Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:6]3[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (7.0 mL, 2.0 M, 14 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (0.67 g, 6.0 mmol) in THF (35 mL) at −78° C. Stirring for 45 min at −78° C. and 30 min at 0° C., 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.86 g, 5.0 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (200 mL), washed with 2N HCl (2×20 mL), NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using CH2Cl2/MeOH (20:1) on silica gel to 0.40 g (18%) of a white solid as the title compound. MS (ESI) (M+H)+=445.98.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:25](OC)(OC)(OC)[O:26][CH3:27].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([N:17]4[C:18]5=[N:19][CH:20]=[CH:21][CH:22]=[C:23]5[N:24]=[C:25]4[O:26][CH3:27])[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Reactant: COC(OC)(OC)OC
Solvent: CCC(=O)O
Solvent: O
Product: COc1nc2cccnc2n1[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N2-(trans-3-((7-chloroquinoxalin-2-yl)amino)cyclobutyl)pyridine-2,3-diamine (118 mg, 0.346 mmol), tetramethyl orthocarbonate (922 μl, 6.92 mmol) and propionic acid (12.91 μl, 0.173 mmol) were combined under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give the crude material as a off-white solid. It was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a hexane to ethyl acetate gradient, to provide 7-chloro-N-(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)quinoxalin-2-amine (85 mg, 0.223 mmol, 64.5% yield). M+1: 380.9.
Reaction SMILES: C([Li])CCC.CCCCCC.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1.[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Prepared according to: Schlosser, M.; Ginanneschi, A.; Leroux, F. Eur. J. Org. Chem. 2006, 2956-2969. In a 500 mL round bottomed flask, THF (75 mL) was cooled to −78° C. and treated with a butyllithium solution, 1.6 M in hexane (23.12 mL, 37.0 mmol), 6-fluoroindole (5.00 g, 37.0 mmol) and triisopropylsilyl chloride (7.92 mL, 37.0 mmol). The solution was then removed from the cooling bath and warmed to RT and stirred for 1 h. The reaction mixture was concentrated on the rotovap and the crude residue was purified on the ISCO Combiflash Companion (40 g Redisep column, using a gradient of 0-10% EtOAc in hexanes) affording 6-fluoro-1-(triisopropylsilyl)-1H-indole (9.78 g, 33.6 mmol, 91% yield) as a clear, viscous colorless oil. MS (ESI, pos. ion) m/z 292.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (1H, dd, J=8.4, 5.9 Hz), 7.13-7.23 (2H, m), 6.83-6.92 (1H, m), 6.59 (1H, d, J=2.3 Hz), 1.68 (3H, quin, J=7.5 Hz), 1.14 (18H, d, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](B(O)O)=[CH:9]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:16]3[CH:17]=[C:18]([CH2:22][N:23]4[CH:27]=[CH:26][N:25]=[C:24]4[CH3:28])[N:19]=[N:20][CH:21]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1ccc2ccc(F)cc2c1
Product: Cc1nccn1Cc1cc(-c2ccc3ccc(F)cc3c2)cnn1

