Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Product: Clc1nc2ccc(I)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
5-Iodo-1,3-dihydro-2H-1,3-benzimidazole-2-one (7 g) [see Preparation 24] was added to a solution of phosphoryl chloride (135 ml). The reaction mixture was then heated to 120° C. and stirred for 2 hours, after which time the phosphoryl chloride was removed under reduced pressure and the residue diluted with water. The residual aqueous solution was neutralised with aqueous potassium hydrogen carbonate solution and the product extracted with 90:10, by volume, dichloromethane:methanol, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-chloro-6-iodo-1H-1,3-benzimidazole (3.68 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:19]([CH:22]=1)[C:20]#[N:21]>>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH2:25][CH2:24]2)=[C:19]([C:20]#[N:21])[CH:22]=1)=[O:9]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: O=C(O)c1sc2ccccc2c1Cl
Product: N#Cc1cc(NC(=O)c2sc3ccccc3c2Cl)ccc1N1CCC(N2CCOCC2)CC1
Yield: 52.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 3-chlorobenzo[b]thiophene-2-carboxylic acid (1.1 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.5 g), the title compound (1.3 g) was obtained. melting point: 227-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][N:8]=2)=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([N:13]([C:10]1[CH:9]=[N:8][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:17])=[CH:12][CH:11]=1)[CH3:14])=[O:29]
Reactant: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2c(Cl)cccc2Cl)cn1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine (32 mg, 0.13 mmol) dissolved in methylene chloride (0.25 mL) was treated with triethylamine (0.026 mL, 0.18 mmol) followed by a solution of 2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol) dissolved in methylene chloride (0.15 mL). The reaction mixture was shaken at 22° C. for 18 hours followed by quenching with saturated aqueous NH4Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na2SO4 then concentrated in vacuo. The crude product was purified by chromatography on SiO2 using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 422/424 (M+H)+ ; C20H15N2O2Cl3 requires 422.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]2[C:14]([I:15])=[C:13]([O:16][CH3:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[C@H:5]([OH:20])[C@@H:4]1[OH:21].CO[C:24](OC)([CH3:26])[CH3:25].CCN(CC)CC>CC(C)=O.CS(O)(=O)=O>[I:15][C:14]1[C:9]([NH:8][C@H:6]2[C@@H:5]3[O:20][C:24]([CH3:26])([CH3:25])[O:21][C@@H:4]3[C@@H:3]([CH2:2][OH:1])[CH2:7]2)=[N:10][C:11]([S:18][CH3:19])=[N:12][C:13]=1[O:16][CH3:17]
Reactant: COC(C)(C)OC
Reactant: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1I
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 5 (4.00 g, 9.36 mmol) was dissolved in acetone (10 mL) and 2,2-dimethoxypropane (5.75 mL, 46.8 mmol) was added. The solution was cooled to 0° C. and methanesulfonic acid (2 drops) was added. The solution was stirred for 15 min and Et3N (1 mL) was added. The acetone was evaporated and the residue was dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified via column chromatography on silica gel (EtOAc/hexanes) to give the title compound as a white solid. 1H NMR (CDCl3) δ 6.21 (d, J=8 Hz, 1H), 4.65-4.59 (m, 2H), 4.45-4.44 (m, 1H), 3.94 (s, 3H), 3.89-3.85 (m, 1H), 3.76-3.73 (m, 1H), 2.61-2.55 (m, 1H), 2.52 (s, 3H), 2.40-2.34 (m, 1H), 1.85 (br s, 1H), 1.65-1.57 (m, 2H), 1.49 (s, 3H), 1.28 (s, 3H); LCMS 2.54 min, 468 (M+H).
