Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.C(O[K])=O>O.C1COCC1.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Agent: [Pd]
Agent: O=CO[K]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
To a suspension of 2-((4-(4-nitrophenoxy)quinolin-7-yl)oxy)ethanol (0.32 g, 1 mmol), HCOOK (0.59 g, 7 mmol) in water (1 mL) and THF (3 mL) was added 10% Pd/C (0.03 g). The reaction was stirred at 45° C. for 4 hours. The mixture was diluted with EtOAc (5 mL), filtered through a Celite pad. The filtrate was concentrated in vacuo, washed with a mixture of 95% ethanol (1 mL) and water (5 mL). The solid was collected by filtration and dried in vacuo at 50° C. overnight to give the title compound as a pale yellow solid (140 mg, 47.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([NH:11][NH2:12])[N:5]=1)[CH3:2].[C:13](=S)=[S:14].OO.C(N(CC)CC)C.Cl>O.C(#N)C>[CH2:1]([O:3][C:4]1[N:5]2[C:13](=[S:14])[NH:12][N:11]=[C:6]2[CH:7]=[C:8]([F:10])[N:9]=1)[CH3:2]
Reactant: S=C=S
Reactant: CCOc1nc(F)cc(NN)n1
Agent: Cl
Agent: OO
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1nc(F)cc2n[nH]c(=S)n12

Procedure:
A mixture containing approximately 5.2 g (30 mmol) of 2-ethoxy-4-fluoro-6-hydrazinopyrimidine in a solvent composed of 50 mL of acetonitrile and 15 mL of water was prepared and to this was added 6.4 mL (107 mmol) of carbon disulfide at ambient temperature with stirring. The heterogeneous white mixture became a pale yellow solution after about 10 min and then 3.8 mL of 30 percent aqueous hydrogen peroxide (37 mmol) and 3.2 mL of water were added over a 30-min period with stirring and cooling to hold the temperature at about 25° C. The mixture was allowed to react another 10 min and then 3.22 g (32 mmol) of triethylamine was added and the resulting mixture filtered to remove sulfur. The filtrate was acidified with 10 mL of 3.75N hydrochloric acid (38 mmol). The resulting mixture was filtered to recover the precipitate that formed. This was washed with water and dried to obtain 4.4 g (66 percent of theory) of the title compound of 97 percent purity as a light beige solid melting at 170° C. Considerable product remained in the filtrate.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[CH:2]1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[CH:16]=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH:11][C:13]3[N:18]=[C:17]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[NH:22][N:21]=4)[CH:16]=[CH:15][N:14]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: NCc1cncc2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cncc3[nH]ccc23)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
A mixture of (1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine (236 mg, 1.61 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (344 mg, 1.46 mmol) and DIPEA (565 mg, 4.38 mmol) in IPA (2 mL) was stirred in a sealed tube at 120° C. for 18 h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude residue was purification by preparative HPLC to afford 56 mg (11.1%) of the title compound as white solid: 1H NMR (500 MHz, CD3OD) δ 8.64 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.59 (d, J=3.0, 1H), 6.72 (d, J=3.0, 1H), 6.17-5.96 (m, 2H), 4.92 (s, 2H), 1.75 (s, 1H), 0.85 (d, J=4.5, 2H), 0.51 (s, 2H); MS (ESI) m/z: 347.2 [M+1]+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)([O-:18])=[O:17]>C(#N)C>[N+:16]([C:19]1[CH:27]=[CH:26][C:25]2[C:21](=[CH:22][N:23]([CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[N:24]=2)[CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 g (62.0 mmol) 1-(2-chloroethyl)-pyrrolidine hydrochloride and 12.9 g (93.0 mmol) K2CO3 are added successively to a solution of 5.00 g (31.0 mmol) 5-nitroindazole in 100 mL acetonitrile. The reaction solution is stirred for 2 h at RT and refluxed for a further 5 h. After the solution has cooled the insoluble salts are filtered off and the solvent is eliminated i.vac. The residue is taken up in EtOAc and water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. A 4:1 mixture of 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole and 5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole is obtained. The purification is carried out by column chromatography on Alox (PE/EtOAc 3:2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.Cl.C(Cl)(=O)C>CO>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)cnn3C2CCCCO2)c1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]ncc3cn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
At 0° C. (with ice-bath) to a stirring solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.78 g, 1.9 mmol) in methanol (10 mL) was added drop-wise a pre-cooled (with ice-bath) HCl solution prepared from acetyl chloride (2.72 mL, 38.2 mmol) in methanol (15 mL). After the addition, the ice-bath was removed. The mixture was stirred at r.t. for 2 h, and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.62 g). LC/MS (M+H)+=324.0.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:49])([F:48])[C:22]1[C:26]([CH2:27]O)=[CH:25][N:24]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Br:51][CH2:27][C:26]1[C:22]([C:21]([F:49])([F:48])[F:20])=[N:23][N:24]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
Triphenylphosphine (0.54 g, 2.1 mmol) was added to a solution of (3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)-methanol (0.6 g, 1.5 mmol) in dichloromethane (25 mL). The resulting solution was cooled to −20° C. and a solution of carbon tetrabromide (0.54 g, 1.6 mmol) in dichloromethane (5 mL) was added in four portions. The solution was stirred for 5 min at −20° C. and then at for 3 h at 0° C. Further portions of triphenylphosphine (0.17 g, 0.65 mmol) and carbon tetrabromide (0.24 g, 0.72 mmol) were added. The solution was stirred for 3 h, and further portions of triphenylphosphine (0.54 g, 2 mmol) and carbon tetrabromide were added. The solution was stirred for 30 min and then the solvent was evaporated and the residue purified by flash chromatography, eluting with 5-10% ethyl acetate/petroleum ether to give 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole (0.30 g, 43%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].ClC(Cl)(O[C:18](=[O:24])[O:19][C:20](Cl)(Cl)Cl)Cl.[N-:26]=[C:27]=[O:28]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:27]([NH:26][C:3]1[C:4]2[NH:5][C:18](=[O:24])[O:19][C:20]=2[CH:8]=[CH:9][CH:2]=1)=[O:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: [N-]=C=O
Reactant: NCc1ccc(C(F)(F)F)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1F)Nc1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 11 %

Procedure:
Commercially available 2-fluoro-4-trifluoromethylbenzylamine (0.5 ml, 3.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.12 g, 3.7 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added drop wise to a solution in DMF (5 ml) of compound 1b (360 mg, 2.4 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 100 mg of a white solid. Yield=11% 1HNMR (DMSO, 400 MHz) δ 4.43 (2H, d, J=6 Hz), 6.99 (3H, m), 7.05 (1H, m), 7.62 (3H, m), 8.53 (1H, bs), 10.98 (1H, bs); [M+1] 370.1 (C16H11F4N3O3 requires 369.27).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17][N:18]=[N+]=[N-])(=[O:14])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17][NH2:18])(=[O:13])=[O:14])[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)C(NS(=O)(=O)CCCN=[N+]=[N-])C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NS(=O)(=O)CCCN)C(=O)OCC
Yield: 105.3 %

Procedure:
A solution of 3-azidopropanesulfonamidomalonate diethyl ester (27.60 g, 0.086 mol,) in ethanol (70 mL) and 1 g of Pd/C (10%) were placed in a Parr hydrogenation apparatus under 60 psi H2 for 8 hours. The hydrogen was replenished every 2 hours. The mixture was filtered through a pad of Celite and a solution of 1 N HCl in ethanol (10 mL) was added to the filtrate. The solvent was removed in vacuo and the residue was purified by column chromatography on Al2O3 using CH2Cl2/MeOH (4/1, v/v) to give 26.84 g of the title compound as the hydrochloride salt: 1H NMR (CDCl3) δ 1.30 (t, 6, CH3), 2.12 (m, 2, OCH2CH3), 3.21 (t, 2, CH2), 3.50 (t, 2, CH2), 4.26 (m, 4, OCH2CH3), 4.84 (d,1, CH), 6.09 (d, 1, NH), 8.29 (br.s, 2, NH3). 13C NMR (CDCl3) 613.6, 26.3, 42.5, 51.2, 58.5, 62.7, 165.9.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CON(C)[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([CH3:24])[CH2:21][C:20]([C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)=[O:25]
Reactant: CON(C)C(=O)CC(C)C
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Product: CC(C)CC(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 29a from 6-bromo-2-phenyl-benzoxazole and N-methoxy-3,N-dimethyl-butyramide.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][C:4]=1[CH3:10].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH3:9])[C:3]=1[CH2:2][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cc1cncc(C)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(C)cncc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a 0° C. mixture of 4-(bromomethyl)-3,5-dimethylpyridine (18.6 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.7 g, 12 mmol) in absolute ethanol (170 mL) was added triethylamine (8 mL, 57.4 mmol). The mixture was stirred at room temperature overnight. The solid precipitate was removed by filtration. Diethyl ether (300 mL) was added to the filtrate. The precipitate was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (1×50 mL). The residue was treated with water (300 mL). The solid material was recovered by filtration, washed with water (4×30 mL), diethyl ether (3×30 mL) and hexanes (2×30 mL), and dried in vacuo, affording 2-{[(3,5-dimethylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.78 g, 57% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][S:6]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1)(=[O:8])=[O:7].ClC1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:30]=[C:29]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:42]=3[N:41]=[C:40]2[CH:50]([F:52])[F:51])[N:28]=1.CCN(C(C)C)C(C)C>CO.C1COCC1.[Pd]>[F:52][CH:50]([F:51])[C:40]1[N:39]([C:29]2[N:30]=[C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:32]=[C:15]([N:12]3[CH2:11][CH2:10][CH:9]([S:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:25])(=[O:7])=[O:8])[CH2:14][CH2:13]3)[N:28]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:42]=2[N:41]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(S(=O)(=O)NCCN(C)C)CC2)n1

