Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1)=[O:20].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.ClCCl>[CH3:34][C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[NH:16][C:7]2[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:17]=[C:5]3[N:6]=2)=[CH:26][CH:25]=1)([CH3:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: COC(=O)CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nc(C)cc3n2)cc1
Reaction time: 72 h
Yield: 15.2 %

Procedure:
In a 50 ml pear flask was added 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 200 mg, 0.89 mmol) in pyridine (5 ml) to give a light yellow solution. A solution of methyl 3-(4-(chlorocarbonyl)phenyl)-3-methylbutanoate (230 mg, 0.89 mmol) in dichloromethane (1 ml) was added to the reaction mixture at room temperature, which was then stirred for 72 h. Saturated NaHCO3 was added and pyridine was mostly removed in vacuo. The residue was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 30-40% ethyl acetate/hexanes) to give the titled product (60 mg, 15% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 8.61 (s, 2H), 8.10-8.15 (m, 8H), 7.87-7.92 (m, 5H), 7.54-7.59 (m, 8H), 7.50-7.54 (m, 5H), 6.28 (s, 2H), 3.54 (s, 8H), 2.68-2.71 (m, 5H), 2.50 (s, 8H), 1.49 (s, 6H); ESI-MS: m/z 443.3 (M+H)+.
Reaction SMILES: [NH2:1]CC1C=CC(C2C=CC=CC=2C#N)=CC=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=1>>[NH2:1][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1

Procedure:
The title compound is prepared similarly to 4-aminomethyl-2'-cyanobiphenyl except 4-bromomethyl-2't-butoxycarbonylbiphenyl is used in place of 4-aminomethyl-2'-cyanobiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][CH2:38][OH:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: OCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1CCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1ccccc1-c1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20FN5O2, 417.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.N1C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-(3-nitrobenzenesulfonyl)ethanol (101) (5.0 g, 21.6 mmol) in dichloromethane (31.5 mL) and pyridine (7 mL) was added methanesulfonyl chloride (4.9 g, 43 mmol). The mixture was stirred at room temperature overnight before it was partitioned between dichloromethane (200 mL) and 0.5 N HCl (200 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to give 102 (4.78 g, 71%).
Reaction SMILES: COC=C.C(O)(=O)/[CH:6]=[CH:7]\[C:8](O)=[O:9].CCC[CH2:16][O:17][C:18](/[CH:20]=[CH:21]\[C:22](O)=O)=[O:19].COC=C>>[OH:9][C:8]1[CH:22]=[CH:21][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)/C=C\C(=O)O
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=COC
Product: COC(=O)c1ccc(O)cc1

Procedure:
Monobutylester of the copolymer of methylvinylether/maleic acid, sold under the tradename "GANTREZ ES 425" by G.A.F.: 0.37 g (active material)
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[Br:11][C:12]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:25].O>ClCCl>[Br:11][C:12]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C@@H:16]2[OH:25]
Reactant: O=C1CCc2c1ccc(C(F)(F)F)c2Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: O[C@H]1CCc2c1ccc(C(F)(F)F)c2Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Triethylamine (3.16 mL, 22.5 mmol) is dissolved in dichloromethane (40 mL) and cooled to 0° C. then formic acid (1.0 mL, 26.46 mmol) is added dropwise with cooling. After 20 minutes stirring 4-Bromo-5-trifluoromethyl-indan-1-one (2.1 g, 7.53 mmol) is added followed by Chloro([(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)-(mesitylene)ruthenium(II) complex (220 mg, 0.35 mmol) and the mixture is stirred overnight under argon at room temperature. Water is added, the mixture shaken and the phases separated. The organic phase is dried and concentrated under vacuum. The residue is purified by flash chromatography (0-15% ethyl acetate in cyclohexane) to give the title compound (yield 2.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][CH:3]=1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.BrC1C=CC(C(=O)C)=C([Cl:46])C=1>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[C:4]([Cl:46])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1Cl
Reactant: C=C(C)c1ccc(Br)cc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C=C(C)c1ccc(Br)cc1Cl
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to 1-bromo-4-isopropenylbenzene (described in example S87) using triphenylphosphonium bromide (2.32 g, 6.51 mmol), nBuLi (5.09 ml, 1.6M solution in hexane, 8.14 mmol) and 1-(4-bromo-2-chlorophenyl)-ethanone (1.52 g, 6.51 mmol) in DMSO (7 ml). The residue which was isolated was purified by filtration through a short pad of silica using pentane as eluant to give 4-bromo-2-chloro-1-isopropenylbenzene (750 mg, 50%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.51 (d, J=2.0 Hz, 1H), 7.34 (dd, J=2.0, 8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 4.96 (m, 1H), 2.07 (m, 3H).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[C:29]([C:31]1[C:35]([CH:36]=O)=[CH:34][N:33]([C:38]2[C:43]([Cl:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[CH:40][C:39]=2[Cl:49])[N:32]=1)#[N:30]>CCOCC>[C:29]([C:31]1[C:35]([CH:36]=[C:2]([CH3:4])[CH3:3])=[CH:34][N:33]([C:38]2[C:43]([Cl:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[CH:40][C:39]=2[Cl:49])[N:32]=1)#[N:30]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Reaction time: 2 h

