Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:14]=[C:15]([SH:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([S:20][C:2]2[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=2[CH:10]=[O:11])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CCn1nc(C)c(C=O)c1Cl
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(C=O)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 9.2 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde, 14.3 g of 3,5-dichlorothiophenol and 11.8 g of potassium carbonate in 40 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 18 hours. Water (200 ml) was added and the mixture was extracted three times with 100 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/petroleum ether (bp 40-60° C.) for the elution to give 12.2 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde as an orange solid. Mass spectrum (ES) m/z 356 [M+CH3CN+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([OH:35])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[N+](=[CH2:38])=[N-].CCOCC>CO>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:38])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Yield: 95 %

Procedure:
Asiatic acid (500 mg) was dissolved in methanol (25 ml), and the solution was cooled to 0° C. An excess amount of diazomethane/ether solution was added, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol=30:1) to give 490 mg of white solid(yield: 95%). The product was recrystallized from ethyl acetate to obtain needle-like crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:24](=[O:27])([O-])[O-:25].[Na+].[Na+].[CH:30]1[C:42]2[CH:41]([CH2:43]Cl)[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:24](=[O:27])[O:25][CH2:43][CH:41]4[C:42]5[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=5[C:35]5[C:40]4=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CNCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: ClCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 4 h
Yield: 100 %

Procedure:
500 mg (0.9 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethylene)thiazolidine-2,4-dione (prepared in Example 12(c)) in 12 ml of aqueous 10% sodium carbonate solution are introduced into a round-bottomed flask. At 0° C., 240 mg of 9H-fluoren-9-ylmethyl chloride in 5 ml of dioxane are added dropwise. The mixture is stirred from 0° C. to room temperature for 4 hours. The reaction medium is immersed in water and extracted with ethyl acetate, after acidification to pH 4. The organic phase is dried over magnesium sulfate, filtered and evaporated. 490 mg (100%) of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:4][CH2:3]1.[C:53]1([S:59](O)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>COC(C)(C)C>[C:53]1([S:59]([O:18][C@H:16]2[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]3[N:11]=[C:10]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]5[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])=[CH:29][N:28]=5)[CH2:25][CH2:26]4)[C:9]([C@@H:40]([F:51])[C:41]4[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=4)=[C:8]([CH:5]4[CH2:4][CH2:3][C:2]([F:1])([F:52])[CH2:7][CH2:6]4)[C:17]2=3)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](O)CC(C)(C)C4)CC2)nc1
Reactant: O=S(=O)(O)c1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OS(=O)(=O)c3ccccc3)CC(C)(C)C4)CC2)nc1
Temperature: 40 °C
Yield: 83.5 %

Procedure:
To a solution of 30.0 mg (0.0408 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 16, in 0.4 ml of tert-butyl methyl ether, 0.013 ml (0.041 mmol) of 3.16 M benzenesulfonic acid aqueous solution was added dropwise with stirring at 40° C. Then, the reaction mixture was cooled to room temperature and stirred for 30 minutes. The precipitated solid was obtained by filtration, washed with tert-butyl methyl ether and then dried under reduced pressure at 60° C. to provide 29.8 mg of the title compound as a white powder (yield: 82%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:26]([C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33](=[O:42])[N:34]2[CH2:39][CH:40]=O)([O-:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:34]4[C:35]5[C:30](=[C:29]([N+:26]([O-:28])=[O:27])[CH:38]=[CH:37][CH:36]=5)[CH:31]=[CH:32][C:33]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)ccc2c([N+](=O)[O-])cccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c([N+](=O)[O-])cccc32)CC1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To 1 mL of a chloroform solution containing 0.20 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (5-nitro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 10 μL of acetic acid and 0.18 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[N:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16](I)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Cl:5][C:6]1[N:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([CH:23]=[O:24])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: Clc1cc2c(cn1)-c1nc(I)cn1CCO2
Reactant: CN(C)C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: O=Cc1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Ethylmagnesium bromide (3.0 M in Et2O, 100 mmol, 33.3 mL) was added dropwise to a solution of 9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (10.0 g, 28.8 mmol) in tetrahydrofuran (173 mL) at −20° C. The mixture was maintained at this temperature 20 min and then allowed to warm to ambient temperature for a 1 hr period. At this point, the reaction was re-cooled to −20° C. and N,N-dimethylformamide (8.9 mL, 115 mmol) was added to the mixture. Stirring was continued for 16 h before quenching with saturated aqueous ammonium chloride solution (220 mL) and further dilution with EtOAc (250 mL). The phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic portions were washed once with brine, dried over MgSO4, filtered and concentrated in vacuo. This provided 7.08 g (98% yield) of 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carbaldehyde as a yellow solid in >95% purity as determined by analytical HPLC. MS (ESI+): m/z 249.8 (M+H), calc. 249.65.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][CH:18]([CH2:20][OH:21])[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:19][CH:18]([CH2:20][OH:21])[CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCC(O)CS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc(SCC(O)CO)cc1