Procedure:
The title compound, MS: m/e=319 (M+H+), was prepared from 7-fluoro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47](CN2C=CC(N)=N2)[CH:46]=1>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:46]=1
Reactant: COC(=O)c1cccc(Cn2ccc(N)n2)c1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (250 mg, 0.76 mmol, prepared as in PCT WO 2004/052869 A1, Example 1) was dissolved in methylene chloride (3.8 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (380 μL, 0.76 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (180 μL, 1.52 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (176 mg, 0.76 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (40 mL), washed with water (2×10 mL), saturated aqueous brine solution (1×10 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (196 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.16, found 544.22 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.21 (m, 2H, CH2), 1.45-1.94 (m, 8H, 4×CH2), 2.15-2.34 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, CO2CH3), 5.19 (s, 2H, NCH2), 6.72 (d, J=2.2 Hz, 1H, Ar), 7.34 (m, 2H, Ar), 7.40 (d, Jo=7.7 Hz, 1H, Ar), 7.44 (dd, Jo=8.3, Jm=1.5 Hz. 1H, Ar), 7.58 (d, Jm=1.5 Hz, 1H, Ar), 7.84-7.91 (m, 2H, Ar and NH), 7.97 (d, Jo=7.7 Hz, 1H, Ar), 8.08 (d, Jo=8.3 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C([O-])(O)=O.[Na+]>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.COCCOC.O>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)(C)S(C)(=O)=O
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: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)(C)S(C)(=O)=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
[2-Methanesulfonyl-2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (700 mg, 1.22 mmol) and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (565 mg, 1.26 mmol) in 3:1 DME/H2O (15 mL) were treated with Pd(PPh3)4 (56 mg, 0.0050 mmol) and NaHCO3 (350 mg, 4.15 mmol). The mixture was stirred in a sealed tube at 80° C. for 24 hours. The mixture was filtered through a fitted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (2-methanesulfonyl-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 15%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.85 (m, 10H), 5.25 (m, 2H), 4.24 (d, J=7.5 Hz, 1H), 4.13 (m, 2H), 3.88 (app d, J=7.5 Hz, 2H), 3.71 (s, 3H), 3.66 (s, 3H), 2.99 (s, 3H), 2.57 (m, 2H), 2.16 (m, 10H), 1.81 (s, 3H), 1.79 (s, 1H), 0.93 (m, 6H); MS (ESI) m/z 818 [M+H]+.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]>CC(O)=O.CCOCC>[NH2:3][C:4]1[N:11]=[CH:10][C:9]([Br:1])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cccnc1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.6 %

Procedure:
Bromine (1.1 mL, 21 mmol) in AcOH (3 mL) was added dropwise to a solution of 2-amino-nicotinonitrile (1.00 g, 8.4 mmol) in AcOH (20 mL) at 10° C. The orange mixture was stirred for 22 hours at ambient temperature then diluted with ether (100 mL). The resultant precipitated salt was filtered, washed with ether and dried on air. The precipitate was suspended in water (100 mL), neutralized with 1N NaOH, filtered, washed with water and dried on air to give 1.29 g (78%) title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 7.13 (s, br, 2H). MS (ESI) m/e: 197.9655 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][S:16][C:17]1[C:28]2[O:27][C:26]([CH3:30])([CH3:29])[O:25][C:24]=2[C:23]([C:31]([C:33]2[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=3[C:41]([S:49][CH3:50])=[C:35]3[O:36][C:37]([CH3:40])([CH3:39])[O:38][C:34]=23)=[O:32])=[C:22]2[C:18]=1[O:19][C:20]([CH3:52])([CH3:51])[O:21]2>C1COCC1.C(OCC)C>[CH3:50][S:49][C:41]1[C:35]2[O:36][C:37]([CH3:39])([CH3:40])[O:38][C:34]=2[C:33]([C:31]([C:23]2[C:22]3[O:21][C:20]([CH3:52])([CH3:51])[O:19][C:18]=3[C:17]([S:16][CH3:15])=[C:28]3[O:27][C:26]([CH3:30])([CH3:29])[O:25][C:24]=23)([C:2]2[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[OH:32])=[C:43]2[C:42]=1[O:46][C:45]([CH3:48])([CH3:47])[O:44]2
Reactant: CSc1ncc(Br)cn1
Reactant: CSc1c2c(c(C(=O)c3c4c(c(SC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ncc(C(O)(c2c3c(c(SC)c4c2OC(C)(C)O4)OC(C)(C)O3)c2c3c(c(SC)c4c2OC(C)(C)O4)OC(C)(C)O3)cn1
Temperature: -75 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-methylthio-pyrimidine (0.250 g, 1.2195 mmol) was dissolved in THF (50 mL, sodium benzophenone ketyl) and cooled to -105° C. n-Butyl lithium (0.455 ml in toluene, 1.2195 ml) was added and the temperature was increased to -75° C. for 15 minutes and thereafter reduced to -105° C. Bis(8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)ketone (0.63146 g, 1.1236 mmol, Example 59) was added in solid form and the temperature was gradually increased to room temperature (removal of cooling bath). The mixture was stirred overnight, NaCl (15 mL, sat.) and diethyl ether (40 mL) were added and the phases separated after 5 minutes stirring. The organic phase was dried (MgSO4) and evaporated yielding 0.59 crude product. Pure product was obtained by crystallization in diethyl ether followed by a second crystallization in diisopropyl ether. Yield 0.115 g (0.1669 mmol, 14.9%).
Reaction SMILES: [CH3:1]I.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:32][CH2:31][C:16]3([C:21]4=[CH:22][CH:23]=[CH:24][N:20]4[C:19]4[CH:25]=[CH:26][C:27]([CH2:29][OH:30])=[CH:28][C:18]=4[O:17]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:33][CH3:34])[CH3:4].[H-].[Na+]>CN(C=O)C>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:17][C:18]4[CH:28]=[C:27]([CH2:29][O:30][CH3:1])[CH:26]=[CH:25][C:19]=4[N:20]4[CH:24]=[CH:23][CH:22]=[C:21]34)[CH2:31][CH2:32]2)=[O:12])=[CH:7][C:6]=1[O:33][CH3:34])[CH3:4]
Reactant: CI
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2cccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(COC)ccc2-n2cccc23)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
MeI (7.2 μL, 0.12 mmol) was added to a solution of (4-ethyl-3-methoxy-phenyl)-[7′-(hydroxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (50 mg, 0.12 mmol) and NaH (4.6 mg, 0.12 mmol) in DMF (1 mL) and was stirred at room temperature for 1 hour. The reaction was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield (4-ethyl-3-methoxyphenyl)(7-(methoxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]1′-yl)methanone. ESI-MS m/z calc. 446.5. found 447.5 (M+1)+; Retention time: 2.11 minutes (3 min run).
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([NH:11][C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][C:21]2([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]2)[CH2:20][CH2:19]3)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O)Nc1cccc2ccccc12

