Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:22]1C=CC=[CH:24][CH:23]=1)[C:18]([F:21])([F:20])[F:19].ClC1C=C2C(=CC=1)NC(=O)N(CC(F)(F)F)C2(O)C(F)(F)F.C([Mg]Br)C=C>>[CH2:22]([C:5]1([C:18]([F:20])([F:21])[F:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:15])([F:17])[F:16])[CH:23]=[CH2:24]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)(C(F)(F)F)N1CC(F)(F)F
Agent: C=CC[Mg]Br
Agent: O=C1Nc2ccc(Cl)cc2C(O)(C(F)(F)F)N1CC(F)(F)F
Product: C=CCC1(C(F)(F)F)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F

Procedure:
Utilizing the general procedure outlined for 6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one, 6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (374 mg, 1.1 mmol) was reacted with 1.0M allyl magnesium bromide (6.4 ml, 6.4 mmol) to afford 4-allyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 9.88 (s, 1H), 7.29 (dd, J=2.4 and 8.6 Hz, 1H), 7.17 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 5.53 (m, 1H), 5.22 (m, 2H), 4.56 (m, 1H), 4.12 (m, 1H), 3.11 (m, 2H). MS (Electrospray): m/z 373.0 (M+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[N:11][N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:4]=2[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[C:58]([CH3:63])[CH:57]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:10]1[C:4]2[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=[C:2]([NH:60][C:59]3[CH:61]=[CH:62][C:56]([F:55])=[CH:57][C:58]=3[CH3:63])[C:3]=2[CH:12]=[N:11]1
Reactant: Cc1cc(F)ccc1N
Reactant: Cn1c(=O)cc(Cl)c2cnn(-c3c(F)cccc3F)c21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1Nc1cc(=O)n(C)c2c1cnn2-c1c(F)cccc1F
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (36 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (6 mg, 0.006 mmol), X-Phos (6 mg) and 4-fluoro-2-methylaniline (3 mg, 0.2 mmol) in toluene (3 mL) was treated with sodium t-butoxide (40 mg, 0.4 mmol), and heated to 100° C. for 18 h. After the mixture was cooled to RT, it was evaporated to dryness with some silica gel, and purified by silica gel chromatography to provide the title compound as an off-white crystalline solid. MS (ESI, pos.ion) m/z: 385.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[C:21]([CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)[CH3:25])([OH:23])=[O:22].O.Cl>C(#N)C.C([O-])([O-])=O.[Na+].[Na+].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:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:28]2[CH:27]=[C:26]([CH:24]([CH3:25])[C:21]([OH:23])=[O:22])[CH:31]=[CH:30][CH:29]=2)[CH:3]=1
Reactant: CC(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)C(=O)O)c2)n1
Temperature: 130 °C

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [170 mg, 0.51 mmol, Intermediate (44)] and 3-(1-carboxy-ethyl)-phenyl boronic acid [119 mg, 0.61 mmol, Intermediate (70)] in acetonitrile (2.5 mL) and aqueous Na2CO3 solution (0.4 M, 2.5 mL) is degassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium (0) (29.5 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130 ° C. for 30 minutes. To the reaction mixture is added 2 mL of water, the pH is adjusted to about 7 using 2 N aqueous hydrochloric acid and this mixture is extracted three times with EtOAc (30 mL). The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The resulting oil is subjected to silica gel chromatography eluting with 0 to 7% MeOH in DCM to give 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propionic acid as a solid, which is treated with 1M hydrogen chloride in ether affording 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propionic acid hydrochloride [122 mg, 50%, Example 49(a)] as a solid. LC/MS: RT=2.47 minutes, MS: 446 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □12.4 (1H, br s), 7.36-7.8 (7H, m), 6.6 (1H, s), 4 (3H, s), 3.78 (1H, q), 3.68 (2H, m), 3.02 (2H, m), 1.42 (3H, d). IC50=1 nM
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[CH2:6]([O:5][CH:4]([O:8][CH2:9][CH3:10])[CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:20])[CH2:22][CH2:23]1)[CH3:7]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(CCCl)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Yield: 53 %

