Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH:8](Cl)[CH:7](Cl)[N:6]([C:11](=[O:13])[CH3:12])[C:5]1=[O:14])(=[O:3])[CH3:2].CN(C)C=O.O>C(OCC)C.[Zn]>[C:11]([N:6]1[CH:7]=[CH:8][N:4]([C:1](=[O:3])[CH3:2])[C:5]1=[O:14])(=[O:13])[CH3:12]
Reactant: CC(=O)N1C(=O)N(C(C)=O)C(Cl)C1Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)n1ccn(C(C)=O)c1=O
Yield: 95.2 %

Procedure:
Activated zinc (from 63.5 g (1.0 mol) of zinc), prepared in accordance with J.Org.Chem. 29, 2049 (1964), are added in portions to a boiling solution of 119.5 g (0.5 mol) of recrystallised 1,3-diacetyl-4,5-dichloro-imidazolidin-2-one and 8 ml of dimethylformamide in 400 ml of dry diethyl ether and the mixture is heated under reflux until conversion is complete (16 hours). After the reaction solution has cooled, 200 ml of water are added to it, and the mixture is filtered. The filter cake is washed with 3×100 ml of benzene and the organic phases are combined and washed until they give a neutral reaction. Drying over sodium sulphate and evaporation gives 80.0 g (about 95%) of 1,3-diacetyl-4-imidazolin-2-one of melting point 106° C., identical with a sample prepared independently in accordance with J.Amer.Chem. Soc. 54, 3413 (1932).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C@@H:16]4[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]4)[NH:13][N:12]=3)[CH:9]=2)[N:4]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:3]=1.[N:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[N:48]1[CH:53]=[CH:52][C:51]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]5)[NH:13][N:12]=4)[CH:9]=3)[N:4]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:3]=2)=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(Br)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Yield: 86.8 %

Procedure:
Stirred a mixture of (R)-tert-butyl 3-(3-(3-bromo-1-trityl-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (500 mg, 0.72 mmol), pyridine 4-boronic acid (150 mg, 1.22 mmol), PdCl2dppf (30 mg, 0.036 mmol) and Cesium carbonate (400 mg, 1.23 mmol) in dioxane (9 mL) and water (1 mL) at 100° C. in a microwave oven for 2 hours. After cooling, diluted with water (50 ml), then extracted with DCM (100 ml). The combined organic layer was dried (Na2SO4), filtered and evaporated to yield crude product, which chromatographed on silica gel eluting with 30% v/v EtOAc/Hexanes to yield (R)-tert-butyl 3-(3-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (430 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[C:13]([OH:21])[CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl>[CH:5]1([C:11]2[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[C:13]([OH:21])[CH:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(C2CCCCC2)cc1O
Solvent: ClCCl
Product: O=C(O)Cc1cc([N+](=O)[O-])c(C2CCCCC2)cc1O
Reaction time: 0.17 h

Procedure:
1.06 ml of 100% nitric acid are slowly added dropwise at -10° to a solution of 5.9 g of 4-cyclohexyl-2-hydroxy-phenylacetic acid in 100 ml of absolute methylene chloride. The mixture is finally stirred for 10 minutes without further cooling, the methylene chloride solution washed several times with water, dried over sodium sulphate and evaporated to yield the title compound.
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3]1.C[Si](C)(C)[C:21]#[N:22].CN(C)C(Cl)=O>ClCCl>[F:1][C:2]1([C:6]2[C:11]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]([C:21]#[N:22])=[N:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(OCC(F)(F)F)c(C2(F)CCC2)c1
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of 3-(1-fluorocyclobutyl)-1-oxido-4-(2,2,2-trifluoroethoxy)pyridin-1-ium (example 127b, 1.65 g, 6.22 mmol) in dichloromethane (25 ml) was added trimethylsilanecarbonitrile (945 mg, 1.19 ml, 9.33 mmol) and dimethylcarbamic chloride (833 μl, 8.71 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separation funnel and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (760 mg, 44%); MS (ESI, m/z): 275.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:38]([CH:41]([CH3:43])[CH3:42])CC)(C)C.[I:44][C:45]1C=CC(N)=[CH:47][C:46]=1[CH3:52]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:38][C:41]1[CH:42]=[CH:47][C:46]([CH3:52])=[C:45]([I:44])[CH:43]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(N)ccc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Yield: 89.5 %

Procedure:
2-Chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol), diisopropylethyl amine (10.9 ml, 63 mmol) and 4-iodo-3-methylaniline (5.00 g, 21 mmol) in dimethylformamide (50 ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150 ml). The organic solution was washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetate:cyclohexane) to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a white solid (7.00 g, 18.8 mmol). LCMS: retention time 3.59 min MH+373. NMR: δH [2H6]-DMSO 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: c1ccc(NC2CC2)cc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(c3ccccc3)C3CC3)c2)C[C@H]1C

Procedure:
N-Cyclopropylaniline was then be coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzamide as a yellow powder. NMR (200 MHz, DMSO-d6): δ 0.44 (m, 2H); 0.70 (m, 2H); 0.93 (d, J=6.1 Hz, 3H); 1.01 (d, J=5.7 Hz, 3H); 1.74 (dd, J1 =7.7 Hz, J2 =11.8 Hz, 1H); 2.05 (dd, J1 =6.8 Hz, J2 =11.1 Hz, 1H); 2.39 (br d, J=10.5 Hz, 1H); 2.41-2.54 (m, 2H); 2.69 (br d, J=11.8 Hz, 1H); 2.83 (dd, J1 =6.6 Hz, J2 =13.6 Hz, 1H); 3.05-3.36 (m, 2H); 4.83 (s, 1H); 5.10 (d, J=9.8 Hz, 1H); 5.17 (d, J=17.4 Hz, 1H); 5.70-5.86 (m, 1H); 6.57 (d, J=7.1 Hz, 1H); 6.63 (s, 1H); 6.65 (d, J=8.2 Hz, 1H); 7.03-7.38 (m, 10H); 9.34 (s, 1H). Mass spectrum (CI--CH4) m/e: 496 (M+1, 100%), 342 (45%), 153 (90%). [α]D20 =+7.1° (abs. ethanol, c=1.1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic orange powder. Calc. for C32H37N3O2HCl 1.50H2O: C, 68.74; H, 7.39; N, 7.51; Cl, 6.34. Found: C, 68.56; H, 7.49; N, 7.26; Cl, 6.37.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][O:24][C:25](=[O:42])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1)=[CH2:27]>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:42])[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1)[CH2:27][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])=[O:13]
Reactant: O=[PH](O)CCCCc1ccccc1
Reactant: C=C(C(=O)OC)c1cccc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CP(=O)(O)CCCCc1ccccc1)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To 4-phenylbutylphosphinic acid (357 mg, 1.8 mmol) in methylene chloride at 0° C. was added DIEA (0.66 mL, 3.8 mmol), followed by TMSCI (0.47 mL, 3.8 mmol). After 1 hour, 2-(3-(t-butoxycarbonylamino)phenyl)propenoic acid methyl ester (0.5 g, 1.8 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 5 hours, the reaction was partitioned between methylene chloride and saturated NaHCO3 solution. The organic layer was washed with 0.1 N sulfuric acid and concentrated in vacuo. The residue was dissolved in 10 mL 3:1 THF:methanol for 18 hours. The reaction was concentrated to provide 2-(3-(t-butoxycarbonylamino)phenyl)-3-((4-phenylbutyl)(hydroxy)phosphinoyl)propanoic acid methyl ester (845 mg) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:25])[C@H:21]([CH2:23][SH:24])[NH2:22])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:24][CH2:23][CH:21]([C:20]([O:19][CH2:17][CH3:18])=[O:25])[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1

Procedure:
4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]([F:28])([F:27])[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]3)=[CH:4][CH:3]=1.COCCOC.C(Cl)Cl>Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]4)=[N:9][N:8]=2)[N:7]=1
Reactant: COCCOc1cnc2ccc(C(F)(F)C(=O)NNc3ccc(Cl)nn3)cc2c1
Agent: Cl
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(Cl)nn34)cc2c1
Temperature: 130 °C
Yield: 56.2 %

