Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:12]2(O)[CH3:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:12]2=[CH2:24])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCN1C(=O)OC2(CCN(Cc3ccccc3)CC2)C1(C)O
Solvent: OCc1ccccc1
Solvent: O
Product: C=C1N(CCCCCCC)C(=O)OC12CCN(Cc1ccccc1)CC2
Yield: 81 %

Procedure:
The solution of 18.7 g of 8-benzyl-3-n-heptyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 40 ml of benzyl alcohol is heated at 160° C. for 5 hours while the water formed in the reaction is azeotropically distilled off. Thereafter, the mixture is evaporated under reduced pressure. After taking up the residue in chloroform the solution is dried over anhydrous magnesium sulfate, filtered off and evaporated under reduced pressure. The crude product obtained is recrystallized from n-hexane under clarifying by activated carbon to obtain the title compound in 81% yield, m.p.: 47°-48° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
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: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccccc2OC)sc1C(=O)OCC
Temperature: 25 °C
Yield: 135.8 %

Procedure:
A mixture of 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (747 mg, 1.49 mmole), 2-methoxyphenylboronic acid (663.3 mg, 4.36 mmole), cesium carbonate (2.13 g, 4.76 mmole) and tetrakis(triphenylphosphine)palladium (252 mg, 0.16 mmole) in dioxane (7 ml) was refluxed for 5 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.07 g). MS: (+) m/z 551.20 (M+Na+)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].Br[CH:14]([CH3:16])[CH3:15].O>CN(C=O)C>[CH:14]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH3:3])=[CH:7][CH:8]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Sodium hydride (1.32 g, 33 mmol, 60% suspension in mineral oil) was suspended in anhydrous DMF (20 mL). A solution of 4-hydroxy acetophenone (4.08 g, 30 mmol) in anhydrous DMF (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. A solution of 2-bromopropane (4.61 g, 37.5 mmol) in anhydrous DMF (10 mL) was added slowly. The reaction mixture was stirred at room temperature overnight. Water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL). Dried over anhydrous Na2SO4. Removal of solvent gave 1-(4-isopropoxy phenyl)ethanone as a pale yellow solid (3.52 g, 66%). To a stirred solution of 2-methoxy-5-pyrrolidin-1-ylmethyl nicotinic acid methyl ester (0.5 g, 2.0 mmol) and 1-(4-isopropoxy phenyl)ethanone in anhydrous DMF (10 mL), sodium hydride (96 mg, 2.4 mmol, 60% suspension in mineral oil) was added in small portions under nitrogen. The reaction mixture was stirred overnight at room temperature. Reaction mixture was stirred at 80° C. for 1 hours. Water (30 mL) was added. The mixture was extracted with chloroform (150 mL). The organic layer was washed with water (30 mL) and brine (30 mL). Dried over anhydrous Na2SO4. Removal of solvent gave brown solid (0.66 g) which was used in next step without further purification. The above solid (0.626 g, 1.58 mmol) and pyridine hydrochloride (1.18 g, 15.8 mmol) were mixed together and stirred at 190° C. for 20 min. Cooled to room temperature. Water (10 mL) was added, neutralized to pH ˜9. The mixture was extracted with chloroform (2×100 mL). The organic layer was washed with brine (50 mL) and dried (Na2SO4). Removal of the solvent gave 2-(4-isopropoxy phenyl)-6-pyrrolidin-1-ylmethyl pyrano[2,3-b]pyridine-one (0.237 g, 41%) as yellow solid. To a solution of the above compound in anhydrous CH2Cl2 (10 mL) was added 1.0 M solution of hydrogen chloride in ether dropwise. The reaction mixture was stirred for 10 min. The solvent was removed under reduced pressure. The residue was washed with hexane and ether. Purified by triturating with 10% methanol in ether to give 2-(4-isopropoxyphenyl)-6-(pyrrolidin-1-ylmethyl)-4H-pyrano[2,3-b]pyridin-4-one hydrochloride (0.20 g, 83%) as yellow solid. MS (ES) m/z: 264 (M); MP 261-263° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:21][P:22]([O:28]CCCC)[O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH3:20]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][P:22](=[O:28])([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Product: CCCCOP(=O)(Cc1ccc(OCc2ccccc2)cc1)OCCCC
Temperature: 50 °C

Procedure:
A mixture of 4-benzyloxybenzyl chloride (4.99 g) and tri-n-butylphosphite is heated at 50° C. for about 4 hours while removing butyl chloride. The mixture is cooled to room temperature and the crude product purified by HPLC on silica, eluting with 25% ethyl acetate in hexane, to give dibutyl 4-benzyloxybenzylphosphonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+]>>[F:16][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:7]=1)[NH2:13]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(-c2cc(Oc3ccc(N)cc3F)ccn2)cn1
Yield: 33.4 %