Procedure:
A mixture of 4.5 parts of 1-chloro-3,3-diethoxypropane, 12.15 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 10.6 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 9 parts (53%) of [1-(3,3-diethoxypropyl)-4-piperidinyl](4-fluorophenyl)methanone.
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]O[Si](C(C)(C)C)(C)C)=[CH:18][C:17]1=[O:32].[H-].[Na+].O>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:8])([CH3:9])[CH:2]=[C:3]([N:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][C:17]3=[O:32])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CCO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Yield: 94.4 %

Procedure:
In 105 ml of anhydrous tetrahydrofuran, is dissolved 3.18 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(2-t-butyldimethylsilyloxyethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 23. Then, 0.28 g of 60% oily sodium hydride is added to the solution at room temperature and reacted under reflux for one hour. After stopping the reaction by adding water, the reaction mixture is extracted with ether. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/4 mixture of ethyl acetate/methylene chloride as a developing solvent to obtain 2.01 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-vinyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][Br:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCC1(c2ccc(Br)cc2)CC1
Product: BrCC1(c2ccc(Br)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 1, using [1-(4-bromo-phenyl)-cyclopropyl]-methanol and phosphorus tribromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1ccc(Nc2nc(-c3ccc(Cl)cc3)cs2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN(c2ccc(C(F)(F)F)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Temperature: 60 °C

Procedure:
[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amine (0.335 mg; 0.95 mmol) was dissolved in acetonitril (4 ml) and methyl 4-(bromomethyl)benzoate (238 mg; 1.04 mmol), potassium carbonate (195 mg; 1.41 mmol) and sodium iodide (212 mg; 1.41 mmol) were added. The reaction mixture was heated to 60° C. for 3 days, then filtered while still hot. The solvent was removed by rotary evaporation, then the residue was dissolved in ethyl acetate (50 ml) and washed with water (50 ml) and brine (50 ml). The organic phase was dried with sodium sulphate, and taken to dryness by rotary evaporation. The residue was striped once with acetonitril to give pure 4-{[[4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoic acid methyl ester as an oil. Yield; 454 mg (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:15](\[C:13]#[N:14])/[C:16]([O:18][CH3:19])=[O:17])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC#N
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 84 %

Procedure:
Following the general method as outlined for Intermediate 1, starting from 6-chloro isatin and methyl cyanoacetate, the title compound was isolated, after evaporation, as a dark brown solid in 84% yield. This was a 5.5:1 mixture of geometric isomers (98% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[C:26]([F:29])([F:28])[F:27])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C)=[CH:7][CH:6]=2.B(Br)(Br)Br>C(Cl)Cl>[OH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][C:16]=1[C:26]([F:27])([F:28])[F:29])=[C:3]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3C(F)(F)F)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2C(F)(F)F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Compound 35 (85 mg, 0.18 mmol, 1 equiv) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. under N2. BBr3 (84 μL, 0.89 mmol, 5 equiv) was added dropwise and the resulting solution was allowed to stir at 0° C. for 2 h. The reaction mixture was then poured into ice and the product extracted into EtOAc (250 mL). The organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (50% EtOAc in hexanes) to provide the title compound (36) (44 mg, 53%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 7.87 (m, 1H), 7.69-7.65 (m, 2H), 7.51-7.01 (m, 9H), 6.43-6.40 (m, 2H), 2.17 (s, 3H). MS m/z 463.5 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=[CH:15][N:14]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N-:29]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.O.C1(C)C=CC=CC=1>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:16]=[CH:15][N:14]=[C:13]([NH:12][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH2:29])[CH:11]=[CH:10]4)[CH:18]=2)=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3cccc4ccc(Cl)nc34)ncn2)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc2cccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Temperature: 105 °C
Reaction time: 96 h

