Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:6]2.Cl.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:33][C:19]([F:18])([F:32])[C:20]1[CH:21]=[C:22]([C:26]2[CH2:31][CH2:30][N:29]([C:14](=[O:16])[CH2:13][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH2:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc2cc(CC(=O)O)ccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(CC(=O)N3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1
Yield: 81 %

Procedure:
A solution of 6-methoxy-2-naphthylacetic acid (1.8 g, 0.009 mol), 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (2.4 g, 0.009 mol), triethylamine (2.4 ml, 0.018 mol), and BOP (3.7 g, 0.009 mol) in methylene chloride (40 ml) is stirred at room temperature for 5 hours. Then it is concentrated to dryness, the obtained residue is dissolved in a mixture ethyl ether/water, the organic phase is separated, and washed sequentially with 1N HCl, water, 5% NaOH, and water. The reaction mixture is then filtered over silica and the filtrate is concentrated to dryness affording 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)ethane (3.1 g). M.p. 102°-105° C.
Reaction SMILES: [CH2:1]([C:7]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]2[CH:18]=[C:17]3[CH:20]=[C:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.C(N)(C)(C)C.[C:40]([NH:44][Si:45](C1C2C(=CC3C(CCCCCC)(CCCCCC)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:47])[CH3:46])([CH3:43])([CH3:42])[CH3:41]>C(OCC)C>[C:40]([NH:44][Si:45]([CH:20]1[C:17]2=[CH:18][C:19]3[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]4[C:13]([C:14]=3[CH:15]=[C:16]2[CH:22]=[C:21]1[CH3:23])=[CH:12][CH:11]=[CH:10][CH:9]=4)([CH3:47])[CH3:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3[Si](C)(C)NC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)(C)N
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C([Si](C)(C)NC(C)(C)C)C(C)=C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
In a 500 mL round flask, 9,9-dihexyl-2-methyl-3,9-dihydrocyclopenta[b]fluorene (40.0 g, 103.5 mmol) was dissolved in 320 mL of diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (2.5 M hexane solution, 42 mL) was slowly injected thereinto, followed by stirring at room temperature for 12 hours. After volatile materials were removed by vacuum, 350 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (40 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 500 mL round flask and dissolved in 320 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (22.7 g, 310.4 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of n-hexane was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, thereby obtaining 48 g of a mixture of N-tert-butyl-1-(9,9-dihexyl-2-methyl-3,9-dihydrocylopenta[b]fluoren-3-yl)-1,1-dimethylsilanamine and N-tert-butyl-1-(9,9-dihexyl-2-methyl-1,9-dihydrocylopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (ratio=˜1:1), (yield: 88.9%), as a highly viscous material.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH:13](I)(I)[I:14]>O1CCCC1.C(Cl)Cl>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[CH:13][I:14])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNc2nc(Br)ccc21
Reactant: IC(I)I
Solvent: ClCCl
Solvent: C1CCOC1
Product: Brc1ccc2c(n1)NCCC2=CI
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (1.5 g) in anhydrous tetrahydrofuran (195 mL) was added a solution of CrCl2 (6.79 g, 8.35 eq) and CHI3 (5.55 g, 2.13 eq) in anhydrous tetrahydrofuran (66 mL). The reaction was stirred at room temperature for 16 hours, diluted with methylene chloride (300 mL), and then washed with saturated NaHCO3 (300 mL). The aqueous phase was extracted twice with methylene chloride (100 mL) and the combined organic layers were washed with brine and then dried over Na2SO4. The solution was filtered and concentrated under reduced pressure. Silica gel chromatography using a gradient of 0-30% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (27% yield). Alkene geometry was determined by nOe. LCMS: m/z=352 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.69 (t, J=6.0 Hz, 2H), 3.43-3.51 (m, 2H), 5.25 (bs, 1H), 6.23 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:27]1([S:33]([NH:1][CH2:2][C:3]([N:5]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:9](=[O:15])[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]3[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=3)=[O:4])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CNS(=O)(=O)c2ccccc2)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of (3aR*,10aS*)-4-aminoacetyl-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (0.2 g, 0.57 mmol) and benzenesulfonyl chloride (0.12 g, 0.69 mmol) in dichloromethane (10 mL) was added triethylamine (70 mg, 0.69 mmol). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with dichloromethane. The extract was washed with water and dried, then, the solvent was distilled off. The residue was purified by silica-gel column chromatography (dichloromethane), which was crystallized from diethyl ether to give 170 mg (yield 61%) of the titled compound, m.p. 185°-187° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:34]=[CH:33][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1>>[NH:12]1[CH:11]=[CH:10][N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:15]2[C:14]([CH3:13])=[CH:34][CH:33]=[C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)=[O:19])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1-c1ccc(-c2ncc[nH]2)cc1