Procedure:
Isopropyltriphenylphosphonium iodide (0.97 g) in anhydrous ether (10 ml) was treated at room temperature with n-butyllithium (0.9 ml of a 2.5M solution in hexanes). To the resulting dark red solution was added 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-formylpyrazole (0.6 g) in ether (20 ml) and the mixture stirred for 2 hours. The solution was washed with water (20 ml) and the separated organic layer dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions provided the title compound as a pale tan solid m.p. 72-74° C.
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH2:15]>O1CCOCC1>[C:1]([C:6]1[S:10][C:9](/[CH:11]=[C:12](\[CH3:13])/[CH:14]=[O:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(C=C(C)C)s1
Reactant: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(/C=C(\C)C=O)s1
Yield: 176.3 %

Procedure:
A mixture of 3.8 g (17.2 mmol) of 1-(5-carbethoxythien-2-yl)-2-methyl-1-propene and 5.0 g (45 mmol) of SeO2 in 60 mL of dioxane and 0.8 mL (44 mmol) of H2O was degassed three times under argon and heated under reflux for 45 min. Cooling, filtration over Celite, and concentration gave 6.8 g of a light-brown solid, which was diluted with 50 mL of Et2O and filtered. The filtrate was concentrated and passed over a column of 150 g of silica gel (15% EtOAc/hexane) to give 2.35 g (60% yield) of the aldehyde as a pale yellow solid, a portion of which was recrystallized from EtOAc/hexane to give white needles, mp 98° C: IR (mull) 1720, 1680, 1620, 1380, 1290, 1250, 1180, 1160, 1100, 1020, 890, 850, 815, 750 cm-1 ; 1H NMR (CDCl3) δ1.42 (t, J=7 Hz, 3, CH2CH3), 2.17 (s, 3, C=CCH3), 4.47 (q, J=7 Hz, 2, CH2CH3), 7.40 (d, J=4 Hz, 1, 3' C=CH), 7.43 (s, 1, C=CH), 7.83 (d, J=4 Hz, 1, 4' C=CH), 9.63 (s, 1, CHO); MS calcd for C11H12O3S 224.0507, found 224.0519.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[S-:14][C:15]#[N:16].[K+]>>[CH3:12][C:6]([CH3:13])([CH2:5][CH2:4][CH2:3][CH2:2][S:14][C:15]#[N:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)(C)CCCCBr
Reactant: N#C[S-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCSC#N

Procedure:
Using ethyl 6-bromo-2,2-dimethylhexanate as obtained in Reference Example 7and potassium thiocyanate, the title compound was produced in the same manner as in Reference Example 11.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1Cl)=[O:5])[CH3:2].[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C([O-])([O-])=O.[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]#[N:13])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1scnc1Cl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1scnc1Oc1cccc(C#N)c1
Temperature: 80 °C
Yield: 39.1 %

