Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[CH3:24][O:23][C:21]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[O:22]
Reactant: COC(=O)C1CCCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCCC2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl piperidine-2-carboxylate (5.2 g, 36.92 mmol) while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one h and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (2.95 g, 99% yield) as a yellow oil. [M+H] calc'd for C14H17N3O6, 324; found, 324.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:7]2.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.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.[Pd].O.C(OC(=O)C)C>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:11]2[C:2]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=3)=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:5]=[CH:4]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 95 °C
Reaction time: 0.08 h

Procedure:
(R)-4-[5-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2079 g, 0.0004516 mol), 4-trifluoromethoxy phenylboronic acid (0.130 g, 0.000632 mol), tetrakis(triphenylphosphine)palladium(O) (0.03 g, 0.00002 mol) and sodium carbonate (0.191 g, 0.00181 mol) were added to a capped 40 mL EPA vial equipped with a magnetic stir bar. The vial was degassed and purged with nitrogen. 1,2-Dimethoxyethane (5.00 mL, 0.0481 mol) was added and the mixture was stirred for 5 minutes. Water (3.00 mL, 0.166 mol) was then added and the mixture was heated at 95° C. After 3 h, HPLC analysis showed that the reaction was complete. Ethylacetate (5 mL) and water (5 mL) were added and the layers were separated. The combined organic phase was then dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-55% EtOAc in hexane) to give 204.1 mg of the title compound (83% yield).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:43])([F:42])[C:5]1[CH:6]=[C:7]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:8][N:9]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[CH:27][C:26]=1[O:33][CH3:34])[C:10](=[O:13])[O:11][CH3:12]>CO>[F:3][C:4]([F:42])([F:43])[C:5]1[CH:6]=[C:7]([CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=1)[CH2:8][N:9]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[CH:28]=[CH:27][C:26]=1[O:33][CH3:34])[C:10](=[O:13])[O:11][CH3:12]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(CO)ccc1OC
Reaction time: 1 h

Procedure:
Sodium borohydride (9.9 mg, 0.262 mmol) was added to a solution of methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-formyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 73, 78 mg, 0.131 mmol) in methanol at room temperature. The reaction was stirred for one hour, then solvent was removed in vacuo. The title compound was obtained by column chromatography using 3:7 acetone/hexane. 1H NMR (CDCl3, 500 MHz) δ 7.25 (s, 1H), 7.30-7.62 (m, 6H), 7.08 (m, 1H), 6.94 (m, 1H), 4.64 (s, 2H), 4.15-4.40 (m, 4H), 3.64-3.74 (m, 6H). LC-MS (M-17) 578.0 (4.09 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1)[CH3:6])[CH3:2].Cl[C:23]1[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:37]([F:40])([F:39])[F:38])([OH:36])[C:27]=2[CH:26]=[C:25]([F:41])[CH:24]=1.C(=O)([O-])O.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[CH:11]=[C:10]([C:23]2[C:35]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([OH:36])([C:37]([F:40])([F:39])[F:38])[C:27]=3[CH:26]=[C:25]([F:41])[CH:24]=2)[CH:9]=[N:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC1(C(F)(F)F)c2ccccc2-c2c(Cl)cc(F)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 115 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester (29.2 g), (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (20.4 g), and sodium hydrogen carbonate (11.1 g) in toluene/water (200 ml/66 ml) were added palladium acetate (743 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.72 g) at room temperature, and the mixture was stirred at 115° C. for 8 hr. To the reaction mixture were added activated carbon (10 g) and Celite (10 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with toluene (100 ml). The filtrate was partitioned, and the aqueous layer was extracted with toluene (60 ml). The combined organic layer was washed 3 times with water (100 ml), and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in toluene/ethyl acetate (3/1, 130 ml) was added silica gel (40 g), and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1 to 2/1) to give the title compound (27.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[Cl:19]>O1CCCC1.[Ni]>[Cl:19][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)c(Cl)c2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Yield: 97 %

