Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].[CH:35]([C@H:37]1[CH2:42][CH2:41][C@H:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39][CH2:38]1)=O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[NH:1][CH2:35][C@H:37]3[CH2:38][CH2:39][C@H:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:41][CH2:42]3)[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C=O)CC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CNc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Intermediate 16; 820 mg; 1.63 mmol) and ethyl (trans-4-formylcyclohexyl)acetate (Intermediate 14; 270 mg; 1.36 mmol) in toluene (8 mL) was heated at reflux for 3 h. The reaction was concentrated in vacuo and redissolved in EtOH (8 mL). Sodium borohydride (103 mg; 2.72 mmol) was added and the reaction stirred at room temperature for 14 h. The reaction was quenched with sat. NH4Cl and partitioned between EtOAc (25 mL) and H2O (25 mL). The aqueous layer was re-extracted with EtOAc (3×25 mL) and the combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}methyl)cyclohexyl]acetate as a yellow gum. LCMS=685.1 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.89 (s, 1 H), 7.73 (s, 2 H), 7.13 (d, J=8.7 Hz, 1 H), 6.92 (d, J=2.3 Hz, 1 H), 6.72 (d, J=9.0 Hz, 1 H), 5.66 (d, J=8.2 Hz, 1 H), 4.74 (d, J=15.6 Hz, 1 H), 4.14-4.02 (m, 4 H), 3.05-2.97 (m, 2 H), 2.19 (d, J=6.9 Hz, 2 H), 1.96-1.90 (m, 2 H), 1.85-1.78 (m, 2 H), 1.71-1.62 (m, 1 H), 1.51-1.39 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H), 1.12-1.03 (m, 3 H), 0.80 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([CH3:25])=[CH:19][C:20](OCC)=[O:21])=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:25])[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)NC(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1cc(=O)n(-c2ccc(Cl)c(C(=O)OC(C)C)c2)c(=S)[nH]1

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethyllformamide mixture there is obtained isopropyl 2-chloro-5-[3,6-dihydro-4-methyl-6-oxo-2-thioxo-1(2H)-pyrimidinyl]-benzoate,
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=3)[N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example A.40) (0.401 g, 1.4 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.286 g, 1.82 mmol) according to the general procedure IVb. Obtained as a light brown solid (0.11 g, 22%). MS (ISP) 364.1 [(M+H)+]; mp 92° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=1[NH:22][C:23](=[O:48])[CH2:24][CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[CH:33][C:32]=1[O:46][CH3:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:11])([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>C(Cl)Cl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=1[NH:22][C:23](=[O:48])[CH2:24][CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][C:32]=1[O:46][CH3:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)O)cc1OC
Temperature: 30 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
1.0 ml (15.0 mmol) of trifluoroacetic acid was added to a solution of 575 mg (1.01 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-t-butoxycarbonylmethoxy-2-methoxyphenyl)octanamide [prepared as described in step (i) above] and 241 μl (2.22 mmol) of anisole in 15 ml of methylene chloride, and the resulting mixture was stirred overnight at 30° C. At the end of this time, the reaction mixture was freed from the solvent and excess reagents by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel using ethyl acetate as the eluent, to give 506 mg (yield 98%) of the title carboxylic acid derivative as a foam-like substance.
Reaction SMILES: FC1(F)C(Cl)=C(Cl)C(F)(F)C(Cl)=C1Cl.FF.F[C:18]1(F)[C:23]([Cl:24])=[C:22]([Cl:25])[C:21]([Cl:27])(F)[C:20]([Cl:28])=[C:19]1[Cl:29].FC1C(Cl)(F)C(Cl)(F)C(Cl)=C(Cl)C=1Cl.CC(=O)[O:47]CC>>[Cl:24][C:23]1[C:18]([OH:47])=[C:19]([Cl:29])[C:20]([Cl:28])=[C:21]([Cl:27])[C:22]=1[Cl:25]
Reactant: CCOC(C)=O
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(Cl)C(Cl)=C1Cl
Agent: FC1(F)C(Cl)=C(Cl)C(F)(F)C(Cl)=C1Cl
Agent: FC1=C(Cl)C(Cl)=C(Cl)C(F)(Cl)C1(F)Cl
Agent: FF
Product: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In run A two principal product fractions are obtained: (1) 60.3 g, bp 91°-97° /31 mm, mp 30°; (2) 18.6 g, semisolid residue. Fraction (1) was identified as 1,1,4,4-tetrafluorotetrachloro-2,5-cyclohexadiene by comparison of its IR and MS data with those of a known sample of the compound (Hasek et al., Jour. Am. Chem. Soc., vol. 82, p. 543, 1960) Fraction (2) was indicated by fluorine NMR, IR, VPC and EA analyses to be a mixture of isomeric 1,1,4-trifluoropentachloro-2,5-cyclohexadiene and 1,5,6-trifluoropentachloro-1,3-cyclohexadiene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:7]([C:8]2[O:10][C:4]([CH3:3])=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12
Reactant: CCn1ncc2c(Cl)c(C(=O)O)cnc21
Solvent: O=S(Cl)Cl
Product: CCn1ncc2c(Cl)c(-c3nnc(C)o3)cnc21
Temperature: 95 °C
Reaction time: 1 h
Yield: 136.9 %

