Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=2)=[CH:9][C:10]#[N:11])[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(F)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(F)c2)c1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (3.4 mL, 22 mmol) in THF (30 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 21 mL, 21 mmol) dropwise. The mixture was stirred at room temperature for 40 min. (3,5-Dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone (3.1 g, 11 mmol) was added to the mixture. The mixture was refluxed for 4 h. The solution was poured into ice water (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3,5-dimethoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrile as an off-white solid (2.9 g, 86% yield) (isomer ratio is 1:0.7 by HNMR): mp: 91-93° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 6H, 2CH3), [3.76 and 3.87 (2s)], 3.92 (s, 3H, CH3), 6.29 (s, 1H, CH), [6.33 (s)], 6.45-6.47 (m, 2H, Ar), 6.62-6.66 (m, 1H, Ar), 7.08-7.41 (m, 3H, Ar); 13C NMR (DMSO-d6) δ 55.42, 56.11, 56.19, 95.17, 96.31, 101.12, 102.04, 106.69, 107.12, 113.64, 113.72, 113.74, 114.85, 115.16, 116.59, 116.89, 117.98, 118.08, 125.53, 125.58, 126.23, 126.28, 129.18; 129.29, 129.95, 130.05, 138.71, 139.90, 148.26, 148.87, 149.15, 152.77, 153.13, 159.85, 159.99, 160.44; Anal. Calcd for C18H16NO3F: C, 69.00; H, 5.15; N, 4.47. Found: C, 68.92; H, 4.95; N, 4.42.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[S:9][CH:10]=[C:11]([CH3:13])[N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1csc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)n1
Product: Cc1csc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)n1

Procedure:
The title compound was prepared from 2'-methyl-4'-(4-methylthiazol-2-yl)biphenyl-4-carboxylic acid (D40) and 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8), following the procedure of Example 1. The oxalate salt crystallised from acetone as a buff powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 95%).
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([C:32](=[O:34])[CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:35])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)(=O)=O>C(O)C>[CH2:2]([S:9][C@@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([C:32](=[O:34])[CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:35])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccccc1

Procedure:
To 13.8 gm. of sodium metal dissolved in 1040 ml. of ethanol is added 47 ml. of benzyl mercaptan, followed by 21 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat to reflux for 72 hours, then cool and filter off insoluble material. Concentrate the filtrate in vacuo to about 150 ml. and precipitate into 1500 ml. of water containing 150 ml. of a 5% aqueous solution of sodium hypochlorite. Extract three times with 500 ml. portions of chloroform which is then washed twice with water. Dry the chloroform extracts over Na2SO4, then vacuum concentrate to dryness. Dissolve the residue in a minimum amount of chloroform/ethyl acetate (1:1) and pass through 300 gm. of silica gel. Take 1 l. fractions utilizing ethyl acetate/chloroform/hexane (1:10:10). Combine desired fractions as determined by thin layer chromatography and evaporate to dryness. Crystallize the resultant residue from ethyl acetate/hexane to obtain the title compound; m.p. 134°-136° C.; λmaxMeOH 237 nm (ε=17,100); [α]D26 +152.5° (DMF).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:27][C:28]1[N:29]([CH3:33])[N:30]=[CH:31][N:32]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][CH2:27][C:28]2[N:29]([CH3:33])[N:30]=[CH:31][N:32]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: Oc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 84.8 %

