Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10](=O)([O:12]C)[NH2:11].C1(C)C=CC=CC=1>C([Sn](=O)CCCC)CCC.CO>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10]([NH2:11])=[O:12])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: COC(N)=O
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCC(CC)CNC(N)=O
Temperature: 110 °C
Yield: 91.7 %

Procedure:
Into a 300 ml reaction vessel equipped with a distillation apparatus were introduced 50 g of 2-ethylhexylamine, 29 g of methyl carbamate and 100 ml of toluene, and to the mixture was added 0.1 g of dibutyl tin oxide as a catalyst and heated with stirring. Methanol formed during the reaction was removed, when the reflux temperature was raised to 110° C., i.e., the boiling point of toluene, the distillation apparatus was taken off and instead a reflux condenser was attached and the mixture was refluxed by heating for 30 minutes with stirring, then allowed to cool. The toluene was distilled off under reduced pressure, and the residue was washed with n-hexane and collected by filtration to obtain 61 g of N-(2-ethylhexyl)urea.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][C:9](=[CH:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][C:17]([CH3:39])([CH3:38])[CH2:18]/[CH:19]=[CH:20]\[C:21]([O:30][Si](CC)(CC)CC)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH2:8][C@@H:7]([O:40]C(=O)C)[CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[F:23][C:22]([F:24])([F:25])[C:21]([OH:30])([C:26]([F:28])([F:29])[F:27])/[CH:20]=[CH:19]\[CH2:18][C:17]([CH3:39])([CH3:38])[CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]/[CH:11]=[C:9]1[CH2:10][C@@H:5]([OH:4])[CH2:6][C@H:7]([OH:40])[CH2:8]1
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/C=C1C[C@@H](OC(C)=O)C[C@H](OC(C)=O)C1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O)C[C@H](O)C1
Reaction time: 8 h

Procedure:
To a solution of 50 mg of acetic acid (1R,3R)-3-acetoxy-5-[(2E,9Z)-12,12,12-trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dienylidene]-cyclohexyl ester in 1.5 ml of CH3OH was added at 22° a solution of 37 mg of K2CO3 in 0.25 ml of water and stirring was continued for 8 h after which time t.l.c. indicated completion of the reaction. The mixture was evaporated and the residue was partitioned between dichloromethane and aqueous sat. NaCl, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica with hexane/AcOEt 2:1 to give 34 mg of the pure (t.l.c.) title compound as a colorless resin. IR (neat): 3345s (OH), 1661w and 1622w (C═C); MS (EI): 444/10 (M), 426/8 (M−H2O).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[ClH:31].C(O)(C)C>N1C=CC=CC=1>[ClH:31].[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:12](=[O:13])[CH:2]3[CH:3]([CH:4]4[CH2:5][CH2:6][CH:1]3[CH2:8][CH2:7]4)[C:9]2=[O:11])[CH2:20][CH2:21]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: O=C1C2C3CCC(CC3)C2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of bicyclo[2.2.2]octane-2,3-dicarboxylic anhydride (541 mg, 3 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (708 mg, 3 mmol) and pyridine (12.1 ml) was refluxed for 10 hours. The solvent was removed from the mixture under reduced pressure. The residue was extracted with chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude crystals (1 g), which were treated with 6% hydrogen chloride/isopropanol. The solvent was removed to give N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.2]octane-2,3-dicarboximide hydrochloride (from ethanol). M.P., 198°-200° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][CH:17]=1.[H][H]>C(O)(C)C.[Pd]>[CH2:15]([C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][CH:17]=1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCc1cccc(O)c1

Procedure:
Cardanol (500 g, 1.64 mol) was dissolved in isopropanol (2 L) and was hydrogenated in presence of 5% Pd/C (1.5 g) catalyst at 70° C. in a Parr autoclave under 600 psi hydrogen pressure. When no more hydrogen absorption was noticed, the hydrogenation was stopped. The reaction mixture was filtered to remove Pd/C. The solvent was evaporated to obtain crude product. Pure 3-pentadecylphenol was obtained after recrystallization from hexane. Yield 480 g, (95%), MP: 50-51° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(OCCC(C)(C)C)=O)[C:10]([C:24]([O-:26])=[O:25])=[CH:9]2.Cl.[CH2:28]1COC[CH2:29]1>O1CCOCC1>[CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:24]([O:26][CH2:28][CH3:29])=[O:25])=[CH:9]2
Reactant: CSCCOc1ccc2c(c1)cc(C(=O)[O-])n2C(=O)OCCC(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2cc(OCCSC)ccc2[nH]1
Reaction time: 5 h
Yield: 61 %

