Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][NH:22][N:21]=2)=[CH:16][CH:15]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C:11](=[S:12])[NH:10][S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:9])=[O:8])[N:21]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: O=S(=O)(N=C=S)N1CCCCC1
Solvent: ClCCl
Product: O=S(=O)(NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)N1CCCCC1
Yield: 63 %

Procedure:
Part A: To a stirred solution of (piperidin-1-yl)sulfonyl isothiocyanate (54.77 g, 266 mmol) in dry dichloromethane (900 mL) in a nitrogen atmosphere is added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (68.3 gram, 266 mmol). After stirring for 16 hours an additional amount of dichloromethane is added. The resulting solution is twice washed with water, dried over Na2SO4, and concentrated in vacuo. After addition of MTBE, the residue crystallizes. The crystalline material is collected and washed with MTBE to give 3-(4-chlorophenyl)-4-phenyl-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (77.6 gram, 63% yield).
Reaction SMILES: S(Cl)(Cl)=O.C(OCCC(O)=O)C.C(OCCC(Cl)=O)C.[CH2:21]([O:23][CH2:24][CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:22].[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1)[NH2:35]>C(O)C.C1(C)C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:29]([NH:28][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH2:21][CH3:22])=[S:30])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1
Reactant: CCOCCC(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCOCCC(=O)Cl
Agent: CCOCCC(=O)O
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-ethoxypropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-ethoxypropanoyl isothiocyanate was prepared using the resultant 3-ethoxypropanoyl chloride as a starting compound according to the description of the literature. 3-Ethoxypropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were 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 (46 mg, yield 62%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[C:21]([F:24])[C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[C:21]([F:24])[C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: COC(=O)Cc1cc(F)c(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Trifluoromethanesulphonic anhydride (0.854 mL, 5.21 mmol) was added dropwise to a stirred solution of methyl 2-(3,5-difluoro-4-hydroxyphenyl)acetate (Intermediate 24-3; 0.702 g, 3.47 mmol) in DCM (15.06 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (1.452 mL, 10.42 mmol) was added dropwise over 5 minutes (keeping internal temperature between 5-10° C.) and the resulting solution stirred at room temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (0.930 g, 80%) as a straw yellow oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([F:19])=[C:15](Cl)[N:14]=1>CO.O>[Cl:12][C:13]1[N:18]=[C:17]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([CH2:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=2)[C:16]([F:19])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(CCCF)cc1
Solvent: CO
Solvent: O
Product: FCCCc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(3-Fluoropropyl)aniline and 2,6-dichloro-5-fluoropyrimidine (1.5 g) were dissolved in methanol (5 mL) and water (1 mL). The reaction solution was stirred at rt for 3 d. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were evaporated and purified by flash column chromatography (EtOAc/hexanes=1/4, 1/2) to give 2-chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=2[CH:29]=O)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.CO>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=2[CH2:29][NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([CH3:15])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1nn(C)c(Oc2ccc(Cl)cc2)c1C=O
Reactant: Cc1cc(N)ccc1NC(=O)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NCc2c(C)nn(C)c2Oc2ccc(Cl)cc2)ccc1NC(=O)C(C)(C)C
Temperature: 170 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(4-Amino-2-methylphenyl)-2,2-dimethylpropionamide (300 mg, 1.45 mmol) and 5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (360 mg, 1.45 mmol) in acetonitrile (4 mL) was heated and stirred at 170° C. under microwave irradiation for 20 minutes. The obtained reaction mixture was added carefully into solution of sodium cyanoborohydride (0.36 g) in methanol followed by acetic acid (1 mL). After 60 minutes it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was evaporated. The title compound was separated by flash chromatography on SiO2 with gradient heptane-ethyl acetate and then precipitated from ethyl acetate with heptane. Yield 112 mg, 18%. LC/MS-TOF (m/z) 441; RT=2.34, (UV, ELSD) 98%, 100%. 1H NMR (DMSO-d6): 1.18 (s, 9H), 1.96 (s, 3H), 2.15 (s, 3H), 3.47 (s, 3H), 3.75 (d, 2H), 5.4 (t, 1H, NH), 6.29 (dd, 1H), 6.33 (d, 1H), 6.24 (d, 1H), 6.99 (d, 2H), 7.41 (d, 2H), 8.58 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:27])=[O:26]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (10.9 mmol) in 150 mL of dichloromethane at 0° C. was added triethylamine (1.53 mL, 10.9 mmol), followed by morpholine (1.34 mL, 15.3 mmol). After 30 minutes, the mixture was poured into ethyl acetate and saturated NaHCO3 solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the titled product. ESI+MS: 557.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].C(N(CC)CC)C.[N+:15]([C:18]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])=[CH:26][C:19]=1[O:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O-:17])=[O:16].C>C(Cl)Cl.C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:28]=[CH:29][C:18]=1[N+:15]([O-:17])=[O:16])[CH3:25]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCC1OCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCC1OCCO1
Temperature: 25 °C