Procedure:
The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. After removal of the solvent, the residue was combined with 0.48 g (1.2 mmol) 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and 0.35 g (2.7 mmol) DIPEA in THF. The mixture was heated under reflux for 1 hr and the solvent was concentrated. After dilution with water, the resulting solid was collected and dried. Chromatography on alumina, eluting with EtOAc, gave 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide: mp (MeOH) 231-234° C.; 1H NMR (CDCl3) δ 7.87 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.91 (br d, J=13.3 Hz, 2H), 4.04 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.25-3.17 (m, 3H), 3.00 (m, 2H), 2.45 (br t, J=5.7 Hz, 2H), 2.27 (m, 2H), 2.23 (s, 6H), 1.83 (dq, J=12.5, 4.4 Hz, 2H); Anal. Calcd. for C25H35F2N9O4S: C, 50.4; H, 5.9; N, 21.2. Found: C, 50.2; H, 5.7; N, 21.3%.
Reaction SMILES: O[C:2]1[CH:7]=C[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)[NH:33]C(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=CC=CN=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N:33]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Brc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3ccccn3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.17 mmol) (Example 82) was coupled with 2-bromopyridine (25 mg, 0.17 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-5-(2-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 42 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].ClCCl.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1c[nH]c2c(C)nc(C)cc2c1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C(=O)OCc2ccccc2)c2c(C)nc(C)cc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
6,8-Dimethyl-4-oxo-1,4-dihydro-[1,7]naphthyridine-3-carboxylic acid ethyl ester (0.2 g, 0.628 mmol), prepared in step (ii), and dichloromethane (10 mL) were added to a 50 mL round bottom flask. This mixture was cooled to 0° C. and stirred, and triethylamine (0.19 g, 1.88 mmol) was then added to the mixture dropwise. Stirring of the reaction mixture was continued at the same temperature for another 0.5 h, after which time benzyl chloroformate (0.16 g, 0.943 mmol) was added to the mixture. The temperature was allowed to increase to RT, and stirring was continued at this temperature for 2 h. Water was added to the reaction mixture and the mixture was extracted with dichloromethane (2×25 mL). The combined organic phase was washed with brine, dried over sodium sulfate, and the organic solvent was evaporated to provide a residue. This residue was purified by column chromatography over 100-200 mesh silica gel, used 5% MeOH and chloroform as eluent, to provide the compound as a yellow solid (0.1 g, 42%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]1([C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]=2[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2[nH]cnc2c1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccccc1)n1cnc2c(Br)cc(C(F)(F)F)cc21
Temperature: 100 °C