Procedure:
A stirred of 665 mg (3.5 mmol) 4-chloro-thiazole-5-carboxylic acid ethyl ester, 416 mg (3.5 mmol) 3-cyanophenol, 2.4 g (7.3 mmol) Cs2CO3 and 60 mL dimethylformamide was warmed to 80° C. in an oil bath for 72 hours. The mixture was then cooled, poured into 70 mL water, and extracted with ethyl acetate (3×40 mL). The combined extracts were washed with water (2×50 mL), brine (1×50 mL), dried over Na2SO4, and concentrated via rotary evaporation. The resulting oil was chromatographed on a Biotage Flash 40S® silica column, loaded with methylene chloride and eluted with 20% ethyl acetate/80% hexanes to give 375 mg of a light yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=2[O:18][CH2:19][CH:20]2[CH2:22][O:21]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]1[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CNC
Reactant: c1ccc(CCCCCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
0.7 ml of 50% by volume aqueous dimethylamine were added to a solution of 0.200 g of 2-[2-(6-phenylhexyl)phenoxymethyl]oxirane [prepared as described in step (a) above] in 7 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 15:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.227 g (yield 99%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CSc1ncc(CO)c(Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (67 mmol) was dissolved in THF (900 mL) to give a yellow solution. The mixture was cooled in a −78° C. bath under nitrogen atmosphere (internal temp. about −70° C.). DIBAL-H (1 M in THF; 200 mmol) was added over 45 min. via syringe. The reaction was warmed to −60° C. after the addition, and then allowed to warm slowly to 0° C. over night. The reaction was quenched by slow addition of saturated aqueous ammonium chloride (200 mL). The mixture was then warmed to room temperature. Ether (400 mL) and saturated aqueous sodium potassium tartrate (200 mL) were added. The mixture was stirred vigorously for 30 min. After separation of the layers, the aqueous layer was extracted with ether and the combined organics washed with brine, dried with sodium sulfate, filtered and concentrated under vacuum to give (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a solid (84%).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([S:20][C:21]3[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[N:9][CH:10]=1)=O)C.C[Mg]Cl>C1COCC1>[C:27]([C:25]1[CH:26]=[C:21]([S:20][CH:17]2[CH2:18][CH2:19][N:14]([S:11]([C:8]3[NH:7][C:6]([C:24]([OH:31])([CH3:25])[CH3:23])=[CH:10][N:9]=3)(=[O:12])=[O:13])[CH2:15][CH2:16]2)[CH:22]=[C:23]([C:32]([CH3:34])([CH3:33])[CH3:35])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1cnc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)[nH]1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SC2CCN(S(=O)(=O)c3ncc(C(C)(C)O)[nH]3)CC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 180.1 %

Procedure:
To 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imidazole-4-carboxylic acid ethyl ester (Ex. 8b, 230 mg, 0.44 mmol) in 3 mL of THF was added dropwise a 3.0 M THF solution of MeMgCl (0.85 mL, 2.55 mmol) at 0° C. The reaction was allowed to warm to room temperature, stirred for 5 h, and then quenched with saturated NaH2PO4 (20 mL). The mixture was extracted with Ethyl acetate (40+20 mL) and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (3-30% Ethyl acetate/hexanes) to afford the title compound as a clear gum (202 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 10.76 (bs, 0.4H), 10.72 (bs, 0.6H), 7.23 (s, 2H), 7.02 (s, 0.6H), 6.97 (s, 0.4H), 5.30 (s, 1H), 3.77-3.74 (m, 2H), 2.97-2.82 (m 3H), 1.98-1.95 (m, 2H), 1.69-1.57 (m, 8H), 1.41 (s, 18H). 13C NMR (100 MHz): δ 154.5, 152.1, 141.2, 140.9, 136.9, 132.9, 132.0, 125.8, 122.1, 113.2, 69.5, 68.4, 46.0, 44.6, 34.5, 31.7, 31.5, 30.6, 30.4, 30.2. ESI/CI-MS m/z 510 ([M+H]+), 508 ([M−H]−). Three HPLC (reverse-phase, C18) methods were used to determine the purity of the title compound. Method 1: gradient elution, 40% to 85% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.6% (238 nm); Method 2: gradient elution, 40% to 95% solvent B (A=10 mM NH4OAc, B=MeCN) in 6 min. Purity (UV-VIS λ): 99.2% (238 nm), 99.4% (254 nm); Method 3: gradient elution, 50% to 99% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.4% (215 nm), 98.9% (254 nm), 98.7 (238 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)[CH2:15][C:14](=[O:27])[NH:13][C:12]=3[CH:28]=2)=[CH:4][CH:3]=1>[Ni]>[NH2:24][C:20]1[CH:19]=[C:18]([C:16]2[CH2:15][C:14](=[O:27])[NH:13][C:12]3[CH:28]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=3[N:17]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Agent: [Ni]
Product: Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 8-(4-fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 67) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a light yellow solid (16 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)COCCO.O>[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1ccccc1N
Solvent: O
Solvent: OCCOCCO
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccccc1C
Temperature: 250 °C
Yield: 76.7 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 2-methylaniline (267 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, amd concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 235 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH3:16])[CH:9]=[N:10]2.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][Br:18])[CH:9]=[N:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(C)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1c(Cl)ccc2ncc(CBr)cc12
Temperature: 40 °C
Yield: 60.3 %