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)amine (1.85 grams; 0.015 mole), triethylamine (5 ml) and methylene chloride (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture was cooled in a dry ice bath to a temperature of -20° C. to -10° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (4.2 grams; 0.01 mole) in methylene chloride (50 ml) was added dropwise with stirring. After the addition was completed the reaction mixture was allowed to warm to room temperature with stirring over a period of about 1 hour. After this time the reaction mixture was transferred to a separatory funnel and washed with water (100 ml) with dilute aqueous sodium bicarbonate (200 ml; 5% concentration) and again with water (100 ml). The washed mixture was then dried by passing it through phase separation paper and was stripped of solvent in a rotary evaporator under reduced pressure leaving a white solid residue. This residue was dissolved in toluene, treated with activated charcoal and filtered. The filtrate was partially stripped of toluene and diluted with hexane to precipitate the desired product N-(1,3-dioxolan-2-yl-methyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as a white crystalline solid melting at 148° to 149.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=C(Cl)[N:15]=1>>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:15]=1
Reactant: O=CNc1ccc([N+](=O)[O-])cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-nitro-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.Cl>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
Acryloylchlorid (0.8 ml, 9.8 mmol, 1 eq) was added dropwise to a stirred ice-cold solution of piperazine 1-carboxylic acid tert butyl ester (2 g, 9.8 mmol, 1 eq) and triethylamine (1.4 ml, 9.8 mmol, 1 eq) in dichloromethane (50 mL) at 0° C. The mixture was then stirred and allowed to come to room temperature over 2 hours. 1M Hydrochloric acid solution (50 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2×50 ml) and saturated sodium chloride solution (50 ml) and dried over MgSO4. After filtration, the solvent is evaporated. The residue was purified by chromatography (ethyl acetate/n-hexane 1/1) to give the product (1.26 g, 49%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)=[CH:6][CH:5]=1)[CH3:3].N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])(=O)=O>C(OCC)(=O)C>[Si:58]([O:1][CH:2]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)=[CH:6][CH:5]=1)[CH3:3])([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(C)O)cc2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(C)O[Si](C)(C)C(C)(C)C)cc2)c2ncnn12
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of 4′-({4-[4-(1-hydroxyethyl)benzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.2 g), 2,6-lutidine (0.41 mL) and tetrahydrofuran (30 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.79 mL) at 0° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.4 g, 100%).
Reaction SMILES: [CH2:1]([I:3])[CH3:2].[CH3:4][O:5][C:6]([CH2:8][CH2:9][CH2:10][C:11]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH2:14][CH2:13][N:12]=1)=[O:7]>>[I-:3].[CH3:4][O:5][C:6]([CH2:8][CH2:9][CH2:10][C:11]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH2:14][CH2:13][N+:12]=1[CH2:1][CH3:2])=[O:7]
Reactant: COC(=O)CCCC1=NCCc2c1[nH]c1ccccc21
Reactant: CCI
Product: CC[N+]1=C(CCCC(=O)OC)c2[nH]c3ccccc3c2CC1
Product: [I-]
Reaction time: 8 h

