Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(CCl)ccn1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
(2-Methyl-pyridin-4-yl)-methanol (40 mg, 0.33 mmol) described in Manufacturing Example 47-1-1, thionyl chloride (0.047 ml, 0.65 mmol) and methylene chloride (4.0 ml) were stirred for 5 minutes at 60° C. Sodium bicarbonate solution and ethyl acetate were added to separate the reaction solution, and the ethyl acetate layer was dried over sodium sulfate. The solvent was evaporated under a reduced pressure to obtain 4-chloromethyl-2-methyl-pyridine as a crude product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45]([O:48][CH2:49][C:50](Cl)=[O:51])(=[O:47])[CH3:46]>ClCCl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([CH3:28])[C:5]2[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:3][C:2]([NH:1][C:50]([CH2:49][O:48][C:45](=[O:47])[CH3:46])=[O:51])=[N:7][CH:6]=2)=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 30 mg (0.21 mmol) acetoxy acetyl chloride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 62 mg (52%) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:5].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37])=[O:32].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:13]1([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:19]=[C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:2]=3[NH:1][C:36]([C:35]3[CH:34]=[C:33]([CH:41]=[CH:40][CH:39]=3)[C:31]([O:30][CH3:29])=[O:32])=[O:37])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (2 g, 3.75 mmol, 1.00 equiv, 70%) in dichloromethane (30 mL) was added 3-(methoxycarbonyl)benzoic acid (1160 mg, 6.12 mmol, 1.20 equiv, 95%), EDC.HCl (2040 mg, 10.20 mmol, 2.00 equiv, 95%), and 4-dimethylaminopyridine (660 mg, 5.14 mmol, 1.00 equiv, 95%) and the resulting solution was stirred for 3 h at 25° C. in an oil bath. The mixture was concentrated under vacuum, diluted with 100 mL of ethyl acetate, washed with 1×100 mL of brine and then the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (2:1) to afford 1200 mg (60%) of product as a green to yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][CH:15]3[CH3:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)=[CH:38][CH:37]=1)(=[O:35])[NH2:34]>>[CH3:21][CH:15]1[CH2:16][O:17][CH2:18][CH:19]([CH3:20])[N:14]1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][CH3:32])=[CH:24][CH:23]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=3)=[O:44])=[CH:7][CH:6]=2)[N:13]=1
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 12.8 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 70 mg, 12.8% yield.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]([O:24]C)(=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(O)(C)(C)C>[CH3:22][O:21][C:19](=[O:20])[C:18](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=1)[CH2:17][C:16]([OH:24])=[O:23]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Yield: 66.5 %

Procedure:
To a refluxing mixture of potassium tert-butoxide (27 g, 242 mmol) and tert-butanol (150 mL) was added a solution of 4-fluoro-benzaldehyde (20 g, 161 mmol) and dimethyl succinate (28 g, 193.2 mmol) in tert-butanol (100 mL) dropwise. After being heated at reflux for 3 hours, the mixture was concentrated in vacuo to remove tert-butanol. The residue was dissolved in 1 N hydrochloric acid (180 mL). The resulting aqueous solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzylidene)-succinic acid 1-methyl ester (25.5 g, 66%) as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.84 (s, 1H), 7.41-7.46 (m, 2H), 7.13-7.20 (m, 2H), 3.81 (s, 3H), 3.49 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:16]([O:22][CH2:23][O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:3][C:4](=[O:5])[CH3:6])=[CH:8][CH:9]=1)=[O:13])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Cc1ccc(C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
Sodium hydride (0.48 g) was added to 4-acetonylbenzoic acid (3.56 g) in acetonitrile and the solution refluxed for 1/2 hour. Chloromethyl pivalate (3.02 g) was then added and the mixture refluxed for 22 hours. Acetonitrile was removed, the residue partitioned between ether and water and the organic layer separated and washed with sodium bicarbonate solution (x2). The ether layer was dried (MgSO4) and evaporated to give the title compound which was crystallised and recrystallised from hexane. τ (CDCl3) 8.77 (9H, s), 7.82 (3H, s), 6.25 (2H, s), 4.02 (2H, s), 2.73 (2H, d, J=9 Hz), 1.96 (2H, d, J=9 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:27]#[N:28])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2CC1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2CC1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 3-(tert-butoxycarbonyl)-7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (4.78 g, 12.1 mmol), zinc cyanide (1.42 g, 15.6 mmol) and tetrakis-triphenylphosphine palladium (0) (1.4 g, 1.2 mmol, 10 mol %), in dry dimethylformamide (50 ml) was stirred at 100° C. for 3 h under argon. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (120 ml) and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate (100 ml), then water (2×50 ml), then brine (50 ml). The organic layer was dried over sodium sulfate and evaporated in vacuo to give brown oil, which was purified by chromatography on silica gel with 20-100% ethyl acetate-hexane elution to give the title compound (0.765 g, 23%) as a brown oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>O1CCCC1>[CH3:25][N:26]([CH2:27][CH2:28][OH:29])[C:22]([C:14]1[NH:13][C:21]2[C:16]([CH:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:24]