Procedure:
Intermediate 11 (0.4 g) was dissolved in thionyl chloride (3 ml) and the mixture was heated at reflux (95° C.) with stirring for 1 h. After cooling to room temperature, excess thionyl chloride was removed by evaporation under reduced pressure and the resultant solid dissolved in anhydrous acetonitrile (2 ml). This solution was added to a solution of acetic hydrazide (0.145 g) and diisopropylethylamine (0.465 ml) in anhydrous acetonitrile (2 ml), and the mixture stirred for a further 2 h. The mixture was concentrated in vacuo and the residue treated directly with phosphorus oxychloride (4 ml). The resultant solution was stirred and heated at reflux (120° C.) for 0.5 h, then allowed to cool and purified by Biotage (silica, 40 g), eluting with cyclohexane:EtOAc (1:1) to afford Intermediate 12 (0.32 g). LCMS showed MH+=264; TRET=2.55 min.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][C:10]([OH:13])=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(C)C=CC=CC=1.[CH2:21]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[CH2:21]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:13][C:10]2[N:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][N:9]=2)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCc1cnc(O)nc1
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(C(=O)Oc2ncc(CCCCCC)cn2)cc1
Yield: 57.2 %

Procedure:
This 5-hexylpyrimidin-2-ol (1.8 g, 10 mmol) was dissolved in pyridine (2 ml), followed by adding dropwise to the solution, a toluene solution (30 ml) of p-hexyloxybenzoyl chloride (2.4 g, 10 mmol), stirring at 50° C. for 4 hours, further adding toluene (50 ml) to the reaction mixture to carry out extraction, washing the toluene layer twice with 6N-HCl aqueous solution (30 ml), further washing 5 times with 2N-NaOH aqueous solution (40 ml), washing with pure water until the aqueous layer became pH 7, drying the toluene layer over anhydrous Na2SO4 and distilling off toluene to obtain raw crystals (3.1 g) (yield 81%), which were then purified by activated alumina chromatography (solvent: toluene) and recrystallized from ethanol to obtain 5-hexylpyrimidin-2-yl p-hexyloxybenzoate (2.2 g) (yield 58%). This compound exhibited liquid crystallinity and as to their phase transition points, C-N point was 28.4° C. and N-I point was 35° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=O)[NH2:27])[CH:21]=2)[C:12]=1[F:30])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(OCC)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[C:12]=1[F:30])[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2cccc(C(N)=O)c2)c1F
Agent: CCOP(=O)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2cccc(C#N)c2)c1F
Reaction time: 24 h

