Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH3:15])(=O)=O>CN(C)C=O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:14]([CH3:15])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 6 h
Yield: 58 %

Procedure:
To a stirred mixture of 14 parts of 1H-1,2,4-triazole and 225 parts of N,N-dimethylformamide are added 6.2 parts of a sodium hydride dispersion 78%. When foaming has ceased, there are added 19.5 parts of 2-(2,4-dichlorophenyl)propyl methanesulfonate and stirring is continued for 6 hours at reflux. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from petroleumether. The product is filtered off and dried, yielding 10.2 parts (58%) of 1-[2-(2,4-dichlorophenyl)propyl]-1H-1,2,4-triazole; mp. 79.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[C:9]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:8][CH:7]=1)=[O:4].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+:32].[Na+]>O.[Fe]>[CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:8][CH:7]=1)=[O:4].[Na+:32]
Reactant: COC(=O)Cc1ccc(S(=O)(=O)O)c2c([N+](=O)[O-])cccc12
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccc(S(=O)(=O)[O-])c2c(N)cccc12
Temperature: 25 °C

Procedure:
1-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid (2 g, 6.15 mmol) was dissolved in water (20 mL), containing 0.5 mL concentrated sulfuric acid, and was added dropwise over 5 minutes to a refluxing suspension of iron (4 g, 71.6 mmol) in water (100 mL). After refluxing for one hour, the dark mixture was cooled to room temperature, made basic with sodium carbonate, and concentrated to approximately 30 mL. The residual mixture was placed on a CG-161 amberchrom resin column (2.5×30 cm). The column was washed with water (200 mL), 10% MeCN/H2O(200 mL), and 25% MeCN/H2O(400 mL), collecting 25 mL fractions. Fractions 21-28 were combined and evaporated to give the title compound as a dark solid (0.675 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10][CH:9]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10][C@H:9]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNC(=O)CC1c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 110 °C

Procedure:
3.8 g of the cis/trans mixture of ethyl 4-(p-fluorophenyl)-6-oxo-3-piperidinecarboxylate obtained in Examples 4 to 6 was added to 100 mL of toluene, and 2.7 mL of a 28% methanol solution of sodium methoxide was added. The reaction mixture was heated at 110° C. for 2.5 hours, then poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain 3.28 g of ethyl trans-4-(p-fluorophenyl)-6-oxo-3-piperidinecarboxylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12](OC(OCC)(OCC)C)[CH3:13]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12]([CH3:13])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)c1cccc(I)c1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: Cc1nnc(-c2cccc(I)c2)o1
Temperature: 150 °C
Yield: 92 %

Procedure:
In a schlenck tube, a mixture of 3-iodobenzohydrazide (510 mg, 1.95 mmol) and 1,1,1-triethoxyethane (1.14 ml, 6.23 mmol) in acetic acid (15 ml) was heated at 150° C. for 3 h. The solvent was evaporated and the crude redissolved in ethyl acetate and washed with 4% solution of NaHCO3, water and brine. The organic layer was dried, filtered and concentrated under vacuum to give the title compound as a white solid (92% yield).
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[Na+]>C1COCC1>[CH2:1]([C:22]1[CH2:21][CH:20]=[CH:19][CH:18]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCO2)cc1
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CCC(CC2CCCO2)=C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a solution of 26.0 g (101 mmol) tetrahydrofurfuryltosylate prepared according to step (a) above in 200 ml THF cooled to 0° C. was added 63 ml of 2.0M (126 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was then added to the mixture and the product extracted with diethyl ether (3×75 ml). The combined organic fractions were dried over sodium sulphate for 16 h, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a brown oil. The crude product was distilled under reduced pressure (b.p. 32-°34° C. at 0.3-0.4 mm Hg) to give 7.1 g of a colourless oil (47.3 mmol, 46.9%).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[CH:4]=1.Cl.C1(C)C=C[C:15]([S:18](O)=O)=CC=1>C(O)C>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[S:18][CH3:15]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1ccc(S(=O)O)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CSc1c(O)cc(C)oc1=O
Yield: 64 %

