Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:24])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[C:21](=O)[CH3:22])=[O:9])[CH3:4].CC(O)=O>CCO.O>[CH2:3]([O:5][C:6]([C:7]1[C:8]([OH:9])=[N:10][C:11]2[C:12]([C:21]=1[CH3:22])=[CH:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=2)=[O:24])[CH3:4]
Reactant: CCOC(=O)CC(=O)Nc1cc(C(C)(C)C)ccc1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)nc2cc(C(C)(C)C)ccc2c1C
Temperature: 80 °C
Yield: 83.9 %

Procedure:
30 mg (0.68 mmol, 60% in mineral oil) sodium hydride were added to a solution of 190 mg (0.62 mmol) 3-(2-acetyl-5-tert-butyl-phenylamino)-3-oxopropanoic acid ethyl ester in EtOH (2 ml) and the mixture was heated for 2 h at 80° C. Then it was diluted with water and acidified with 5N AcOH. It was then extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 150 mg (0.52 mmol, 84%) 7-tert-butyl-2-hydroxy-4-methyl-quinoline-3-carboxylic acid ethyl ester were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH:17]=[CH2:18])[CH:10]=1.N1C=CC=CC=1.Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34](=[O:35])[NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C@@H:15]([NH:19][C:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:16][CH:17]=[CH2:18])[CH:10]=2)=[C:2]([NH2:1])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(N)cc2N)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2N)ccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a cooled (−78° C.) clear, brown solution of 1E (2.63 g, 7.42 mmol) and pyridine (0.600 ml, 7.42 mmol) in dichloromethane (74.2 ml) was added dropwise over 30 min methyl chloroformate (0.516 ml, 6.68 mmol). The reaction was stirred at −78° C. After 1.5 h, the reaction was quenched with sat. NH4Cl and the reaction was allowed to warm to rt. The reaction was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM (1×). The combined organic layers were washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue dissolved in DCM (˜10 mL) and then hexane (˜300 mL) was added to give a brown suspension with brown gummy sticky substance at the bottom. The mixture was sonicated to give a mostly clear solution with the brown substance at the bottom. The solution decanted and the bottom substance rinsed with hexane, dried to give 1F (2.7 g, 88%) as a slightly brown foam. MS (ESI) m/z: 413.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].F[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
To a solution of 3-trifluoromethylphenol (29 g, 0.18 mol) dissolved in dimethylformamide (100 ml) was added finely-powdered potassium hydroxide (15 g, 0.19 mol). The reaction mixture was heated to approximately 60° C., with stirring, for one hour after which time 2,5-difluorobenzonitrile (25 g, 0.19 mol) was added and the temperature increased to 110° C. After approximately half an hour, the reaction mixture was allowed to cool and excess dimethylformamide was removed in vacuo before 500 ml of a 50:50 mixture of water and trichloromethane was added. The organic layer was separated, washed and dried and the residue purified by chromatography using a silica column with trichloromethane as eluant, followed by distillation and recrystallisation to yield the title compound as a solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=2[C:47]([F:50])([F:49])[F:48])[CH2:36][CH2:35]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:44][C:43]5[CH:45]=[CH:46][C:40]([N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)=[C:41]([C:47]([F:50])([F:49])[F:48])[CH:42]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline with yield 46 mg (34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.72 (m, 6 H) 1.99 (br. s., 2 H) 2.23 (s, 3 H) 2.47 (br.s., 4 H) 2.85 (t, J=4.29 Hz, 4 H) 3.99 (s, 3 H) 4.07 (t, J=12 Hz, 2 H) 4.80 (t, J=7.96 Hz, 1 H) 7.46-7.73 (m, 3 H) 7.97-8.10 (m, 2 H) 8.14 (d, J=2.53 Hz, 1 H) 8.29 (s, 1 H) 8.38 (d, J=8.34 Hz, 1 H) 10.31 (s, 1 H). [M+H] calc'd for C33H37F5N8O3, 689; found 689.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1>O=S(Cl)Cl>[Cl:1][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[N:8]=1
Reactant: Cl
Reactant: Cc1cccc(CO)n1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(CCl)n1
Yield: 70.6 %

