Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine (prepared in the above Example 297(3)) 71 mg and 2-hydroxymethylpyridine 25 mg in tetrahydrofuran 3 ml is added potassium tert-butoxide 26 mg under ice cooling. The mixture is stirred for 30 minutes at the same temperature and diluted a 10% aqueous citric acid solution. The solution is extracted with ethyl acetate and the extract is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is purified and separated with silica gel chromatography (silica gel 5 g, solvent; chloroform:ethyl acetate=3:1) and crystallized from isopropyl ether to give 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxy)pyrazine as a pale yellow crystalline powder, 25 mg. mp 132–133° C., MS(m/z): 415(M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2].[OH-].[Na+].[CH3:25]OS(OC)(=O)=O>CO.O>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2]
Reactant: O=Cc1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of N-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide (2.2 g, 6.6 mmol) in methanol (11 mL) is treated with a solution of sodium hydroxide (275 mg, 6.9 mmol) in water (2.4 mL). To this is added dimethylsulfate (0.64 mL, 6.8 mmol). The reaction is stirred at rt overnight, evaporated, and chromatographed on silica gel in 5% and 10% ethyl acetate-methylene chloride. The product fractions are further purified by crystallization from toluene-hexane to afford N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide in 68% yield.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([C:9]1[CH2:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:8])[CH3:7].[CH3:24][Si:25]([CH3:28])(Cl)Cl.[Cl-].[NH4+]>[Cu]C#N.CCCCCC.C(OCC)C>[CH3:24][Si:25]([CH3:28])([CH:17]1[C:16]2[C:11](=[C:12]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:6]([CH3:8])[CH3:7])[CH:1]1[C:22]2[C:4](=[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=3)[CH:19]=[CH:20][CH:21]=2)[CH:3]=[C:2]1[CH:6]([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)C1=Cc2cccc(-c3ccccc3)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)C1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C(C)C)=Cc2c(-c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Under nitrogen atmosphere, 24.5 ml of 1.63 M hexane solution of n-butyllithium (40 mmol) was dripped down at -78° C. into 90 ml of a diethyl ether suspension of 9.37 g (40.0 mmol) of 2-i-propyl-7-phenylindene and 0.1 g (1.0 mmol) of copper (I) cyanide. After completion of the dripping, the temperature was slowly elevated to room temperature and the mixture was stirred at room temperature for 2 hours. Again, the mixture was cooled down to -78° C. and 2.58 g (20.0 mmol) of dimethyldichlorosilane was added thereto slowly. After completion of the dripping, the temperature was slowly elevated to room temperature, and the mixture was stirred for 7 hours. The reaction mixture was poured into aqueous saturated ammonium chloride solution and extracted with diethyl ether. After it was washed with saturated saline, the organic phase was dried over anhydrous magnesium sulfate, followed by distilling off the solvent to obtain viscous solids. The solids were fractionated by column chromatography (silica gel, development solvent: n-hexane) to obtain 9.69 g (18.5 mmol, yield: 92.5%) of dimethylbis(2-i-propyl-4-phenylindenyl)silane. By 1H-NMR, this was confirmed to be a mixture of two isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N+:24]([O-:26])=[O:25]>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:23][N+:24]([O-:26])=[O:25])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A mixture of 4-benzyloxy-3-cyclopentyloxybenzaldehyde (6.3 g, 21.3 mmol) in AcOH (13 mL) and CH3NO2 (5.8 mL, 106.5 mmol) was created. NH4OAc (3.3 g, 42.5 mmol) was added and the mixture was heated under reflux for 2 h. After cooling to r.t., the mixture was extracted with CH2Cl2. The organic layer separated and washed with water, sat. NaHCO3, and sat. NaCl, and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography on silica gel (CH2Cl2/hexane) gave 3.2 g of yellow solids. Yield: 44%.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([OH:18])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:19]([N:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:18])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:11])=[CH:9][C:2]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([N:21]([CH2:19][CH3:20])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])#[N:5]