Procedure:
A sample of 1,2-dichloro-4-[2-(4nitrophenyl)ethenyl]benzene (98.0 g, 0.33 mol) in tetrahydrofuran (THF) (1.6 L) was reduced in the presence of Raney Nickel (Ra—Ni) (20 g) at 25° C. to 40° C. (ΔP=13.5 psi) under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give an orange solid, 85.0 g (0.32 mol, 95.8%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10](/[CH:17]=[CH:18]/[N:19]3[N:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C(N2C(C(OC)=O)=CC(/C=C/N3C(C(F)(F)F)=NN=N3)=N2)=NC=CC=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10](/[CH:17]=[CH:18]/[N:19]3[N:23]=[N:22][C:21]([C:24]([F:26])([F:25])[F:27])=[N:20]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(/C=C/n2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Agent: COC(=O)c1cc(/C=C/n2nnnc2C(F)(F)F)nn1-c1ncccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(/C=C/n2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
88.7 mg (0.23 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{(E)-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]vinyl}-1H-pyrazole-5-carboxylate and methyl 1-(3-chloropyridin-2-yl)-3-{(E)-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]vinyl}-1H-pyrazole-5-carboxylate in a ratio of 66:34 were dissolved in 5.0 ml of ethanol, and 26.6 mg (0.29 mmol) of 45% strength aqueous sodium hydroxide solution were added. After 1 hour of stirring at room temperature, the mixture was diluted with water and acidified with dilute hydrochloric acid. The aqueous phase was extracted repeatedly with ethyl acetate and dried over magnesium sulphate. The solvent was distilled off under reduced pressure, which gave 43 mg (48% of theory) of 1-(3-chloropyridin-2-yl)-3-{(E)-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]vinyl}-1H-pyrazole-5-carboxylic acid and 1-(3-chloropyridin-2-yl)-3-{(E)-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]vinyl}-1H-pyrazole-5-carboxylic acid in a ratio of 70:30. (logP: 2.79/2.86; MH+: 386.0/386.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 7.40 (m, 1H), 7.59 (m, 1H), 7.75 (m, 1H), 8.05 (m, 1H), 8.31 (m, 1H), 8.53 (m, 1H).)
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[OH-].[Na+]>C(O)C>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CCOC(=O)Cc1ccc(OC)c(OCc2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC(=O)O)cc1OCc1c(C)cccc1C
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)-4-methoxyphenyl)acetate (Step B, 7.86 g, 24 mmol) in absolute ethanol (120 ml) was added 1N NaOH (50 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1)=[O:5])[CH3:2].[F-].[CH2:20]([N+:24](CCCC)(CCCC)CCCC)CCC>CC#N>[C:20]([CH2:12][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1)#[N:24]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl-5-(bromomethyl)benzene-1,3-dioate (1.9 g, 6.0 mmol) in 69 mL MeCN was added trimethylsilyl cyamide (1.2 mL, 9.0 mmol) and tetrabutylammonium fluoride (1M in THF, 9.0 mL, 9.0 mmol). The reaction was stirred for 0.5 h and concentrated. Flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl 5-(cyanomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.20 (app t, J=0.7 Hz, 2H), 4.43 (q, J=7.1 Hz, 4H), 3.86 (s, 2H), 1.43 (t, J=7.1 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41][CH2:40][CH2:39][O:38]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CCC[C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C:37]5[O:38][CH:39]=[CH:40][CH:41]=5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Agent: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCc5ccco5)c4)cc23)CC1
Yield: 43.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-furanyl)methanamine (50 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 24.8 mg of the title compound (43.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:18])[C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)/C=C/C(O)=O>CCOC(C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:18])[C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccn1)C(N)c1cccc(F)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(c1ccccn1)[C@@H](N)c1cccc(F)c1