Procedure:
A mixture of 1-naphthyl isocyanate (9.5 mg, 0.056 mmol), (±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione hydrochloride (described in Intermediate 2) (15 mg, 0.056 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.056 mmol) was stirred in THF (0.5 mL) at ambient temperature for 18 h. The crude mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=401 (M+1). HRMS: m/z=401.1638; calculated m/z=401.1608 for C23H21N4O3.
Reaction SMILES: Cl[CH2:2][Si:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH:6]=[CH2:7])[CH:4]=[CH2:5].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[K]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:4]([Si:3]([CH:6]=[CH2:7])([CH2:2][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[CH2:5]
Reactant: C=C[Si](C=C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: C=C[Si](C=C)(Cn1ccnc1)c1ccc(-c2ccccc2)cc1

Procedure:
To a solution of 1.14 g (0.004 mol) of chloromethyl(4-phenylphenyl)divinylsilane in 10 ml of toluene is added 0.54 g (0.005 mol) of potassium imidazole and 0.05 g of tetrabutylammonium bromide. The mixture is refluxed under nitrogen for two days, cooled, diluted with ether-hexanes, and washed with water and brine. Removal of solvent gives an oil which is purified by silica gel chromatography, eluting with 9:1 dichloromethane-ether, to give the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])[N:5]2[N:4]=1.Cl[CH2:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[O:24]=[S:23]1(=[O:25])[CH2:22][CH2:21][CH2:20][N:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:5]2[C:6]([CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[CH:9][CH:10]=1
Reactant: CSc1ncc2ccc(-c3ccccc3N)n2n1
Reactant: O=S(=O)(Cl)CCCCl
Product: CSc1ncc2ccc(-c3ccccc3N3CCCS3(=O)=O)n2n1
Yield: 8 %

