solution of Example 109A (1.0 g, 5.1 mmole) in 7N NH3 in methanol (1000 ml) was added Raney nickel (10 g) under argon atmosphere. The reaction mixture was kept on shaker under 60 psi H2 atmosphere. After 6 hours at room temperature, the reaction mixture was filtered through a micro pore filter and concentrated to yield 0.9 g (88%) of product. MS (ESI+) m/z 202 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[C:12]=1[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
208 mmole concentrated nitric acid and 270 mmole concentrated sulfuric acid were mixed and cooled to ambient temperature. 200 mmole 2,3-dichlorotoluene was added to a reaction flask and was cooled in an ice-water bath. The acid mixture was added slowly with stirring to the dichlorotoluene keeping the dichlorotoluene in the ice-water bath. After all the acid had been added, the mixture in the ice-water bath was stirred for about 10 minutes. A drying tube was attached to the reaction flask and the reaction mixture warmed to ambient temperature. The reaction mixture was heated at 50° C. with stirring for three hours.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14](=[O:29])[CH2:15][CH:16]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[C:17](=O)[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C=O)C>[CH2:6]([O:13][C:14](=[O:29])[CH2:15][C:16]1[N:20]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[O:22][C:17]=1[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)C(CC(=O)OCc1ccccc1)NC(=O)C1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(C2CCCCC2)nc1CC(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
Phosphorous oxychloride (22 mL, 0.235 moles, 3.0 eq) was added dropwise to a solution of 3-(cyclohexanecarbonyl-amino)-4-oxo-pentanoic acid benzyl ester (26.0 g, 0.078 moles) in DMF (330 mL). The mixture was heated to 90° C. for 30 min, and then cooled to ambient temperature before diluting by slowly adding DI water (600 mL, Caution, exothermic). The mixture was cooled to ambient temperature and extracted with MTBE (3×150 mL). The combined organic phases were washed with DI water, brine (150 mL), dried over MgSO4 and concentrated to obtain 21.1 g as a brown oil. Further purification was not necessary.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]([N:18]1[CH:31]2[C:22]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])([C:23]3[C:28]([O:29][CH2:30]2)=[C:27]([F:32])[CH:26]=[CH:25][C:24]=3[F:33])[CH2:21][CH2:20][CH2:19]1)=[O:17])(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]([N:18]1[CH:31]2[C:22]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])([C:23]3[C:28]([O:29][CH2:30]2)=[C:27]([F:32])[CH:26]=[CH:25][C:24]=3[F:33])[CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)N1CCCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (2 mL, 27.0 mmol) was dissolved in 16 ml of dichloromethane. The solution was added to {2-[4a-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-9-oxa-1-aza-phenanthren-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (260 mg, 0.467 mmol). The solution was stirred at room temperature overnight. The reaction was quenched by washing with Sat. sodium carbonate solution. The organic layer was dried over sodium sulfate and concentrated. Yield: 20.0 mg, 9%. %. 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.06 (td, J=8.8, 4.4 Hz, 1H), 6.61-6.52 (m, 1H), 5.41 (bs, 1H), 4.52 (dd, J=11.0, 3.7 Hz, 1H), 4.21 (dd, J=11.7, 5.1 Hz, 1H), 3.53 (bs, 2H), 2.86 (bs, 1H), 2.70-2.61 (m, 1H), 2.55-2.45 (m, 1H), 2.15-2.03 (m, 1H), 1.75-1.44 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.N1C=CC=CC=1>ClCCCl>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC

Procedure:
A mixture of 0.379 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.2 g of (1H-1,2,4-triazole, 0.2 ml of pyridine and 15 ml of 1,2-dichloroethane was reacted at 80° C. for 18 hours. After the reaction mixture was concentrated, the concentrate was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent:dichloromethane/ethyl acetate 4:1), to give 0.19 g of the title compound as yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.O[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of [5-cyclopropyl-3-(2,6-dichlorophenyl) -4-isoxazolyl]methanol (0.10 g, 0.36 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 g, 0.36 mmol) and triphenylphosphine (0.10 g, 0.39 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.071 mL, 0.39 mmol) dropwise. The solution was heated in a microwave reactor to 90° C. for 10 minutes and then allowed to sit overnight. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-45% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (62 mg, 32%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.50 (m, 3H), 6.95 (d, J=9 Hz, 2H), 4.93 (s, 2H), 3.93 (s, 3H), 2.50-2.42 (m, overlapping DMSO ˜1H), 1.20-1.12 (m, 4H). LRMS (APCI) m/z 545 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: C=CCOc1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 2-(4-allyloxybenzyl)phenol (0.20 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.45 g) in dichloromethane (8.5 mL) was added boron trifluoride diethyl ether complex (0.12 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g).
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[CH:5]/[C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[CH3:2].ClC(Cl)C(O)=O>>[CH2:1]([O:3][NH:4][CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[CH3:2]
Reactant: CCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Product: CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 80 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-5-(ethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (97.7 mg, 80% in 2 steps).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.S=[C:7]1[CH2:11][S:10][C:9](=[O:12])[NH:8]1>C(O)C>[O:1]1[CH2:4][CH:3]([NH:5][C:7]2[CH2:11][S:10][C:9](=[O:12])[N:8]=2)[CH2:2]1
Reactant: O=C1NC(=S)CS1
Reactant: NC1COC1
Solvent: CCO
Product: O=C1N=C(NC2COC2)CS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of oxetane-3-amine (4.94 g) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (6 g), and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and washed with ethanol to give the title compound (6.39 g).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[K+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1>CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:2][CH:18]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:16]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C\c1ccc(OC)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with 14 mL of dimethylsulfoxide. To the stirred solvent was added trimethylsulfoxonium iodide (1.53 g, 6.93 mmol). The reaction mixture was cooled to 0° C. and powdered potassium hydroxide (0.42 g, 7.49 mmol) was added portion wise, stirred for 10 minutes at room temperature. Then ethyl (2Z)-3-(4-methoxyphenyl)-acrylate (1.3 g, 6.31 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and diethyl ether was added. The layers were separated and the organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutant. The product was obtained as pale pink solid (0.6 g, yield: 43.22%). 1H NMR (300 MHz, CDCl3): δ 6.95-6.98 (d, 2H), 6.74-6.77 (d, 2H), 4.06-4.13 (q, 2H), 3.72 (s, 3H), 2.38-2.44 (m, 1H), 1.72-1.78 (m, 1H), 1.43-1.61 (m, 2H), 1.25-1.29 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH2:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])[CH:7]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[Br:18][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[O:15]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCC(O)CCc1cc(F)ccc1OC
Solvent: ClCCl
Product: COc1ccc(F)cc1CCC1CCC(CBr)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8 (3.24 g, 18.0 mmol) in dry CH2Cl2 (50 mL) at 0° C. was added N-bromosuccinimide (3.56 g, 20.0 mmol) portion-wise and the reaction was warmed to room temperature and stirred for 12 h. Solvent was then removed in vacuo and the product was purified by flash column chromatography (EtOAc/hexane, 5:95, v:v, Rf=0.1) and resulted in a colorless oil as a 2:1 mixture of trans:cis diastereomers; 1H NMR (CDCl3, 500 MHz): δ 6.86-6.81 (m, 2 H), 6.72 (dd, J=4.6, 8.6 Hz, 1 H), 4.22 (m, 1 H), 4.03 (m, 1 H), 3.78 (s, 3H), 3.44 (dd, J=4.3, 9.7 Hz, 1 H), 3.34 (dd, J=6.4, 9.7 Hz, 1 H), 2.6 (t, J=7.3 Hz, 2 H), 2.13 (m, 1 H), 2.05 (m, 1 H), 1.75 (m, 1 H), 1.67-1.46 (m, 5 H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:14]=1)=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>O1CCOCC1>[O:13]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:18]=[C:15]([CH3:16])[S:17][CH:2]=3)=[CH:14][C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: O=C(CCl)c1ccc2c(c1)CCCO2
Reactant: CC(N)=S
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)CCCO3)cs1
Yield: 87.5 %