Procedure:
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine is prepared is prepared starting from racemic 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. The free base was dissolved in EtOAc and a solution of fumaric acid (1.0 eq) in MeOH is added. The solvent is removed in vacuo and the residue is triturated with Et2O/hexanes (1:1), collected by filtration and air-dried. 1HNMR (300 MHz, DMSO-d6) δ 1.19 (s, 3 H), 1.31 (s, 3 H), 4.48 (s, 1 H), 6.55 (s, 2 H), 6.85-6.95 (m, 2 H), 7.01 (t, J=8.9 Hz, 1 H), 7.18-7.34 (m, 3 H), 7.64-7.77 (m, 1 H), 8.59 (d, J=3.8 Hz, 1 H). MS: m/z 245.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(I)ccc2n(C)c1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(-c3ccccc3)ccc2n(C)c1=O
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (200 mg, 465 μmol), phenylboronic acid (85 mg, 697 μmol), 2M Sodium carbonate (0.7 ml, 1395 μmol), Tetrakis(triphenylphosphine) palladium(0) (5 mg, 5 μmol) and N,N-Dimethylformamide (10 ml) was stirred at 100° C. After 8 hrs, an additional equivalent of the phenyl boronic acid was added, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated on a roto-evaporator and extracted with EtOAc. This product was then washed with water and brine, then dried with MgSO4 and concentrated on a roto-evaporator to give the crude product as a red-orange oil. The crude product was purified by silica flash chromatography (10-75% EtOAc:Hex step gradient) to give the desired product as a white solid. Yield=120 mg. In some cases, ester hydrolysis was observed and the carboxylic acid was isolated.
Reaction SMILES: [H][H].C([NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[OH:22][CH:17]([C@@H:14]1[CH2:15][CH2:16][C@H:11]([NH2:10])[CH2:12][CH2:13]1)[C:18]([F:19])([F:20])[F:21]
Reactant: OC([C@H]1CC[C@@H](NCc2ccccc2)CC1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@@H](C(O)C(F)(F)F)CC1

Procedure:
At 50° C. and a hydrogen pressure of 30 bar, 33.6 g of cis-1-benzylamino-4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexane were hydrogenated in the presence of 2 g of palladium (10% on carbon) in 250 ml of methanol. The catalyst was filtered off and the mixture was concentrated to give the title product as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=3[Cl:19])[O:10][C:6]=2[CH:5]=[C:4]([O:20]C)[CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[Cl:19])[O:10][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(Cl)cc(OC)cc3o2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(-c2nc3c(Cl)cc(O)cc3o2)c(Cl)c1
Yield: 73.7 %