Procedure:
A mixture of the monosodium salt of 4-hydroxy- 6-methyl-2-pyrone (14.8 g., 0.100 mol), methyl p-toluenethiolsulfonate (20.2 g., 0.100 mol), and 2B absolute ethanol (250 ml.) was heated at reflux for 21 hours. The ethanol was removed by distillation in vacuo; on attempted trituration with water (200 ml.), an oil separated. The oil was removed and the aqueous phase extracted with chloroform (2 × 100 ml.). The oil and chloroform washings were combined, dried over anhydrous Na2SO4, and the chloroform removed by distillation in vacuo. The resulting solid product, 4.5 g. (m. 130°-136°C., 26% yield) was twice recrystallized from 2-propanol to obtain the pure product, m. 141°-141.5°. The aqueous layer was acidified with dilute HCl producing 10.0 g. (64 percent yield) of the by-product p-toluenesulfinic acid, m. 79°-85°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH:7]=[N:8][C@H:9]([C:17]([O-:19])=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:10]([C@H:9]1[C:17](=[O:19])[O:18][C@@H:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=2)[N:8]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(C=N[C@@H](Cc2ccccc2)C(=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](Cc3ccccc3)N2C(=O)OCc2ccccc2)cc1

Procedure:
(2S,4S)-4-Benzyl-N-benzyloxycarbonyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (13) was prepared from sodium N-(para-methoxybenzylidene)-(L)-phenylalaninate (3.05 g, 10.0 mM) and benzyl chloroformate (1.43 mL, 10.0 mM) following general procedure C and obtained as a white solid after crystallisation from diethyl ether (2.87 g, 69%): [α]D20 +50.1 (c 1.0, CHCl3); mp 85° C.; IR (KBr): 1795, 1700 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.49-7.08 (m, 14H), 6.04 (s, 1H), 4.92 (d, J=12 Hz, 1H), 4.83 (d, J=12 Hz, 1H), 4.19 (dd, J=4, 6 Hz, 1H), 3.39 (s, 3H), 3.25 (dd, J=6, 14 Hz, 1H), 3.08 (dd, J=4, 14 Hz, 1H); 13C NMR (50.3 MHz, CDCl3): δ 171.4, 160.3, 151.5, 135.3, 129.2, 128.8, 128.5, 128.2, 127.3, 113.4, 89.3, 67.8, 58.4, 55.3, 34.5; LRMS (EI): 418 (MH+). Anal. Calcd for C25H23NO5 : C, 71.93; H, 5.55; N, 3.35. Found: C, 72.22; H, 5.36; N, 3.28.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[O:17][CH3:18])=[O:7].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:17][CH3:18])=[CH:10][C:11]([O:15][CH3:16])=[C:12]([NH:14][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH:13]=1)=[O:7]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(=O)CCCCCl)cc1NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 5-chloro-1-(5-amino-2,4-dimethoxyphenyl)-1-pentanone (0.27 g, 1 mmol), prepared as in Example 14, α,α,α-trifluoro-p-tolyl isocyanate (0.16 mL, 1.1 mmol), toluene (3 mL) and ethyl acetate (0.5 mL) was heated 10 minutes with stirring at approximately 50° C. The mixture was concentrated and the residue was recrystallized from hexane/ethyl acetate. The solids were collected and dried at 70° C. to give 1-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-3-(4-trifluoromethylphenyl)urea (0.43 g, 0.94 mmol), m.p. 154°-156° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 60 %

Procedure:
26.8 g of 4-bromophenol was taken under protective gas in 1000 ml of dioxane, mixed with 90 g 3-tributylstannylpyridine [preparation according to litt.: Org. Magn. Resonance, 7 (1975), 610] and 11.1 g of bis-(triphenylphosphine)-palladium(II) chloride and refluxed for 15 hours. After concentration by evaporation in a vacuum and purification on silica gel, 15.92 g of the above compound is isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.O1CCCC1.[CH3:17][NH2:18]>>[OH:10][C:6]1[N:5]=[C:4]([CH3:11])[CH:3]=[C:2]([NH:18][CH3:17])[C:7]=1[C:8]#[N:9]
Reactant: CN
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Solvent: C1CCOC1
Product: CNc1cc(C)nc(O)c1C#N
Temperature: 90 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a pressure vessel were added 4-chloro-2-hydroxy-6-methylnicotinonitrile (337 mg, 2.0 mmol), methylamine tetrahydrofuran solution (2 mol/L, 15 mL), and magnetic stirrer. The pressure vessel was sealed, and it was stirred at 90° C. for 2 hours. After being cooled to room temperature, the vessel was opened, and the reaction solution was transferred to an eggplant-shaped bottle. The solvent and excess methylamine were removed by rotary evaporation. The residue was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 2-hydroxy-6-methyl-4-(methylamino)nicotinonitrile (200 mg, 61% yield) as a brown solid. 1H NMR (300 MHz, methanol-d4): δ 5.89 (s, 1H), 3.56 (d, J=10.8 Hz, 3H), 2.94 (s, 1H), 2.55 (s, 1H), 2.24 (s, 1H).
Reaction SMILES: [OH-].[Na+].O.[N+:4]([C:7]1[CH:8]=[C:9]([CH2:17][C:18]([O:20]C)=[O:19])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]#[CH:16])([O-:6])=[O:5].Cl>CO>[N+:4]([C:7]1[CH:8]=[C:9]([CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]#[CH:16])([O-:6])=[O:5]
Reactant: C#CCOc1ccc(CC(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOc1ccc(CC(=O)O)cc1[N+](=O)[O-]

