Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][S-:32].[Na+]>CS(C)=O.C(OCC)(=O)C.O>[OH:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([S:32][CH3:31])[CH:7]=2)=[CH:10][C:11]=1[C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[OH:30])=[O:22]
Reactant: C[S-]
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccnc(Cl)c2)c2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1cc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(O)c3ccccc23)ccn1
Temperature: 100 °C

Procedure:
To a solution of 4-[(2-chloropyridin-4-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide (0.050 g, 0.12 mmol) in 1 mL of DMSO was added sodium thiomethoxide (0.025 g, 0.35 mmol). The mixture was heated in a sealed tube at 100° C. for 18 hours, then cooled to room temperature. Additional sodium thiomethoxide (0.025 g, 0.35 mmol) was added, and the reaction was heated to 120° C. for 3 hours, then recooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was extracted 3× with ethyl acetate and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[2-(methylthio)pyridin-4-yl]methyl}-2-naphthamide that gave a mass ion (ES+) of 423.0 for [M+H]+.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=O)C.O.[NH2:30]N>C(O)(=O)C>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:8]3([C:6]4[N:5]=[CH:4][NH:2][N:30]=4)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:15][CH:16]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: c1nc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n[nH]1
Temperature: 100 °C
Yield: 24.5 %

Procedure:
N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.15 g, 0.39 mmol), hydrazine hydrate (0.048 mL, 0.98 mmol) and acetic acid (1 mL) were combined and heated at 100° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and washed with 10% aqueous sodium carbonate (20 mL). The organic was dried over sodium sulphate and evaporated to provide a clear oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:0.8 to 90:10:1) to produce a clear oil which was triturated with diethyl ether (3 mL), a white solid was isolated as the title compound (0.034 g, 24%). 1H NMR (400 MHz, CDCl3) δ 1.82-1.95 (m, 4H), 2.0-2.10 (m, 2H), 2.30 (m, 2H), 2.60-2.70 (m, 2H), 2.70-2.80 (m, 6H), 3.62 (t, 2H), 3.89 (m, 2H), 3.95 (t, 2H), 6.80 (d, 2H), 7.20 (d, 2H), 7.95 (d, 1H). HRMS ESI+ m/z 357.2279 [MH]+.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[CH:56]([C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][CH:66]=1)[C:61]([OH:63])=O)=[O:57].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[F:53][C:50]([F:51])([F:52])[C:48]1[CH:47]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:55])[F:54])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][N:44]([CH3:45])[C:61](=[O:63])[C:60]3[CH:64]=[CH:65][CH:66]=[C:58]([CH:56]=[O:57])[CH:59]=3)=[O:39])[CH2:26][CH2:27]2)([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[O:10][CH2:9]1)=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCCN(C)C(=O)c1cccc(C=O)c1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reaction time: 15 h
Yield: 83.6 %

Procedure:
The compound (150 mg, 0.193 mmol) obtained in Example 1k was dissolved in dichloromethane (6 mL), 3-formylbenzoic acid (43 mg, 0.289 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.289 mmol) and 4-N,N-dimethylaminopyridine (2 mg, 19.3 μmol) were added under ice cooling, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 15 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (147 mg; yield, 83.8%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([S:31][CH2:32][CH:33]([CH3:37])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 ml.) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column chromatography (silica gel-chloroform), yield 7.9 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([F:12])[F:11])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][NH:19][C:20]([C:22]2[S:26][C:25]([N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])=[N:24][C:23]=2[CH3:33])=[O:21])=[CH:16][CH:15]=1>>[F:11][CH:10]([F:12])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH:29]2[CH2:30][CH2:31][N:27]([C:25]3[S:26][C:22]([C:20]([NH:19][CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:35][CH:34]=4)=[O:21])=[C:23]([CH3:33])[N:24]=3)[C:28]2=[O:32])=[CH:4][CH:5]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 31 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene to react with N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 31% yield: mp 143-145° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.34-7.22 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.06-6.93 (m, 4H), 6.45 (t, J=73.9 Hz, 1H), 6.08 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.09-3.99 (m, 1H), 3.91-3.78 (m, 1H), 3.25-3.12 (m, 1H), 3.05-2.94 (m, 1H), 2.83-2.73 (m, 1H), 2.59 (s, 3H), 2.32-2.18 (m, 1H), 1.98-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.7, 162.3, 162.2, 160.6, 155.4, 152.7, 149.9, 135.4, 133.8, 130.3, 129.6, 119.8, 115.6, 112.4, 45.9, 44.3, 43.3, 35.6, 24.2, 17.2; MS (ES+) m/z 490.3 (M+1).
Reaction SMILES: CO.[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:7]=[C:6]([SH:18])[N:5]=1.[OH-].[Na+].S(OC)(O[CH3:25])(=O)=O>O>[CH3:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:7]=[C:6]([S:18][CH3:25])[N:5]=1
Reactant: Cc1nc(S)nn1-c1ccc([N+](=O)[O-])cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nc(C)n(-c2ccc([N+](=O)[O-])cc2)n1
Reaction time: 1 h
Yield: 66 %

