Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.II>CO>[F:23][C:22]([F:24])([F:25])[C:19]1[CH:18]=[CH:17][C:16]([N:15]=[C:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: II
Solvent: CO
Product: FC(F)(F)c1ccc(N=c2ccc3nc4ccccc4sc-3c2)cc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
Phenothiazine (2.0 g, 10 mmole) and 4-aminobenzotrifluoride (1.77 g, 11 mmole) were dissolved in methanol (MeOH) (100 mL) with warming to 45° C., treated with a solution of I2 (5.0 g, 19.4 mmole) in MeOH (80 mL) in one portion and allowed to stir for 3 h at 45° C. The reaction mixture was filtered and the collected solid was washed with MeOH (100 mL). The solid was dissolved in CHCl3 (60 mL) containing triethylamine (NEt3) (6 mL) then this solution was diluted with hexane (200 mL) and chilled in an ice bath for 2 h. The purple solid that separated was collected by filtration and redissolved in CHCl3 /NEt3 (10:1, v:v) (50 mL) and chromatographed on silica gel (250 g) using CHCl3 /acetone (96:4, v:v) development. The purple product band was collected and evaporated to dryness in vacuo to afford 4 (0.26 g, 7.3%) with mp=207°-8° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N:9]([CH2:12][C:13](OCC)=[O:14])=[C:10]=[S:11].C(N(CC)CC)C>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]1[C:13](=[O:14])[CH2:12][NH:9][C:10]1=[S:11])[CH3:3]
Reactant: CCOC(=O)CN=C=S
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)CNC1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Glycine ethyl ester hydrochloride (140 mg, 1 mmol) and ethyl isothiocyanatoacetate (145 mg, 1 mmol) were dissolved in acetonitrile (6 mL), triethylamine (0.6 mL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/1 (volume ratio)) as an eluent, to give ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate in a yield of 170 mg (yield 84.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11]2[NH:20][N:19]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2sccc2Cl)CC1=O
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Yield: 60 %

Procedure:
A solution of 5-(3-chlorothiophen-2-yl)-2-(1-hydroxyethylidene)-cyclohexane-1,3-dione (2.2 g) and hydrazine hydrate (0.45 g) in ethanol (60 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(3-chlorothiophen-2-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([NH:34][CH2:33][CH2:31][OH:32])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Reactant: NCCO
Product: O=C(NCCO)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and ethanolamine were reacted in the general amide coupling procedure to give 375. NMR: (CDCl3): 2.72 (1 H, s, OH), 3.01-3.04 (2 H, m), 3.57-3.61 (2 H, m), 3.72-3.81 (2 H, m), 4.20-4.23 (2 H, m), 6.68-6.72 (1 H, m, NH), 6.79 (1 H, s, Ar), 6.94 (1 H, d, J 8.4, Ar), 7.02-7.06 (2 H, m, Ar), 7.33-7.40 (1 H, m, Ar), 7.50-7.53 (1 H, m, Ar), 7.89-7.90 (1 H, m, Ar) and 8.16 (1 H, s, Ar). MS: (ESI+) MH+=469.04
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH2:16][CH2:15][O:14][C:12]3=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH2:16][CH2:15][O:14][C:12]3=2)[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2ccc3c(c21)OCC3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2ccc3c(c21)OCC3

Procedure:
To a stirred solution of 4.2 g. of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[3,2-h]quinazolin-2(1H)-one in 180 ml. of dioxane cooled to 8°±5°C. is added dropwise a solution of 2.3 g. of potassium permanganate in 100 ml. of water. After the addition is completed 1.5 ml. of formalin solution is added. The solids which precipitate are removed by filtration and the filtrate concentrated in vacuo to obtain an oil of 1-isopropyl-7,8-dihydro-4-phenyl-furo[3,2-h]quinazolin-2(1H)-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.CN(C)C=O.[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:27](=[O:33])[NH:26][C:25](=[O:34])/[C:24]/2=[CH:35]/OC>C(N(CC)CC)C>[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:27](=[O:33])[NH:26][C:25](=[O:34])[C:24]2=[CH:35][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1
Reactant: CCCOc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3cc(OC)c(Br)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-Aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 μL, x mmole) were stirred for 15 minutes. Then (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The product is isolated as before, to give an off-white solid, 119 mg, (51%), mp 212-214° C. dec; MS (ESI): m/z 459.1, 461.2 (M−H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:31])[N:9]([CH3:30])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][CH:19]([CH3:20])[CH3:21])=[CH:28][CH:27]=1