Reactant: Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Reactant: CCN(C(=O)c1cccc(O)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cccc(Oc2cc(C(C)(O)c3cncn3C)ccc2C#N)c1)c1ccccc1
Temperature: 60 °C

Procedure:
2-Fluoro-4-[1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile (0.054 g, 0.220 mmol), N-ethyl-3-hydroxy-N-phenyl-benzamide (0.053 g, 0.220 mmol) and Cs2CO3 (0.143 g, 0.440 mmol) were dissolved in anhydrous DMF (5 mL) and heated at 60° C. under Ar for 4 days. The reaction was diluted with EtOAc, washed with satd. NaHCO3 solution, water, and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2) to give the title compound. FAB MS (M+1)=467.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:24]CCCCC>C(O)=O.C=O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH3:24])[CH2:17]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2C1CCCNC1
Reactant: CCCCCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCCC(C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Yield: 76 %

Procedure:
Dissolved 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperidine (0.75 g, 2.7 mmol) in 1.1 mL of formic acid and 1.5 mL of 37% aqueous formaldehyde. Heated in a 90°-95° C. oil bath for 20 hours. Cooled to room temperature, and made basic with 5% NaOH. Extracted with ether. Dried combined organic extracts with MgSO4, filtered, and evaporated. Crystallized product from hexane to give 0.60 g (76% yield) of 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-piperidine as white solid. Dissolved the free base in ether, and added 19 weight % HCl-EtOH to precipitate the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][P:22](=[O:33])([O:28]C(C)(C)C)[O:23]C(C)(C)C)[C:16](=[O:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5].C(O)(=O)C.O>C(#N)C>[Cl:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][P:22](=[O:23])([OH:33])[OH:28])[C:16](=[O:34])[CH:15]=2)=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)OP(=O)(OCn1ccc(-c2ccc(CNC(=O)c3c(Cl)cccc3Cl)cc2)cc1=O)OC(C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(NCc1ccc(-c2ccn(COP(=O)(O)O)c(=O)c2)cc1)c1c(Cl)cccc1Cl
Yield: 56 %

Procedure:
Phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl ester from the previous step was dissolved in 20 mL acetonitrile, 20 mL acetic acid and 20 mL water, and heated at 70° C. for four hours. All volatile components were evaporated under vacuum and the residue was dissolved in 10 mL DMF. Slow addition of acetonitrile (˜60 mL) precipitated the product which was filtered, washed with more acetonitrile and dried, giving phosphoric acid mono-(4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl)ester (1.17 g, 56% over three steps) as a white powder.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[N+:8]([O-:22])([O:10][C@@H:11]([C@H:13]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:15][CH2:16][OH:17])[CH3:12])=[O:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:18][N+:19]([O-:21])=[O:20])[C@H:11]([O:10][N+:8]([O-:22])=[O:9])[CH3:12]
Reactant: C[C@@H](O[N+](=O)[O-])[C@@H](CCCO)O[N+](=O)[O-]
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reaction time: 16 h

Procedure:
1-Chloroethyl chloroformate (1.55 mL, 14.2 mmol) was added dropwise to a stirred dichloromethane (50 mL) solution of (2R,3R)-6-hydroxyhexane-2,3-diyl dinitrate (intermediate 1, 2.60 g, 11.6 mmol), followed by pyridine (1.20 mL, 14.8 mmol). After 16 hours, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.41 (q, J=5.7 Hz, 1H), 5.18-5.28 (m, 2H), 4.18-4.32 (m, 2H), 1.83 (d, J=5.7 Hz, 3H), 1.68-1.90 (m, 4H), 1.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:7]([C:6]4[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=4[O:4][C:1](=[O:3])[CH3:2])=[O:8])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)Oc1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 3, making variations only as required to use acetylsalicyloyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (39% yield). 1H NMR (500 MHz, CDCl3) δ 8.06, 8.00, 7.00, 7.47, 7.34-7.29, 7.18, 6.98, 4.00-3.72, 3.60-3.48, 2.28, 1.52, 0.76, 0.48, 0.10. MS (ES+) m/z 438 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COCCBr