Procedure:
A solution of 1-(1,1-dimethylethyl)2-ethyl 5-{[2-(methylthio)ethyl]oxy}-1H-indole-1,2-dicarboxylate (0.500 g, 1.31 mmol) in THF was treated with 4 M HCl in dioxane and stirred for 5 hours. The solvent was evaporated to an oil and the residue was dissolved in DCM and TFA was added and stirred until no starting material remained as evident by TLC. The mixture was evaporated to a solid and purification was accomplished by silica gel column chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.228 g, 61%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.21-9.37 (m, 1H), 7.32 (d, 1H), 7.12-7.16 (m, 1H), 7.09 (d, 1H), 7.00 (dd, 1H), 4.42 (q, 2H), 4.19 (t, 2H), 2.91 (t, 2H), 2.22 (s, 3H), 1.42 (t, 3H). LCMS: m/z=279.9 (M+1).
Reaction SMILES: [CH:1]1([C:6]([CH:9]2[CH2:33][C:32]([CH3:35])([CH3:34])[C:12]3[CH:13]=[C:14]4[C:22](=[CH:23][C:11]=3[C:10]2([CH3:37])[CH3:36])[CH2:21][C:20]2[CH:19]=[C:18]3[C:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][C:27]([CH3:29])([CH3:28])[C:17]3=[CH:16][C:15]4=2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:44]([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[CH3:45][Si:44]([CH3:47])([CH3:46])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([CH:9]2[CH2:33][C:32]([CH3:35])([CH3:34])[C:12]3[CH:13]=[C:14]4[C:22](=[CH:23][C:11]=3[C:10]2([CH3:37])[CH3:36])[CH2:21][C:20]2[CH:19]=[C:18]3[C:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][C:27]([CH3:29])([CH3:28])[C:17]3=[CH:16][C:15]4=2)([CH3:8])[CH3:7])[CH:2]=1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC=C1)C2(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC([Si](C)(C)C)=C1)C2(C)C
Yield: 93.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.66 g (1.34 mmol, 1 eq) of 2-(cyclopentadienyl)-2-(1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorenyl)propane was placed at room temperature. Then, 10 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light brown solution). To the solution, 0.88 ml (1.43 mmol, 1.07 eq) of n-BuLi (hexane solution) was dropwise added over a period of 1 to 2 minutes. The ice bath was removed, and the solution was stirred at room temperature for 66 hours (dark violet solution). After the solution was cooled with an ice bath, 0.8 ml (6.31 mmol, 4.71 eq) of chlorotrimethylsilane was dropwise added by a syringe (reddish brown solution). The ice bath was removed, and the solution was stirred at room temperature for 2.5 hours. The resulting light yellow solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 30 ml of diethyl ether, the organic phase was washed with a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a slightly yellow amorphous product. The amorphous product was purified by silica gel column chromatography (developing solvent: hexane) to obtain 0.71 g of a white solid (yield: 93%).
Reaction SMILES: CC[O-].[Na+].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].C([O:15][C:16](=O)[C:17](=[N:23][O:24][CH3:25])[C:18](OCC)=[O:19])C.Cl>C(O)C.C(#N)C>[CH3:25][O:24][N:23]=[C:17]1[C:18](=[O:19])[NH:12][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:16]1=[O:15]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=NOC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: CON=c1c(=O)[nH]c2ccccc2[nH]c1=O
Temperature: 70 °C
Yield: 75.7 %

