Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.C[Mg]Br.[CH3:16][N:17]=[C:18]=[O:19]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:16][NH:17][C:18]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[CH3:12])=[O:19]
Reactant: CN=C=O
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)[nH]c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a stirred solution of 6-methoxy-2-methyl-1H-indole (500 mg, 3.1 mmol) (prepared according to JACS 1988, 110, 2242) in 8 mL anhydrous THF maintained at room temperature was added methylmagnesium bromide (1.13 ml, 3.0 M solution in diethyl ether, 3.41 mmol). After stirring for 1 hour at room temperature, a solution of 0.5M zinc chloride in THF (7.44 ml, 3.72 mmol) was introduced and the mixture was stirred for 1 hour at room temperature before addition of methyl isocyanate (424 mg, 7.44 mmol). The resulting mixture was stirred at ambient temperature overnight, quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 2-5% MeOH in CH2Cl2 to give 200 mg product (30% yield). 1H NMR (300 MHz, CD3OD) δ7.55 (1H, d, J=8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 6.70 (1H, dd, J=2.2, 8.6 Hz), 3.73 (3H, s), 2.90 (3H, s), 2.52 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 219, found 219.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](N3CCCC(C4CCCCC4)C3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH2:5][CH2:1][CH2:2][CH3:3])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3CCCC(C4CCCCC4)C3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCO
Product: CCCCc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(3-cyclohexyl-piperidino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylene chloride/ethanol=9:1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.ClCCl.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(C(F)(F)F)ccc2N)C1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Temperature: 80 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (326 mg) and (S)-tert-butyl 3-(2-amino-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (485 mg) was dissolved in dioxane (4 ml), p-toluenesulfonic acid (26 mg) was added. The reaction mixture was heated at 80° C. for about 5 h. The mixture was diluted with dichloromethane and 10% aq. K2CO3 solution. The organic layer was separated, passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica gel; solvent:100% iso hexane→4:1 H:E).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OCC)C.Cl.[N:25]([O-])=[O:26].[Na+]>O>[N:25]([N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:26]
Reactant: COc1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(4-chlorobenzyl)-4-methoxyaniline hydrochloride salt (141.4 g; 497.5 mmol), prepared as above, in 1500 mL water, 750 mL diethyl ether, and 525 mL aqueous 1N HCl was treated with a solution of sodium nitrite (37.7 g; 547 mmol) in 150 mL water. After stirring for 2 hours at ambient temperature the reaction mixture was extracted twice with diethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to give N-nitroso-N-(4-chlorobenzyl)-4-methoxyaniline as a yellow solid.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CC2)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), cyclopropylboronic acid (78.5 mg, 0.914 mmol), saturated aqueous sodium carbonate solution (3 ml), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.0172 mmol) in dimethoxyethane (5 ml) was stirred at 90° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (70.0 mg, 39.8%) as an oil.
Reaction SMILES: [C:1]([N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].C(C(O)=O)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:24]1([C:1](=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of tert-butyl 4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 3 mmol) in CH2Cl2 (20 mL) at 0° C. was added CF3CO2H (7 mL, 91 mmol). The mixture solution was stirred (0° C., 2 h) and then 10% Na2CO3 was added to adjust pH=10. The mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (CH2Cl2: CH3OH, 20:1) to afford 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 97.5%) as a colorless oil. Mass calculated for C26H40N2O=396.61. found: [M+H]+=396.7, 398.2.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[N:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].Br[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1.CC(C)([O-])C.[K+]>CN(C)C=O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])/[N:6]([CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:5]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc(C)c(C(C)=O)s1
Reactant: BrCC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)=O)c(C)n1CC1CCC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Example 238A (0.75 g, 2.3 mmol), (bromomethyl)cyclobutane (0.31 mL, 2.8 mmol), and potassium t-butoxide (0.41 g, 3.5 mmol) in 7 mL N,N-dimethylformamide was warmed to 65° C. and stirred for 16 hours. The mixture was cooled to ambient temperature, quenched with 5 mL of saturated aqueous NH4Cl and diluted with 10 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with 7 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 40% hexanes in ethyl acetate) afforded the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.88-2.15 (m, 6H), 2.51 (s, 3H), 2.75 (s, 3H) 2.83-2.96 (m, 1H), 3.89 (s, 3H), 4.46 (d, J=7.5 Hz, 2H), 7.11 (d, J=9.2 Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS (DCI/NH3) m/z 393 (M+H)+. Anal. Calculated for C19H21ClN2O3S: C, 58.08; H, 5.39; N, 7.13. Found: C, 58.06; H, 5.20; N, 7.06
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH:20]1([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=2[F:30])[NH2:26])[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:26][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[CH:27]=[CH:28][C:29]=2[F:30])[CH2:22][CH2:21]1
Reactant: Nc1ccc(F)c(C2CC2)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(C3CC3)c2)nc(N2CCOCC2)cc1=O
Yield: 24.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 220 mg of 3-cyclopropyl-4-fluoroaniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. After extractions with ethyl acetate and silica column purification, eluent 90/10 CH2Cl2/MeOH, the residue is taken up with ml of diisopropyl ether, and the precipitate is spin-filter-dried and dried under vacuum, so as to obtain 69 mg of N-(3-cyclopropyl-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16](=[O:19])[CH2:17]Br>C(OCC)C>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)C(N)CCC2
Reactant: COC(=O)CBr
Solvent: CCOCC
Product: COC(=O)CNC1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 70 h