Procedure:
To a stirred solution of 3-bromo-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.2073 g, 0.671 mmol) in anhydrous DMF (10 ml) under nitrogen was added cesium carbonate (0.8731 g, 2.680 mmol), then solid 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.1703 g, 1.014 mmol). The mixture was stirred at room temperature for 22.5 h, then at 60° C. for 2.33 h. This was then partitioned between water (40 ml) and ethyl acetate (40 ml). The aqueous layer was further extracted with ethyl acetate (2×40 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to give 0.2299 g (85%) of the title compound as a white solid: mp=215-219° C. (CH2Cl2-EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 3.87 (3H, s), 5.52 (2H, s), 7.28 (1H, m), 7.39 (1H, t, J=7.5 Hz), 7.65 (1H, m), 7.77 (1H, t, J=7.5 Hz), 7.87 (1H, s), 9.22 (1H, s); MS (ES+) m/e 404/406 [MH]+. Anal. Found C, 44.41; H, 2.53; N, 24.04%. C15H11BrFN7O requires C, 44.57; H, 2.74; N, 24.26%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH2:34])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:34][C:41]([C:38]2[CH:39]=[CH:40][C:35]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:36][CH:37]=2)=[O:42])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1cccc(CN2CCCC2)c1
Product: O=C(NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1cccc(CN2CCCC2)c1)c1ccc(-c2ccccc2)cc1
Yield: 18 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (10.54 mmol) in tetrahydrofuran (75 mL) at −78° C. was slowly added a 0.25M solution of [3-(1-pyrrolidinylmethyl)phenyl]magnesium bromide in tetrahydrofuran (12.50 mmol, 1.2 eq.) and stirring at −78° C. was continued for 20 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (10 mL) and allowed to warm to room temperature. The mixture was then diluted with saturated aqueous ammonium chloride solution (65 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give 2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethanol as a yellow oil that was purified by column chromatography using 70/29/1 dichloromethane/acetone/diisopropylethylamine. The 2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethanol was subjected to the general conditions described above for conversion of alcohols to azides to give 7-[2-Azido-2-(3-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-8-benzyloxy-5-chloro-quinoline. 7-[2-Azido-2-(3-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-8-benzyloxy-5-chloro-quinoline (5.34 mmol) was subjected to the general conditions described above for Staudinger reduction of azides to give 2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethylamine an amber oil and was used directly in the ensuing step. 2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (0.675 mmol) was subjected to the general conditions described above for N-acylation with 4-biphenylcarbonyl chloride to give an off-white solid which was purified by twice recrystallizing from dichloromethane/hexanes to give the title compound as a white solid (0.311 mmol, 18% for 4 steps). MS (ESI) m/z 652.5; HRMS: calcd for C42H38ClN3O2+H+, 652.27253; found (ESI, [M+H]+ Obs'd), 652.2730.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:39])[CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:18]=2)=[CH:14][C:13]=1[Cl:42].N1C=CC=CC=1.CN(C)C=O>O>[Cl:42][C:13]1[CH:14]=[C:15]([CH:40]=[CH:41][C:12]=1[NH:11][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:39])[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:28][CH2:27]2)[CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc(N)c(Cl)c3)ccn2)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Phenyl chloroformate (210 mg) was added dropwise to a solution of 570 mg of tert-butyl 4-(2-{[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}-2-oxoethyl)-1-piperidinecarboxylate, 110 mg of pyridine and 5 ml of dimethylformamide while stirring at room temperature, and the mixture was further stirred for 30 minutes. Water was added and extraction was performed with ethyl acetate. The organic layer was washed twice with water and once with saline, and then silica gel was added and the solvent was distilled off under reduced pressure. This was then charged into a dry column packed with silica gel and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), to obtain 440 mg of tert-butyl 4-{2-[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]-2-oxoethyl}-1-piperidinecarboxylate as a light yellow oil. After adding 71 mg of aniline and 5 ml of dimethylformamide to the oil, it was stirred at 130° C. for 15 minutes. The reaction solution was returned to room temperature, NH type silica gel was added, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1). The solvent was distilled off under reduced pressure to obtain 80 mg of the target substance.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Cl[C:21]1[C:30]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[CH3:36])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([C:21]2[C:30]([N:31]3[CH2:35][CH2:34][CH2:33][C@@H:32]3[CH3:36])=[N:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=3)[N:22]=2)=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
To a solution of 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.30 g, 4.92 mmol) in ethylene glycol dimethyl ether (100 mL) was added (S)-methyl 2-chloro-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (1.0 g, 3.27 mmol), sodium carbonate (1.05 g, 9.91 mmol), and Pd(dppf)2Cl2 (0.12 g, 0.17 mmol). The resulting solution was stirred for 40 min at 90° C. under an N2 atmosphere, and then concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% to 10% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(4-amino-3-nitrophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as an orange solid (1.0 g, 57%).
Reaction SMILES: O[C:2]1[C:15]2C(=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.CC1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1>>[CH:15]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:18][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=c1c2ccccc2oc2ccccc12