Procedure:
To a solution of 4-bromo-6-trifluoromethylbenzimidazole (1.00 g, 3.77 mmol) in DMF (10 mL) was added potassium carbonate (520 mg, 3.77 mmol) and ethyl phenylpropiolate (690 μL, 4.15 mmol). The suspension was then warmed to 100° C. for 4 hours, cooled to room temperature, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99:1), to afford the title compound as a mixture of geometric isomers (ca. 6:1 as determined by 1H NMR). 1H NMR: (CDCl3) of the mixture, 8.16 (s), 8.13 (s), 7.76 (br), 7.57-7.17 (m), 6.61 (s), 6.30 (s), 4.18 (q, J=7.32), 4.07 (q, J=7.32), 1.21 (t, J=7.32), 1.10 (t, J=7.32).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1)=[O:11].[CH2:18]([N:25]([CH2:31]OC)[CH2:26][Si](C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:8][O:9][C:10]([C@@:12]12[CH2:31][N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C@@H:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11]
Reactant: COC(=O)C1=CCCCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]12CCCC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclohexene-1-carboxylic acid methyl ester (25.0 g, 178 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (46.6 g, 196 mmol) in 1,2-dichloroethane (178 mL) at room temperature, and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution (200 mL) was added to the reaction solution, followed by extraction with chloroform (150 mL×1, 100 mL×1). The organic layer was washed with brine (450 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→85:15→75:25) to give 21.3 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:23][CH:20]2[CH2:22][CH2:21]2)=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC2CC2)s1

Procedure:
3.8 g (0.014 mole) of 2-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-1,3,4-thiadiazole and 1.0 g (0.018 mole) of cyclopropylamine are reacted by the method described in Example 1. 2.2 g (48% of theory) of yellow crystals are obtained from toluene; melting point 144°-145° C.
Reaction SMILES: [CH2:1]([NH2:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][NH2:11].[S:13](Cl)([C:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:21]([N:22]([CH3:24])[CH3:23])[C:20]=2[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>C(#N)C>[NH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][CH2:1][NH:12][S:13]([C:16]1[C:28]2[C:20](=[C:21]([N:22]([CH3:24])[CH3:23])[CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: NCCCOCCOCCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: O
Solvent: CC#N
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCOCCOCCCN)cccc12
Reaction time: 1.5 h
Yield: 60.7 %

Procedure:
4,7-Dioxadecane-1,10-diamine (32.6 g, 0.185 mole) in acetonitrile (100 mL) was chilled in an ice bath. To this was slowly added dropwise dansyl chloride (5 g, 0.0185 mole) dissolved in acetonitrile (60 mL) over a 20 min. period. Stirring in an ice bath was continued for 1.5 hr. The reaction mixture was poured into water (about 300 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were washed with water and dried to give an oil. The oil was purified by column chromatography (silica gel eluting with acetonitrile containing increasing amounts of ethanol) to provide 4.6 g of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonapthalene-1-sulfonamide as a viscous oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:10](=[O:11])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:8][C:7]1=[O:17].[H-].[Na+].I[CH2:21][CH2:22][CH3:23]>CN(C)C=O.O>[CH2:21]([N:8]1[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10](=[O:11])[N:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:7]1=[O:17])[CH2:22][CH3:23]
Reactant: O=C1NC2(CCCCC2)C(=O)N1c1nccs1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(c2nccs2)C(=O)C12CCCCC2
Reaction time: 1 h
Yield: 67 %

Procedure:
5.05 g of the product from Example 2, stage 2 were dissolved in 20 ml of dimethylformamide. 1.10 g of sodium hydride (50% suspension in mineral oil) were added in portions with stirring at 200C. After 1 hour's stirring, 4 ml of 1-iodopropane were added. Stirring was continued for a further 3 hours. The mixture was then diluted with 100 ml of distilled water, extracted three times with 30 ml portions of ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulphate. Once the solvent had been removed by distillation, the residue was purified by passage through a silica gel column with ethyl acetate/n-hexane=8/5. 3.95 g of l-propyl-3-thiazol-2-yl-1,3-diazaspiro[4.5]decane-2,4-dione (67% of th.) were obtained in the form of white crystals (mp 135-138° C.).