Procedure:
Using a procedure analogous to Example 95, 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3 g, 11.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.4 g, 16.4 mmol), Na2CO3 (2.7 g, 25.2 mmol) and Pd(Ph3)4 (1.5 g, 0.1 eq) were combined to give 3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (1.1 g, 34%). 1H NMR (400 MHz, DMSO-d6): 6 (8.31 (d, J=5.6 Hz, 1 H), 8.22 (s, 1 H), 7.93 (s, 1 H), 7.14 (s, 1 H), 6.98 (m, 1 H), 6.55-6.49 (m, 2 H), 6.42 (d, J=7.2 Hz, 1 H), 5.44 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z: (M+H+): 285.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]3[CH2:19][CH2:20][CH2:21][C:14]=3[C:13]=2[CH:22]=1)(=O)=O.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>C(O)(C)C.C(O)C>[CH3:24][O:23][C:10]1[C:9]([O:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:13]2[C:14]3[CH2:21][CH2:20][CH2:19][C:15]=3[C:16](=[O:18])[O:17][C:12]=2[CH:11]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 93 %

Procedure:
Method B (16 h at 60° C.); starting materials: 2,3-dihydro-8-[2-(methanesulfonyloxy)ethoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 81) and 4-phenylpiperidine; yield 93%; fusion point 150°-152° C. (from isopropanol). Fumarate: method E; yield 84%; fusion point 185°-187° C. (from ethanol and isopropanol).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:2]3[N:3]=[CH:4][C:5]4[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=4[N:7]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)N1C(=O)C(C)(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(CC)N1C(=O)C(C)(C)c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 88.8 %

Procedure:
To a solution of 2-chloro-7-(1-ethyl-propyl)-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (20 mg, 0.075 mmol) in 1,4-dioxane (1 mL) and DMF (0.2 mL) are added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (24.5 mg, 0.11 mmol) and p-toluenesulfonic acid (17 mg, 0.089 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with 1N NaOH solution. The organics is dried over Na2SO4, filtered, and concentrated. The residue is purified by prep-HPLC to give 30 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a pale yellow solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.CS(C)=O.Br.[Br:14][C:15]1[CH:16]=[N:17][C:18](O)=[N:19][CH:20]=1>O>[Br:14][C:15]1[CH:20]=[N:19][C:1](=[O:4])[N:17]([CH3:18])[CH:16]=1
Reactant: Oc1ncc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: Cn1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
With cooling with ice, potassium carbonate (7.56 g, 54.7 mmol) and methyl iodide (1.27 ml, 20.3 mmol) were added to a dimethyl sulfoxide (100 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (4.0 g, 15.6 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was suspended in ethyl acetate, then filtered and dried to obtain the entitled compound (1.33 g, 45%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([N:3]([CH3:4])[CH3:2])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In THF (10 mL), dimethylamine hydrochloride (2.04 g, 25.0 mmol) and triethylamine (3.48 mL, 25.0 mmol) were dissolved, and 3-bromobenzenesulfonyl chloride (0.721 mL, 5.00 mmol) was added thereto at 0° C., and then, the mixture was stirred at room temperature for 1 hour. To the mixture, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-N,N-dimethylbenzenesulfonamide (1.23 g, 4.66 mmol, yield: 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)NCc1cccnc1
Yield: 63 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methyl-1H-imidazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 63% yield: mp 203-204° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.70 (br s, 1H), 8.58-8.51 (m, 2H), 8.43 (d, J=3.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.50-7.29 (m, 6H), 6.23 (dd, J=7.8, 2.6 Hz, 1H), 6.07 (d, J=2.6 Hz, 1H), 5.16 (s, 2H), 4.40 (d, J=6.3 Hz, 2H), 2.47 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.2, 162.9, 162.0, 148.8, 147.8, 137.3, 135.9, 135.6, 135.4, 135.1, 130.8, 128.5, 128.2, 128.0, 127.4, 123.3, 101.6, 97.5, 70.0, 10.5; MS (ES+) m/z 416.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]2)=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15].C(N(CC)CC)C>ClCCl>[NH3:19].[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:3]([O:2][CH3:1])=[O:4])[CH2:21][CH:20]2[CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]2)=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COC(=O)Cl
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNCC1CN1CCC(O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCC(O)C2)C1
Product: N
Reaction time: 0.5 h
Yield: 165.5 %