Procedure:
Dissolve 21 wt % NaOEt in EtOH solution (164 g, 0.507 mol) in 2B-3 ethanol (331 mL) and add 1,2-phenylenediamine (27.4 g, 0.253 mol). Stir the resulting mixture allow to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution. Add 2-methoxyimino-malonic acid diethyl ester (51.5 g, 0.253 mol). Heat the resulting mixture to 70° C. and stir under nitrogen for approximately 4 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Allow the reaction mixture to cool to ambient temperature. Lower the pH of the reaction mixture from 11.6 to 1.2 by the addition of 700 mL of aqueous 1N HCl solution. Concentrate the reaction mixture in vacuo to remove the ethanol. Filter the resulting amber slurry through a glass frit. Collect the solid and rinse with aqueous 1N HCl and dry under vacuum at 50° C. to afford 42 g (76% yield) of the title compound as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 11.1 (s, 1H), 10.9 (s, 1H), 7.22 (s, 4H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7; 159.4, 148.1, 128.5, 127.8, 125.8, 125.7, 122.8, 122.7, 63.1; IR (CHCl3) 3062, 2970, 2902, 1704, 1656, 1606, 1505, 1414, 1058, 1043, 754 cm−1; UV (EtOH) λmax 278 nm (ε 4623), 276 nm (ε 4618), 216 nm (ε 41495); HRMS (ES+) exact mass calc'd for C10H9N3O3 242.0542, Found 242.0553; Anal. calc'd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.60; H, 4.15; N, 18.94.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[NH:19][N:18]=[N:17]3)=[C:12]([F:22])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:24][CH2:25][CH2:26][F:27])[N:18]=[N:17]3)=[C:12]([F:22])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 75.8 %

Procedure:
A mixture of 7.0 g (0.023 mole) of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-5H-tetrazol-5-one, 4.23 g (0.030 mole) of 1-bromo-3-fluoropropane, and 4.14 g (0.030 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide was heated at 70° C. for approximately seventeen hours. The mixture was allowed to cool to room temperature before being poured over ice. The solid that formed was removed by filtration and dried. This solid was then placed on a silica gel column and eluted with with methylene chloride. The product-containing fractions were combined and the solvents evaporated under reduced pressure, leaving 6.35 g of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, m.p. 86°-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=O)[O:24]C(C)(C)C)[CH3:21])=[CH:16][C:15]=3[F:32])[C:12]=2[F:13])[CH:9]=1)[CH3:2].Cl.[C:34](OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:24])[CH3:34])[CH3:21])=[CH:16][C:15]=3[F:32])[C:12]=2[F:13])[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc2c(F)c(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)nn2c1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCOc1ccc2c(F)c(-c3ccc(OC[C@H](C)NC(C)=O)cc3F)nn2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl {(1S)-2-[4-(6-ethoxy-3-fluoropyrazolo[1,5-a]pyridin-2-yl)-3-fluorophenoxy]-1-methylethyl}carbamate (52 mg), 4 M hydrogen chloride/ethyl acetate (2 mL), and ethyl acetate (1 mL) was stirred at room temperature for 6 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (1 mL) and acetic anhydride (1 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (18.7 mg) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:32]1[CH:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[CH:35]=[CH:36][C:31]=1[Cl:30]
Reactant: Cc1cccc(CO)c1Br
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(COc2cc(C(F)(F)F)ccc2Cl)c1Br
Temperature: 25 °C

Procedure:
To a solution of (2-bromo-3-methylphenyl)methanol (0.5 g, 2.49 mmol), triphenylphosphine (1.31 g, 4.97 mmol) and 2-chloro-5-(trifluoromethyl)phenol (0.37 mL, 2.74 mmol) in DCM (12.4 mL) at 0° C. was added diethyl azodicarboxylate (1.97 mL, 4.97 mmol) and the reaction warmed to RT for 30 min. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-50% Hexene/EtOAc) to afford 2-bromo-1-((2-chloro-5-(trifluoromethyl)phenoxy)methyl)-3-methylbenzene as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:10]=2[C:9](=[O:21])[C:8]2[C:7]([O:22]C)=[CH:6][CH:5]=[CH:4][C:3]1=2.C(O)(=O)C.Br>>[O:1]=[C:2]1[C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:10]=2[C:9](=[O:21])[C:8]2[C:7]([OH:22])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COc1cccc2c1C(=O)c1sc(-c3ccccc3)nc1C2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2cccc(O)c2C(=O)c2sc(-c3ccccc3)nc21
Temperature: 10 °C
Yield: 32.8 %