Procedure:
Step 4 A mixture of {(R)-1-[3-(3-carbamoyl-benzoyl)-2-fluoro-4-methoxy-phenyl]-propyl}-carbamic acid tert-butyl ester (269 mg, 0.62 mmol) from Step 3, ethyl dichlorophosphate (0.14 mL, 1.25 mmol, 2 eq.) and DBU (0.28 mL, 1.87 mmol, 3 eq.) in DCM (3 mL) was stirred for 24 hours. The mixture was then diluted with DCM (15 mL) and water (15 mL) and the organic phase was washed with brine, isolated by phase separation and concentrated to give crude {(R)-1-[3-(3-cyano-benzoyl)-2-fluoro-4-methoxy-phenyl]-propyl}-carbamic acid tert-butyl ester which was used in the next step. [M−H]− 411
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Cl[CH2:20][C:21](=O)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][C:10](=[O:15])[C:11]3[C:21]([CH3:22])=[CH:20][O:14][C:12]=3[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2cccc(Br)c2)C1
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1cccc(Br)c1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(3-bromophenyl)cyclohexane-1,3-dione (mp182-183° C.; 1.34 g) in DMF (20 ml) was added sodium methoxide (0.30 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 90° C. for 2 hours. To the mixture was added potassium carbonate (0.69 g), and the mixture was stirred at 150° C. overnight (13 hours). The reaction solution was cooled, to which was added ice-water. The mixture was extracted with ethyl acetate, and the upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(3-bromophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g).
Reaction SMILES: [C:1]([C:9]([O-:11])=[O:10])(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C1C=C(O)C(O)=C(O)C=1.O=C([C@H](CC1C=C(O)C(O)=CC=1)[NH2:28])O.C1(CC(=O)C([O-])=O)C=CC=CC=1.OC1C=C(C([O-])=O)C(=CC=1O)C([O-])=O.N1C=C(C([O-])=O)C(=O)NC1=O.C1C=C[C@](O)(C(O)=O)[C@@H](O)C=1>O>[NH2:28][CH2:5][CH2:4]/[CH:3]=[CH:2]/[C:1](=[O:8])[C:9]([OH:11])=[O:10]
Reactant: O=C([O-])C(=O)c1ccccc1
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C(O)[C@@]1(O)C=CC=C[C@@H]1O
Agent: O=C([O-])C(=O)Cc1ccccc1
Agent: O=C([O-])c1c[nH]c(=O)[nH]c1=O
Solvent: O
Product: NCC/C=C/C(=O)C(=O)O

Procedure:
There are no enzymes known in the art that catalyze the substrate L-2,3-dihydropicolinate to produce 5,6-dihydropyridine-2-carboxylate. However, there are a few decarboxylases that are able to decarboxylate ring mounted carboxylic acids. One skilled in the art would appreciate that it is likely that these enzymes may have, or could be engineered to have, activity towards L-2,3-dihydropicolinate. Examples of such decarboxylases include, but are not limited to, benzoylformate decarboxylase (EC 4.1.1.7), 3-hydroxy-2-methyl pyridine-4,5-dicarboxylate decarboxylase (EC 4.1.1.51), pyrrole-2-carboxylase (EC 4.1.1.-), gallate decarboxylase (4.1.1.59), Dopa decarboxylase (EC 4.1.1.28), Phenylpyruvate decarboxylase (EC 4.1.1.43), 4,5-dihydroxyphthalate decarboxylase (EC 4.1.1.55), 5-dihydroxybenzoate decarboxylase (EC 4.1.1.62), Uracil-5-carboxylate decarboxylase (EC 4.1.1.66), and Cis-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylate dehydrogenase (EC 1.3.1.25). In a subsequent step, the 5,6-dihydropyridine-2-carboxylic acid ring is opened in the presence of water to produce (E)-6-amino-2-oxohex-3-enoic acid. This reaction is similar to the hydration of 2,3,4,5-terahydropyridine-2-carboxylic acid (in the lysine degradation pathway) and is likely to be spontaneous in the presence of water.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:18])[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
(a-1) To a stirred solution of 16 parts of phenyl (3-amino-4-nitrophenyl) methanone in 195 parts of dichloromethane were added 7.8 parts of acetyl chloride. After stirring for 17 hours at room temperature, the reaction mixture was evaporated. The residue was crystallized from a mixture of ethyl acetate and 2,2'-oxybispropane. The product was filtered off and dried, yielding 15 parts (81%) of N-(5-benzoyl-2-nitrophenyl)acetamide; mp. 97.8° C. (int. 48).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([F:13])[CH3:12]>C1COCC1>[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]3=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)([F:13])[CH3:12]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(F)(F)c1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)c1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 306 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.483 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)pyridin-2-amine (499 mg) in THF (dry) (15 mL) was added at 0° C. and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with water/THF then water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo and washed with IPE to give the title compound (254 mg) as a white solid. A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:10].[CH3:35][N:36]1[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:10]
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(OC2CCN(C)CC2)c1Cl
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a slurry of methyl 3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 25, 0.18 g, 0.35 mmol) and 1-methyl-4-piperidinol (0.12 g, 1.1 mmol) in DCM (10 mL) was added triphenylphosphine (0.18 g, 0.70 mmol) and di-tert-butyl azodicarboxylate (0.16 g, 0.70 mmol). The clear, yellow solution was stirred for 1 h, and then silica gel (3 g) was added. The volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide:DCM) to give 0.20 g (0.34 mmol) of methyl 3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate which was then dissolved in a solution of 7 N ammonia in MeOH (10 mL). The mixture was heated in a sealed tube to 80° C. for 40 h and then cooled to rt. Silica (1 g) was added, the volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide:DCM) to afford 0.18 g (86%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.45 (d, J=8.79 Hz, 1H), 7.31 (m, 2H), 7.17 (d, J=7.51 Hz, 1H), 7.10 (d, J=8.24 Hz, 1H), 6.97 (s, 1H), 6.05 (q, J=6.29 Hz, 1H), 4.56 (m, 3H), 2.72 (br m, 2H), 2.47 (br m, 2H), 2.33 (s, 3H), 1.95 (br m, 4H), 1.77 (d, J=6.41 Hz, 3H): MS (ESI): 595 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[CH2:18][C@@H:17]1[C:25]([O:27]CC#C)=[O:26].[OH-].[Na+].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[CH2:18][C@@H:17]1[C:25]([OH:27])=[O:26]
Reactant: C#CCOC(=O)[C@H]1CN(CC#C)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C#CCN1CC[C@@H](CCCc2ccnc3ccc(OC)cc23)[C@@H](C(=O)O)C1
Temperature: 70 °C
Reaction time: 17 h
Yield: 69.5 %