Procedure:
To a round-bottomed flask containing (2-chloroquinolin-8-yl)-[6-(4-trifluoromethyl-phenyl)pyrimidin-4-yl]amine, Example 32(e), (0.090 g, 0.22 mmol) in DMSO (10 mL) was added NaN3 (0.53 g, 8.1 mmol, Aldrich). The reaction mixture was stirred at 105° C. for 4 days and then at 115° C. for 1 day. The reaction mixture was cooled to room temperature and then diluted with H2O and extracted with EtOAc. The combined extracts were washed with H2O (3×), brine, dried over Na2SO4, and concentrated in vacuo to afford a tan solid. The tan solid was dissolved in toluene (5 mL), triphenylphosphine (0.12 g, 0.44 mmol, Aldrich) was added with stirring at room temperature and the mixture was stirred at reflux for 8 h. After cooling to room temperature, the mixture was concentrated in vacuo to remove the toluene. To the residue was added AcOH/H2O (2:1, 7 mL) and the mixture was stirred at 55° C. for 1 day. The reaction mixture was cooled to room temperature and then diluted with satd NaHCO3 (75 mL) and extracted with EtOAc (2×75 mL). The combined extracts were washed with brine, dried over K2CO3 and concentrated in vacuo. The residue was dissolved in EtOAc and concentrated in vacuo onto silica gel. Purification by silica gel chromatography with gradient from 20% to 60% EtOAc in hexane afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 382 (M+1). MP: 211-213° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.C(O[C:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[Cl:28])=[CH:25][CH:24]=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])=[O:17])C.O>C1COCC1>[Cl:28][C:27]1[C:26]2[C:21](=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][C:18]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
2-Bromopyridine (0.74 mL, 7.90 mmol) was taken into THF (30 mL) and cooled to −78° C. Then BuLi (4.8 mL, 7.90 mmol, 1.6 M solution in hexane) was added dropwise and then stirred for 30 minutes. Next, 4-Chloro-8-(trifluoromethyl)-3-quinolinecarboxylic acid ethyl ester (2.0 g, 6.58 mmol) in THF (10 mL) was added rapidly and stirred at −78° C. for 4 hours. The reaction was poured into water/saturated NH4Cl solution and then extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The resulting material was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to yield 0.823 g of (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone as a yellow solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([CH2:3][OH:2])[CH:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1c1ccc(F)c(F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CO)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.5 g (4.2 mmol) (3SR,4SR)-3-(3,4-Difluoro-phenyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester and 0.16 g (4.2 mmol) LiAlH4 in 50 mL THF was stirred at room temperature for 1 h. Ethyl acetate, THF, water and NaOH aq. was added. Na2SO4 was added, the mixture was filtered off and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to afford after evaporation of the product containing fractions 1.06 g (77%) of the title compound as viscous colorless oil. MS (m/e): 228.1 [(M+H-Boc)+].
Reaction SMILES: FC1C=C(C=CC=1C1C(C2C=CN=CC=2)=CN(C)N=1)OCC1C=CC2C(=CC=CC=2)N=1.[F:32][C:33]1[CH:34]=[C:35]([OH:55])[CH:36]=[CH:37][C:38]=1[C:39]1[C:43]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[CH:42][N:41]([CH2:50][C:51]([F:54])([F:53])[F:52])[N:40]=1.Cl[CH2:57][C:58]1[CH:67]=[N:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]=1>CC(C)=O>[F:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[C:39]1[C:43]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[CH:42][N:41]([CH2:50][C:51]([F:52])([F:53])[F:54])[N:40]=1)[O:55][CH2:57][C:58]1[CH:67]=[N:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]=1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Reactant: ClCc1cnc2ccccc2n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Solvent: CC(C)=O
Product: Fc1cc(OCc2cnc3ccccc3n2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[3-Fluoro4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 3-Fluoro4-[4-pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol, 2-Chloromethyl-quinoxaline and acetone as the solvent provided the title compound. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1 H), 8.46 (m, 2H), 8.15 (m, 1H), 8.09 (m, 1 H), 7.81 (m, 3H), 7.43 (t, J=8.7Hz, 1H), 7.12 (d, J=6.2 Hz, 2H), 6.93 (dd, J=7.9, 2.0 Hz, 1 H), 6.81 (dd, J=11.6, 2.5 Hz, 1 H), 5.43 (s, 2H), 4.80 (q, J=8.3 Hz, 2H); MS: (M+H m/z=480.1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:15][C:16]1[CH:17]=[N:18][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:20][C:21]=1N.Cl.Cl.C1(N)C=CC=CC=1N.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C(O)C.O>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[NH:15][C:16]3[CH:17]=[N:18][C:19]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:20][C:21]=3[N:12]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)c(N)cn1
Reactant: CC(C)(C)c1ncc(C#N)cn1
Agent: Cl
Agent: Nc1ccccc1N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2nc(-c3cnc(C(C)(C)C)nc3)[nH]c2cn1
Reaction time: 0.5 h