Procedure:
A solution of methylchloroformate (243 mg) in dry dichloromethane (3 ml) was added dropwise to a stirred solution of 1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyrrolidinyl)methyl]piperazine dihydrochloride (1.0 g) and triethylamine (495 mg) in dry dichloromethane (25 ml) at -25° under nitrogen. The resulting solution was stirred at -30°--25° for 30 min, quenched with aqueous 2N sodium carbonate solution (30 ml) and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried and evaporated to give a foam. The residue was purified by flash column chromatography eluting with dichloromethane:methanol:0.880 NH3 (150:8:1) to give the title compound as a foam (800 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:22]C(=O)C1C=CC=CC=1)=[N:10]2.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:20])([F:19])[F:21])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-Difluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (2.00 g) was dissolved in methanol (250 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.53 g) was added, and the solution was heated to reflux (heating block temperature 80° C.). After 3 h, the reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4, evaporated, and the residue purified by silica gel column chromatography (0% to 50% EtOAc in hexanes) to afford the title compound (1.42 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (dd, J=13.6, 3.8 Hz, 1 H), 3.15 (dd, J=13.8, 3.2 Hz, 1 H), 3.27-3.42 (m, 1 H), 3.93 (dd, J=8.2, 1.9 Hz, 1 H), 4.39-4.78 (m, 4 H), 6.96-7.25 (m, 3 H)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:32][CH:33]([NH:40]S(C(C)(C)C)=O)[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:40][CH:33]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:32][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(CC(NS(=O)C(C)(C)C)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CNC1CCN(C(=O)OCc2ccccc2)CC1)c1ccncc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of benzyl 4-((tert-butoxycarbonyl){2-[(tert-butylsulfinyl)amino]-2-pyridin-4-ylethyl}amino)piperidine-1-carboxylate (230 mg, 0.412 mmol) in dichloromethane (10 mL). After 1 h, the reaction was concentrated, dissolved in methanol (5 μL), and treated with 4 N HCl in dioxane (4.12 mmol). After 1 h, the reaction was concentrated to give the title compound. MS 355.2 (M+1)
Reaction SMILES: [N:1]1([CH:6]([CH3:19])[CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].N>CCO.CO.C(Cl)Cl>[N:1]1([CH:6]([CH3:19])[CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CN1CCCc2cc(N)ccc21)N1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CC(CN1CCCc2cc(NC(=N)c3cccs3)ccc21)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-(2-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (130 mg, 0.50 mmol) in 10 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (285 mg, 1.00 mmol) and stirred at room temperature for 3 days. Argon was bubbled through the solution for 20 minutes. The solution was partitioned between CH2Cl2 (100 mL) and saturated sodium carbonate (15 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 2.5% MeOH/CH2Cl2 then 5-10% 2M NH3 in MeOH/CH2Cl2. A light orange solid was obtained (100 mg, 54.3%). 1H-NMR (DMSO-d6) δ: 7.67 (d, J=3.6 Hz, 1H), 7.55 (d, J=4.2 Hz, 1H), 7.08-7.05 (m, 1H), 6.56-6.48 (m, 3H), 6.25 (br s, 2H), 3.44 (dd, J=4.5, 14.4 Hz, 1H), 3.33-3.25 (m, 2H), 2.95 (dd, J=8.7, 13.8 Hz, 1H), 2.72-2.58 (m, 7H), 1.86-1.82 (m, 2H), 1.67 (br, 4H), 1.03 (d, J=6.3 Hz, 3H).
Reaction SMILES: II.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)#[N:4].COC1C=CC(S([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:24]=2[CH3:37])(=O)=O)=CC=1>CN(C=O)C>[NH4+:4].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[N:25]([CH2:33][C:34]([O-:36])=[O:35])[C:24]=2[CH3:37])=[CH:7][CH:6]=1)#[N:4]
Reactant: COc1ccc(S(=O)(=O)c2c(C)n(CC(=O)O)c3ccc(C)cc23)cc1
Reactant: N#Cc1ccc(S)cc1
Agent: II
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(Sc1ccc(C#N)cc1)c(C)n2CC(=O)[O-]
Product: [NH4+]

Procedure:
Iodine (0.51 g) was added to a solution of 4-cyanobenzenethiol (0.27 g) and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by reverse phase HPLC. The solvent was evaporated in vacuo and the oily residue treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (0.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: COc1ccc(CCl)cc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)cc1

Procedure:
Prepared from compound 1 and 4-methoxybenzylchloride as described for compound 78. Crystallized from diethyl ether. M.p. 77°-78° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=O)=[C:4]([NH:15][CH3:16])[CH:3]=1.[CH2:17]([NH2:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH2:17]([NH:19][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:9][C:10](=[O:12])[N:15]2[CH3:16])=[CH:6][N:7]=1)[CH3:18]
Reactant: CCN
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCNc1cc2c(ccc(=O)n2C)cn1
Temperature: 150 °C

Procedure:
A vial was charged with (E)-ethyl 3-(6-chloro-4-(methylamino)pyridin-3-yl)acrylate (45 mg), 70% aqueous ethyl amine (1 mL) and NMP (1 mL). The vial was sealed and heated with microwave irradiation for 35 min at 150° C. Aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (50% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 204.0 (M+1).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([S:14]N2C(=O)C=CC2=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:1]1([S:7][S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C1C=CC(=O)N1Sc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(SSc2ccccc2)cc1
Yield: 84.3 %

Procedure:
5.5 Grams (0.05 mole) of thiophenol are stirred with 10.2 grams (0.05 mole) of N-(phenylthio)maleimide in 150 ml of benzene at room temperature for 1 hour. The benzene is removed from the reaction mixture by evaporation and the residue is added to 200 ml of methanol. A white solid forms upon contact with the methanol which is recovered by filtration. The solid recovered is 9.2 grams (84% yield) of phenyl disulfide. Recrystallized from methanol, the product melts sharply at 60° C.