Reactant: CNCCO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1cc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (1.11 g) is added to a solution of indole-2-carboxylic acid (1.0 g) in tetrahydrofuran (15 ml). The mixture is stirred 1 hour at 20°-25° and 2-(methylamino)ethanol (5.0 ml) is added. The mixture is stirred 21 hours at 20°-25° and 24 hours at reflux. The mixture is concentrated under reduced pressure, diluted with methylene chloride and extracted with water and saturated sodium bicarbonate. The phases are separated and the organic phase is dried with saline and sodium sulfate and concentrated to give the crude product. Chromatography on silica gel with a methanol/chloroform gradient followed by recrystallization from chloroform/ether to give the title compound, mp 141°-142.5°.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:16][N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH2:14][NH:8][CH2:9]2
Reactant: [H][H]
Reactant: CN1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CN1C2CCC1CNC2

Procedure:
To a degassed by argon solution of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane (17.6 g, 0.08 mol) in methanol (50 ml), 10% Pd/C (1.0 g) was added and hydrogen passed into reaction mixture for 24 h. The catalyst was filtered off, the filtrate evaporated and the residue distilled on Büchi oven for distillation at 100° C. and 0.1 mbar. Yield 8.5 g (85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][S:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:45][C:44]1[CH:46]=[CH:47][C:41]([S:40][CH3:39])=[CH:42][CH:43]=1)=[N:6]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: CSc1ccc(N)cc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: CSc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1
Yield: 50.8 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 4-(methylthio)aniline (0.022 mL, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-N-[4-(methylthio)phenyl]-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (30 mg) as a yellow solid. MS m/z 348 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C@H:8]([CH3:13])[CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:14].[CH3:15]N1C[C@H](C)C2C(Cl)=C(Cl)C=CC=2CC1>>[CH3:15][N:10]1[CH2:9][C@@H:8]([CH3:13])[C:7]2[C:2]([Br:1])=[C:3]([Cl:14])[CH:4]=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: C[C@H]1CN(C)CCc2ccc(Cl)c(Cl)c21
Reactant: C[C@@H]1CNCCc2ccc(Cl)c(Br)c21
Product: C[C@@H]1CN(C)CCc2ccc(Cl)c(Br)c21

Procedure:
Compound 11 was prepared from (S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 3.94-3.88 (m, 1H), 3.29 (ddd, J=15, 12, 2 Hz, 1H), 2.98-2.93 (m, 1H), 2.90 (ddd, J=15, 6, 1 Hz; 1H), 2.36-2.32 (m, 4H) 2.13 (t, J=11 Hz, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated for C12H15Cl2N+H: 288, observed: 288.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].ClC(Cl)C.Cl>N1C=CC=CC=1>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
8.96 g (50 mmol) of 4-fluoro-2-trifluoromethylaniline is dissolved in 100 ml of pyridine and under cold conditions combined under stirring with 9.52 g (50 mmol) of 3-chlorosulfonylpropionic acid methyl ester (98.5%). The mixture is agitated for 20 minutes, heated for 4 hours to 40° C., and the pyridine is exhausted under vacuum. The residue is distributed between dichloroethane and 4N hydrochloric acid. The organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is purified by column chromatrography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[NH:7][N:6]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:24])C(=O)C1.[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C>[Cl:24][C:9]1[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])=[N:6][NH:7][C:8]=1[C:10]([F:12])([F:13])[F:11]
Reactant: CCCN(CCC)c1cc(C(F)(F)F)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CCC)c1n[nH]c(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To N,N-dipropyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (250 mg, 1.06 mmol) in DMF (5.3 mL) was added NCS (142 mg, 1.06 mmol). The resulting reaction mixture was stirred at 100° C. for 1 h and then poured into sat. aq. NH4Cl solution and EtOAc (1:1). The organic layer was washed sat. aq. NH4Cl solution (3×), and the combined aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (287 mg, 100%). 1H NMR (CDCl3) δ 3.23-3.14 (m, 4H), 1.59-1.44 (m, 4H), 0.88 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 270.1 (M+H)+.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])N=1.C[OH:15]>>[CH3:12][C:6]1([CH3:13])[NH:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4](=[O:15])[CH2:3]1
Reactant: CO
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
17.2 g of acetonine hydrate, 3 g of methanol and 0.5 g of ammonium chloride are heated to 60° C. After a reaction time of 12 hours, it is shown by a gas-chromatographical analysis that about 80% of the employed amount of acetonine has been reacted to form triacetoneamine, which is isolated by distillation.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[O:10]
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1=C(O)c2ccsc2S(=O)(=O)C1
Temperature: 5 °C