Procedure:
367.0 g of 1-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene are solved in 1500 ml of diethyl ether. To this solution is dropwise added a solution of 158.3 g of bromoacetic acid methyl ester in 450 ml of diethyl ether. The mixture is stirred at room temperature for 70 hours. The precipitate is separated and the solution is concentrated to dryness, yielding N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) glycine methyl ester quantitatively.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([I:23])C(=O)C1>C1COCC1>[I:23][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(I)cnn2C)cs1
Temperature: 75 °C
Reaction time: 10 h
Yield: 42.9 %

Procedure:
To a solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (700 mg, 3.15 mmol) in THF (5 mL) was added NIS (922 mg, 4.09 mmol) in one portion. The reaction mixture was stirred at 75° C. for 10 h, and then cooled to room temperature. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-20%) to give the title compound (470 mg, 43%) as an off white solid: LC-MS (ES) m/z 350 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:26])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](N(OC)C)=[O:21])=[N:12]3)[C:4]=2[O:3]1.[CH3:27][Mg+].[Br-]>C1COCC1>[C:20]([C:13]1[C:14](=[O:19])[C:15]([O:17][CH3:18])=[CH:16][N:11]([C:10]2[C:4]3[O:3][C:2]([F:26])([F:1])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[N:12]=1)(=[O:21])[CH3:27]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (2.7 g, 7.2 mmol) in THF (70 mL) was added dropwise 1 M MeMgBr in THF (14 mL, 14 mmol) at −78° C. for 15 min. After stirring at −78° C. for 1 h, the mixture was quenched with 1 M HCl aqueous solution (30 mL). The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.3 g, 99% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.95 (3H, s), 7.17 (1H, dd, J=7.9, 1.1 Hz), 7.26-7.32 (1H, m), 7.55 (1H, dd, J=8.7, 1.1 Hz), 8.00 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 73 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:18]>CC(CC)=O>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([SH:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: Clc1ccc(OCc2ccccc2)nn1
Solvent: CCC(C)=O
Product: Sc1ccc(OCc2ccccc2)nn1
Yield: 15.2 %

Procedure:
A mixture of 3-benzyloxy-6-chloro-pyridazine (18.2 mmol, 4 g), thiourea (36.3 mmol, 2.8 g) and ethyl methyl ketone (75 mL) was refluxed overnight. Excess ethyl methyl ketone was evaporated, the residue was extracted with 2M sodium hydroxide (25 mL) and the sodium hydroxide solution was washed with EtOAc (2×30 mL). The aqueous layer was collected and sufficient conc. HCl was added to bring the pH to 5 and extracted with EtOAc (2×30 mL). The EtOAc extract was collected, dried, filtered and the filtrate was evaporated to yield 3-benzyloxy-6-mercapto-pyridazine (15%, 605 mg); mp 155° C.-157° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:17]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)#[N:18]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2cc(CCl)ccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2cc(CC#N)ccc2o1
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A mixture of ethyl 5-chloromethylbenzofuran-2-carboxylate (3.0 g, 0.0126 mol), sodium cyanide (1.23 g, 0.025 mol), tetrabutylammonium bromide (0.50 g, 0.0013 mol), water (10 cm3) and dichloromethane (10 cm3) was vigorously stirred for 18 hr. at room temperature. The mixture was separated and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give ethyl 5-cyanomethylbenzofuran-2-carboxylate (1.92 g, 0.0084 mol, 66.6%) m.p. 76°-77° C.-t.l.c./silica/toluene, RF 0.11.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](S(C)(=O)=O)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH3:31][NH:32][CH3:33]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([N:32]([CH3:33])[CH3:31])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N(C)C)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Add 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (100 mg, 0.23 mmol) to 3 mL of 2N dimethylamine in THF and stir under nitrogen at room temperature for 90 minutes. Evaporate to a tan solid which is used without further purification. MS(ES+, m/e)=402 (M++1); HPLC=89%.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][C:7]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:8][N:9]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH:1]([S:4]([C:5]1[S:6][C:7]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:8][N:9]=1)=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1nnc(S(=O)(=O)C(C)C)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)c1nnc(S(=O)(=O)C(C)C)s1

Procedure:
13.3 g 2-isopropylthio-5-isopropylsulfonyl-1,3,4-thiadiazole are dissolved in 50 ml dichloromethane and to the solution is added drop by drop at 10° to 15° C. under agitation and cooling a solution of 8.63 g m-chloroperbenzoic acid in 200 ml dichloromethane. The reaction mixture is stirred for another thirty minutes, then extracted with aqueous soda ash solution for removing the m-chlorobenzoic acid, the organic phase is separated and dried with magnesium sulfate. After distilling off the solvent a residue is obtained, which is recrystallized from acetonitrile.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-])=O)=[CH:18][N:19]=1)[C:13]([NH:15][CH3:16])=[O:14])[CH2:3][CH2:2]2.[H][H]>CO.[Pd]>[NH2:20][C:17]1[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][C:10]([N:4]2[CH:5]3[CH2:6][CH2:7][N:1]([CH2:9][CH2:8]3)[CH2:2][CH2:3]2)=[N:19][CH:18]=1
Reactant: [H][H]
Reactant: CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1N
Reaction time: 8 h

Procedure:
To a solution of 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-5-nitroisonicotinamide (Intermediate 28A) (50 mg, 0.16 mmol) in methanol (0.3 mL) under nitrogen was added palladium on carbon (25 mg). Reaction subjected to a hydrogen atmosphere and stirred overnight. The reaction mixture was filtered and concentrated to afford 5-amino-2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methylisonicotinamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:16][CH2:17]1
Reactant: Clc1nccs1
Reactant: c1ccc2cc(CN3CCNCC3)ccc2c1
Solvent: CN(C)C=O
Product: c1ccc2cc(CN3CCN(c4nccs4)CC3)ccc2c1
Yield: 54.9 %

Procedure:
In a manner similar to that described above, but starting from 45.2 g (0.2 mole) of 1-(2-naphthylmethyl)-piperazine and 12 g (0.1 mole) of 2-chlorothiazole in 150 ml of dimethylformamide at 150° C., there were obtained 17 g of 1-(2-naphthylmethyl)-4-(2-thiazolyl)-piperazine as beige crystals melting at 83°-84° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16](=[S:18])[NH2:17])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].[F:24][C:25]([F:31])([F:30])[C:26]([CH2:28]Br)=[O:27]>O1CCCC1>[Br:1][C:2]1[C:3]([C:16]2[S:18][CH2:28][C:26]([OH:27])([C:25]([F:31])([F:30])[F:24])[N:17]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(C(N)=S)c(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a 2 L round bottom flask was charged tert-butyl 5-bromo-4-carbamothioylpyridin-2-ylcarbamate (Intermediate 85, 50 g, 151 mmol) in tetrahydrofuran (800 mL), then solid sodium bicarbonate (25.4 g, 302 mmol) was added followed by 1,1,1-trifluoro-3-bromoacetone (31 mL, 290 mmol). The resulting mixture (yellow suspension) was allowed to stir at room temperature overnight. The white suspension was filtered and the solid was washed with water (2.2˜2.5 L). The white solid was dried under vacuum to give 56.8g of white powder (85%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:21][C:18]1([CH3:22])[O:17][CH:16]([CH2:15][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]3)[CH2:20][O:19]1
Reactant: CC1(C)OCC(CCl)O1
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OCC1COC(C)(C)O1)CCC2=O
Temperature: 95 °C
Reaction time: 72 h

Procedure:
A mixture of 5-Hydroxy-6-indan-1-one, Intermediate H, (0.50 g, 0.0028 mol), 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (0.766 mL, 0.0056 mol), potassium carbonate (1.54 g, 0.011 mol) and DMF (20.0 mL) was stirred at 95° C. for 3 days. Water (150.0 mL) was added and the mixture was extracted with ethyl acetate (2×150 mL). The organic layer was washed with sat. NaHCO3, brine and dried over Na2SO4. The solvent was then removed in vacuo to yield 5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methoxy-indan-1-one (Intermediate I) as light brown solid. MS m/z 293 (M+H)+.