Procedure:
1,4-dihydroxyanthraquinone; anthraquinone; 2-methylanthraquinone,
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.C(O)C>CC(O)C.O>[Cl:13][C:14]1[N:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:17]([C:21]([F:24])([F:22])[F:23])=[CH:18][N:19]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2nc(Cl)ncc2C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Alternatively, 33.7 g 4-nitrophenol are dissolved in 250 mL 2-propanol. 18.3 g aqueous sodium hydroxide solution (50%) diluted with 42 mL of purified water are added. Additionally 50 mL of purified water are added. The reaction mixture is stirred for 30 minutes at 50° C. and then cooled to −15° C. 50 g 2,4-Dichloro-5-trifluoromethylpyrimidine are added at −15° C. under vigorous stirring. An additional amount of 50 mL of cooled (−15° C.). 2-propanol is added. The suspension is stirred for 2 hours at −15° C. and then warmed up to 20° C. during 2 hours. 100 mL ethanol are added. The mixture is heated to reflux. The solution is cooled to 20° C. while seeding with the title product at about 60° C. After stirring the suspension for 30 minutes at 20° C. the precipitate is filtered and washed with a mixture of 150 mL 2-propanol and 75 mL purified water and then with 150 mL purified water. The product is dried at 50° C. in a vacuum drying oven. 54.3 g (74% of theory) regioisomeric pure colorless title product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]2[CH3:14])=[N:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C#N)cn1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol) was dissolved in dry DMF (10 mL) taken in a shield tube. To the reaction mixture was added 6-chloronicotinonitrile (70 mg, 1.0 mmol) followed by potassium carbonate (140 mg, 1.0 mmol) and the mixture was heated to 150° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The product was extracted with EtOAc and the organic layer was washed with H2O and brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 30% EtOAc in petroleum ether) to afford compound tert-butyl 4-(5-cyanopyridin-2-yl)-3-methylpiperazine-1-carboxylate (120 mg, yield 40%) as yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.63 (dd, J=9.0 Hz, J=2.4 Hz, 1H), 6.56 (d, J=9.0 Hz, 1H), 4.53 (m, 1H), 4.13-3.91 (m, 3H), 3.29-3.16 (m, 2H), 3.02 (m, 1H), 1.49 (s, 9H), 1.20 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH2:8][O:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:21]([O:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH2:8][O:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOCC2(C)C
Temperature: 65 °C
Yield: 90.1 %

Procedure:
Ethyl 3-hydroxy-10,10-dimethyl-4-oxo-6,7,9,10-tetrahydro-4H-pyrimido[1,2-d][1,4]oxazepine-2-carboxylate (790 mg, 2.8 mmol) and benzyl bromide (580 mg, 3.4 mmol) were placed together in 10 mL DMF under N2 and treated with K2CO3 (512 mg, 4 mmol). After warming for 2.5 h at 60-70° C., the DMF was removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with H2O. The CH2Cl2 solution was dried over MgSO4, filtered and concentrated to give the title compound (940 mg, 90%) as a solid. 1H NMR (300 MHz, CDCl3) δ: 1.27 (t, J=7.3 Hz, 3H), 1.54 (s, 6H), 3.59 (s, 2H), 3.65-3.95 (m, 2H), 4.30 (q, J=7.3 Hz, 2H), 4.40-4.80 (m, 2H), 5.19 (s, 2H), 7.29-7.34 (m, 3H), 7.39-7.49 (m, 2H). LC/MS (M+H): 373.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][CH2:28][C:29]#[N:30])[CH3:25]>>[C:29]([CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])#[N:30]
Reactant: CCNCCC#N
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: CCN(CCC#N)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-ethylamino-propionitrile LC-MS: rt=0.91 min, 417 (M+1, ES+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:6]3=[N:7][C:2]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[CH:3][N:4]=[C:5]3[N:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2nnc3ncc(Br)nc32)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(Cn2nnc3ncc(-c4cccs4)nc32)cc1
Yield: 18.1 %

Procedure:
A mixture of 6-bromo-1-(4-fluoro-benzyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (100 mg, 0.32 mmol), 2-thiopheneboronic acid (44.8 mg, 0.35 mmol), Pd(PPh3)2Cl2 (11.3 mg, 0.016 mmol), and NaHCO3 (80.6 mg, 0.96 mmol) in DME (2 mL) and water (0.4 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 120° C. for 15 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a silica gel column eluting with EtOAc-Hexane to provide 1-(4-fluoro-benzyl)-6-thiophen-2-yl-1H-[1,2,3]triazolo[4,5-b]pyrazine (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[H][H]>[Ni].CO>[C:28]([O:27][C:25]([NH:24][CH:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:32])=[CH:11][CH:10]=2)=[CH:14][CH:15]=1)[C:21]([OH:23])=[O:22])=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)C=Cc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Yield: 54.9 %

Procedure:
Raney nickel 2800 (15.4 g) was added to a degassed solution of the unsaturated ester 3 (14.7 g) in MeOH (100 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 4 (8.1 g, 55%). 1H NMR (400 MHz, DMSO-d6): 12.7 (br, 1H), 7.22 (overlapped d, J=8.4 Hz, 4H), 7.08 (d, J=8.0 Hz, 1H), 6.88 (overlapped d, J=8.0 Hz, 4H), 4.07 (br, 1H), 3.00 (m, 1H), 2.82 (t, J=7.6 Hz, 2H), 2.79 (m, 1H), 2.62 (t, J=8.0 Hz, 2H), 1.33 (s, 9H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:25][CH:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:29][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)[CH3:25]
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC(C)CO)cn1
Yield: 75 %

Procedure:
As described in example 4, 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol), using DL-2-amino-1-propanol instead of ethanolamine, was converted to the title compound (170 mg, 75%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 93:7). MS: m/e=364.4 [M+H]+.