Procedure:
Example 4 was prepared using 2-(4-bromophenyl)-1H-imidazole and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[N:16]1([C:22]2[N:23]=[C:24]3[NH:32][C@H:31]([C:33]([F:36])([F:35])[F:34])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:32]2[C:24]3=[N:23][C:22]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:27][C:26](=[O:28])[N:25]3[CH2:29][CH2:30][C@H:31]2[C:33]([F:34])([F:35])[F:36])=[CH:10][CH:11]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccc(F)cc1
Temperature: 80 °C

Procedure:
0.536 g of caesium carbonate and 0.44 ml of 1-(bromomethyl)-4-fluorobenzene are added, under an argon atmosphere, to a solution of 300 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 3 ml of acetonitrile. The resulting mixture is then heated at 80° C. for 2 hours. The reaction mixture is then evaporated under reduced pressure and the residue obtained is then purified by silica chromatography (eluent: CH2Cl2/MeOH 98/02) so as to give 61 mg of (8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.CC(C)([O-])C.[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:10]1[CH2:11][CH2:12][CH:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]1=[O:13]
Reactant: O=C1NCCC1Cc1ccccc1
Reactant: BrCCCCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(Cc2ccccc2)CCN1CCCCBr
Reaction time: 18 h

Procedure:
To a solution of 3-(phenylmethyl)-2-pyrrolidinone (0.23 g, 1.3 mmol) and 1,4-dibromobutane (0.57 g, 4.2 mmol) in DMF (5 ml) was added sodium t-butoxide (0.151 g, 1.6 mmol) and the solution stirred for 18 h. The solution was concentrated and the residues chromatographed over silica (20 g SPE, eluting first with cyclohexane then with DCM) to provide the title compound as a colourless oil containing a trace of DMF (0.25 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.C(O[CH:12]=[C:13]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])C>C1(C)C=CC=CC=1>[C:17]1([S:14]([C:13]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:12][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:12]=[C:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:15])=[O:16])[S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[N:3]=2)(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(N)n1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(C(=CNc1cccc(NC=C(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)n1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 22.7 %

Procedure:
A stirred mixture of 2,6-diaminopyridine (0.3 g) and 2-ethoxy-1,1-bis(phenylsulphonyl)ethene (2.1 g) in toluene (50 ml) was heated at reflux for 2 hours. The mixture was cooled, and concentrated in vacuo, and the resulting solid was subjected to medium pressure chromatography on silica gel, eluting with acetone, to give 2,6-bis[2,2-bis(phenylsulphonyl)ethen-1-ylamino]pyridine (0.45 g), in the form of a white powder, m.p. 299°-300° C.
Reaction SMILES: C=O.[C:3](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:17]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH:18]1[CH2:26][NH:27][C:28]([C:30]1[C:31]([NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([Cl:52])[CH:45]=2)=[N:32][C:33]([N:36]2[CH2:41][CH:40]3[CH:38]([CH2:39]3)[CH2:37]2)=[N:34][CH:35]=1)=[O:29]>C1COCC1>[CH:38]12[CH2:39][CH:40]1[CH2:41][N:36]([C:33]1[N:32]=[C:31]([NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([Cl:52])[CH:45]=3)[C:30]([C:28]([NH:27][CH2:26][CH:18]3[CH2:19][C:20]4([CH2:21][CH2:22][N:23]([CH3:3])[CH2:24][CH2:25]4)[CH2:17]3)=[O:29])=[CH:35][N:34]=1)[CH2:37]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCNCC3)C2)cc1Cl
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCN(C)CC3)C2)cc1Cl
Reaction time: 1 h
Yield: 21 %

Procedure:
In THF (20 mL) was dissolved the above N-(7-azaspiro[3.5]nonan-2-ylmethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-formamide. Formalin (1 mL) was added. The reaction was conducted at ambient temperature for 1 h, sodium triacetoxyborohydride (134 mg, 0.63 mmol) was added and the reaction was continued for 4 h. The reaction was quenched with water. The reaction mixture was filtrated. The organic phase was dried and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methyl) pyrimidine-5-formamide (39 mg, 21% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:12][CH3:17])=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(C(C)(C)C)cc(Br)cc1C(C)(C)C
Yield: 107.1 %