Reactant: CC(C)Oc1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (55 mg, 0.13 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (10.9 mg, 0.26 mmol). The reaction was stirred at RT for 15 min then diluted with water (20 mL) and extracted with EA (3×15 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 37% yield) as a white solid. 1H NMR (CDCl3) δ: 8.33 (s, 1H), 7.18 (s, 4H), 4.73 (s, 2H),), 4.68-4.68 (m, 1H), 4.28-4.15 (m, 2H), 3.69 (s, 3H), 3.52 (dd, J=11.8, 6.2 Hz, 2H), 3.16 (t, J=7.0 Hz, 1H), 1.97-1.82 (m, 2H), 1.34 (d, J=6.0 Hz, 6H). LCMS: MH+ 418 and TR=2.915 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:38])[CH:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:26][S:27]2)=[CH:22][CH:21]=1.O>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:24]2([OH:38])[C:23]3[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:27][CH2:26][CH:25]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(C3OCCO3)c2)cc1
Reaction time: 0.83 h
Yield: 50 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (3.04 g, 13.28 mmol) in dry tetrahydrofuran (35 ml) was added n-butyl lithium (8.37 ml, 13.316 mmol, 1.59 mol/l tetrahydrofuran solution) dropwise as −78° C. over 10 minutes and stirred for 50 minutes at the same temperature. Then to the reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.658 mmol) dissolved in tetrahydrofiuran at the same temperature over 10 minutes. The reaction mixture was stirred for 6 h at −78° C. and followed at −10C for 2 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:1 to 7:3) to give 1.50 g (yield: 50%) of the title compound as a colorless oil. In this reaction, 0.77 g (38%) of the unreacted starting compound was recovered.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:23])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. The resulting solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1:1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%).
Reaction SMILES: O[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.S(=O)(=O)(O)O.[CH:18]([OH:20])=[O:19]>>[C:2]12([C:18]([OH:20])=[O:19])[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1
Reactant: O=CO
Reactant: OC12CCCC(C1)C1CCC2C1
Agent: O=S(=O)(O)O
Product: O=C(O)C12CCCC(C1)C1CCC2C1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
5 g of 1-hydroxytricyclo[4.3.1.12,5 ]undecane dissolved in 20 ml of formic acid was added dropwise with stirring to 40 ml of conc. sulfuric acid over a period of 1.5 hours while the temperature was kept at 0° to 10° C. The mixture was further stirred for 1 hour and allowed to stand. Separated solids were collected by filtration and dried to afford 5.7 g (yield: 97.5%) of tricyclo[4.3.1.12,5 ]undecane-1-carboxylic acid of the formula (1a). The data on the melting point, elemental analysis, IR, MS and 13C NMR spectra were in complete agreement with that in Example 1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]2[S:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:15][C:11]=2[CH:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:27]=[CH:26][C:12]2[S:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:15][C:11]=2[CH:10]=1)[CH2:34][C:30]1[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=1
Reactant: CCCN(CCC)CCCc1cc2cc(CNCc3ncc[nH]3)ccc2s1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCc1cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (197.9 mg) obtained in Example 120-6 was dissolved in methanol (10 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (68.0 mg) and sodium cyanoborohydride (64.7 mg). After that, the solution was adjusted to pH 5 with acetic acid, followed by stirring overnight at room temperature. After the solvent had been distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (228.7 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.Cl[C:14]1[C:23]2[C:18](=[C:19]([C:24](F)(F)F)[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:14]1[C:23]2[C:18](=[C:19]([CH3:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: COc1ccc2[nH]c(C)c(-c3ccnc4c(C)cccc34)c2c1
Temperature: 140 °C
Yield: 93.7 %

Procedure:
A mixture of 5-methoxy-2-methylindole (346 mg) and 4-chloro-8-trifluoromethylquinoline (380 mg) in NMP (1 ml) and 4M HCl in dioxane (0.1 ml) was heated at 140° C. for 50 min. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-acetone as eluent) to give the sub-title compound (465 mg).
Reaction SMILES: [H-].[Na+].[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)C=CC=CC=1.[C:30]1(=[O:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[N:32][NH:31]1>CCCCCC.CS(C)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:40]\[C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30](=[O:42])[NH:31][N:32]=2)[CH:13]=1
Reactant: O=Cc1n[nH]c(=O)c2ccccc12
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=c1[nH]nc(/C=C\c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under N2 atmosphere, 723 mg NaH (60% in oil; 18.1 mmol) is washed twice with hexane, 21 ml DMSO is added, and the mixture heated for 20 min to 70° C. (gas evolution). After cooling to RT, the mixture is diluted with 15 ml DMSO, 6.71 g (17.2 mmol) triphenyl(pyridin-3-yl-methyl)phosphonium chloride (for preparation, see 1a) is added in portions, and the blackish-yellow solution is stirred for 10 min (Wittig reagent). A second flask is prepared with 3.0 g (17.2 mmol) phthalazin-1(2H)-one-4-carbaldehyde in 39 ml DMSO under an inert gas. The above Wittig reagent is added and a little DMSO is then rinsed in. After stirring for 75 min at RT, the mixture is poured onto water/EtOAc, the aqueous phase separated off and extracted again twice with EtOAc. The organic phases are washed with water and brine, combined and extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately adjusted to alkaline pH with sat. Na2CO3 solution and extracted three times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. This yields the title compound as an E/Z mixture: TLC (EtOAc) Rf=0.18/0.22; HPLC5-40 tR=9.2/9.6; FAB-MS (M+H)+=250.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([O:19][CH:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:10][C:11]([F:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[Cl:7][C:8]1[C:9]([O:19][CH:20]2[CH2:25][CH2:24][C:23](=[CH2:1])[CH2:22][CH2:21]2)=[CH:10][C:11]([F:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc(Cl)c(OC2CCC(=O)CC2)cc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCC(Oc2cc(F)c(C(=O)OC)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.61 g, 4.51 mmol) in anhydrous tetrahydrofuran (20 mL) was added a solution of potassium tert-butoxide (0.541 g, 4.82 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes at 0° C. The mixture was stirred under a nitrogen atmosphere at 0° C. for 1 h. To this solution was added a solution of methyl 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate (1.05 g, 3.48 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes. The mixture was stirred at ambient temperature for 21 h, then diluted with water (200 mL). The mixture was extracted with ethyl acetate (200 mL) and the organic phase was washed with water (50 mL) and brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound as a colorless syrup (0.866 g, 83% yield): 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=7.7 Hz, 1H), 6.67 (d, J=12.2 Hz, 1H), 4.68 (s, 2H), 4.56-4.50 (m, 1H), 3.87 (s, 3H), 2.48-2.40 (m, 2H), 2.17-2.09 (m, 2H), 1.92-1.86 (m, 4H); MS (ES+) m/z 299.00 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][CH2:2][C:3]([NH:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([OH:10])=[O:9])=[O:4])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(-c2ccccc2)cc1)Nc1ccccc1C(=O)O

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-aminobiphenyl (13.12 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. The resulting air-sensitive material was triturated with ethyl acetate (100 mL), filtered, and rinsed with ethyl acetate (2×25 mL) to yield, after drying, 8.18 g (76%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.4 (broad s, 1H), 12.05 (s, 1H), 8.75 (d, J=8.4, 1H), 7.95 (dd, J=7.4, J=1.2, 1H), 7.60 (td, J=7.2, J=1.2, 1H), 7.54 (d, J=7.6, 2H), 7.45 (d, J=8.8, 2H), 7.37 (t, J=7.6, 2H), 7.22 (t, J=7.6, 1H), 7.13 (t, J=7.6, 1H), 6.69 (d, J=8.4, 2H), 6.7 (broad s, 1H), 3.90 (s, 2H); 13C NMR (DMSO-d6) a 170.74, 169.12, 147.71, 140.60, 140.36, 134.20, 131.14, 128.87, 128.74, 127.28, 125.96, 125.55, 122.69, 119.40, 115.97, 112.85, 48.87; MS (EI, m/z) 328 (M-H2O+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.ClC(OCC(C)C)=O.[NH3:47]>C(N(CC)CC)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:47])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (0.2 g) in a tetrahydrofuran (10 ml) were added isobutyl chloroformate (0.15 ml.) and triethylamine (0.2 ml) at 0° C. under N2. After being stirred for 30 minutes, NH3 (5 ml, 4M solution in methanol) was added to the mixture. After being stirred for 30 minutes, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N-NaOH and the organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue and 10% Pd/C (0.2 g) in methanol (20 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give and the obtained residue was purified by chromatography on silica gel to give 3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}benzamide (0.11 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: C1=COCCC1
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCCCCC1=C[C@@H](OC2CCCCO2)CC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1.74 parts of methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate in 12 parts by volume of dry benzene is added 0.005 part of p-toluenesulfonic acid and 1.74 parts of dihydropyran. The reaction mixture is stirred for 5 minutes under a nitrogen atmosphere and then allowed to stand at room temperature for a further 2 hours. The resulting solution is diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent under reduced pressure to afford methyl 7-(3(S)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)-heptanoate.