Procedure:
A sealable microwave vial was charged with N′-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide (46.98 mg, 111 μmol), 1,2-dimethoxyethane (1.5 mL), and 1 drop of conc. HCl. The vial was sealed and heated at 130° C. for 40 min. The solution was concentrated and purified by MPLC (Teledine Isco combiFlash Companion). The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep®(D pre-packed silica gel column (12 g) using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH to afford 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline (25.3 mg, 56.2% yield) as a colorless solid. LRMS (ESI) m/z calcd for C18H15ClF2N5O2 (M+H) 406.1, found 406.2.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[CH2:30]([N:19]1[CH2:20][CH2:21][N:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:17][CH2:18]1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5.0 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole and 2.7 g of potassium carbonate in 50 ml of dimethylformamide was added 2.4 g of allyl bromide. The reaction mixture was stirred at 70° C. for 16 hours, poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield 3-[4-(2-propenyl)-1-piperazinyl]-1-phenyl-1H-indazole as an oil. The oil was diluted with diethyl ether and filtered. Treatment of the filtrate with ethereal hydrogen chloride precipitated the hydrochloride salt. Recrystallization from ethanol/diethyl ether gave 2.0 g (21%) of 3-[4-(2-propenyl)-1-piperazinyl]-1-phenyl-1H-indazole hydrochloride, mp 234°-236°.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:6](=[O:7])[CH2:5][C:4]([CH3:10])([CH3:9])[CH:3]=1.[O:11]=O>CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cr].[Cr].[Cr].[Cr].[Cr].[Cr+6].N1C=CC=CC=1>[O:11]=[C:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:7])[CH:8]=[C:2]1[CH3:1]
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: O=O
Agent: [Cr+6]
Agent: [Cr]
Solvent: CC(=O)CC(C)=O
Solvent: c1ccncc1
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
3,5 g. of chromium (III) acetylacetonate in 100 ml. of pyridine are treated with 69 g. of β-isophorone. The mixture is gassed with oxygen at 70° C. for 2 hours with intensive stirring and subsequently worked up by distillation. The conversion of β-isophorone used amounts to 49,6 g. corresponding to 72%. Ketoisophorone is obtained in a yield of 41 g. corresponding to 75%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[C:17]1([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Diisopropylethylamine (14 mL, 80 mmol) was added dropwise to a suspension of 4-imidazole methanol (5.4 g, 40 mmol) in CH3CN (15 mL) at 0° C. A homogeneous yellow solution was formed. To this solution was added triphenylmethyl chloride (11.2 g, 40 mmol). The reaction mixture was stirred at room temperature for 2 h. The resultant white precipitate was filtered and washed successively with saturated NaHCO3 aqueous solution (2×20 mL) and water (2×20 mL), then dried in a vacuum oven (45° C.) for 12 h to afford a white solid 11.2 g (82%) which was used in next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:15])=[CH:8]2)=[O:4].O1CCCC1.CO.O.[OH-].[Li+:25]>O>[Li+:25].[Br:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([O-:4])=[O:2])=[CH:14][CH:13]=2
Reactant: COC(=O)c1ccc2ncc(Br)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-quinoline-6-carboxylic acid methyl ester described in Preparation Example 162 (26 mg, 0.098 mmol) and tetrahydrofuran (2 mL) were added methanol (0.2 mL), lithium hydroxide monohydrate (4.1 mg, 0.098 mmol) and water (0.2 mL), and the solution was stirred overnight at room temperature. The solvent was evaporated in vacuo, and the title compound (27 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[C:14]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][CH:10]2[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (600 mg, 4.03 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (1.07 g, 4.43 mmol) in EtOH (20 mL) was added Et3N (815.6 mg, 8.06 mmol). After addition, the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 1/1) to give the product as a white solid (528 mg, 37.2%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:16]([O:18]CC)=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[N:6]=1.[OH-].[K+].Cl.C(Cl)Cl>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[N:6]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1cc(Cl)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1nc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g, 3.72 mmol), potassium hydroxide (278 mg) in THF (40 mL) and water (10 mL) was stirred for 20 hours at ambient temperature. The mixture was treated with 1M HCl aq. (ca. 8 mL, 2 eq.), DCM was added, and the organics separated and evaporated to dryness to give 1.23 g (95%) of 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid as a yellow solid. LCMS (ESI) m+H=350.1. 1H NMR (400 MHz, DMSO-d6): δ 7.47 (dd, 1H); 7.39 (d, 1H); 7.13 (d, 1H); 3.73 (s, 3H).
Reaction SMILES: [Li][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.CN(OC)[C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.Cl>C1COCC1.CCOCC>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][C:9]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: [Li]c1cccs1
Reactant: COc1ccc(CC(=O)N(C)OC)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2cccs2)cc1OC
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
2-Lithiothiophene (1.0 M in THF, 33.0 mL, 33.0 mmol, Aldrich Chemical Co.) was added dropwise to N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide (5.26 g, 22.0 mmol) in anhydrous THF at -78° C. The reaction was allowed to proceed 90 min., then diluted with 100 mL Et2O and poured into 1 N aq. HCl. The aqueous phase was extracted with Et2O and the combined organic fraction was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography (25% EtOAc/hexanes) yielded 2.91 g (50%) 2-(3,4-dimethoxyphenyl)-1-(thien-2-yl)ethanone as a brown oil. MS 263 (M+H)+, 280 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](Cl)=[O:11].[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[NH2:19].C(=O)([O-])[O-].[Ca+2].[Cl:29][S:30](O)(=[O:32])=[O:31]>C1COCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:19][C:18]1[CH:20]=[C:21]([CH3:23])[C:22]([S:30]([Cl:29])(=[O:32])=[O:31])=[C:16]([CH3:15])[CH:17]=1)=[O:11]
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Cl)Cc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Cc2ccccc2C(F)(F)F)cc(C)c1S(=O)(=O)Cl
Yield: 47 %