Procedure:
Under argon atmosphere, to a solution of 4-bromo-2,6-di-tert-butylphenol (50 g, 0.175 mol) and potassium carbonate (96.7 g, 4.0 equivalents) in acetone (750 mL) was added dimethyl sulfate (38.6 g, 1.75 equivalents) at 22° C. The mixture was stirred under reflux for 13 hours. Insoluble substances were filtered off and the solvent was distilled off under reduced pressure. By adding ethyl acetate (150 mL) and water (100 mL) to the residue, the reaction mixture was allowed to separate into layers. An organic layer was washed successively with water (100 mL), a 5% NaHCO3 aqueous solution (100 mL) and a 5% NaCl aqueous solution (100 mL), dried over anhydrous magnesium sulfate and then naturally filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (56.1 g, brown oil). Yield 95.2%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C:19]([C@@H:15]2[CH2:16][CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14]2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine (2.134 g, 30 mmol) in N,N-dimethylformamide (240 mL) was added (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (6.878 g, 30 mmol). Then hydroxybenzotriazole (1.028 g, 6 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (5.751 g, 30 mmol), and triethylamine (7.59 g, 75 mmol) were added sequentially. The mixture was stirred at 30° C. for 16 h. The solvent was removed under reduced pressure and an aqueous solution of sodium bicarbonate (200 mL, 0.1M) was added. The mixture was extracted with ethyl acetate (200 mL×3) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate, which was used in the next step without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26]CC)=[O:25].[O-]CC.[Na+].O>C(O)C>[N:13]1([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:22]([CH2:29][CH2:30][CH3:31])=[C:23]([C:24]([OH:26])=[O:25])[N:3]=[N:2]3)=[CH:20][CH:19]=2)=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCCCC2)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
4-Azido-N-(2-piperidin-1-ylethyl)benzamide obtained in Example 62a) and ethyl 3-oxohexanoate (1.08 ml, 6.44 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (487 mg, 6.44 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 13 hr. Water (40 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was washed twice with ethyl acetate-hexane (2:1, 50 ml). The aqueous layer was neutralized (pH 6-7) with 6N hydrochloric acid and concentrated. The residue was dissolved in isobutanol, THF and ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate and THF were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale-brown powder (purity 90%, 2.05 g, 4.78 mmol, 92.9%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:11][CH3:12])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: CCI
Reactant: Cc1cscc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cscc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Methyl-3-thiophenecarboxylic acid (1.42 g) (synthesized in accordance with the method described in J. Org. Chem., 51, 230 (1986)) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.8 ml) and potassium carbonate (1.38 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water. and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-methyl-3-thiophenecarboxylate (1.7 g). Ethyl 4-methyl-3-thiophenecarboxylate (1.7 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.2 ml) in acetonitrile (20 ml) was added. The mixture was stirred at room temperature for 1 hour, and then 10% aqueous sodium thiosulfate (100 ml) was added and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and ethyl 2,5-dichloro-4-methyl-3-thiophenecarboxylate. The mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and 2,5-dichloro-4-methyl-3-thiophenecarboxylate was dissolved in ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours, and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-4-methyl-3-thiophenecarboxylic acid and 2,5-dichloro-4-methyl-3-thiophenecarboxylic acid. The mixture was suspended in toluene (15 ml). Oxalyl chloride (1.31 ml) was added dropwise and then N,N-dimethylformamide (1 drop) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and added dropwise into a mixture of 25% aqueous ammonia solution (16 ml) and ethyl acetate (50 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature for 10 minutes. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-4-methyl-3-thiophenecarboxamide (0.83 g) and 2,5-dichloro-4-methyl-3-thiophenecarboxamide (0.61 g).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[O:1]1[C:9]2[C:4](=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cnc2ccoc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc2occc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of Furo[3,2-b]pyridine (1.5 g, 13.0 mmol) in CHCl3 (30 mL) was added MCPBA (2.9 g, 17.0 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was filtered through a alumina (140 g, basic) and washed with ethyl acetate/hexane (1:1) and DCM/MeOH (20:1) to give Furo[3,2-b]pyridine 4-oxide (1.49 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 8.25 (m, 1H), 7.81 (m, 1H), 7.51 (m, 1H), 7.23 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[S:27])[NH:16][CH3:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cnn(-c2cccc(Cl)c2)c1Cl
Solvent: Cc1ccccc1
Product: CNC(=S)c1cnn(-c2cccc(Cl)c2)c1Cl
Yield: 56 %

Procedure:
A solution of 3.0 g of 5-chloro-1-(3-chlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide and 6.5 g of Lawesson's Reagent in 150 ml toluene was refluxed for one hour. The solution was cooled and the volatiles were removed under reduced pressure. The residue was chromatographed over silica gel eluting with methylene chloride. The fractions containing the major component were combined and the solvent was evaporated therefrom to afford 1.6 g, following recrystallization from toluene, of 5-chloro-1-(3-chlorophenyl)-N-methyl-1H-pyrazole-4-thiocarboxamide. Yield 56%. mp=128°-130° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)=[CH:30][CH:29]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 61 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 4-[(4-methylpiperazin-1-yl)methyl]aniline (260 mg, 1.3 mmol) to afford the desired product (250 mg, 58%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 11.04 (br s, 1H), 9.01 (s, 1H), 8.14 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 3.52 (s, 2H), 2.58 (s, 3H), 2.48 (br s, 8H), 2.30 (s, 3H); ESI MS m/z 410 [M+H]+