Procedure:
14.0 g (0.07 mol) of 4-chlorobenzophenone, 10.0 g (0.93 mol) of 1-thioglycerol and 28.5 g (0.21 mol) of potassium carbonate in 60 ml of dimethylacetamide are kept at 110° C. for 6 hours, under N2 gas and with stirring. After cooling, the reaction mixture is poured into 200 ml of water. The crude product, which is obtained in the form of an oil, is taken up in ethyl acetate, the solution is washed with water until neutral, dried over K2CO3 and concentrated, isopropanol is poured over the concentrate and the resulting mixture is stirred. The product, which is obtained in the form of crystals, is filtered off. 9.4 g (47%); melting point 86°-88° C.
Reaction SMILES: C([S:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.C[O:49][C:50](=[O:71])[C:51]1[CH:56]=[CH:55][C:54]([CH2:57][N:58]2[C:62]([CH2:63][NH2:64])=[CH:61][N:60]=[C:59]2[CH2:65][CH2:66][CH2:67][CH3:68])=[C:53]([F:69])[C:52]=1[F:70]>CN(C=O)C>[CH2:65]([C:59]1[N:58]([CH2:57][C:54]2[CH:55]=[CH:56][C:51]([C:50]([OH:71])=[O:49])=[C:52]([F:70])[C:53]=2[F:69])[C:62]([CH2:63][NH:64][C:6](=[O:8])[C@@H:5]([SH:4])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:61][N:60]=1)[CH2:66][CH2:67][CH3:68]
Reactant: CC(=O)S[C@@H](CC(C)C)C(=O)O
Reactant: CCCCc1ncc(CN)n1Cc1ccc(C(=O)OC)c(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ncc(CNC(=O)[C@@H](S)CC(C)C)n1Cc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) was dissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA (170 μL, 1.0 mmol) were added and the mixture was stirred at room temperature for 30 minutes. 4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved in DMF (1 ml) with DIPEA (170 μL, 1.0 mmol) and added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with acetic acid and the mixture was concentrated. The product was purified by preparative HPLC (2-90%) to yield 108 mg of the title compound as a white solid. MS m/z: [M+H+] calcd for C22H29F2N3O3S, 454.19; found 454.2. 1H-NMR (DMSO): 8.44 (1H, t), 7.59 (1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14 (2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:46]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:49]2[CH2:48][CH2:47][N:46]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) (5.4 g, 20.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.22 g, 32.15 mmol), and tert-butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in methylene chloride (20 mL) was treated with triethylamine (8.4 mL, 60.3 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane) to yield 7.10 g (81%) tert-butyl 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate as a white foam. HRMS: calcd for C23H33ClN2O4, 436.2129; found (ESI_FT), 437.21996.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9]([OH:11])=[O:10].[N+:17]([O-])([O-:19])=[O:18].[K+]>>[F:6][C:7]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Concentrated sulfuric acid (5 mL) was added into 2,6-difluoro benzoic acid (1.4 g, 9 mmol) and potassium nitrate (1 g, 9.9 mmol) was added gradually at 0° C. After the temperature of the reactant was elevated to a room temperature, the reactant was stirred for 24 hours. After pouring ice water into the reaction solution, extracting with ethylacetate, drying with sulfuric anhydride magnesium, and vacuum concentrating, the filtrate solid was washed with diethyl ether, and dried, so that 1.3 g of the target compound, 2,6-difluoro-3-nitro benzoic acid (percentage yield: 71%), was obtained.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:29]([C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])#[N:30]>>[C:47]([NH:46][C:32]1[CH:33]=[CH:34][C:35]([C:14]2[C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]([C:8]3[CH:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][NH:1]4)=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:36][C:31]=1[C:29]#[N:30])(=[O:49])[CH3:48]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccc(NC(C)=O)c(C#N)c1