Procedure:
A solution of (6-methylpyridin-2-yl)methanol hydrochloride (1.0 g, 0.008 mol) in SOCl2 (3 mL) was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude product. The crude material was azeotroped with toluene and the resulting residue was filtered and dried in vacuo to afford 2-(chloromethyl)-6-methylpyridine (800 mg, 63%) as a light brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl>CO.O>[C:20]([O:19][C:17]([C:5]1([C:3]([OH:4])=[O:2])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C1(C(=O)OC(C)(C)C)CCc2cccc(OC)c2C1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cccc2c1CC(C(=O)O)(C(=O)OC(C)(C)C)CC2

Procedure:
The methyl ester from Example 33B was dissolved in a mixture of MeOH (10 mL) and water (2.0 mL) followed by addition of LiOH monohydrate (1.9 g, 45 mmol). The mixture was stirred for 18 hours after which 10% HCl was added until pH=4 was achieved. This mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with MgSO4, filtered, concentrated under reduced pressure to provide the titled compound (4.3 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][O:13][C:7]=2[N:6]=[CH:5]1.[Br:16]Br>CN(C=O)C>[Br:16][C:12]1[O:13][C:7]2[N:6]=[CH:5][N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: BrBr
Reactant: O=c1c2ccoc2ncn1CC(F)(F)F
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)oc2ncn1CC(F)(F)F
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of 3-(2,2,2-trifluoroethyl)furo[2,3-d]pyrimidin-4(3H)-one (0.64 g, 2.93 mmol) in anhydrous DMF (11 ml) at 0° C. was added bromine (0.333 ml, 6.45 mmol) and the mixture stirred for 30 min. The mixture was partitioned between ethyl acetate (30 ml) and an aqueous mixture (3:1:4, water, saturated sodium hydrogen carbonate solution and 20% w/w sodium thiosulfate solution, 110 ml). The aqueous phase was separated and extracted with ethyl acetate (3×30 ml). The combined ethyl acetate fractions were washed with brine/water (1:1, 4×30 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-30% ethyl acetate in cyclohexane) to afford the title compound (673 mg, 77%). LCMS RT=1.04 min, [M+H+(79Br)]=297.0, [M+H+(81Br)]=298.9.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[C:23]2[NH2:31])=[CH:17][CH:16]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.O.C(O)C.CC1C=CC=CC=1>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[C:23]2[NH:31][CH:2]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 33.3 parts of ethyl hexahydro-4-oxo-1H-azepine-1-carboxylate, 36.15 parts of 1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine, 320 parts of methylbenzene and 0.1 parts of 4-methylbenzenesulfonic acid was stirred overnight at reflux temperature using a water separator. After cooling to 50° C., 80 parts of ethanol were added. 4.2 Parts of sodium tetrahydroborate were added portionwise and upon completion, stirring was continued for 2 hours at 50° C. After cooling, water and 4.8 parts of methanol were added while stirring. The layers were separated and the aqueous layer was extracted with methylbenzene. The combined organic layers were dried, filtered and evaporated, yielding 73 parts (100%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]hexahydro-1H-azepine-1-carboxylate as a residue (compound 20).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:5])=[CH:22][C:10]=2[CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccccc3)ccc2o1

Procedure:
The product from Example 71E and phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.15 (d, 3H), 1.45 (m, 1H), 1.80 (m, 2H), 2.00 (m, 1H), 2.30 (m, 1H), 2.50 (m, 2H), 3.30 (m, 4H), 6.63 (s, 1H), 7.55 (m, 3H), 7.65 (m, 1H), 7.80 (m, 3H), 7.98 (d, 1H); MS (ESI) m/z 334 (l+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([OH:8])[CH2:6][CH3:7].S(=O)(=O)(O)O.CS(O)(=O)=O.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](O)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+]>C1CCCCC1.O1CCCC1>[CH3:39][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:8][C@:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:1])[CH3:18])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC[C@](OS(=O)(=O)c1ccc(C)cc1)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 20 °C