Procedure:
To 4-chloro-2-(2-chloro-4-methoxy-phenyl)-6-methoxybenzooxazole (52 mg) in CH2Cl2 (2 mL) placed in and ice water bath was added drop wise 1.0 M BBr3 in CH2Cl2 (0.96 mL, 6 eq). After the reaction stirred over night, the mixture was placed in an ice water bath and excess MeOH was added drop wise to quench excess BBr3 and the mixture was stirred for an additional 20 min and concentrated. Flash chromatography on silica gel eluting with 0% to 40% ethyl acetate-hexane afforded 35 mg (74%) of the title compound as a solid. MS: 296 (MH+), HPLC tR: 2.32 min.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([CH2:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>O1CCCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([CH2:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1
Reactant: Cn1ccnn1
Reactant: CCc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.17 mL, 0.43 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (38.3 mg, 0.461 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1.5 mL) at −50° C. After 20 minutes at −50° C., a solution of (4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.145 g, 0.307 mmol, Intermediate 25: step b) in tetrahydrofuran (1.5 mL) was added dropwise. After 5 minutes at −50° C., the flask was allowed to warm to 0° C. After 30 minutes, the mixture was partitioned between half-saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (3 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as an off-white solid. The solid was further purified by chiral SFC (Chiralpak AD-H, 5 μm, 250×20 mm, mobile phase: 75% CO2, 25% ethanol containing 0.03% isopropylamine) to provide two enantiomers. The first eluting enantiomer was Example 25b: 1H NMR (600 MHz, CDCl3) δ ppm 8.30 (d, J=2.1 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.57-7.49 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.17 (s, 1H), 6.18 (s, 1H), 4.91 (s, 1H), 4.49 (s, 2H), 3.95 (s, 3H), 3.40 (s, 3H), 3.00-2.90 (m, 2H), 2.30 (s, 3H), 1.35-1.28 (m, 3H); MS (ESI): mass calcd. for C28H26ClF3N6O, 554.2. m/z found, 555.2 [M+H]+. and the second eluting enantiomer was Example 25c: 1H NMR (600 MHz, CDCl3) δ ppm 8.32 (d, J=2.1 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.56-7.51 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.12 (s, 1H), 6.14 (s, 1H), 5.83 (s, 1H), 4.48 (s, 2H), 3.93 (s, 3H), 3.38 (s, 3H), 2.98-2.90 (m, 2H), 2.24 (s, 3H), 1.34-1.27 (m, 3H); MS (ESI): mass calcd. for C28H26ClF3N6O, 554.2. m/z found, 555.0 [M+H]+.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[C:12]([C:19]([OH:21])=O)[CH:11]=2)[CH:2]=1.Cl.[CH3:24][O:25][C:26]([C:28]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1([NH:35][C:19]([C:12]2[CH:11]=[C:10]([O:9][CH2:8][CH2:7][C:3]3[CH:2]=[C:1]([CH3:22])[CH:6]=[CH:5][CH:4]=3)[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:21])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:27]
Reactant: Cc1cccc(CCOc2cc(C(=O)O)cc3c2OCO3)c1
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2cc(OCCc3cccc(C)c3)c3c(c2)OCO3)CCCCCC1

Procedure:
The title compound was synthesized from 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid and 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride in analogy to example 126, step 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[F:19][C:20]([F:41])([F:40])[C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])=[C:25](B(O)O)[CH:26]=1.B(O)O>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:22]=[C:21]([C:20]([F:40])([F:41])[F:19])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Agent: OBO
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-trifluoromethyl-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of 5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].Cl.[CH:6]1[CH:7]=[CH:8][C:9]2[C:16](=[O:17])[C:15]([OH:18])=[CH:14][C:12](=[O:13])[C:10]=2[CH:11]=1>C(O)(=O)C>[OH:18][C:15]1[C:16](=[O:17])[C:9]2[C:10]([C:12](=[O:13])[C:14]=1[CH:1]=[CH:2][CH3:3])=[CH:11][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CCC=O
Agent: Cl
Solvent: CC(=O)O
Product: CC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Propionaldehyde (RCHO, R=propyl, 5.0 mL, 69.3 mmol) was added to a solution of concentrated HCl (2 mL) and lawsone (2.00 g, 11.5 mmol) in acetic acid (35 mL) at 60° C. After stirring for 1.25 hours, another portion of propionaldehyde was added (5.0 mL, 69.3 mmol). The solution was then stirred for an additional 1 hour. The solution was allowed to cool to room temperature, and then ice water (200 mL) was added to quench the reaction. The solution was extracted with diethyl ether (3×200 mL) and the organic fractions pooled. The combined organic layers were re-extracted with 5% Na2CO3 (8×150 mL). The aqueous extracts were also pooled and acidified with concentrated HCl. A precipitate formed which was collected by filtration to afford (20) as an orange solid. 2-Hydroxy-3-propenyl-1,4-naphthoquinone (20) (983 mg, 40%): mp 133-134° C.; 1H NMR (CDCl3, 300 MHZ) δ 8.13 (d, J=7.7 Hz, 1H), 8.06 (d, J =7.5 Hz, 1H), 7.80-7.62 (m, 3H), 7.15-6.95 (m, 1H), 6.63 (d, J=16.1 Hz, 1H), 1.99 (d, J=6.8 Hz, 3H).