Procedure:
Methyl 3-(4-acetamido-3-cyanophenyl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (37C) was prepared following a similar procedure as that described in example 29, except methyl 6-(1,2,3,4-tetrahydroquinolin-7-yl)-3-(trifluoromethylsulfonyloxy)picolinate (29F) was used instead of tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E), and N-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (37B) was used instead of phenylboronic acid in step 7 of example 29.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6]2)=[CH:26][CH:25]=1
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (6-methylpiperidin-3-yl)carbamate (8.03 g) in dimethylformamide (90 ml) were added potassium carbonate (10.4 g) and 4-methoxybenzyl chloride (5.34 ml), and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=100/3) to give the title compound (8.87 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([NH:7][CH3:8])[NH:4][CH:5]=[O:6].C(O[C:15](=[O:17])[CH3:16])(=O)C>>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([NH:4][CH:5]=[O:6])[N:7]([CH3:8])[C:15](=[O:17])[CH3:16]
Reactant: CNC(NC=O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)C(NC=O)C(Cl)(Cl)Cl

Procedure:
A mixture of 1,1,1-trichloro-2-methylamino-2-formamidoethane (6.85g) and acetic anhydride (17ml) was heated on a water bath for 11/2 hours. The reaction mixture was concentrated to give a oily residue which was triturated with water. The solid formed was collected, washed with water and dried (3.6g). Recrystallisation from benzene gave pure 1,1,1-trichloro-2-formamido-2-(N-methylacetamido)ethane (3.2g, m.p. 126-8)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1F.[Cl:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:27][C:23]1[CH:22]=[C:21]([Cl:20])[CH:26]=[N:25][CH:24]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a 0.08 M solution of N-(2-furanylmethyl) 2-fluoro-5-nitrobenzamide (2.64 g, 10 mmol, from Example 35.1) in anhydrous DMSO was added 5-chloro-3-pyridinol (1.36 g, 10.5 mmol, Acros) followed by K2CO3 (1.38 g, 10 mmol). The resulting mixture was stirred at ambient temperature for 1 hr. The crude reaction mixture was diluted with a 1 M solution of aqueous hydrochloric acid (125 mL) and extracted 3× with EtOAc (125 mL). The organic layers were combined and washed twice with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 3.7 g (100%) of N-(2-furanylmethyl) 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide as a pale yellow foam which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCCN1CCOCC1
Temperature: 110 °C
Yield: 68.3 %

Procedure:
4-(3-Chloropropyl)morpholine (0.9 g, 4.5 mmol), (J. Am- Chem. Soc. 1945, 67, 736, 174 mg, 1.06 mmol), was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.7 mmol), potassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml). The mixture was heated at 110° C. for 4 hours and then allowed to cool. The solids were removed by filtration, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol, (96/4) to give 6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (1.0 g, 68%).
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([F:28])[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:18]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[F:28][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:18]=[C:13]([OH:12])[CH:14]=1
Reactant: Fc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1cc(F)cc(C=Cc2ccc(F)cc2)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3,4′-difluorostilbene (0.97 g, 3 mmol) in dry CH2Cl2 (120 ml) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water. Flash chromatography gave the 3,4′-difluoro-5-hydroxystilbene (0.60 g, 86%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.46 (m, 2H), 7.08-6.73 (m, 6H), 6.48 (dt, 1H), 4.85 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 165.05 (d), 161.78 (d), 157.06 (d), 140.43 (d), 133.06 (d), 129.40 (s), 128.45 (d), 127.25 (t), 115.95 (d), 109.42 (d), 105.91 (d), 102.60 (d); 19F NMR (CDCl3, 282 MHz) δ −31703.17 (t), −32099.92 (t); HRMS (EI+) found 232.0714 M+, calcd 232.0700 for C14H10F2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:12]=1
Reactant: COc1ccc(Cn2cc(CO)cn2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cn2cc(CCl)cn2)cc1
Reaction time: 3 h

Procedure:
To (1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol (5.01 g, 23.0 mmol) in DCM (20 mL) was added thionyl chloride (8 mL). The reaction mixture was stirred for 3 hours and concentrated to provide the desired product (6.37 g).