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCSc1ccccc1N
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 2-aminothiophenol (93%, 123 g, 0.910 mol) and sodium hydroxide (40.2 g, 1.00 mol) in 90% aqueous ethanol (637 ml) was added dropwise 2-bromoethylmethylether (127 g, 0.910 mol) at room temperature. When the addition was complete, the reaction mixture was refluxed for 2 hours, cooled to room temperature, and then concentrated in vacuo. The resulting residue was diluted with water (1400 ml) and extracted with methylene chloride (3×500 ml). The extracts were washed with water (2×500 ml) and brine (500 ml), dried with (MgSO4), filtered and concentrated to give a dark oil. Distillation of the crude product gave 2-(2-methoxyethylthio)benzenamine (148 g, 89%) as a light yellow oil; bp 90°-103° (0.1 mm).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([N:6]([C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:22]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: COc1ccc(Nc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N-(4-methoxyphenyl)aniline (1c) (90.78 g, 0.418 mol) and 3-fluoro-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) were mixed together and dissolved in anhydrous THF (200 mL) in a dry 1 L three-necked round-bottomed flask fitted with a stirring bar, a reflux condenser and an argon inlet. Anhydrous pyridine (132.22 g, 1.672 mol) was added via a syringe at room temperature under argon. The reaction mixture was stirred and heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered to remove pyridine salt. The solution was concentrated to remove THF solvent. The residue oil was washed with 200 mL of 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with a saturated aqueous Na2CO3 solution (150 mL) to remove excess benzoyl chloride and acid, dried over MgSO4 (50 g), filtered, and concentrated under reduced pressure to give an oil. The residue was purified by flash column chromatography using silica-gel with CH2Cl2/acetone (50/1 v/v) to afford the pure corresponding benzamide compound as a yellow solid. M.p. 54-56° C. MS (ESI) m/z 370.1 [M+H]+, 1H NMR (CDCl3/TMS) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:20]([OH:22])=[O:21].[CH3:23]O>O>[CH2:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([O:22][CH3:23])=[O:21]
Reactant: CO
Reactant: O=CO
Agent: CCCCCCN(CCCCCC)CCCCCC
Solvent: O
Product: COC=O

Procedure:
Example 2 was carried out in laboratory plant 2. By means of metering pumps, 2280 g/h of methyl formate as stream (1a) and 950 g/h of water as stream (1c) were metered into the stirred vessel A1. Stream (1c) was taken off from the mixing vessel X and was composed of fresh water via stream (1b) and recycle water from the distillation apparatus B2 via stream (3c). Stream (1b) was selected so that the sum of stream (1b) and stream (3c) gave the desired stream (1c). The stirred vessel A1 was operated at 110° C. and 1.3 MPa abs. The output was introduced into tube reactor A2 which was operated at 108° C. and 1.3 MPa abs. The output from tube reactor A2 was introduced into tube reactor A3.1603 g/h of tri-n-hexylamine were fed via stream (8a) into the latter. The output from tube reactor A3 was introduced into tube reactor A4. A further 1603 g/h of tri-n-hexylamine were fed via stream (8b) into the latter. Streams (8a) and (8b) were taken off from the vessel Y which served to distribute tri-n-hexylamine recirculated via stream (8) over the two tube reactors A3 and A4. Tube reactor A3 was operated at 105° C. and 1.3 MPa abs, and tube reactor A4 was operated at 106° C. and 1.3 MPa abs. A product mixture comprising 49.8% by weight of tri-n-hexylamine, 16.9% by weight of formic acid, 12.3% by weight of methanol, 7.9% by weight of water and 11.5% by weight of methyl formate was obtained as stream (2).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[C:9]([C:16]2[S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[N:24]=2)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1.[OH2:25]>ClCCl>[Br:7][C:8]1[C:9]([C:16]2[S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[N:24]=2)=[N:10][C:11]([S:14]([CH3:15])(=[O:1])=[O:25])=[N:12][CH:13]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CSc1ncc(Br)c(-c2nc3ccncc3s2)n1
