Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([NH:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CCc1csc(Nc2ncccc2OCc2ccccc2)n1)NCCN1CCCC1
Temperature: 0 °C

Procedure:
3-(2-(3-(Benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoic acid (40 mg, 0.113 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.0171 mL, 0.135 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (22.4 mg, 0.146 mmol) and 4-methylmorpholine (0.0173 ml, 0.158 mmol) were placed in an 8.5 mL screw-cap vial. The reaction mixture was cooled to 0° C. in an ice bath, and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (33.0 mg, 0.172 mmol) was added as a solid. The mixture was stirred at 0° C. and then allowed to warm to room temp overnight. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was partitioned between dichloromethane and saturated aqueous NaHCO3 diluted with an equal part of water. The organic phase was washed with once with water, then with brine, and dried by passing through a plug of anhydrous sodium sulfate. The solution was concentrated in vacuo and dried under high vacuum to provide the title compound as a colorless oil. 1H NMR (CDCl3) δ 1.76 (s, 4H), 2.56 (m, 4H), 2.59 (dd, J=5.6, 12.9 Hz, 4H), 3.01-2.94 (m, 4H), 3.37 (dd, J=11.3, 5.5 Hz, 2H), 5.13 (s, 2H), 6.75 (bs, 1H), 6.47 (s, 1H), 6.82 (dd, J=8.2, 5.1 Hz, 2H), 7.10 (dd, J=1.2, 7.9, Hz, 1H), 7.42 (br s, 4H), 7.94 (dd, J=1.2, 5 Hz, 1H), 8.59 (bs, 1H); Mass spectrum (apci) m/z=452.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccccc2)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-iodoethyl)piperidine (339 mg, 1.0 mmol) and phenol (188 mg, 1.0 mmol) in DMF (5 mL) was added anhydrous K2CO3 (828 mg, 6.0 mmol) at room temperature under Ar protection. After stirring overnight, the reaction mixture was poured into 2N aqueous NaOH. The mixture was extracted three times with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. After evaporation, the residue was purified by CC (SiO2, hexane/EtOAc 8:1, then 4:1) to afford 1-(tert-butoxycarbonyl)-4-(2-phenoxyethyl)piperidine (220 mg, 72%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.27 (t, 2H, J=7.6 Hz), 6.95-6.88 (m, 3H), 4.10 (m, 2H), 3.99 (t, 2H, J=6.0 Hz), 2.70 (m, 2H), 1.72-1.63 (m, 5H), 1.47 (s, 9H), 1.23-1.15 (m, 2H). 13 C NMR (CDCl3, 100 MHz) δ 158.5, 154.4, 129.0, 120.2, 144.0, 78.8, 64.8, 43.5, 35.4, 32.6, 31.7, 28.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCSCc1cc[nH]n1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1cc[nH]n1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]pyrazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-pyrazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-pyrazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH:10]=O)[CH:4]=1.C[O-].[Na+].CO.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]2[C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[CH:30]=[CH:29][C:28]2=[O:39])[CH2:21][CH2:20]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31]([CH:30]=[CH:29][C:28](=[O:39])[N:27]2[CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][CH:19]([NH:18][CH2:10][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=3)[CH2:24][CH2:23]2)=[N:32][CH:33]=1
Reactant: COc1cc(C=O)ncc1C
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc(OC)c(C)cn4)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
To a solution of 71 mg of 4-methoxy-5-methylpyridine-2-carbaldehyde in 2 mL of methanol, 0.27 g of a 28% sodium methoxide/methanol solution, 0.19 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride and 27 μL of acetic acid were added. Then, 59 mg of sodium cyanoborohydride was added thereto and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=19:1 to 86:14 to obtain 0.13 g of 7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(N)c3)c2cc1OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3cccc(N=[N+]=[N-])c3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
Dissolved 643 mg (2.00 mmol) 4-(3-amino-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile in 25 ml 80% acetic acid in water. Chilled to 0° C. and added 152 mg (2.21 mmol) sodium nitrite in 2.2 ml water. After 10 minutes, added 144 mg (2.21 mmol) sodium azide in 2.2 ml water. At 1.5 hours stripped solvent and dissolved residue in hot ethyl acetate. Washed with saturated sodium bicarbonate, water and brine and dried with sodium sulfate. Stripped solvent and redissolved in 60% ethyl acetate/methylene chloride and filtered through a pad of silica gel. Stripped solvent and dried in vacuo, giving 526 mg of brown solid: mass spectrum (electrospray m/e): M+H=347.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:26])[CH:21]=[C:22]([S:24][CH3:25])[CH:23]=1)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:21]2[N:20]([CH3:26])[C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:23][C:22]=2[S:24][CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(SC)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(SC)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