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>C(#N)C>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([N:3]=[C:2]2[NH:21][CH2:20][CH2:19][CH2:18][NH:17]2)=[CH:9][CH:8]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: ClC(Cl)=Nc1ccc(C2CCCCC2)cc1
Reactant: NCCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCc1ccc(N=C2NCCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 g of N-dichloromethylene 4-cyclohexylaniline in 40 ml of acetonitrile is added dropwise to a solution of 1 ml of 1,3-diaminopropane in 20 ml of acetonitrile in 15 minutes at room temperature. After the addition of 1 ml of triethylamine, the solution is stirred for 1 hour at room temperature, after which the reaction mixture is filtered while warm. After distilling off the solvent the residue is taken up in ether and successively washed with 2 N sodium hydroxide solution and water. The ether layer is dried and evaporated, after which the residue is recrystallized from acetonitrile. The resulting 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine has a melting point of 180°-182° C. 2-(4-n-hexylphenyl)imino-hexahydropyrimidine was prepared in a corresponding manner.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].O>CN(C)C=O>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCOC(=O)CCCBr
Reactant: CCc1ccc(Cc2ccc(O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(Cc2ccc(CC)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside (0.051 g) and cesium carbonate (0.13 g) in N,N-dimethylformamide (2 mL) was added ethyl 4-bromobutyrate (0.028 mL), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to ambient temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=9/1) to give 5-[3-(ethoxycarbonyl)propyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.028 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:8].[NH:19]1[CH2:23][CH2:22][C@H:21]2[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C@@H:20]12>>[F:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:6]2[CH:18]=[C:2]([N:19]3[C@H:20]4[C@H:21]([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]4)[CH2:22][CH2:23]3)[CH:3]=[N:4][CH:5]=2)=[O:8])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)[C@@H]2C1

Procedure:
The product from Example 53A and (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (prepared as described in WO2001081347) were processed as described in Example 53B to provide the title compound. MS (APCI) m/z=445 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH2:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.ClC(Cl)Cl.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 20 h
Yield: 80.9 %

Procedure:
To a stirred solution of 10 parts of trans-3-methoxy-1-(phenylmethyl)-4-piperidinamine and 5.95 parts of N,N-diethylethanamine in 75 parts of trichloromethane was added dropwise a solution of 10.4 parts of 3-(trifluoromethyl)benzoyl chloride in 15 parts of N,N-diethylethanamine while cooling in an ice bath. Upon completion, stirring was continued for 20 hours at room temperature. The mixture was washed twice with a sodium hydroxide solution 5% and once with water and then dried, filtered and evaporated in vacuo. After crystallization of the residue from 27 parts of methylbenzene, the product was filtered off, washed with 45 parts of methylbenzene and dried, yielding 14.4 parts (80.9%) of trans-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-3-(trifluoromethyl)benzamide; mp. 135.2° C. (interm. 8).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH:15]=3)[S:10][C:9]([CH3:31])([CH3:30])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH:15]=3)[S:10][C:9]([CH3:31])([CH3:30])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of ethyl 4-[[4-(5-methylthiophen-2-yl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 230, 143.0 mg, 0.322 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (160.0 mg, 4.0 mmol, 4.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 110.0 mg (82%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.03 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.3 Hz), 7.60 (1H, s), 7.44 (2H, s), 6.87 (1H, d, J=3.5 Hz), 6.79 (1H, m), 6.10 (1H, s), 2.49 (3H, s), 1.45 (6H, s).
Reaction SMILES: Br([O-])(=O)=[O:2].[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1>C(#N)C.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:2])=[O:12])=[CH:9][CH:8]=1
Reactant: [O-][Br+2]([O-])[O-]
Reactant: OCc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(F)cc1
Yield: 89.7 %

Procedure:
The separated catalyst was added to a fresh batch of sodium bromate (0.3 g) and 4-fluorobenzyl alcohol (0.256 g, 2 mmol) in acetonitrile:water (1:1, 10 ml). The above procedure was repeated to give 4-fluorobenzoic acid as a white solid (0.25 g, 88%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)(OC)=O.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][N:22]1[C:23](=[O:31])[C:24]2[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:26]=[C:1]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Examples 23 or 24 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M) and p-toluenesulfonic acid (˜200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C. oil bath temperature 170-180° C.) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (28 g, Y=23%, P=98%).