Procedure:
Accordingly the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol of Formula-V was charged in the solvent tetrahydrofuran and under stirring charged concentrated sulfuric acid at temperature of 20-30° C. The reaction mixture is stirred and charged methanesulfonic acid or para toluenesulfonic acid and solvent cyclohexane. Stirred and raised the temperature to reflux. Maintained the reaction mass at reflux temperature for 3-5 hours with simultaneous removal of water. Cooled the reaction mass to 20° C. and quenched with water. The pH of the quenched reaction solution was adjusted to 8-9 using dilute sodium hydroxide solution. The reaction solution was extracted with cyclohexane. Separated the organic layer and concentrated under reduced pressure to get the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-yl methane sulfonate of Formula IXA or (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-yl 4-methylbenzenesulfonate of Formula IXB.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH2:12][CH3:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][CH2:15][CH2:16][CH2:17][N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[CH2:31][CH2:30]1)[CH2:12][CH3:13]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(Cl)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 5-chloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]4[NH:38][N:37]=[N:36][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1nnn[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.1 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (200 mg, 0.496 mmol) obtained in Example 1 was dissolved in toluene (5 mL), trimethylsilylazide (1.3 mL, 9.92 mmol) and dibutyltin oxide (123 mg, 0.496 mmol) were added, and the mixture was stirred at 90° C. for 24 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the title compound (compound 4) (111 mg, 50%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:34]([F:46])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:46])=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cc(Cl)ncc2F)OC1(C)C
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: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3F)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (104 mg, 0.21 mmol), 2-Chloro-5-fluoropyridine-4-boronic acid pinacol ester (80 mg, 0.31 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2.0 mL) and to this was added 2M aqueous K2CO3 (0.30 mL, 0.60 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C27H26Cl2FN2O3S: 547.1 (M+H+); Found: 547.2 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([F:36])[CH:16]=[C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C@H:29]4[CH2:33][O:32]C(C)(C)[O:30]4)[CH:22]=3)=[O:19])[C:11]=2[N:10]=1>Cl.CO>[F:37][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([F:36])[CH:16]=[C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C@H:29]([OH:30])[CH2:33][OH:32])[CH:22]=3)=[O:19])[C:11]=2[N:10]=1
Reactant: CC1(C)OC[C@H](COc2cccc(NC(=O)c3cc(F)cc4[nH]c(-c5ccccc5C(F)F)nc34)c2)O1
Agent: Cl
Solvent: CO
Product: O=C(Nc1cccc(OC[C@H](O)CO)c1)c1cc(F)cc2[nH]c(-c3ccccc3C(F)F)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Ten drops of concentrated HCl were added to a solution of (S)-2-(2-(difluoromethyl)phenyl)-N-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide (147; 200 mg, 0.391 mmol) in methanol (15 mL). The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to afford (R)-2-(2-(difluoromethyl)phenyl)-N-(3-(2,3-dihydroxypropoxy)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide (Compound 811) (160 mg, 87%). MS (ESI) calcd for C27H24F3N3O4: 511.17; found: 512 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15](O)[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)[CH3:2].C(N(S(F)(F)[F:38])CC)C.O>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@@H:15]([F:38])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC[C@H](O)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC[C@@H](F)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Temperature: -78 °C
Reaction time: 48 h

Procedure:
Using 174 mg of 3-{3-[3-(2,4-dichlorophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester (Production example 279e) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to −78° C. To the solution was added 0.15 ml (diethylamino) sulfur trifluoride, and stirring was continued at room temperature for 2 days. Water was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed. The residue was purified by silica gel column chromatography, to give 79 mg of 3-{3-[3-(2,4-dichlorophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester in the 7:1→5:1 hexane-ethyl acetate fraction. This product was dissolved in 4 ml of ethanol and 0.5 ml of tetrahydrofuran and 0.5 ml of 1N lithium hydroxide were added, and stirring was continued overnight at room temperature. The solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed. The residue was purified by silica gel column chromatography, to give 61 mg of the title compound in the 3:1→1:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: COc1ccc(CN)cc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(OC)cc1
Yield: 87 %

Procedure:
The compound prepared in Example 3 was reacted with 4-methoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 87%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([Cl:16])=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:13][C:12]=2[CH:22]=1.CN(C)C=O>O1CCCC1>[Cl:16][C:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:4][C:1]([CH3:2])=[O:3])=[CH:22][C:12]=2[S:13][C:14]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(COC(C)=O)ccc2c1Cl
Temperature: 80 °C
Yield: 63 %

Procedure:
Sodium acetate (3.3 g, 40.5 mmol) was added to a stirred solution of ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 4.5 g, 13.5 mmol) in a mixture of anhydrous dimethylformamide (20 ml) and anhydrous tetrahydrofuran (10 ml), under a nitrogen atmosphere. The mixture was heated at 80° C. for 20 hours, then the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using dichloromethane as eluant to give the title compound as a colourless gum (2.66 g).