Procedure:
A solution of 2-chloro-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (9b) (270 mg, 1.28 mmol) and thioacetamide (106 mg, 1.41 mmol) in dioxane (10 mL) was refluxed for 20 hours, then the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane (20 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired thiazole (13a) as a yellow oil (260 mg, 1.12 mmol, 88%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])#[CH:8]>>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:7]#[C:8][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccs1
Product: C[Si](C)(C)C#Cc1cccs1
Yield: 81 %

Procedure:
Use a method similar to the General Procedure 8 to couple 2-bromo-thiophene (0.97 nm, 10 mmol) with ethynyl-trimethylsilane (2.82 mL, 20 mmol). Purify by chromatography on silica gel eluting with isohexane to give the desired intermediate (1.46 g, 81%). GC-MS m/z 180 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:21]=[CH:23][N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(CNc3ncc(Cl)cc3N)cc2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CSc1nc2ccc(Cn3cnc4cc(Cl)cnc43)cc2s1

Procedure:
6-((6-Chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a white foam (62 mg, 80%) using a procedure analogous to that described in Step 3 of Example 41, substituting 5-chloro-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from Step 2 of this Example for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([N:45]4[CH:49]=[CH:48][CH:47]=[N:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>C(O)(C(F)(F)F)=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([N:45]4[CH:49]=[CH:48][CH:47]=[N:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:51])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(-n4cccn4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(-n2cccn2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-(1H-pyrazol-1-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (91.4 mg, 0.126 mmol) in dioxanes (2 mL) was added lithium hydroxide (0.5 M, 1.0 mL, 0.505 mmol). The system was heated to 40° C. and was stirred for 1.5 hrs. The reaction was cooled to room temperature and TFA (100 μL) was added to the reaction before volatiles were removed. The crude material was purified by reverse phase HPLC to yield 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-(1H-pyrazol-1-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (86.1 mg, 0.104 mmol). LCMS calc.=711.2. found=711.2. 1H NMR (CD3OD, 500 MHz) δ 8.62 (s, 1H), 7.88 (m, 8H), 7.34 (m, 4H), 6.56 (s, 1H), 5.81 (m, 1H), 4.84 (m, 1H), 4.24 (m, 2H), 3.90 (br s, 3H), 3.36 (br s, 3H), 0.67 (d, J=33.5 Hz, 3H). RTA=14.8 nM
Reaction SMILES: [CH2:1]([OH:12])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([OH:12])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CO
Reaction time: 2 h

Procedure:
To a solution of 2-Undecyn-1-ol (48) (0.5 g, 3 mmol) in EtOAc (10 mL) was added Lindlar catalyst (25 mg). Hydrogen was bubbled through the reaction mixture. After 2 hours, the reaction was judged complete by TLC (90:10 EtOAc/Petroleum ether, Rf (13)=0.61, Rf (14)=0.55). The reaction mixture was filtered and the filtrate was concentrated by rotary evaporation to yield cis-2-Undecen-1-ol (14) as a colorless oil: 1H NMR (CDCl3) δ 5.60 (m, 2 H), 4.21 (s, 2 H), 2.14 (m, 2 H), 1.35 (m, 12 H), 0.82 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 132.98, 128.32, 58.42, 31.85, 29.57, 29.29, 29.19, 27.38, 22.63, 14.04. ##STR23##
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B(O)O)[CH:31]=2)[CH:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:31]=[C:32]5[C:27]([CH:26]=[CH:25][NH:24]5)=[CH:28][CH:29]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccc4cc[nH]c4c3)c(C)sc2n1
Temperature: 120 °C
Yield: 16.9 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (16.6 mg, 0.038 mmol) was dissolved in 1,4-dioxane (0.6 mL) and water (0.2 mL). 1H-Indol-6-ylboronic acid (9.28 mg, 0.058 mmol), tetrakis(triphenylphosphine)palladium(0) (4.44 mg, 3.84 μmol) and potassium carbonate (10.63 mg, 0.077 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min. The crude mixture was purified by MDAP (acidic conditions) and then further purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (3 mg). LCMS (A) m/z: 468 [M+1]+, Rt 1.45 min (acidic).