Procedure:
15 ml of ethyl iodide were added to 1.80 g of 3,4-dihydro-1-(3-methoxycarbonylpropyl)-β-carboline [cf. Rec. Trav. Chim., Vol. 84, No. 9-10, pp 1183-1199(1965)], and the mixture was stirred at 70°-80° C. overnight. After the reaction was completed, the mixture was concentrated to dryness, whereby 3,4-dihydro-1-(3-methoxycarbonylpropyl)-2-ethyl-β-carbolinium iodide was obtained as a crude product. The crude product was dissolved in 20 ml of ethanol, and one g of sodium borohydride was added thereto. The mixture was stirred at room temperature for one hour. Then, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove solvent. The residue thus obtained was purified by silica gel chromatography (Solvent: 5% methanol-chloroform), whereby 0.2 g of 1,2,3,4-tetrahydro-1-(3-methoxycarbonylpropyl)-2-ethyl-β-carboline was obtained. Yield: 11%
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]1[CH2:10][C:9]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:11]2)[CH2:8]1)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH:7]1[CH2:8][C:9]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:11]2)[CH2:10]1
Reactant: CCOC(=O)C1CC2(CC(O[Si](C)(C)C(C)(C)C)C2)CN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2(CC(O)C2)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 7-ethyl 6-(phenylmethyl) 2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-6-azaspiro[3.4]octane-6,7-dicarboxylate (151) (1.87 g, 4.2 mmol) in THF (20 mL) was added glacial acetic acid (0.48 mL), followed by TBAF (8.5 mL, 1M solution in THF) and the reaction heated to 45° C. for 18 h. The reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 followed by brine, and then dried over MgSO4 and concentrated in vacuo to afford the title compound as a clear oil in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.48 (m, 5H) 4.83-5.15 (m, 3H) 3.88-4.34 (m, 4H) 3.35-3.47 (m, 2 H) 2.02-2.39 (m, 3H) 1.65-1.96 (m, 3H) 1.00-1.22 (m, 3H). LC-MS ESI (M+H)+=334.17.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc(C#Cc2csc(C)n2)cn1
Temperature: 80 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-methoxyphenylboronic acid (2.0 mmol, 304 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 18 h at 80° C., then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a pale yellow solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.02 (s, 1H), 8.73 (d, 1H), 8.34 (d, 1H), 7.97 (s, 1H), 7.68-7.77 (m, 2H), 7.32 (d, 1H), 7.24 (dd, 1H), 3.99 (s, 3H), 2.77 (s, 3H). MS (ESI) 307.2 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:22][CH3:23])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]3[CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:21]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C>[CH3:23][O:22][C:9]1[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[C:15](=[O:17])[O:16][C:11]=2[CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCCBr)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 97 %

Procedure:
Method B (10 h at 80° C.); starting materials: 8-(5-bromopentyloxy)-2,3-dihydro-7-methoxycyclopenta[c][1]benzopyran-4(1H)-one (example 85) and 1-phenylpiperazine; yield 97%; fusion point 118°-120° C. (from isopropanol). Fumarate (x 0.5 C4H4O4): method E; yield 93%; fusion point 153°-155° C. (from isopropanol and TBME).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH3:18]>C(O)(=O)C>[C:11]1([C:10]2[CH:2]=[C:1]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:2]=[C:1]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Reactant: N
Solvent: CC(=O)O
Product: c1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Yield: 68 %

Procedure:
"Simple aldehydes and ketones without activating groups require mildly forcing conditions and produce the fully aromatic pyridines; accordingly, acetophenone, benzaldehyde, and ammonia in refluxing acetic acid gave a 68% yield of 2,4,6-triphenylpyridine and a 25% yield of β-phenylpropionophenone."
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH:10]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=2[N:14]=1)=[CH:11][CH3:12].C(Cl)(=O)/C=C/C.NC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[O:19]=[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=1[NH:14][C:13](=[O:18])[CH:10]=[CH:11][CH3:12])[CH2:2][C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:3]
Reactant: CC=Cc1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: C/C=C/C(=O)Cl
Agent: Nc1c(C(=O)O)cccc1C(F)(F)F
Product: CC=CC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 70.6 %

Procedure:
Using the procedure of Step A of Example 1, 19.44 g of 2-acetylamino thiazole and 17.3 g of 2-(1-propenyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one [prepared by Step A of Example 12 of European Pat. No. 40,573 from crotonyl chloride and 2-amino-trifluoromethyl benzoic acid] were reacted to obtain 19.03 g of β-oxo-2-[(1-oxo-2-butenyl)-amino]-N-(2-thiazolyl)-3-trifluoromethyl-benzene-proponamide melting at 206°-208° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.Br.Br.[O:47]=[C:48]1[NH:56][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][C:50]=2[N:49]1[CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1.CS(C)=O>[O:24]=[C:3]1[C@H:2]([NH:1][C:35]([N:60]2[CH2:61][CH2:62][CH:57]([N:49]3[C:50]4[CH:55]=[CH:54][N:53]=[CH:52][C:51]=4[NH:56][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:36])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: O=c1[nH]c2cnccc2n1C1CCNCC1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: Br
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3cnccc32)CC1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.030 g, 0.090 mmol) and 4-nitrophenylchloroformate (0.018 g, 0.090 mmol) in dry tetrahydrofuran (0.5 mL) was cooled to 0° C. under argon. Triethylamine (0.013 mL, 0.090 mmol) was added and the reaction stirred for 1 h. A solution of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazol[4,5-c]pyridine dihydrobromide (0.034 g, 0.90 mmol) and triethylamine (0.065 mL) in dimethylsulfoxide (0.5 mL) was added. The reaction was allowed to come to room temperature and stirred until complete. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give the title compound (0.028 g, 45% yield). MS 578.2108 (M+1)