Yield: 21.3 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (5.2 g, 0.02 mole), 2-aminothiazole (3.0 g, 0.03 mole) and xylene (175 ml) is warmed and filtered from the polymeric products. The filtrate is refluxed for 30 min. when some more polymeric product is formed. It is filtered again, and the filtrate refluxed for 1.5 hrs. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline product is collected. It is dissolved in THF, treated with charcoal and filtered. The filtrate is concentrated to give the desired product (1.4 g, 21%), m.p. 215-216° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH2:24][C:25](O)=[O:26])[N:19]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH4+].[Cl-]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH2:24][N:20]2[C:21]([CH3:23])=[CH:22][C:18]([CH3:17])=[N:19]2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccccc1N1CCNCC1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCN(C(=O)Cn2nc(C)cc2C)CC1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a vial containing the 2-piperazin-1-yl-benzoic acid methyl ester (0.667 g, 3.03 mmol) is added a pre-mixed solution containing (3,5-dimethyl-pyrazol-1-yl)-acetic acid (0.428 g, 2.78 mmol) and carbonyl diimidazole (0.567 g, 3.50 mmol). The mixture is stirred overnight and then diluted with 200 mL of EtOAc followed by 200 mL of sat. NH4Cl. The organic phase is washed with 2×200 mL of H2O and 1×200 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated to give 0.849 g of 2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid methyl ester.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]([CH2:9][OH:10])=O.C(N(CC)CC)C>CO>[NH2:4][C:3]1[O:10][CH:9]=[C:7]([CH3:6])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: CC(=O)CO
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1coc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a mixture of malononitrile (0.96 g, 14.6 mmol), acetol (1.08 g, 14.6 mmol) in methanol (10 mL) at 0° C. was added, dropwise, triethylamine (2.0 mL). The reaction mixture was stirred at room temperature overnight. After removal of solvent under reduced pressure the crude solid washed with cold isopropanol to give product as white powder (0.54 g, 30%). HPLC/MS: (M+H)+ 123.3 m/z. Retention time (LC-MS)=1.81 min. 1H NMR (CD3OD): 6.58(s, 1H,); 1.95 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(CCO)(=O)=[O:26].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:26])[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.3 %

Procedure:
To a cooled stirring solution of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.50 g, 4.61 mmol), and 2-(methylsulfonyl)ethanol (876 mg, 6.92 mmol) in anhydrous DMF (15 mL), under nitrogen, was added, portionwise, sodium hydride (553 mg, 13.8 mmol, 60% oil dispersion). The solution foamed upon the sodium hydride addition. The resulting dark orange solution was stirred, at 0° C., for 30 minutes upon completion of sodium hydride addition. The reaction solution became viscous and additional DMF (5 mL) was added, via syringe, the ice bath removed and the dark solution stirred at room temperature, under nitrogen, for 2 h. The reaction was cooled in an ice bath, quenched with 0.1N hydrochloric acid solution, and transferred to a separatory funnel with ethyl acetate (100 mL). This organic phase was washed with brine (75 mL×3). The aqueous washings were combined and extracted with ethyl acetate (75 mL×3). The organic extracts were combined and washed with saturated aqueous sodium bicarbonate solution (100 mL), brine (100 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed to give an amber colored oil (2.21 g). This oil was adsorbed onto silica and purified by column chromatography, eluting with 50% ethyl acetate in hexane to afford the product as a light yellow colored solid (1.37 g, 92%). Mass Spectrum (+ESI): 324 [M+H]+, 322 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[N:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:10][C:4]2[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1
Reactant: COc1cc(O)cc(Cl)c1
Reactant: OB(O)c1cncc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(Oc2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 372 mg (2.346 mmol) of 3-chloro-5-methoxyphenol (B-1), 947 mg (4.692 mmol) of 5-bromopyridine-3-boronic acid (13-1), 426 mg (2.346 mmol) of copper (II) acetate and 4.0 g of freshly activated powdered 4A molecular sieves was stirred in 20 mL of DCM in a screw top glass sealed tube. The reaction was then treated with 1.635 mL (11.73 mmol) of triethylamine and the vessel was loosely capped. The mixture was vigorously stirred at room temperature for 48 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to a black residue. The residue was purified on a CombiFlash silica column eluted with an ethyl acetate:hexanes gradient to give the desired product 13-2 as an oil (Rf=0.7, EtOAc:hexanes 1:4). MS: M+1=314. 1H NMR(CDCl3): 3.79 (s, 3H), 6.47 (m, 1H), 6.61 (m, 1H), 6.74 (m, 1H), 7.46 (m, 1H), 8.33 (d, 1H), 8.46 (d, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]1[N:19]2[C@@H:13]([S:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]2=[O:20])[CH2:12][CH2:11][CH2:10]1.IC>C1COCC1>[CH3:1][O:7][CH2:8][C@H:9]1[N:19]2[C@@H:13]([S:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:18]2=[O:20])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A solution of potassium tert-butoxide (1 M in THF, 1.55 mL, 1.55 mmol) was added dropwise to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (513 mg, 1.55 mmol) in THF (5 mL). The reaction mixture turned yellow in color. After 15 min of stirring, iodomethane (441 mg, 3.10 mmol) was added. The ice bath was removed and the reaction mixture was stirred at rt overnight. Water was added to the reaction and the mixture was concentrated to remove most of the THF. The aqueous solution was then extracted with EtOAc. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (83 mg, 0.24 mmol, 16% yield) as a colorless oil. Anal. Calcd. for C16H28N2O4S m/z 344.4. found: 345.1 (M+H)+.