Procedure:
To 80 parts of methanol are added 4.7 parts of 5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole-3-thiol and 1.2 parts of sodium hydroxide and the whole is stirred till all solid enters solution. Then there are added 2.66 parts of dimethyl sulfate and stirring is continued for 1 hour at room temperature. 100 Parts of water are added. The precipitated product is filtered off, washed with water, dried, and crystallized from 2,2'-oxybispropane, yielding 3.3 parts (66%) of 5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole; mp. 121°-125° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Nc1ccc(F)cc1
Product: COc1ccc2c(Nc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-fluoro-phenylamine to give N1-(4-fluoro-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 364(MH+).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][NH:7]1.[C:19](Cl)(=[O:21])[CH3:20].N1C=CC=CC=1>CN(C)C=O>[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][N:7]1[C:19](=[O:21])[CH3:20]
Reactant: ClCCCC1NCCc2c1[nH]c1ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1CCCCl
Temperature: 5 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
17.1 g (60 millimoles) of 1-(3'-chloropropyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride were dissolved in 240 ml of dimethylformamide while heating, and the solution was then cooled to 5° C. in an ice bath. 11.5 g (150 millimoles) of acetyl chloride and immediately thereafter 23.7 g (300 millimoles) of pyridine were added dropwise to the thoroughly stirred solution, the temperature not rising above 5° C. during this operation. Thereafter, stirring was continued for a further 2 hours at this temperature, after which the reaction mixture was poured onto ice water. The precipitate was filtered off under suction and washed thoroughly with water. 16.9 g (97%) of crystals of melting point 166°-168° C. (ethanol) were isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[OH:20])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:10](=[O:11])[CH2:9][N:6]1[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([NH:21][C@@H:22]2[CH2:27][C@@H:26]3[CH2:28][C@@H:24]([C:25]3([CH3:30])[CH3:29])[C@H:23]2[CH3:31])[CH:4]=[N:5]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3O)c(=O)c1Cl)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cnccc1CNC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-hydroxypyridin-4-yl)methyl]acetamide (12.7 mg, 0.03 mmol) in acetone (2 mL) was mixed with ethyl bromoacetate (4.4 μL, 0.04 mmol) and potassium carbonate (5.9 mg, 0.04 mmol) at room temperature and stirred at 50° C. for 1 hour. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=20/1) to give the desired product (4.8 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:5]23)[CH:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3(=O)=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3(=O)=O
Yield: 87.9 %

Procedure:
Tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (94 mg, 88%) was prepared via coupling of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (93 mg, 0.210 mmol) with 2,4-dichlorophenyl boronic acid (60 mg, 0.315 mmol) using the procedure described in Example 450 Step A. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 1.82-2.05 (m, 2H), 3.30-3.60 (m, 6H), 3.60-4.00 (m, 4H), 7.20-7.32 (m, 3H), 7.45 (s, 1H), 7.51 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:31]3[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:23]4[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=4)[CH2:29][CH2:30]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: c1cc(CCN2CCNCC2)ccn1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(N1CCN(CCc2ccncc2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 291.3 %

Procedure:
The title compound of Example 2 (0.38 g, 1.3 mmol) was combined with the product of Example 88 (0.25 g, 1.3 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic separation, 1.7 g of the white solid title product was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:15][NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>ClCCl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:16]([CH3:15])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CNCC(=O)OC
Solvent: ClCCl
Product: COC(=O)CN(C)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl 2-(methylamino)acetate (1.9 g, 18.47 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one hour and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified using flash column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield 2.60 g (99% yield) of the title compound as a yellow oil. [M+H] calc'd for C11H13N3O6, 284. found, 284.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:22][N:23]1CCCC1=O>>[C:22]([C:2]1[C:10]2[C:9]([NH:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1)#[N:23]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(C(C)Nc2ncnc3scc(Br)c23)cc1
Product: COc1ccc(C(C)Nc2ncnc3scc(C#N)c23)cc1
Temperature: 130 °C
Yield: 30 %