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ncc(Br)c(-c2nc3ccncc3s2)n1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of oxone (179 mg, 0.29 mmol) in water (10 mL) was added dropwise to a stirred solution of 2-(5-bromo-2-(methylthio)pyrimidin-4-yl)thiazolo[5,4-c]pyridine (66 mg, 0.19 mmol) in dichloromethane (12 mL) at 0° C. The bright yellow suspension was allowed to warm to r.t. overnight. After 14 h the organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexane 25:75 to 50:50) to yield 2-(5-bromo-2-(methylsulfonyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridine (59 mg, 82%) as a white amorphous solid. 1H NMR: δ (CDCl3, 400 MHz) 3.47 (s, 3 H), 8.13 (d, J=5.5 Hz, 1 H), 8.79 (d, J=5.5 Hz, 1 H), 9.29 (s, 1 H), 9.39 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncco1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1ncco1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (85 mg, 0.416 mmol) and 4-bromo-3-(oxazol-2-yl)thiophen-2-amine (51 mg, 0.208) mmol) according to protocol A. Retention time (min)=3.245, method [7], MS (ESI) 433.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J=5.1, 1.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (dd, J=8.4, 5.5 Hz, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 4.93 (s, 2H), 3.51-3.46 (m, 2H), 3.05-3.00 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.[NH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:13][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 10.1 g of 3-fluoro-4-methylbenzoic acid and 15.2 g of diethyl aminomalonate hydrochloride in 200 ml of N,N-dimethylformamide, 9.7 g of 1-hydroxybenzotriazole, 23 ml of triethylamine and 13.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added sequentially, and stirred for 1 hour at room temperature. After addition of water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with water, 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution sequentially and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized by addition of isopropyl ether to provide 15.1 g of the objective compound as colorless crystals. M.p. 102–103° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: C1COCCN1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (50 mg, 0.1009 mmol, example 58), morpholine (22 μl, 0.252 mmol) and 2,6-di-tert-butylpyridine (45.4 μl, 0.202 mmol) in DMA (1 ml) was heated in a sealed tube at 100° C. overnight. Then additional morpholine (8.8 μl, 0.1009 mmol) was added and the solution was stirred another 2 h at 100° C. The mixture was then cooled to room temperature and diluted with water. The pH was adjusted to 10 by addition of saturated Na2CO3 solution and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed two times with Na2CO3 solution (pH 10) and with brine, dried over Na2SO4 and evaporated. The remaining light brown solid was purified by silica gel chromatography (DCM/EtOAc 4:1-1:1) to obtain the title compound (33 mg, 65%) as white foam. MS (EI): 502.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.O1CCCC1.[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH:8]([OH:9])[C:18]([F:20])([F:19])[F:17])=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(C=O)c1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)cnc(C(O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
To a solution of 5-bromo-3-chloro-4-methyl-pyridine-2-carbaldehyde (123.9 mg; 0.5284 mmol) in tetrahydrofuran (5.0 mL; 62 mmol) at 0° C. was added (trifluoromethyl)trimethylsilane (0.170 mL; 1.1 mmol) followed by tetrabutylammonium fluoride (1 mol/L) in THF (1.6 mL; 1.6 mmol). The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 119.7 mg (74%) of the title compound. LCMS (ESI): M+H=304.0; 1H NMR (400 MHz, DMSO) 8.76 (s, 1H), 6.92 (d, J=6.9 Hz, 1H), 5.58 (p, J=6.9 Hz, 1H), 2.55 (s, 3H).