Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]3[CH3:23])=[CH:14][CH:15]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])C>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]3[CH3:23])=[CH:14][CH:15]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:9]1[C:30]([NH:39][C@H:38]([C:37]([OH:44])=[O:36])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2Cc1ccccc1
Agent: Cl
Solvent: O
Product: Cc1ccc(C)n1-c1ccc2c(c1)c(-c1ccccc1)c(C(=O)N[C@@H](CC(C)C)C(=O)O)n2Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenyl-1H-indole-2-carboxylic acid and L-leucine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as an off-white solid: 1H NMR (DMSO-d6) δ 0.77 (d, J=6.3 Hz, 3 H), 0.78 (d, J=6.3 Hz, 3 H), 1.25-1.40 (m, 1 H), 1.40-1.50 (m, 1 H), 1.90 (s, 6 H), 4.30-4.40 (m, 1H), 5.56 (d, J=16.0 Hz, 1 H), 5.63 (d, J=16.0 Hz, 1 H), 5.76 (s, 2 H), 7.05-7.65 (m, 13 H), 8.95 (d, J=13.3 Hz, 1 H), 12.35 (br s, 1 H); MS (ESI) m/z 534 (MH−); MS (ESI) m/z 532 ([M-H]−); HRMS calcd for C34H36N3O3: 534.2757; found (ESI+): 534.2745; Anal. calcd for C34H35N3O3.0.65 H2O: C, 74.88; H, 6.71; N, 7.70. Found: C, 74.55; H, 6.31; N, 7.68.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CSc1ccc(Cl)cc1)OCC
Yield: 50 %

Procedure:
In a 250 mL 2-neck round flask, 4-chlorobenzenethiol (10.0 g, 69 mmol), K2CO3 (9.52 g, 69 mmol), and dimethylformamide (DMF) (100 mL) were poured and stirred, and then 2-bromo-1,1-diethoxyethane (16.3 g, 82.8 mmol) was dissolved in dimethylformamide (100 mL) and gradually added to the aforementioned mixture solution at 0° C. After the reaction, an organic solvent was extracted with ethyl acetate (EtOAc) (250 mL) and water (200 mL), and then dried over MgSO4. After column chromatography using ethyl acetate/petroleum ether (EtOAc/PE=1:60), the solution was distilled in vacuum to give 9.0 g of yellow oil (50% yield).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:26]=1)(=O)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:26]=1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)C4CC4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cn2nc(Oc3cccc(NC(=O)C4CC4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
A mixture of N-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}cyclopropanecarboxamide (465 mg, 1.32 mmol), 4N hydrochloric acid-ethyl acetate solution (10 mL) and methanol (10 mL) was stirred at room temperature for 14 hr. The reaction mixture was neutralized by the addition of 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound (376 mg, 92%) as a pale-green powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 84 mg (0.26 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (10 mL) was added NaH (19 mg, 0.40 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (45 mg, 0.32 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 66 mg (60%) of the title compound as a colorless oil. ES-MS m/e: 420.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(OCc3ccccc3)c(C(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
To a solution of 2-benzyloxy-5-(2-hydroxyethyl)benzamide (519 mg) in dichloromethane (6 ml) were added triethylamine (290 μl), N,N-dimethylaminopyridine (24 mg) and p-toluenesulfonyl chloride (400 mg) subsequently, and the mixture was stirred for 17 hours at room temperature. After concentration of the reaction mixture under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:diethyl ether/dichloromethane=1/1) gave 2-benzyloxy-5-[2-(p-toluenesulfonyloxy)ethyl]benzamide (627 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Aminoethyl)piperazine (4.93 g) was dissolved in tetrahydrofuran (40 ml), and the solution was added with triethylamine (10.6 ml). The mixture was added with a solution of benzyl chloroformate (4.9 ml) in tetrahydrofuran (40 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with ethyl acetate and saturated aqueous sodium hydrogencarbonate, the layers were separated, and then the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (400 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([NH:17][NH2:18])=[O:16])[N:9]=2)[CH:5]=[C:4]([O:19][CH3:20])[N:3]=1.[CH:21](OC)(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:16][CH:21]=[N:18][N:17]=3)[N:9]=2)[CH:5]=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(Cl)n1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(Cl)n1

Procedure:
In a 100-mL, 3N round-bottomed flask equipped with Thermometer pocket fitted with nitrogen inlet, condenser and a rubber septum, (Z)-3-(3-(2-chloro-6-methoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.7 g, 1.0 eq.), trimethyl orthoformate (0.3 mL, 1.1 eq.) and methane sulfonic acid (0.07 mL, 0.5 eq) was dissolved in THF (70 mL) resulting reaction mixture was stir at reflux temperature. The progress of the reaction was followed by TLC analysis on silica gel with 80% EtOAc-hexane as mobile phase which shows that starting material was consumed after 3 h. Reaction was quenched by water, solid material was observed that was filter on Buchner funnel to give crude material (0.490 g). The crude material was subjected to combiflash purification using ethyl acetate:hexane as mobile phase; Yield: 0.03 g (4.14%); (Z)-2-(2-(3-(2-chloro-6-methoxypyridine-4-yl)-1H-1,2,4-triazol-1-yl)vinyl)-1,3,4-oxadiazole: 1H NMR: (400 MHz, DMSO) δ=9.45 (s, 1H), 9.36 (s, 1H), 7.737-7.762 (d, J=10 Hz, 1H), 7.48 (s, 1H), 7.24 (s, 1H), 6.719-6.745 (d, J=10.4 Hz, 1H), 3.92 (s, 3H). LC-MS: Calculated for C12H9ClN6O2 (M+H)+ 304.69 Found: 304.81 Retention time: 3.354 min (100%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH:35]N)=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]=[CH:26][CH:27]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=444.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:4][C:5]([NH:9]CC2C=CC(OC)=CC=2)=[C:6]([F:8])[CH:7]=1.FC(F)(F)C([O-])=O>>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([NH:19][CH:20]([CH3:22])[CH3:21])[N:4]=1
Reactant: COc1ccc(CNc2nc(NC(C)C)c(F)cc2F)cc1
Agent: O=C([O-])C(F)(F)F
Product: CC(C)Nc1nc(N)c(F)cc1F
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
To 1.9 g of 3,5-difluoro-2-isopropylamino-6-(p-methoxybenzylamino)pyridine was added 4 ml of trifluoroacetate, and the mixture was allowed to stand at room temperature for 15 minutes. The solution was concentrated under reduced pressure, and 25 ml of chloroform was added to the residue, and the solution was washed with 25 ml of 5% aqueous solution of sodium carbonate. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, 40 g; eluent:chloroform) to obtain 0.6 g of the title compound as a brown oil.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[C:15](OC([O-])=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(OCC)(=O)C>[C:18]([O:17][C:15]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Yield: 85.2 %

Procedure:
4-Piperidone monohydrate hydrochloride (5 g, 0.033 mol) was added to 50 mL distilled water and stirred until dissolved. To this solution was added solid sodium bicarbonate (3 g, 0.035 mol) followed by tert-butyl dicarbonate (7.2 g, 0.033 mol), and the resulting clear solution was stirred for 20 hours at room temperature. The slurry was treated with 100 mL of ethyl acetate and stirred until all solids dissolved. The layers were separated, and the organic layer was washed with 30 mL of 1N H3PO4 and 30 mL of 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5.6 g (86%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 3.75-3.68 (t, 4H), 2.47-2.40 (t, 4H), 1.5 (s, 9H). MS (DCl/NH3) m/e 200 (M+H)+, 217 (M+H+NH3)+.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:4]2[S:3][CH2:2]1.C[Al](C)C.C[O:19][C:20](=O)[NH:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([CH3:30])[N:23]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH3:30])[N:23]=[C:22]([NH:21][C:20]([NH:13][S:10]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[O:1][CH2:2][S:3][C:4]=23)(=[O:12])=[O:11])=[O:19])[N:27]=1
Reactant: NS(=O)(=O)c1cccc2c1SCO2
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SCO3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.2 g 1,3-benzoxathiole-4-sulfonamide, prepared in Example 13, in 50 ml methylene chloride at ambient temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature, 2.0 g of methyl[4-methoxy-6-methylpyrimidin-2-yl]carbamate, prepared according to the procedure of Example 3, is added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid, and 10 drops hydrochloric acid are sequentially added. The organic phase is separated, dried, and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from n-butyl chloride/ether gives a solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=2)[CH2:2]1.[C:22]1([C:28]2[O:32][C:31]([C:33](OCC)=[O:34])=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[O:32][C:31]([C:33]([N:1]3[CH2:4][CH:3]([O:5][C:6]4[CH:17]=[CH:16][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:7]=4)[CH2:2]3)=[O:34])=[N:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: FC(F)(F)c1cc(OC2CNC2)ccc1CN1CCCC1
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CCCC3)c(C(F)(F)F)c2)C1
Yield: 74.9 %