Procedure:
To a solution of (6-chloro-3-methyl-quinolin-5-yl)-acetic acid methyl ester (1.70 g, 6.81 mmol) in tetrachloromethane (140 mL) was added N-bromosuccinimide (1.28 g, 6.8 mmol). The reaction mixture was heated to 40° C. for 1 h under simultaneous irradiation by a 300 W UV lamp. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 100:0 to 80:20) to afford the title compound as a white powder (1.34 g, 4.1 mmol, 60%). %). 1H NMR (400 MHz, CDCl3, 298 K): δ=8.97 (s, 1H), 8.30 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 4.69 (s, 2H), 4.30 (s, 2H), 3.73 (s, 3H). MS (ES+): 328 (M(Cl3H1179Br35ClNO2)+H)+.
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Br:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([CH2:20]Cl)[C:14]=1[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:20][C:15]1[C:14]([CH3:22])=[C:13]([Br:12])[C:18]([CH3:19])=[CH:17][N:16]=1
Reactant: Nc1nc(Br)c2nc[nH]c2n1
Reactant: Cc1cnc(CCl)c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2cnc3c(Br)nc(N)nc32)c(C)c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 6-bromo-9H-purin-2-ylamine (2.4 g, 11 mmol), 4-bromo-2-chloromethyl-3,5-dimethyl pyridine (3.5 g, 15 mmol), K2CO3 (2.07 g, 15 mmol) and DMF (50 mL) was stirred at 50° C. for 2 h. Work-up and flash chromatography gave the title compound as a white solid (2.6 g, 56%). HPLC Rt: 5.415 min. 1H-NMR (CDCl3): δ 8.17 (s, 1H), 7.88 (s, 1H), 5.38 (s, 2H), 5.05 (s, 2H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]([F:24])([F:23])[C:18](B(O)O)=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]([C:17]([F:24])([F:23])[F:16])=[CH2:19])[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Reactant: C=C(B(O)O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 98.8 %

Procedure:
4-bromo-2,6-bis(trifluoromethyl)pyridine (1.53 g), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (purity: 40%, 2.00 g) and potassium carbonate (1.58 g) were dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichlorobis(triphenylphosphine) palladium (II) (0.07 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with pentane. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.59 g) at a yield of 98%.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:8]([O:10][C:11]([N:13]=[C:14]=[S:15])=[O:12])[CH3:9]>O1CCCC1>[CH2:8]([O:10][C:11](=[O:12])[NH:13][C:14]([N:5]1[CH2:6][CH2:7][C@@H:3]([OH:2])[CH2:4]1)=[S:15])[CH3:9]
Reactant: O[C@@H]1CCNC1
Reactant: CCOC(=O)N=C=S
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)N1CC[C@@H](O)C1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
(3R)-3-hydroxypyrrolidine hydrochloride (15 g, 121.4 mmol) was dissolved in tetrahydrofuran (450 ml), and ethoxycarbonyl isothiocyanate (15.7 ml) was added thereto in an ice bath. The mixture solution was brought to room temperature in 10 minutes and then stirred overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to afford [(3R)-3-hydroxypyrrolidine-1-carbothioyl]carbamic acid ethyl ester (24.62 g, yield 93%) as a yellow crystal.