Procedure:
5-Bromo-N-[1-(4-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (250 mg, 0.69 mmol) and cuprous cyanide (310 mg, 3.4 mmol, 5 eq.) were combined in dry N-methylpyrrolidinone (NMP) (4 mL) and heated to 130° C. for 19 hours. After cooling, the volatiles were removed by Kugelrohr distillation at 0.1 mm and the residue was taken up in EtOAc/2 molar NH4OH. The organic phase was washed with water, brine, dried (Na2SO4) and evaporated. The residue was chromatographed on a 50 mm×250 mm YMC-AQ RP HPLC column eluting with 70 percent acetonitrile (ACN) to give 61 mg (30 percent) of the purified off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH3:17])=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C>CO.Cl>[CH3:17][C:15]1[S:14][C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=1
Reactant: Cc1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: Cc1cc2c(s1)CCNC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-t-Butoxycarbonyl-2-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.40 mmol) was dissolved in hydrochloric acid methanol solution and stirred at room temperature for 14 hours. By evaporating the solvent from the reaction solution under a reduced pressure, 60 mg (0.39 mmol, 99% in yield) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:31]1>CC(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[O:31]2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OO1
Reactant: CCCC/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCC1OC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-[2-benzyloxy-4-((E)-hex-1-enyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.275 mmol) in acetone (10 mL) is added a solution of DMDO (0.56 mM, 4.9 mL, 0.413 mmol) in acetone. This mixture is stirred at RT for 1 h, at which point LCMS of the reaction shows clean conversion to the desired epoxide. The reaction mixture is diluted with EtOAc and concentrated 3× to fully remove the volatile DMDO. The remaining EtOAc is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[Cl:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[C:20]([CH3:27])[N:19]=1>>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:21]=[C:20]([CH3:27])[N:19]=1
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Cl)n1
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (480 mg, clear colorless oil) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (450 mg, 1.7 mmol, Amine-1, single enantiomer) and 2-chloro-6-methylpyrimidine-4-carboxylic acid (300 mg, 1.7 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C#CCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(F)cc(Cl)c2)cc1
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(F)cc(Cl)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-chloro-5-fluoro-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (110 mg, 98%); 1H NMR δ (CDCl3): 7.16 (s, 1H), 7.02-6.94 (m, 2H), 2.43 (t, J=7.13 Hz, 2H), 1.62 (p, J=7.12 Hz, 2H), 1.45-1.29 (m, 4H), 0.92 (t, J=7.22 Hz, 3H); LCMS m/z: 224.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26]N=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.O1C=[N:33][N:32]=[C:31]1C1C=CC(N)=CC=1>>[O:26]1[CH:31]=[N:32][N:33]=[C:22]1[C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13]2[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[NH2:1])[N:14]=2)=[CH:21][CH:20]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1ccc(-c2nnco2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2nnco2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(1,3,4-oxadiazol-2-yl)aniline in step 1. MS: 395.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C@@H:7]([CH3:23])[C@H:8]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C@@H:7]([CH3:23])[C@H:8]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C=C[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 2.12c (360 mg, 1.07 mmol) in ethyl acetate (5 mL) was added Pd/C (5% on charcoal, 114 mg, 0.107 mmol) and the resulting mixture was stirred under 1 atm of H2 for 1 hour. The solid was then removed by filtration and the filtrate was concentrated in vacuo to afford 2.12d (360 mg) which was used in the next step without further purification. MS m/z (M+23) 362.3. 1H NMR (400 MHz, CDCl3) δ ppm 0.91-0.97 (m, 3H) 1.24 (t, J=7.16 Hz, 3H) 1.36-1.47 (m, 7H) 1.47-1.52 (m, 5H) 1.52-1.57 (m, 4H) 2.66 (s, 3H) 4.10 (d, J=7.24 Hz, 2H) 6.31 (d, J=1.91 Hz, 2H) 6.32 (s, 1H) 7.26 (s, 3H) 7.35 (ddd, J=1.23, 0.78, 0.67 Hz, 1H).