p-Chlorobenzoyl chloride (2.75 ml, 20 mmol), dissolved 20 ml of methylene chloride and 2.6 g (20 mmol) of aluminum chloride are mixed well at room temperature. After about 5 minutes 1.87 g (10 mmole) of 2-methoxycarbonyl-4-methylthio-1-methylpyrrole is added dropwise. The reaction mixture turns immediately into a dark red colored solution. The reaction is stirred for one hour before it is diluted with 75 ml of methylene chloride and extracted with water. The methylene chloride layer is separated, washed sucessively with 25 ml sodium bicarbonate solution and 50 ml of saturated brine, dried over anhydrous sodium sulfate and concentrated to an oil. The oil is crystallized from ethanol to give 1.0 g of 5-(p-chlorobenzoyl)-2-methoxycarbonyl-4-methylthio-1-methylpyrrole.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=1[CH2:17][CH:18]([CH3:20])[CH3:19])(=O)=O.[CH2:23]([C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.CCO.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>[CH2:17]([C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][C:15]#[N:16])[CH:11]=[CH:12][C:7]=1[C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH:28]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CC(C)C
Reactant: CC(C)Cc1cc(CCC#N)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1CC(C)C
Temperature: 80 °C
Yield: 100 %

Procedure:
294.8 mg (0.88 mmol) 4-(2-Cyanoethyl)-2-isobutylphenyl-trifluormethanesulfonate (6), 312.9 mg (1.08 mmol, 1.23 eq.) 2-(3-Isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11) and 156 mg (135 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 20 ml DME/EtOH (9+1). To this yellow solution 0.88 ml (1.76 mmol, 2.00 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 17 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Colunm chromatography (CH2Cl2) yielded 305.9 mg (0.88 mmol, 99.45%) 3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) as a clear oil. Rf (CH2Cl2)=0.68. 1H-NMR (500 MHz, CDCl3): δ=0.67 (d, 6H, J=6.62 Hz, 2*CH3), 0.85 (d, 6H, J=6.62 Hz, CH2), 2.59 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.91 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.79 (s, 3H, OCH3), 6.80 (d, 1H, J=8.36 Hz), 6.94 (d, 1H, J=2.21 Hz), 6.98-7.04 (m, 3H), 7.09 (d, 1H, J=7.57 Hz). MS (EI): m/z=350 (23), 349 (90), 307 (10), 306 (35), 290 (39), 250 (15), 248 (17), 247 (100), 246 (24), 209 (21), 191 (16), 178 (10), 174 (10), 147 (10), 145 (17), 144 (19), 117 (13), 105 (25), 83 (11), 57 (18). HR-MS (EI): Calcd. for C24H31NO: 349.240564. Found: 349.240765.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[CH:18]2)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28]I>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[CH3:28])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Reactant: CI
Product: Cc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 5 from 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-4-phenyl-1H-imidazole and methyl iodide. MS (ESI) m/z 393 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.[NH3:14]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH2:14])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(N)cnc1OC
Reactant: N
Solvent: CO
Product: COc1ncc(N)nc1C(N)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 70 mL of methanol is dissolved 3.50 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate. Gaseous ammonia is introduced to saturate the solution with ammonia. The solution is stirred at ambient temperature for 14 hours. The solvent is distilled off from the reaction mixture under reduced pressure to obtain 3.1 g of 6-amino-3-methoxy-2-pyrazinecarboxamide.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].ClC(O[CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=O.N1C=CC=CC=1>O1CCCC1>[C:1]([O:6][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)C(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of 3.3 g (37.5 mmole) of pyruvic acid and 7.9 g (37.5 mmole) of trichloroethyl chloroformate in 20 ml of dry tetrahydrofuran at 0° is added dropwise 0.6 ml of pyridine. After stirring for 2 hours at room temperature, the mixture is concentrated in vacuum, diluted with water and extracted with ethyl acetate. The extract is washed with 5% HCl, dried over MgSO4, evaporated and distilled in vacuum to give 4.0 g (50%) trichloroethyl pyruvate, bp 75°-82° (17 mm).