Procedure:
0.3 g of (prop-2-ynyl) (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 3 cm3 of dioxane and 1.48 cm3 of N sodium hydroxide were heated, with stirring, at a temperature in the region of 70° C. for 17 hours. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. 1.48 cm3 of normal aqueous hydrochloric acid were added to the solid residue obtained, followed by 10 cm3 of water. The solution obtained was extracted with 5 times 20 cm3 of dichloromethane. The organic extracts were combined and then concentrated under reduced pressure (5 kPa). 0.189 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylic acid was obtained in the form of a foam with a white color.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:34]([F:37])([F:36])[F:35])=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][C:14]([C:19]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([C:21]1[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:79][N:80](C)C(=O)C>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].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([C:8]1[C:9]([C:34]([F:37])([F:35])[F:36])=[N:10][C:11]2[C:16]([C:17]=1[C:79]#[N:80])=[CH:15][C:14]([C:19]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([OH:20])[C:21]1[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=1)=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(C(F)(F)F)c(Cc3ccccc3)c(Cl)c2c1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(C(F)(F)F)c(Cc3ccccc3)c(C#N)c2c1
Temperature: 120 °C

Procedure:
A pressure tube containing (3-benzyl-4-chloro-2-(trifluoromethyl)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol•TFA (167 mg, 0.220 mmol, Example 100), Pd2(dba)3 (30 mg, 0.033 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (X-Phos, 16 mg, 0.034 mmol), zinc cyanide (15 mg, 0.13 mmol) and zinc nanopowder (3.5 mg, 0.054 mmol) in N,N-dimethylacetamide (1 mL) was sparged with nitrogen for 8 minutes, and then heated at 120° C. for 4 hours. The mixture was allowed to cool to room temperature and filtered through a syringe filter. The filtrate was concentrated in vacuo, EtOAc and saturated NH4Cl aqueous solution were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.34 (d, J=9.09 Hz, 1H), 8.31 (d, J=1.52 Hz, 1H), 8.01 (dd, J=2.02, 9.09 Hz, 1H), 7.44-7.49 (m, 4H), 7.24-7.30 (m, 2H), 7.18-7.24 (m, 1H), 7.06 (d, J=7.58 Hz, 2H), 7.03 (d, J=2.02 Hz, 1H), 4.64 (s, 2H), 3.71 (s, 3H); MS m/e 533.3 [M+H]+.