Procedure:
Using a similar protocol as described in Example 16 employing 45A (0.19 g, 0.65 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.15 g, 0.71 mmol) as starting materials afforded 230 mg (77%) of 45 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.81 (s, 4H), 2.55 (s, 4H), 3.74 (s, 2H), 4.35 (dd, 1H), 4.67 (dd, 1H), 4.78 (dd, 1H), 5.14 (m, 2H), 6.93 (d, 1H), 7.05 (d, 1H), 7.54 (t, 2H), 7.60 (t, 1H), 7.73 (d, 1H), 8.17 (d, 2H), MS (APCI+) m/z 473 [M+H]+, LC purity: 97%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCl>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:12][C:11]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Triethylamine (6.24 ml, 44.8 mmol) was added to a solution of 4-methoxy-3-(trifluoromethyl)aniline (4.29 g, 22.4 mmol) in dichloromethane (45.0 ml), and the resulting mixture was ice-cooled, followed by adding dropwise thereto pivaloyl chloride (2.84 g, 23.5 mmol) at 0 to 5° C. The resulting mixture was warmed up to room temperature and stirred for 1 hour while maintaining the temperature. The mixture was partitioned by the use of a 5%-aqueous sodium hydrogencarbonate solution and ethyl acetate, and the organic layer was washed with a 5% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain N-[4-methoxy-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (6.16 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.C(NC1SC[C@@H]2C[C@H](C(O)=O)OC[C@]2(C2C=CC(F)=CC=2F)N=1)(=[O:38])C1C=CC=CC=1>>[C:23]([NH:22][C:11]1[S:12][C@H:13]([CH3:21])[C@@H:14]2[CH2:15][C@H:16]([C:19]([OH:38])=[O:20])[O:17][CH2:18][C@:9]2([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(=O)O)C[C@H]2CS1)c1ccccc1
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(=O)O)C[C@@H]12

Procedure:
The product, obtained as a pink/white solid, was prepared from N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a, 5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P5) according to the procedure for the synthesis of (4aR,6R,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylic acid (P2) in Preparation 2. Yield: 2.92 g, 6.54 mmol, 95%. LCMS m/z 447.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.08-8.12 (m, 2H), 7.52-7.58 (m, 1H), 7.41-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.34 (dd, J=12.1, 2.7 Hz, 1H), 4.20 (br d, J=11.9 Hz, 1H), 3.98 (d, J=11.9 Hz, 1H), 3.18-3.26 (m, 1H), 3.06 (ddd, J=12.1, 3.9, 3.9 Hz, 1H), 2.15 (ddd, J=13.6, 4.0, 2.9 Hz, 1H), 1.71-1.83 (m, 1H), 1.27 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:4]=1[CH3:25].C[OH:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:27])[C:4]=1[CH3:25]
Reactant: CO
Reactant: COc1c(C)cnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Reaction time: 1 h

Procedure:
31.4 g of 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole are dissolved in 1.3 l of methylene chloride and 50 ml of methanol and then cooled to -20°. 16.9 g of m-chloroperbenzoic acid, recrystallized from a methyene chloride/petroleum ether, are then introduced within 10 minutes. The solution is stirred further at -20° for 60 minutes and then poured into a mixture of 120 ml of 2N sodium carbonate solution and ice. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. Crystallization from methylene chloride/methanol/petroleum ether gives 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphinyl]-5-(trifluoromethyl)benzimidazole of melting point 152°-154°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:18]=1[OH:19])[C:8](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: NNC(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(=NNC(N)=O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
1.60 g of 3,5-di-t-butyl-4-hydroxybenzophenone and 0.67 g of semicarbazide hydrochloride were dissolved in 12 ml of pyridine, and the solution was refluxed for 6 hours. After the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed with 5% hydrochloric acid and water and dried. The solvent was removed by concentration, and the residue was chromatographed on a silica gel column and recrystallized from diethyl ether to give 3,5-di-t-butyl-4-hydroxybenzophenone semicarbazone.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(CC4OCCO4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(1,3-dioxolan-2-ylmethyl)benzoic acid (1.0 g, 4.80 mmol) in pyridine (5 mL) and N,N-dimethylformamide (5 mL) was treated with 1,1′-carbonyldiimidazole (0.856 g, 5.28 mmol) at 45° C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.08 g, 4.80 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue heated in acetic acid (30 mL) at 80° C. for 3 hours. After cooling, the mixture was concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. After filtering, the filtrate was concentrated and the residue purified by flash chromatography on silica gel (0-15% methanol in 2:1 ethyl acetate/hexane) to give 1.14 g of the title compound. MS (DCI) m/z 324 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([OH:15])[CH2:6][O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.[CH3:23][S:24]([CH2:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:3][CH2:4][CH:5]([OH:15])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:29](=[O:30])[CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOCC(O)COc1ccc(N)cc1
Reactant: CS(=O)(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(O)COc1ccc(NC(=O)CCS(C)(=O)=O)cc1
Yield: 94.2 %

Procedure:
A 2.11 g quantity of 4-(3-ethoxy-2-hydroxypropoxy)aniline and 1.53 g of triethylamine were dissolved in 50 ml of dichloromethane. To the solution was added 1.71 g of 3-(methylsulfonyl)propionyl chloride with ice cooling. The same subsequent procedure as in Example 2 was repeated and recrystallization from benzene was performed, giving 3.25 g of N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-(methylsulfonyl)propionamide in a yield of 94.2 %. M.p. 111° to 112° C.