Procedure:
Analogous to Example 1506b, 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine (0.777 g, 3.03 mmol) was reacted with 3-Chloropropane-1-sulfonyl chloride to afford 7-[2-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfanyl)pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (83 mg, 8%). 1H-NMR (DMSO-d6): 8.79 (s, 1H), 7.84 (dd, 1H, J=5.04 Hz), 7.72 (dd, 1H, J=5.04 Hz), 7.46 (m, 2H), 7.29 (d, 1H, J=4.72 Hz), 6.91 (d, 1H, J=4.72 Hz), 3.38 (t, 2H, J=6.81), 3.19 (t, 2H, J=7.49), 2.48 (s, 3H), 2.27 (quin, 2H, J=7.49).
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[NH:4][C:5](=[O:11])[NH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[F-].[K+].[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([CH2:15][N:22]2[CH2:23][CH2:24][N:25]([C:2]3[C:3](=[O:12])[NH:4][C:5](=[O:11])[NH:6][C:7]=3[CH2:8][CH2:9][CH3:10])[CH2:26][CH2:27]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCc1[nH]c(=O)[nH]c(=O)c1Br
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CCCc1[nH]c(=O)[nH]c(=O)c1N1CCN(Cc2ccccc2)CC1
Temperature: 140 °C
Yield: 58.6 %

Procedure:
A mixture of 53.3 g (0.229 mole) of 5-bromo-6-propyl-2,4(1H,3H)pyrimidinedione and 23.7 g (0.252 mole) of anhydrous potassium fluoride in 176 ml (1.0 mole) of 1-benzylpiperazine was heated under reflux at 140° C. for 14 hours. The reaction mixture was cooled to 80° C. and 100 ml of ethanol was added. The mixture was poured into one liter of ice water. The solid was collected and washed with one liter of water. Recrystallization from ethanol and drying in vacuo at 59° C. for 16 hours gave 44.1 g of the product as an off-white solid; mp 233°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:18]=1[CH2:19][SH:20].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11])/[CH:13]=[CH:14]\[CH:19]([S:20][CH:19](/[CH:14]=[CH:13]\[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:18]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[C:18]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15]
Reactant: COc1cc(OC)c(OC)cc1CS
Reactant: C#Cc1ccc(OC(C)=O)c(OC)c1
Agent: [Na]
Product: COc1cc(OC)c(C(/C=C\c2ccc(OC(C)=O)c(OC)c2)SC(/C=C\c2ccc(OC(C)=O)c(OC)c2)c2cc(OC)c(OC)cc2OC)cc1OC

Procedure:
A solution of 3-methoxy-4-acetoxyphenylacetylene (0.02 mol), 2,4,5-trimethoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to General Procedure 2 to form (Z)-3-methoxy-4-acetoxystyryl-2,4,5-trimethoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to General Procedure 2.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>CCOCC>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
Triethylamine (42 ml) is added dropwise to a stirred solution of 4-hydroxybenzaldehyde (33.5 g) and chlorotrimethylsilane (42 ml) in ether (300 ml). After 15 min, the mixture is filtered through diatomaceous earth and the filtrate is concentrated and distilled in vacuo, providing 4-(trimethylsiloxy)benzaldehyde as a colorless oil (43 g). This material is reacted with methoxymethyl triphenylphosphonium chloride and potassium tert-butoxide in THF, using the procedure described in Example 1 (A) above, to provide 1-(2-methoxyethenyl)-4-(trimethylsiloxy)benzene (35%) as a colorless oil after distillation in vacuo, as a mixture of (E) and (Z) isomers. This material (3.0 g) is dissolved in methanol (30 ml) containing methanesulfonic acid (0.4 ml), and the solution is refluxed for 3 hr. Sodium bicarbonate (8 ml of 1.0N solution) is added, and the mixture is concentrated in vacuo. The residue is taken up in ethyl acetate, dried, and concentrated to provide 4-[(2,2-dimethoxy)ethyl]phenol as a pale red oil (2.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]([CH3:21])[N:13]=1.S(Cl)([Cl:25])(=O)=O>C(O)(=O)C.O>[Cl:25][C:16]1[C:12]([C:3]2[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])=[N:13][N:14]([CH3:21])[C:15]=1[C:17]([F:18])([F:19])[F:20]
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Reaction time: 6 h

Procedure:
To 5.00 g of 3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole dissolved in 50 ml of acetic acid was added 15 ml of sulfuryl chloride. The mixture was mildly refluxed with 2 ml portions of sulfuryl chloride added every 15 minutes. After 6 hours, the mixture was cooled, then diluted with water and extracted with ether. The ether was washed 3 times with water, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed to give a quantitative yield of 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole.