Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[OH-].[Na+].[CH3:4][CH:5]([CH2:7][C@@H:8]1[N:17]2[C:18]([C@@:20]([NH:25][C:26]([C@@H:28]3[CH:43]=[C:42]4[C@@H:31]([CH2:32][C:33]5[C:37]6[C:38]4=[CH:39][CH:40]=[CH:41][C:36]=6[NH:35][CH:34]=5)[N:30]([CH3:44])[CH2:29]3)=[O:27])([CH:22]([CH3:24])[CH3:23])[O:21][C@@:16]2([OH:45])[C@H:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:10])=[O:19])[CH3:6].[OH-].[NH4+]>CS(C)=O.ClCCl.O>[CH3:6][CH:5]([CH2:7][C@@H:8]1[N:17]2[C:18]([C@@:20]([NH:25][C:26]([C@@H:28]3[CH:43]=[C:42]4[C@@H:31]([CH2:32][C:33]5[C:37]6[C:36](=[CH:41][CH:40]=[CH:39][C:38]=64)[NH:35][C:34]=5[Br:1])[N:30]([CH3:44])[CH2:29]3)=[O:27])([CH:22]([CH3:23])[CH3:24])[O:21][C@@:16]2([OH:45])[C@H:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:10])=[O:19])[CH3:4]
Reactant: Br
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dry gaseous hydrogen bromide is introduced to 70 ml. of anhydrous dimethylsulphoxide at room temperature. The amount of the introduced hydrogen bromide is measured by titrating against 0.1N sodium hydroxide solution. The hydrogen bromide is introduced until reaching a hydrogen bromide content of 0.0003 to 0.0005 mole/ml. in the dimethylsulphoxide. Then 10 g (0.01737 mole) of α-ergocryptine are dissolved in an amount containing 12 equivalents of hydrogen bromide as taken out from the thus-obtained mixture containing hydrogen bromide in dimethylsulphoxide. The reaction mixture is stirred at room temperature for 15 minutes beginning from the complete dissolution of α-ergocryptine, then poured in 5 volumes of water as calculated for the volume of dimethylsulphoxide. Then the mixture is alkalinized to a pH value of 8 to 9 by adding ammonium hydroxide, the precipitated 2-bromo-α-ergocryptine is filtered off, washed twice with 10 ml. of water each, dissolved in 200 ml. of dichloromethane and dried over anhydrous sodium sulphate. After filtering off the drying agent, 200 ml. of diisopropyl ether are added to the solution and dichloromethane is distilled off under atmospheric pressure. 2-bromo-αergocryptine separated from the distillation residue is filtered off and washed to give a yield of 8.4 g. (74%), m. p.: 215°-217° C., [α]D20 =-190° c=1%, dichloromethane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[N:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:11][CH2:12]2
Reactant: O=[N+]([O-])c1ccc(N2CCN3CCC2CC3)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCN3CCC2CC3)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 4-(4-nitrophenyl)-1,4-diaza-bicyclo[3.2.2]nonane (0.50 g, 2.0 mmol), palladium on carbon (100 mg, 10%) and methanol (60 ml) was stirred for 15 minutes under hydrogen (130 ml of hydrogen was consumed). The crude mixture was filtered through celite and the product was isolated as an oil in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[CH:23][C:24](OCC)=[O:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C=Cc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CCCO)nc3N21
Yield: 50.5 %

Procedure:
To a solution of 245.0 mg (0.63 mmol) (4R,9aR)-6-(2-ethoxycarbonyl-vinyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 12, intermediate) in 10 ml diethyl ether were added 50.0 mg (1.32 mmol) lithium aluminium hydride. After 2 h the reaction mixture was poured into saturated aqueous potassium sodium tartrate solution and ethyl acetate then filtered through a short pad of dicalite speed plus. The aqueous phase was extracted four times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane as eluant to afford the compound as a colorless solid (50.5%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[S:20][CH:19]=[N:18][C:17]=1[CH:21]([CH3:23])[CH3:22])=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:22][CH:21]([C:17]1[N:18]=[CH:19][S:20][C:16]=1[CH2:14][OH:13])[CH3:23]
Reactant: CCOC(=O)c1scnc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)c1ncsc1CO
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 68.3 %

Procedure:
Diisobutylaluminum hydride (1.5M in toluene; 2.4 mL, 3.6 mmol) was added dropwise over 10 min to a solution of 4-(1-methylethyl)thiazole-5-carboxylic acid ethyl ester (Example 8; 650 mg, 3.26 mmol) in toluene (5 mL) at −75° C. After 80 min, a second portion of diisobutylaluminum hydride (1.5M in toluene; 1.1 mL, 1.65 mmol) was added dropwise over 5 min at −75° C. After 20 min the cold reaction mixture was treated with saturated aqueous potassium sodium tartrate (5 mL) and the reaction mixture was allowed to warm to room temperature over 15 min. The liquid phase was decanted from the colorless solids and the filter cake was washed with toluene. The combined organic layers were washed with 5% aqueous potassium sodium tartrate (20 mL) and brine, then dried (MgSO4), filtered and evaporated in vacuo. The resulting residue was chromatographed over silica gel (0-25% ethyl acetate/hexanes) to give 4-(1-methylethyl)thiazole-5-methanol (350 mg, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2(C(C3CCCCO3)=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]=[CH:22][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:20]=4)[CH:17]=3)[NH:12][NH:11]2)=[CH:4][CH:3]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]=[CH:22][NH:21][N:20]=4)[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(C1CCCCO1)C1(/C=C/c2ccc(Cl)cc2)NNc2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(/C=C/c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Reaction time: 6.5 h
Yield: 56.6 %

Procedure:
Hydrolysis was performed by stirring 2-{3-[(1E)-2-(4-chlorophenyl)vinyl]-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazoyl}perhydro-2H-pyran in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 6.5 hours. The title compound was purified by column chromatography (5% MeOH in dichloromethane) and was isolated as a 98:2 mixture of isomers (0.040 g, 56.6% yield): 1H NMR (DMSO-d6) δ 14.4, 14.0 (2s, 1H), 13.4, 13.3 (2s, 1H), 8.7 (m, 1H), 8.1 (m, 2H), 7.8–7.4 (m, 7H); ES-MS (m/z) 322 [M+1]+.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH2:28][C@H:27]1[C:30]([OH:32])=[O:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:29][CH2:28][C@H:27]3[C:30]([OH:32])=[O:31])=[N:7][CH:6]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(F)nc2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(N3CC[C@H]3C(=O)O)nc2)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-[3-(6-Fluoropyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (15.0 g, 43.1 mmol), (2S)-azetidine-2-carboxylic acid (5.23 g, 51.7 mmol) and tripotassium phosphate (18.3 g, 86.0 mmol) are flushed and purged with N2(g) (3×) and DMSO (107 mL) was added. The reaction mixture was heated to 130° C. for 6 hours, then cooled to room temperature and was stirred overnight. The CELITE was added to the reaction mixture, filtered and precipitated by addition of acetonitrile (ca. 300 mL). The crude product was collected by filtration and purified by reverse phase chromatography to yield (2S)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azetidine-2-carboxylic acid. MS ESI calc'd for C21H19F3N5O2 [M+H]+ 430. found 430. 1H NMR (600 MHz, CDCl3) δ 8.64 (d, J=4.7 Hz, 1H), 8.29 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 7.06-6.94 (m, 2H), 6.50 (d, J=8.6 Hz, 1H), 4.88 (t, J=8.1 Hz, 1H), 3.90 (dd, J=8.2 Hz, 16.3 Hz, 2H), 3.03-2.88 (m, 1H), 2.49 (d, J=8.3 Hz, 1H), 2.40 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN1CCCC1=O.CO>[Cl:25][C:24]1[C:19]([N:14]2[CH2:13][CH2:12][C:9]3([C:8](=[O:17])[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:11][CH2:10]3)[CH2:16][CH2:15]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccnc1Cl
Reactant: O=C1N(C2CCCCC2)CCC12CCNCC2
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: O=C1N(C2CCCCC2)CCC12CCN(c1ncccc1Cl)CC2

Procedure:
A mixture of 2-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one (20 mg, 0.00008 mol), 2,3-dichloropyridine (15.0 mg, 0.000102 mol) and N,N-diisopropylethylamine (44 μL, 0.00025 mol) in N-methylpyrrolidin-2-one (1.0 mL) was irradiated under microwave at 200° C. for 15 min. The mixture was adjusted acidic (pH to −2.0) with trifluoroacetic acid (TFA), and was diluted with methanol (0.8 mL). The resulting solution was purified by Prep-HPLC to give 8-(3-chloropyridin-2-yl)-2-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+H)+=348.20/350.20.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:16][N:17]([CH2:30][CH2:31][CH2:32]O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=2[Cl:29])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.OC1C=C(C=CC=1)CC1N(COCC)N=NN=1.BrCCCO.Cl.C(OCC)C>C(OCC)C>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:32][CH2:31][CH2:30][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=2[Cl:29])[CH2:16][CH:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)n1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CCOCn1nnnc1Cc1cccc(O)c1
Agent: Cl
Agent: OCCCBr
Solvent: CCOCC
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(Cl)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Yield: 32 %

Procedure:
Following the procedure of Example 6(d), except 6-chloro-2-pyridinol (Aldrich) and N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine were used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole and 3-bromo-propanol in step 6(d), the title compound was synthesized as the free base. The tertiaryamine was then dissolved in diethyl ether and acidified with 1.0 M HCl/diethyl ether to give 90 mg (32% yield) of the title compound as a white solid. MS (ESI) 559.0 (M+).
Reaction SMILES: [OH-].[K+].[CH:3]1([C:6]([C:12]2[S:16][C:15]([SH:17])=[N:14][CH:13]=2)([OH:11])[C:7]([F:10])([F:9])[F:8])[CH2:5][CH2:4]1.Br[C:19]1[CH:28]=[C:27]2[C:22]([C:23]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1>CO>[CH:3]1([C:6]([C:12]2[S:16][C:15]([S:17][C:19]3[CH:28]=[C:27]4[C:22]([C:23]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[CH:24][C:25](=[O:29])[O:26]4)=[CH:21][CH:20]=3)=[N:14][CH:13]=2)([OH:11])[C:7]([F:8])([F:10])[F:9])[CH2:5][CH2:4]1
Reactant: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Reactant: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(-c2cccnc2)c2ccc(Sc3ncc(C(O)(C4CC4)C(F)(F)F)s3)cc2o1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Powdered KOH (0.111 g, 1.98 mmol) was added to a solution of (−)-1-cyclopropyl-2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanol (0.507 g, 1.98 mmol) in dry MeOH (2 mL). When a solution was obtained, the reaction mixture was concentrated to dryness. Dry toluene was then added and the mixture was concentrated to dryness again. The residue was dissolved in NMP (2 mL) and 7-bromo-4-pyridin-3-yl-2H-chromen-2-one (0.500 g, 1.65 mmol) was added and the resulting mixture was stirred at 120° C. for 16 h. Once cooled, the mixture was directly applied onto a column of silica gel and chromatographed (acetone/toluene 5:95 to 20:80), affording the title compound. 1H NMR (500 MHz, CDCl3): δ 8.76 (brd, 1H), 8.68 (d, 1H), 7.85 (s, 1H), 7.79 (brd, 1H), 7.50 (m, 2H), 7.31-7.36 (m, 2H), 6.39 (s, 1H), 3.05 (br s, 1H), 1.48 (m, 1H), 0.71 (m, 2H), 0.62 (m, 1H), 0.56 (m, 1H); [α]D=−31.1° (c=1.05, EtOH).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)CCCC)[CH:19]=[CH2:20].C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:20]([C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1)[CH:19]=[CH2:18]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 8 h
Yield: 30.5 %

Procedure:
In toluene (4 mL) was dissolved 200 mg (0.797 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 305 mg (0.921 mmol) of allyl-(tributyl)tin, and then, 96.8 mg (0.0838 mmol) of tetrakis-(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, and then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 62.1 mg (0.243 mmol, Yield: 30.5%) of 6-allyl-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.[C:15]1([N:21]2[C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[N:12]([C:25]2[N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:22]=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: O=c1ccc(-c2ccccc2F)c[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: O=c1ccc(-c2ccccc2F)cn1-c1ccnn1-c1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 1.4 %

Procedure:
5-(2-Fluorophenyl)pyridin-2(1H)-one (0.0281 g), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0802 g) and copper(II) acetate (0.0539 g) were suspended in pyridine (1.48 mL), and the suspension was stirred at room temperature for 12 hr and further at 90° C. for 6 hr. To the reaction mixture were added 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0802 g) and copper(II) acetate (0.0539 g) at room temperature, and the mixture was heated under reflux for 1.5 days. The reaction mixture was cooled to room temperature, purified by NH silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (0.0007 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Temperature: 95 °C
Yield: 56 %

Procedure:
A mixture of methyl 3-formyl-4-(trifluoromethyl-sulfonyloxy)benzoate (66.60B) (7.57 g, 24.2 mmol), 2-fluoro-5-methoxy-phenylboronic acid (commercially available from Aldrich) (12.4 g, 72.7 mmol), cesium carbonate (27.6 g, 84.9 mmol), and tetrakis(triphenylphosphine) palladium (2.80 g, 2.42 mmol) in 1,2-dimethoxyethane (DME) (75 mL) was degassed with N2 at room temperature The mixture was heated at 95° C. for 9 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:19 EtOAc/hexane) and gave 66.60C, a white solid, in 56% yield (2.9 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (dd, J=4 Hz, 1H), 8.45 (s, 1H), 8.28 (m, 1H), 7.69 (d, j=8 Hz, 1H), 7.29 (t, J=9 HZ, 1H), 7.08 (m, 2H), 3.92 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>>[Cl:9][C:6]1[CH:5]=[CH:4][C:3](=[O:10])[C:2]([NH:1][C:14](=[O:15])[CH2:13][C:12](=[O:16])[CH3:11])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)ccc1=O
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)Nc1ccc(Cl)ccc1=O
Temperature: 100 °C

Procedure:
A mixture of 2-amino-5-chloro-2,4,6-cycloheptatrien-1-one (1.55 g, described in example 9) and diketene (5 ml) were heated at 100° C. for 1 hr. The mixture was cooled and then purified by chromatography on silica gel using chloroform as the eluant. The appropriate fractions were pooled and the residue was crystallized from diethyl ether to give 650 mg of 1-[(4-chloro-7-oxo-1,3,5-cycloheptatrien-1-yl)amino]-1,3-butanedione, nmr (DMSO-d6) δ2.17 (s, 3H), 3.85 (s, 2H), 7.3 (m, 3H), 8.7 (d, 1H), 10.75 (s, 1H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH:27]4[CH2:29][CH2:28]4)=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(C2CC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(C2CC2)cc1

Procedure:
The title compound, light yellow solid (85 mg, 72%), MS (ISP) m/z=471.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-cyclopropyl-benzoic acid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[N:28][CH:29]=1>>[CH3:12][C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:24]3[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[N:28][CH:29]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cncc(S(N)(=O)=O)c3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (example B.1) (278 mg, 0.9 mmol) according to general procedure II. Obtained as an off-white solid (290 mg, 63%). MS (ISP) 457.1 [(M+H)+]; mp 294° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[S:12][CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:14]([OH:18])[C:15](O)=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[OH:18][CH:14]1[CH:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[S:12][C:3]2[C:4]3[C:9]([CH:10]=[CH:11][C:2]=2[NH:1][C:15]1=[O:16])=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: COc1ccc(C(Sc2c(N)ccc3ccccc23)C(O)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(C2Sc3c(ccc4ccccc34)NC(=O)C2O)cc1

Procedure:
A mixture of 1.0g (0.0027 mol) of (-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid and 0.1 g of p-toluenesulfonic acid in 50 ml of xylene was stirred and heated at reflux for 1.5 hours using a Dean-Stark water strap. After cooling the crystals were collected to provide 0.80 g (80%) of [2R-(2α,3α)] 2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b] [1.4]thiazepin-4(5H)-one, mp 238-239°, [α]D 25 -22.97° (C 0.51, acetone).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[N:14][N:13]([CH:16]([F:18])[F:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:45]=3)[C:40]2=[O:54])=[N:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:51])([CH3:50])[CH3:52])[CH:45]=3)[C:40]2=[O:54])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[N:14][N:13]([CH:16]([F:18])[F:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Br)cc(Nc2cnn(C(F)F)n2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cnn(C(F)F)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 32.1 %

Procedure:
Following the procedure of Example 152c, and starting with 159c (150 mg, 0.46 mmol, 1.0 eq.) and 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid (116c) (285 mg, 0.69 mmol, 1.5 eq.) afforded 159d as a yellow solid (90 mg, 32%). MS-ESI: [M+H]+ 609.3
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:14])=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O>O>[CH3:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: Cc1cc(CCCCC(=O)O)c(C)s1
Solvent: O
Product: Cc1sc(C)c2c1CCCCC2=O
Temperature: 25 °C
Yield: 72.7 %

Procedure:
5-(2,5-Dimethyl-3-thiophenyl)pentanoic acid (12 g, 56.6 mmol) is heated in 30 g of polyphosphoric acid at 140° C. for 2 hr. After the reaction mixture is cooled to room temperature, water is added to dissolve the residual PPA. The mixture is then extracted with ether and the ether layer is washed with water, aqueous NaOH and again with water. The ether layer is then dried over sodium sulfate and the solvent evaporated under reduced pressure to yield 1,3-dimethyl-5,6,7,8-tetrahydro-4 H-cyclohepta[1,2-c]thiophen-4-one as a dark oil (8 g, 73%). 1H NMR (CDCl3) 2.70 (t, J=6.0 Hz, 2 H), 2.64 (dd, J=5.0, 7.0 Hz, 2 H), 2.55 (s, 3 H), 2.28 (s, 3 H), 1.79 (m, 4 H).