Procedure:
In a mixed solution of 0.5g of sodium hydroxide, 5 ml of water and 2ml of metanol 0.7g of methyl 3-nitro-4-propargyloxyphenylacetate was added and heated on a water bath for 30 minutes. After cooling, the solution was neutralized with 10% hydrochloric acid and the thus obtained crystals were recrystallized from ether-n-hexane to give the object compound having m.p. 135° - 137° C in a yield of 0.6g (90.6%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([C:14]#[N:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[NH4+].[OH-].CO.[Ni]>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH2:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN1CC[C@H](C#N)C1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NN1CC[C@@H](CN)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
A solution of (S)-1-(tert-butoxycarbonylamino)-3-cyanopyrrolidine (13.5g, 67 mmol) in 50 mL of 3% NH4OH/methanol and Raney Nickel (0.5 g, 50% slurry in water) was pressurized to 40 psi under H2 atmosphere. After stirring for 12 h at room temperature, the reaction mixture was filtered through a pad of Celite and the residue was washed with 100 mL of methanol. The filtrate was concentrated to dryness to give an oil (S)-1-(tert-butoxycarbonylamino)-3-aminomethylpyrrolidine (10 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH3:16].[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([N:27]2[CH2:32][CH2:31][CH:30]([N:41]3[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]3)[CH2:29][CH2:28]2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH3:16]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
Sodiumtriacetoxyborohydride (2.59 g, 12.2 mmol) was added to a stirring suspension of 1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinone (2.15 g, 8.14 mmol), 1-(methylsulfonyl)piperazine (2.67 g, 16.3 mmol), acetic acid (0.70 mL, 12.2 mmol), and TEA (1.13 mL, 8.14 mmol) in 1,2-DCE (100 mL). The reaction was stirred at rt overnight then poured into saturated NaHCO3 (aq). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were then dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-{1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.50 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (d, J=9.4 Hz, 1H), 6.58 (dd, J=9.5, 2.4 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.99-4.08 (m, 2H), 3.04-3.12 (m, 4H), 2.90-2.99 (m, 2H), 2.86 (s, 3H), 2.55-2.61 (m, 4H), 1.77-1.88 (m, 2H), 1.39-1.50 (m, 2H), 1.35 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(C)cccc2c(O)c1C
Product: Cc1nc2c(C)cccc2c(Cl)c1C

Procedure:
Prepared according to procedure S using 2,3,8-trimethylquinolin-4-ol (1.7 g, 9.1 mmol) in POCl3 (12.5 mL, 136 mmol). The resulting precipitate was collected by filtration to give 4-chloro-2,3,8-trimethylquinoline. Mass Spectrum (ESI) m/e=206 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[N:15]=[CH:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:18]([C:16]3[N:15]=[CH:14][S:13][CH:17]=3)=[O:19])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cscn1
Reactant: Nc1cccc2ccc(Cl)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2ccc(Cl)nc12)c1cscn1
Yield: 67 %