Procedure:
4-(2-[2-Trifluoromethylphenyl]acetyl)-3,5-dimethylaniline (obtained as a solid, m.p. 168° C., by reacting 2-(2-trifluoromethylphenyl)acetyl chloride with 3,5-dimethylaniline in THF solution in the presence of calcium carbonate) was reacted with an excess of chlorosulfonic acid at 60° C. using an analogous procedure to that described in Organic Synthesis, Coll. Vol. I, at page 85, to give 4-(2-[2-trifluoromethylphenyl]acetamido)-2,6-dimethylbenzenesulfonyl chloride, as a solid in about 47% yield, which was used without purification.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([CH2:18][C:19]#[N:20])[C:12]=1[O:21][CH3:22].Cl>CN(C)C=O.O>[C:19]([C:18]1([C:13]2[CH:14]=[C:15]([Br:17])[CH:16]=[C:11]([Br:10])[C:12]=2[O:21][CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:20]
Reactant: BrCCCCCBr
Reactant: COc1c(Br)cc(Br)cc1CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)cc(Br)cc1C1(C#N)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (7 g) in dry dimethylformamide (200 ml) was added a solution of 1,5-dibromopentane (20 ml) and the product of stage (d) in dimethylformamide (40 ml), keeping the temperature at 20°-30° C. The mixture was stirred for 30 minutes, water was added cautiously, and was then poured into ice water. Hydrochloric acid was added and the mixture was extracted with dichloromethane, washed with water and brine, dried over magnesium sulphate and filtered, and the solvent was removed to give a pale brown oil which slowly crystallised. Recrystallisation from ethanol gave the title product as yellow crystalls, mp 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([Cl:17])=[CH:11][C:12]([O:15]C)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.CN(C=O)C.CC([S-])(C)C.[Na+]>O.Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([Cl:17])=[CH:11][C:12]([OH:15])=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2c(F)c(OC)cc(Cl)c12
Agent: CC(C)(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2c(F)c(O)cc(Cl)c12
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 84.6 %

Procedure:
To a mixture of methyl(4-chloro-7-fluoro-6-methoxy-1-benzothiophen-3-yl)acetate (284.8 mg) and DMF (dry) (8.0 mL) was added sodium 2-methyl-2-propanethiolate (443 mg). The mixture was stirred at 160° C. for 45 min. After cooling, the mixture was diluted with water and 1N HCl and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in MeOH (6.0 mL). To the solution was added conc. H2SO4 (0.100 mL). The mixture was stirred at 70° C. for 1 h. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residual solid was washed with toluene and hexane to give the title compound (229.3 mg).