Reaction SMILES: [OH:1][CH:2]1[CH2:15][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:24]([O:1][CH:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5]2)[CH2:15]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CC(O)C2)C1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CC(OS(C)(=O)=O)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (505 mg, 2.37 mmol) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (330 μL, 2.37 mmol) and DMAP (3.0 mg, 0.0237 mmol) were added. Methanesulfonyl chloride (184 μL, 2.37 mmol) was then added dropwise by syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (684 mg, 99%) as a white solid.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[O:13][CH2:12][CH:11]([C@H:20]3[CH2:25][CH2:24][C@H:23]([N:26]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:22][CH2:21]3)[N:10]([CH3:37])[C:9]2=1>C(O)C>[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[O:13][CH2:12][CH:11]([C@H:20]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]3)[N:10]([CH3:37])[C:9]2=1
Reactant: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N)CC1)CO3
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Hydrazine hydrate (2M solution in methanol, 90 μL, 0.18 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (105 mg, 0.18 mmol, 1.0 eq) in ethanol (3 mL). After 16 hours stirring at 50° C., solvent is removed to afford trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine as an orange semisolid (80 mg, 93% yield).
Reaction SMILES: Cl[C:2]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([Cl:17])(=[O:16])=[O:15])=[O:3].[CH3:18][OH:19]>C(Cl)(Cl)Cl>[CH3:18][O:19][C:2]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([Cl:17])(=[O:15])=[O:16])=[O:3]
Reactant: Cc1ccc2c(S(=O)(=O)Cl)c(C(=O)Cl)sc2c1
Reactant: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc2cc(C)ccc2c1S(=O)(=O)Cl

Procedure:
Prepared analogous to Example 1(c) from 2-chlorocarbonyl-6-methyl-benzo[b] thiophene-3-sulfonic acid chloride and methanol in the presence of chloroform.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])C.O.[OH-].[Na+].Cl>CO>[CH2:13]([CH:5]([CH2:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[C:4]([OH:20])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 g of 2-benzyl-3-tert.-butylsulphinyl-propionic acid ethyl ester are dissolved in 30 ml of methanol, and 30 ml of water and 10.8 ml of 1N sodium hydroxide solution are added thereto. The mixture is stirred at room temperature for 16 hours, neutralised with 10.8 ml of 1N hydrochloric acid and concentrated in vacuo. The residue is purified by flash chromatography on 150 g of silica gel 60 (eluant J). Rf (J)=0.38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].C[Si](C)(C)[O:14][K].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:10])=[O:14])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(CC#N)ccc1F
Reactant: C[Si](C)(C)O[K]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(CC(N)=O)ccc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
4-Fluoro-3-methylphenylacetonitrile (1.1 g) was dissolved in toluene (35 ml), and trimethylsiloxypotassium (3.7 g) was added. After stirring at 110° C. for 2.5 hours, saturated sodium bicarbonate water was added, followed by separation with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 863 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[CH:40]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)(c1ncc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)s1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (380 mg, 1.13 mmol) in 10 mL THF was cooled to −78° C., then LDA (2.5 mmol, freshly prepared) was added and the resulting mixture was stirred at the same temperature for 30 min. Then a solution of methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (1.13 mmol) in THF (3 mL) was added and the reaction was warmed to rt over a period of 4 h, then stirred for an additional 15 h at rt. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated, and the residue was purified by silica gel chromatography to afford racemic methyl 3-hydroxy-3-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate, which was resolved by chiral SFC (Column: Chiralcel OD-H 150×4.6 mm I.D., 5 um; Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL/min; Wavelength: 220 nm) to give each enantiomer. MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[F:14][C:15]1[CH:16]=[C:17]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:18]=[C:19]([F:28])[C:20]=1[CH:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1.CN1CCOCC1>ClCCl>[O:27]=[S:24]1(=[O:4])[CH:25]=[CH:26][CH:21]([C:20]2[C:19]([F:28])=[CH:18][C:17]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:16][C:15]=2[F:14])[CH2:22][CH2:23]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCS(=O)CC3)c(F)c2)C(=O)O1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Trifluoroacetic anhydride (2.24 ml, 15.8 mmol) was added dropwise at room temperature to a solution of N-[[(5S)-3-[3,5-difluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.04 g, 5.28 mmol and N-methylmorpholine (2.90 ml, 26.4 mmol) in dichloromethane (50 ml). The reaction mixture was stirred overnight at room temperature and then evaporated to dryness. The resulting crude N-({(5S)-3-[4-(3,4-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (1.95 g) was dissolved in tetrahydrofuran (100 ml) and peracetic acid (5.6 ml of a 32% solution in acetic acid, 26.4 mmol) added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate) to give white solid (1.80 g, 85%).