Procedure:
A solution of 2-chloroquinolin-8-amine (222 mg), thiazole-4-carboxylic acid (129 mg, 1 eq), HATU (570 mg, 1.5 eq), and DIEA (246 uL, 2.0 eq) in DMF (3 mL) was stirred at room temperature overnight. The product was precipitated by the addition of water (20 mL), the product was collected by filtration and recrystallized from methanol to obtain the product as a grey solid (194 mg).
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7]>>[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:3])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
In 75 cm3 (1.0 mol) of SOCl2, 128 g (0.52 mol) of 4-(trans-4'-propylcyclohexyl) benzoic acid was refluxed for 3 hours. The excess SOCl2 was distilled off under a reduced pressure and the residue was distilled under reduced pressure (158° C./3.0 mmHg) to yield 133 g (0.50 mol) of 4-(trans-4'-propylcyclohexyl) benzoic acid chloride.
Reaction SMILES: Cl.[CH2:2]1[C:7]2=[C:8]([C:15]([N:17]3[CH2:22][CH2:21][C:20]4([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH2:24][O:23]4)[CH2:19][CH2:18]3)=[O:16])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][NH:3]1.[CH2:31](N(CC)CC)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:31][N:3]1[CH2:4][CH2:5][N:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]([C:15]([N:17]3[CH2:22][CH2:21][C:20]4([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH2:24][O:23]4)[CH2:19][CH2:18]3)=[O:16])=[C:7]2[CH2:2]1
Reactant: O=C(c1c2n(c3ccccc13)CCNC2)N1CCC2(CC1)OCc1ccccc12
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CCn2c(c(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccccc32)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 0.050 g (0.12 mmol) 1′-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine]hydrochloride, 0.033 ml (0.24 mmol) triethylamine and 0.028 g (0.94 mmol) paraformaldehyde in 2 ml methanol was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. on an ice-water bath and treated with 0.011 g (0.18 mmol) sodium cyanoborohydride. After completed addition the mixture was allowed to warm to room temperature and stirred for 2 h. Quenching with water and dilution with 2 M aqueous sodium carbonate solution was followed by extraction with dichloromethane (2×50 ml). The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.036 g, 76%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O1CCCC1.C(N(CC)CC)C>[C:19]1(=[O:28])[N:7]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: COc1ccc(CN)cc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzylamine (0.836 grams, 5.00 mmol) and N-carbethoxyphthalimide (1.10 grams, 5.00 mmol) in 20 milliliters of tetrahydrofuran was added 1 drop of triethylamine and the mixture stirred overnight. After 24 hours at room temperature, the mixture was refluxed for 16 hours, then allowed to cool to room temperature without stirring. Crystals formed on cooling. The mixture was filtered, the solid dried in vacuo to afford 0.89 grams (60%) of 1-phthalimido-1-(3′,4′-dimethoxyphenyl)methane as small white needles: mp 160-161° C.; 1H NMR (CDCl3/TMS) δ 7.8 (m, 2H), 7.7 (m, 2H), 7.03 (m, 2H), 6.8 (m, 1H), 4.78 (s, 2H), 3.88 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); 13C NMR (CDCl3/TMS) δ 168.0, 148.9, 148.7, 133.9, 132.1, 129.0, 123.3, 121.3, 112.1, 111.1, 55.9, 41.4. Anal. Calcd for C17H15NO4. Theory: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.49; H, 4.99; N, 4.67.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:19]1[C:20]2[CH:27]=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][N:11]([C:19]3[C:20]4[CH:27]=[CH:26][NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: NCC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NCC1(Cc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 55.8 %

Procedure:
A solution of C-[4-(4-chlorobenzyl)piperidin-4-yl]methyl amine hydrochloride (0.063 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 24 hours. Concentration and purification by SCX-2 Isolute column (2 g), eluting with 1M NH3/MeOH, followed by silica column chromatography (15% methanol in DCM) gave a white solid (0.040 g, 56%). LC-MS (LCT2) m/z 356 [M+H+], Rt 2.97 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1>>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][C:36]=2[O:43][CH3:44])=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Product: COc1cc(F)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide and (4-fluoro-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 4-fluoro-1-(4-fluoro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=1.5 Hz, 1H), 8.49 (s, 2H), 8.00 (dd, J=1.7, 8.9 Hz, 1H), 7.86-7.78 (m, 1H), 7.38 (dd, J=6.9, 8.3 Hz, 1H), 7.16 (dd, J=2.3, 11.4 Hz, 1H), 6.97 (dt, J=2.3, 8.4 Hz, 1H), 3.67 (s, 3H). m/z (ESI) 435.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[N:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[S:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)[N:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(c2nc(Sc3ccc(C(C)=O)cc3)cs2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2nc(Sc3ccc(/C(C)=N/O)cc3)cs2)CCOCC1
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[2-(4-methoxytetrahydropyran-4-yl)thiazol-4-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[2-(4-methoxytetrahydropyran-4-yl)thiazol-4-ylthio]acetophenone oxime in 95% yield, m.p. 89° C.;