Procedure:
Preparation analogous to 16), S43, using 16.1 g (100 mmol) of 2-tert-butyl-5-cyanopyrimidine [126230-72-6] and 71.4 g (300 mmol) of 3,4-diamino-6-tert-butylpyridine dihydrochloride (S50) instead of 25.9 g (100 mmol) of 2-N-pivaloylamido-3-cyano-6-tert-butylpyridine (S42) and 90.5 g (500 mmol) of o-phenylenediamine dihydrochloride [615-28-1]. After cooling, the violet melt is dissolved in a mixture of 150 ml of ethanol and 300 ml of water at elevated temperature, and a solution of 25 g of sodium carbonate in 100 ml of water is then added dropwise with vigorous stirring (note: foaming, evolution of carbon dioxide). When the addition is complete, the mixture is stirred for a further 30 min., the brown solid is then filtered off with suction, washed three times with 100 ml of water each time and dried in vacuo. Yield: 23.8 g (77 mmol), 77%. Purity: >95% according to 1H-NMR.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:22])=[CH:16][CH:15]=1)=[O:4].[OH-].[Na+].Cl>CO>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:9]3[CH:8]=[N:7][C:6]4[C:10]3=[N:11][CH:12]=[N:13][C:5]=4[C:3]([OH:4])=[O:2])=[CH:15][CH:16]=2)=[CH:25][C:26]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COC(=O)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(-n2cnc3c(C(=O)O)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
In 3 mL of methanol, 45 mg (0.092 mmol) of 9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purine-6-carboxylic acid methyl ester, and 2 mL of a 0.1 N sodium hydroxide aqueous solution was added thereto and the mixture solution was stirred at room temperature overnight. The reaction solution was neutralized with 0.1 N hydro-chloric acid, and then the deposited product was washed with water to obtain 30 mg (69%) of a target product as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=2)=[CH:5][CH:4]=1.Cl>C1COCC1>[F:35][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)F)cc3)sc3cc(O)ccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)F)cc3)sc3cc(O)ccc23)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
To a vial containing (E)-tert-butyl 3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.061 mmol) in THF (1.0 mL) was added HCl (4.0 N in dioxane, 0.4 mL, 1.600 mmol). The resulting mixture was stirred at 50° C. for 12 h after which time the reaction was concentrated in vacuo and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 10-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (21 mg, 0.048 mmol, 79% yield). LC/MS (m/z, M−H): 437.5.
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[F:57][C:58]([F:67])([F:66])[C:59]1[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1.CC([O-])(C)C.[Na+]>>[CH3:54][N:44]1[C:45]2[C:50](=[CH:49][C:48]([NH:65][C:62]3[CH:63]=[N:64][C:59]([C:58]([F:67])([F:57])[F:66])=[CH:60][CH:61]=3)=[CH:47][C:46]=2[C:52]#[N:53])[C@@H:42]2[CH2:41][NH:40][CH2:56][CH2:55][C@H:43]12
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3ccc(C(F)(F)F)nc3)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as an oil (25 mg, 13%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 6-trifluoromethyl-pyridin-3-ylamine (141 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 374 (base, M+H).