Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][NH+:5]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:23][C:17]=2[N:16]=1>C(O)C.O.[OH-].[Na+]>[CH3:11][O:10][C:9]1[C:4]([CH2:3][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:23][C:17]=3[N:16]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:12][CH3:13]
Reactant: FC(F)C(F)(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: COc1cc[nH+]c(CCl)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.38 g (1.7 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium chloride is added to a solution of 0.46 g (1.7 mmol) of 2-mercapto-5-(1,1,2,2-tetra fluoroethoxy)-1H-benzimidazole in 10 ml of ethanol, 10 ml of water and 1.8 ml of 2N sodium hydroxide solution; after the mixture has been stirred at 20° C. for one hour, a further 10 ml of water are added dropwise. The mixture is then stirred at 20° C. for a further four hours. The solid which has precipitated out is filtered off, washed with 0.01N sodium hydroxide solution and then with water until neutral and dried to constant weight. 0.63 g (90% of theory) of the title compound is obtained as a colorless crystalline powder of m.p. 98°-102° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([NH2:21])=[NH:20])[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([CH2:25][C:26](=O)[CH3:27])(=O)[CH3:23]>>[CH2:2]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[N:21]=[C:26]([CH3:27])[CH:25]=[C:22]([CH3:23])[N:20]=2)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CC(C)=O
Reactant: N=C(N)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Product: Cc1cc(C)nc([C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)n1

Procedure:
Using trans-4-(benzyloxycarbonylamino)-1-cyclohexanecarboxamidine-hydrochloride (a compound of Reference Example 8-35 (5)) (348 mg) as a starting material, by reacting the same with acetylacetone according to the method of Libman et al. (J. Chem. Soc., p. 2305, 1952), trans-1-benzyloxycarbonylamino-4-(4,6-dimethylpyrimidin-2-yl)cyclohexane (220 mg) was obtained. By treating this compound (205 mg) with trimethylsilyl iodide in the same manner as in Reference Example 8-35 (7), trans-4-(4,6-dimethylpyrimidin-2-yl)cyclohexylamine (Reference Example 8-36 in Table 9) (129 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([C:20](=O)[CH3:21])=[C:16](Cl)[N:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][NH2:26]>CC(O)C.O>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[NH:25][N:26]=[C:20]([CH3:21])[C:17]3=[N:18][CH:19]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ncc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc1Cl
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Cc1n[nH]c2nc(-c3ccc(NC(=O)OC(C)(C)C)cc3)cnc12
Temperature: 120 °C

Procedure:
[4-(5-Acetyl-6-chloro-pyrazin-2-yl)-phenyl]-carbamic acid tert-butyl ester (2.18 g) was suspended in a mixture of 21 ml iPrOH and 21 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by trituration in boiling EtOAc and subsequent filtration afforded [4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acid tert-butyl ester as a yellow solid. Yield: 1.42 g (70%).
Reaction SMILES: [CH2:1]([N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:19][O:20][C:21]([O:35][CH3:36])([C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(N(CCOC1C=CC(CCC(OC)=O)=CC=1)C)CCCCCCCCCCC>>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][CH2:17][O:18][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][C:21]([O:20][CH3:19])([O:35][CH3:36])[C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=1)[CH3:15]
Reactant: CCCCCCCCCCCCN(CC)CCO
Reactant: COC(CCc1ccc(O)cc1)(OC)C(F)(F)F
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Product: CCCCCCCCCCCCN(CC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Yield: 45.6 %

Procedure:
2-[N-Dodecyl-N-ethylamino]ethanol (250 mg, 0.96 mmol) and 4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenol (230 mg, 0.87 mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The usual work-up followed by chromatography on silica gel (Hexane/ethyl acetate 95:5 to 80:20) afforded the title compound (200 mg, 46%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=[O:17])[CH2:14][CH2:15][S:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.BrC1C=CC=CC=1.[Mg].[Cl-].[NH4+]>C(OCC)C>[OH:17][C:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]2[CH:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[S:16][CH2:15][CH2:14]1
Reactant: O=C1CCSC2CN(Cc3ccccc3)CC12
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: OC1(c2ccccc2)CCSC2CN(Cc3ccccc3)CC21
Reaction time: 3 h

Procedure:
A solution of 21.15 g of (4aRS,7aSR)6-benzyl-4-oxoperhydrothiopyrano[2,3-c]pyrrole in 150 cm3 of anhydrous ethyl ether are added over 30 minutes to a solution of phenylmagnesium bromide prepared from 19.8 cm3 of bromobenzene and 4.52 g of dry magnesium in 120 cm3 of anhydrous ethyl ether. The reaction mixture is stirred at the reflux temperature for 3 hours, and then for 20 hours at 20° C. The mixture, to which 200 cm3 of ethyl ether has been added, is stirred with 600 cm3 of a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted with 200 cm3 of ethyl ether, the two pooled etherial extracts are washed twice with 300 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.4 kPa) at 35° C. 12.2 g of (4RS,4aSR,7aRS)-4-hydroxy-4-phenyl6-benzylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 137° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1)=O.[NH4+].[Cl-].CC(C)=O>CCO.C(Cl)Cl>[OH:2][CH2:3][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1
Reactant: CC[C@@H](C(N)=O)N1CC(C(=O)OC)CC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 2 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, a solution of 133 g (583 mmoles, 1 eq) of (2S)-2-(4-methoxycarbonyl-2-oxo-1-pyrrolidinyl)butanamide 11 in 200 ml of EtOH is added to 300 ml of EtOH, and the mixture cooled down to 0° C. 66.2 g (1.74 mole, 12 eq) of solid NaBbe are then added by portions over 1.5 hour, all the while maintaining the temperature between 2 and 4° C. After 2 hours, the temperature is raised to 12° C. for 1 hour, and lowered again to 24° C. 240 ml of a saturated solution of NH4Cl are added dropwise over 1 hour, followed by 120 ml of acetone, and the mixture is left overnight at room temperature. The mixture is filtered, the precipitate washed with 3×70 ml of EtOH and the combined organic fractions concentrated to dryness to give 148 g of crude 6. It is suspended in 300 ml of CH2Cl2 and stirred for 30 min, filtered, washed with 2×100 ml of CH2Cl2 and dried to give 114 g of pure 6, 98%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1.IC.[C:22](=O)(O)[O-].[Na+]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.ClCCl.C(O)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:19])[CH:12]([C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1)[CH3:22]
Reactant: O=C([O-])O
Reactant: O=C(Cc1cnccn1)c1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C(=O)c1ccc(F)cc1F)c1cnccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of sodium hydroxide (1.98 g) in water (40 ml) was added dropwise to a stirred, ice-cooled solution of the product of part (i) (5.80 g), iodomethane (8.79 g) and tetra-n-butylammonium hydrogen sulphate (8.40 g) in chloroform (40 ml). The mixture was stirred vigorously at room temperature for 3 hours and then diluted with water and dichloromethane. Acetic acid (3 ml) was added and the pH of the aqueous layer was adjusted to 7 with sodium bicarbonate. The organic layer was separated, washed twice with water and dried (Na2SO4). Evaporation of the solvent gave the crude product as an oil (5.57 g) which was used without further purification (the presence of 10% of the starting material [the product of part (i)] was indicated by N.M.R. spectroscopy).
Reaction SMILES: C(OC(NC1C(=O)N2C(C)(C(O)=O)CCC2=NC=1)=O)C1C=CC=CC=1.C([O:30][C:31]([C:33]1([CH2:54][CH3:55])[N:37]2[C:38](=[O:53])[C:39]([NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:40][N:41]=[C:36]2[CH2:35][CH2:34]1)=[O:32])(C)(C)C>>[CH2:46]([O:45][C:43]([NH:42][C:39]1[C:38](=[O:53])[N:37]2[C:33]([CH2:54][CH3:55])([C:31]([OH:32])=[O:30])[CH2:34][CH2:35][C:36]2=[N:41][CH:40]=1)=[O:44])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: CC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: CCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 0 %

Procedure:
According to the procedure for the preparation of intermediate 19b, intermediate 22a (41 mg, 413.47 mmol) was deprotected to afford 35 mg (99%) of intermediate 22b. MS (ESI) 358.3 (M+H+), 356.2 (M−H+).
Reaction SMILES: C(OC(OCC)[C@@H](OC)CN=[N+]=[N-])C.[N:15]([CH2:18][C@H:19]([O:28][CH3:29])[C@H:20]([OH:27])[C@H:21]([OH:26])[C:22](=[O:25])[CH2:23][OH:24])=[N+:16]=[N-:17]>>[N:15]([CH2:18][C@H:19]([O:28][CH3:29])[C@@H:20]([OH:27])[C@@H:21]([OH:26])[C:22](=[O:25])[CH2:23][OH:24])=[N+:16]=[N-:17]
Reactant: CO[C@@H](CN=[N+]=[N-])[C@H](O)[C@H](O)C(=O)CO
Agent: CCOC(OCC)[C@H](CN=[N+]=[N-])OC
Product: CO[C@@H](CN=[N+]=[N-])[C@@H](O)[C@@H](O)C(=O)CO
Yield: 38 %