Procedure:
A suspension of 1.00 g (0.003 mol) of 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-naphtho[2,3-d]-thiazole (Example 23) in 67 mL (1.160 mol) of acetic acid and 67 mL (0.570 mol) of hydrobromic acid is heated to reflux for 5 h 30 min. After cooling to 10° C., the reaction medium is filtered through fritted glass. The precipitate consists of 200 mL of chloroform. The organic phase is washed with a 3% ammonia solution (3×40 mL) and dried over calcium chloride. The yellow solid obtained after evaporation at reduced pressure of the solvent is purified on a medium-pressure column (support: silica 6-35 mm, eluant: toluene/dichloromethane, 100/0, 50/50, 0/100), then recrystallized 3 times in a toluene/heptane mixture, 50/50, to produce 0.302 g of 4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-naphtho[2,3-d]thiazole.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:13])[CH3:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:14][CH2:12][C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)=[O:13]
Reactant: CC(=O)c1cc2c(Cl)cccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 124 %

Procedure:
A mixture of 1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (1.67 g), phenyltrimethylammonium tribromide (2.98 g) and tetrahydrofuran (40 ml) was stirred under nitrogen at ambient temperature for 22.5 hours then it was filtered and diluted with water (150 ml). The product was extracted into dichloromethane (3×30 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (1.65 g) as an off-white solid, m.p. 116-118° C.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:14][N:15]([CH2:16][CH:17]=[O:18])[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:7][N:8]=1)=[O:13]
Reactant: CNCC=O
Reactant: O=C=Nc1nnc(C2CCCC2)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCC2)s1

Procedure:
A mixture of 5-cyclopentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-ureido] acetaldehyde.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH:14]([CH3:19])[O:15][CH:16]([CH3:18])[CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC1CN(c2nn(N)c(=O)c3ccccc23)CC(C)O1
Product: CC1CN(c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)CC(C)O1

Procedure:
The product from Example 60A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54-11.55 (m, 1H), 8.30-8.34 (m, 1H), 8.01-8.04 (m, 1H), 7.96-8.01 (m, 1H), 7.87-7.92 (m, 1H), 7.11-7.19 (m, 3H), 3.84-3.93 (m, 2H), 3.73 (s, 2H), 3.32-3.36 (buried m, 2H), 2.40-2.47 (m, 2H), 1.12 (d, J=6.2 Hz, 6H); MS (APCI+) M/Z 429 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:19]=[O:20]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
To a stirring mixture of 6-amino-1-pentylpyrimidine-2,4(1H,3H)-dione (4.0 g, 0.020 mol) and acetic acid (20 mL, 0.4 mol) in water (20 mL) was slowly added sodium nitrite (1.5 g, 0.022 mol). Stirring was continued at room temperature for 2 h at which time the reaction mixture became pink and precipitate formed. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in aqueous NaOH solution and extracted with methylene chloride to remove byproducts. The aqueous solution was neutralized with HCl and concentrated. The residue was treated with methanol and filtered. The filtrate was concentrated to give the desired product as pink solid. LCMS calculated for C9H15N4O3 (M+H): 227.1. found: 227.1 (M+H), 249.1 (M+Na).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([C:45]#[N:46])[N:40]=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.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>[C:45]([C:41]1[N:42]=[C:43]([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:44]=[CH:39][N:40]=1)#[N:46]
Reactant: N#Cc1nccc(Br)n1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)c12
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: COCCOC
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4ccnc(C#N)n4)c3)c12
Temperature: 95 °C

Procedure:
A mixture of ethyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (54.4 mg, 0.104 mmol), 4-bromopyrimidine-2-carbonitrile (38.2 mg, 0.208 mmol), and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) in 2 M aqueous sodium carbonate (150 uL) and DME (500 μL) was purged with argon. The reaction vessel was then sealed and heated at 95° C. overnight. The reaction mixture was filtered through Celite and rinsed with ethyl acetate. The reaction solution was concentrated under reduced pressure and the residue purified by chromatography on silica eluting with 40-60% ethyl acetatehexane to give the desired product. LRMS calc'd for C26H29N6O3Si [M+H]+: 501, found 501.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[C:27]1([CH:33]([CH3:37])[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([CH3:37])[C:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: CC(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-phenyl-propionyl chloride. Off-white solid. MS (ESI): 447.3 (MH+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:31]4[S:32][C:28]([CH3:27])=[CH:29][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cncs1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 5-methylthiazole