Reaction SMILES: C[Li].[CH2:3]([Mg]Br)[CH2:4][CH2:5][CH:6]=[CH2:7].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24]I)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)#[N:11].[Cl-].[NH4+]>CCCCCC.O1CCCC1.[Cu]I>[CH2:24]([C@H:21]1[CH2:22][CH2:23][C@H:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CI)CC2)cc1
Reactant: C=CCCC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 705 mg of dry copper-(I) iodide and 7 ml of tetrahydrofuran was treated dropwise with 2.5 ml of a 1.5M solution of methyl lithium in hexane at -78° C. while stirring vigorously and then warmed slowly to 0° C. Subsequently, the mixture was again cooled to -78° C. and treated dropwise by means of a syringe with a 4-pentenyl-magnesium bromide solution (prepared from 90 mg of magnesium and 0.44 ml of 5-bromo-1-pentene in 2 ml of tetrahydrofuran). The reaction mixture was warmed gradually until a red-violet suspension had formed and was then held at 5° C. for 20 minutes. Thereafter, the reaction mixture was again cooled to -78° C., treated dropwise with a solution of 600 mg of trans-4-(p-cyanophenyl)-iodomethylcyclohexane in 5 ml of tetrahydrofuran and then warmed slowly to room temperature. The reaction mixture was stirred at room temperature for a further 30 minutes and then treated with saturated ammonium chloride solution and extracted with diethyl ether. The organic phases were dried over magnesium sulphate and concentrated. Chromatographic separation on silica gel with ethyl acetate/petroleum ether (vol. 5:95) and two-fold recrystallization from methanol gave 165 mg of p-[trans-4-(5-hexenyl)cyclohexyl]benzonitrile (purity 99.75%) as colourless crystals of m.p. (C-N) 45.5° C. and cl.p. (N-I) 52.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([Cl:26])=[N:10][C:11]([Cl:25])=[C:12]([C:16]=1[NH:17]C(OC(C)(C)C)=O)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:16]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:25])[N:10]=[C:9]([Cl:26])[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1c(C(=O)O)c(Cl)nc(Cl)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)c1c(Cl)nc(Cl)c(C(=O)O)c1N

Procedure:
In scheme (V), 5-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)-2,6-dichloronicotinic acid (4) is first treated with 25% trifluoracetic acid (TFA) in dichloromethane (DCM) at room temperature (25° C.) for 2 hours, removing one of the two Boc groups and forming 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5). A stronger condition (reflux at 60° C., 25% TFA in DCM, 2 h) is then used to maximize hydrolysis of the tert-butyl ester of 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5) and obtain 4-amino-2,6-dichloropyridine-3,5-dicarboxylic acid (6).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C(OCC)(=O)C>O.O1CCOCC1>[C:17]([O:16][C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-aminobenzoic acid (5 g, 36.5 mmol) in water (40.0 ml) was added aq. solution of sodium hydroxide (2.187 g, 54.7 mmol) followed by (BOC)2O (10.16 ml, 43.8 mmol) in dioxane (20.0 ml) under ice cooling. The mixture was stirred under ice cooling for 30 min and further at room temperature for 12 hrs. To the reaction mixture ethyl acetate (50.0 ml) was added and the aq. layer was separated. The aq. layer was acidified up to pH 4 using 2N HCl and precipitated crystals were collected by filtration (7.2 gm).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([C:10](OC)=[O:11])[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9]1
Reactant: COC(=O)C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of methyl 1-[2,4-bis(trifluoromethyl)benzyl]azetidine-3-carboxylate (341 mg) in THF (5 mL) was added a suspension of lithium aluminum hydride (38 mg) in THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution under ice-cooling. The precipitate was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (180 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Reactant: ClCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(OCc3ccccc3)nc2-c2ccc(F)cc2)cc1

Procedure:
6-(4-Fluorophenyl)-1,2-dihydro-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 6) (200 mg, 0.54 mMol), silver carbonate (150 mg, 0.54 mMol) and benzyl chloride (1 ml) were stirred in acetone (100 ml) and dimethylformamide (25 ml) at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to a white solid which was recrystallized from chloroform-methanol: m.p. (DSC): 204.81° C. Anal. Calc'd. for C26H19N2O3SF (458.52): C, 68.11; H, 4.18; N, 6.11. Found: C, 67.81; H, 4.16; N, 6.04.
Reaction SMILES: Cl.[NH4+].[Cl-].[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[C@:15]12[CH2:23][O:22][C@H:21]([CH2:24][F:25])[C@H:20]1[CH2:19][S:18][C:17]([NH2:26])=[N:16]2.[OH-].[Na+]>C(O)C.[Fe]>[NH2:12][C:8]1[CH:9]=[C:10]([F:11])[C:5]([F:4])=[C:6]([C@:15]23[CH2:23][O:22][C@H:21]([CH2:24][F:25])[C@H:20]2[CH2:19][S:18][C:17]([NH2:26])=[N:16]3)[CH:7]=1
Reactant: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To iron (8.03 g, 0.144 mol, 6.0 equiv.) was added ethanol (66.56 mL), followed by conc. HCl (62%, 1.2 mL, 0.014 mol, 0.60 equiv.). The mixture was heated to 65° C. for 2 h, and then sat NH4Cl (33%, 33.3 mL) was added and the reaction temperature was maintained at 55° C. A solution of (4aS,5S,7aS)-7a-(2,3-difluoro-5-nitrophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (8.32 g, 0.024 mol, 1.0 equiv.) and conc. HCl (1.93 mL, 0.024 mol, 1.0 equiv.) in ethanol (41.6 mL) was added to the iron suspension. The reaction was stirred for 30 min at 55° C., then ethanol (50 mL) was added and the suspension was allowed to cool down to 20° C., filtered through celite (8.3 g) and rinsed with ethanol (125 mL). The filtrate was concentrated under reduced pressure then water (66 mL) was added, followed by 3.0 M aq.NaOH (24 mL, 0.0179 mol, 3.0 equiv.). The resulting mixture was extracted with CH2Cl2 (2×83 mL). The organics phases were combined and filtered over celite and concentrated under reduce pressure to give the title compound (7.60 g). 1H NMR (500 MHz, DMSO) δ ppm 6.42-6.35 (m, 2H), 6.02 (brs, 2H), 4.66-4.41 (m, 2H), 4.37-4.25 (m, 1H), 4.21 (d, J=8.0 Hz, 1H), 3.69 (dd, J=7.8, 2.2 Hz, 1H), 2.97 (qd, J=13.5, 3.4 Hz, 3H), 2.74-2.64 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 151.08 (dd, JCF=240.1, 14.8 Hz), 148.88, 145.40 (d, JCF=10.7 Hz), 139.33 (dd, JCF=233.5, 13.8 Hz), 132.53 (d, JCF=8.1 Hz), 109.90, 100.70 (d, JCF=20.0 Hz), 83.99 (d, JCF=169.9 Hz), 78.79 (d, JCF=18.3 Hz), 77.99 (d, JCF=5.5 Hz), 66.22, 36.24, 23.14.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11](OC)=[O:12])[CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][OH:12])[CH2:6]1
Reactant: COCO[C@@H]1CCC[C@H](C(=O)OC)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCO[C@@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
9.0 g of methyl cis-3-methoxymethoxycyclohexanecarboxylate are dissolved in 280 ml of diethyl ether, 2.2 g of LiAlH4 are added and the mixture is stirred at room temperature. After 4 h, at 0° C., 10 ml of ethyl acetate and then 15 ml of 10N NaOH are added dropwise. The suspension is stirred for 1 h, MgSO4 is added, the mixture is filtered through Celite and the filtrate is concentrated, giving 7.0 g of (cis-3-methoxymethoxycyclo-hexyl)methanol as a colorless oil. C9H18O3 (174), MS(ESI): 175 (MH+).