Procedure:
A solution of 3-azido-2(S)-methoxy-propanal diethyl acetal 25 (832 mg, 4.1 mmol) prepared in the same way as above as for compound 26 from the S-enatiomer was treated in the same manner as described for the R enantiomer. In this case rhamnulose-1-phosphate aldolase was added (0.5 mL, 80 units) and after usual monitoring and work-up, 380 mg (38%) of (3R,4S,5S)-6-azido-5-methoxy-1,3,4-trihydroxyhexan-2-one 27 were obtained. The NMR data were identical to those of 26.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:25](Br)[CH:26]([CH3:28])[CH3:27]>O>[CH3:25][CH:26]([CH3:28])[CH2:27][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydride (21 gram, 0.482 mole) was added to 200 ml dimethylformamide at 20° C. under nitrogen atmosphere. Then 80 grams (0.325 mole) of triethyl ethane-1,1,2-tricarboxylate (compound [3] made in example I) was added to the solution at a temperature of below 30° C. The reaction mixture was maintained at room temperature for 4 hours and 52 ml (0.482 mole) of isobutyl bromide (R2-X) was added drop wise after which the reaction mixture was stirred for another 20 hours at room temperature. When the reaction was complete 1 liter of cold water was added and the organic materials were extracted with dichloromethane (500 ml). The organic extracts were dried over sodium sulfate filtered and evaporated to give an oily substance, which was vacuum distilled to give 88 gram (89% of the theoretical maximum yield) triethyl 4-methylpentane-1,2,2-tricarboxylate, compound [4].
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]6[S:42][CH:43]=[CH:44][CH:45]=6)[CH:33]=5)=[N:25][N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[CH:11][CH:12]=2)[CH2:7]1)=O.[Li+].[OH-]>CO>[NH2:5][CH:6]1[CH2:7][C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]6[S:42][CH:43]=[CH:44][CH:45]=6)[CH:35]=[CH:36][CH:37]=5)=[N:25][N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15]1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)CC4)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 97.2 %

Procedure:
The title compound was prepared by treating 2,2,2-trifluoro-N-(7-{[4-(2-{3-[(2-thienylacetyl)amino]phenyl}pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide (60 mg, 0.09 mmol) with LiOH in MeOH as described in Example 54, Step D. Purification yielded 50 mg (51%) of the desired amine. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.34 (s, 1H), 8.80 (d, J=6.8 Hz, 1H), 8.46 (d, J=8.8 Hz, 1H), 8.18 (d, J=5.4 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.48-7.34 (m, 4H), 7.24 (d, J=7.6 Hz, 1H), 7.09 (t, J=6.7 Hz, 1H), 6.95-6.89 (m, 3H), 6.41 (d, J=5.2 Hz, 1H), 3.85 (s, 2H), 2.96 (m, 1H), 2.79-2.60 (m, 3H), 2.41-2.31 (m, 1H), 1.90-1.74 (m, 3H), 1.46-1.33 (m, 1H). ES-LC/MS m/z=572 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]([C:15]1[O:16][C:17]([CH3:20])=[CH:18][N:19]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]([CH3:14])([C:15]1[O:16][C:17]([CH3:20])=[CH:18][N:19]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1ncc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1ncc(C)o1)C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To NaH (60%, 0.085 g, 2.1 mmol) in 5 mL of DMF at 0° C. was added dropwise malononitrile (0.141 g, 2.13 mmol) in 3 mL of DMF. After stirring at room temperature for 15 minutes, the intermediate from Step C in 5 mL of DMF was added. After stirring overnight the reaction mixture was quenched with saturated aqueous NH4Cl. The solution was extracted with EtOAc, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (a pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 6.82 (1H, s), 4.86 (1H, s), 3.87 (3H, s), 2.38 (3H, s), 2.05 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][S:12][C:13]#[N:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:16].[OH-].[Na+].O>C(O)(=O)C>[Br:16][C:13]1[S:12][CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]=1
Reactant: N#CSCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2csc(Br)n2)cc1
Yield: 45 %

Procedure:
2-(4-Nitrophenyl)-2-oxoethyl thiocyanate (3.0 g; 15.4 mmol) and 50 mL of 30% HBr in acetic acid were stirred at room temperature under nitrogen overnight. The yellow paste was neutralized with 60 mL of 2N NaOH and 60 mL of H2O. The residue was collected by suction filtration. Purification of the residue on silica gel using a stepwise gradient of 5-50% ethyl acetate:hexane gave 2-bromo-4-(4-nitrophenyl)-1,3-thiazole (2.0 g, 45%), MS (ES) m/z 286[M+H]+.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.CCOC(C)=O.O.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:22]([C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)c2ccc(I)cc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)CCC2=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
To a solution of 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.3 g, 1.0 mmol) in DMF (5 mL) was added Zn(CN)2 (0.12 g, 1.0 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol). The reaction mixture was allowed to stir at 80° C. for 3.5 h. After being allowed to cool to rt, EtOAc (20 mL) and H2O (20 mL) were added, the organic solution was separated, and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, washed with H2O and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to provide 8-cyano-3,4-dihydro-1H-1-benzazepine-2,5-dione (140 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:36].[K+].[K+].O>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]4[CH:28]=[CH:27][C:24]([C:25]([NH2:26])=[O:36])=[CH:23][N:22]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 159.6 %

Procedure:
To a solution of 6-((S)-3-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidin-1-yl)nicotinonitrile (520 mg, 1.19 mmol) in DMSO (10 mL) was added H2O2 (30%, 1 mL) and K2CO3 (82 mg, 0.59 mmol). The mixture was stirred at rt for 1 d. After water and EtOAc were added, the mixture was extracted with EtOAc. The organic layers were dried and concentrated to give 6-((S)-3-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidin-1-yl)nicotinamide (430 mg, 79%). LC-MS Method 2 tR=0.99 min, m/z=457. 1H NMR (400 MHz, CDCl3): 1.29-1.30 (m, 1H), 1.58-1.63 (m, 2H), 1.82-1.86 (m, 2H), 1.91-2.00 (m, 3H), 2.21-2.32 (m, 1H), 2.49-2.52 (m, 1H), 2.65-2.71 (m, 1H), 2.81-2.96 (m, 3H), 3.39 (m, 1H), 3.42-4.48 (m, 2H), 3.87(m, 1H), 4.21-4.24 (m, 1H), 4.30 (s, 1H), 6.75-6.78 (d, 1H), 7.39-7.72 (t, 2H), 7.94-7.97 (m,1H), 8.59-8.60 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH3:9]>C1COCC1>[CH2:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](=[O:15])[S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)Sc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Following the general procedure,18 a solution of 2-mercaptopyridine (11.1 g, 100 mmol) in THF (100 mL) was treated with 4-ethylbenzoylchloride (16.9 g, 100 mmol). The resulting slurry was stirred for 30 min. The precipitate was collected by filtration and washed with hexanes (150 mL) in a Buchner funnel. The filtered material was added into a biphasic solution of saturated aqueous NaHCO3 (100 mL) and diethyl ether (100 mL). The mixture was stirred until the foaming subsided. The organic layer was removed and the water layer was extracted with diethyl ether. The combined organic extract was dried (Na2SO4), and filtered. The filtrate was concentrated to afford pale yellow solid. The solid was washed with hexanes (˜20 mL) to afford a pale yellow solid (20.9 g, 86%): mp 48-50° C.; 1H NMR δ 1.27 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 7.31-7.35 (m, 3H), 7.72-7.74 (m, 1H), 7.77-7.81 (m, 1H), 7.94-7.96 (m, 2H), 8.67-8.69 (m, 1H); 13C NMR δ 15.3, 29.1, 123.7, 127.9, 128.5, 131.0, 134.3, 137.3, 150.5, 151.2, 151.6, 189.0; FAB-MS obsd 244.0812, calcd 244.0796 [(M+H)+, M=C14H13NOS]. Anal. Calcd for C14H13NOS: C, 69.10; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.38; N, 5.70.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].CO[C:21](OC)(OC)[CH2:22][Cl:23]>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:21]([CH2:22][Cl:23])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: COC(CCl)(OC)OC
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Product: CCCC(CCC)NC(=O)c1ccc2oc(CCl)nc2c1
Yield: 65 %

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and trimethyl chloro-orthoacetate. Yield: 65%. mp 108.5-109° C. MS (M+H, 309.05).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.I[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:12][CH2:11][CH2:10][N:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]1=[O:8]
Reactant: OCCI
Reactant: O=c1cc(I)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(I)ccn1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To the mixture of 4-iodopyridin-2(1H)-one (50 mg, 0.213 mmol) in DMF (3 mL) was added 2-iodoethanol (73 mg, 0.426 mmol), K2CO3 (88 mg, 0.638 mmol) at rt. The mixture was stirred for 2 h at rt. After the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by TLC to provide 1-(2-hydroxyethyl)-4-iodopyridin-2(1H)-one (60 mg 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:16](Cl)(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([NH:24][S:16]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1)(=[O:18])=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1NS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 34.3 %

Procedure:
3-Methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) was added to tetrahydrofuran (40 ml) containing t-butylamine (0.65 g), and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated and extracted with chloroform. The extract was washed with 5% hydrochloric acid and water in order, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from benzene and then from toluene to give 0.57 g of N-t-butyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 16). M.P., 139.5°-140.5° C.