Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:6]2[N:2]([CH3:1])[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:5]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1cccn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
To a solution of (22.0 g. (0.131 mole) of ethyl N-methylpyrrole-2-acetate and 24.5 g. (0.14 mole) of p-chlorobenzoyl chloride in 120 ml. of carbon disulfide is added 35.0 g. (0.262 mole) of anhydrous aluminum chloride over a period of 20 minutes with intermittant cooling to keep the temperature at 25° C. The mixture is stirred for an additional 20 minutes. The carbon disulfide solvent is then decanted and discarded. The red gummy residue is washed with hexane and dilute hydrochloric acid and ice is added to the mixture. The mixture is extracted with ether. The ether solution is shaken with an aqueous solution of dimethylaminopropylamine and washed with dilute hydrochloric acid followed by brine. The solution is dried over magnesium sulfate and treated with charcoal. After removal of the charcoal, the solvent is evaporated in vacuo leaving a partially crystalline red oil as a residue. This material is extracted with three 500 ml. portions of boiling pentane. The combined pentane extracts are evaporated in vacuo, and the residue is crystallized from 60 ml. of cold methanol. The resulting solid is collected and washed with cold methanol; there is obtained about 6.3 g of a white crystalline solid, ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate, m.p. 74-76° C. Recrystallization from methyl cyclohexane raises the melting point to 78-80° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH:26]1[CH2:27][CH2:28][N:23]([C:20]2[N:21]=[N:22][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Reactant: Fc1cccc2c1CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5c(F)cccc54)CC3)nn2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 4-fluoroindoline (62 mg, 0.45 mmol) and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one, prepared as in STEP 3 above (77 mg, 0.3 mmol) in CH2Cl2 (3 mL) was added NaBH(OAc)3 (126 mg, 0.6 mmol). The resulting mixture was stirred at room temperature for 24 h and then concentrated. The resulting mixture was purified by column using 90-100% EtOAc/(CH2Cl2/hexane=1/1) as the eluent to yield the 4-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)indoline as a residue. The title compound was then converted to its corresponding HCl salt.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[C:16]([O:28]C)[C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[C:19]=2[O:22]C)[CH2:14]1)(=[O:3])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]([O:24][CH3:25])=[C:17]([O:26][CH3:27])[C:16](=[O:28])[C:15]=2[CH2:14]1)(=[O:3])[CH3:2]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOC(C)=O)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCOC(C)=O)C2)C1=O
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octyl acetate (1.25 g) in acetonitrile (13 ml) was dropwise added a solution of CAN (4.19 g) in water (13 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=10:1) and then with recrystallization from hexane-diethyl ether to yield the entitled compound (700 mg) as crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Br[C:9]1[CH:10]=[C:11]([CH2:23][C@H:24]([NH:36][S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C:25]2[NH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][N:29]=2)[CH:12]=[CH:13][C:14]=1[CH:15]1[S:19](=[O:21])(=[O:20])[NH:18][C:17](=[O:22])[CH2:16]1.[CH3:46][N:47](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:46]([C:9]1[CH:10]=[C:11]([CH2:23][C@H:24]([NH:36][S:37]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)(=[O:39])=[O:38])[C:25]2[NH:26][C:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:28][N:29]=2)[CH:12]=[CH:13][C:14]=1[CH:15]1[S:19](=[O:20])(=[O:21])[NH:18][C:17](=[O:22])[CH2:16]1)#[N:47]
Reactant: CN(C)C=O
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3ncc(-c4ccccc4)[nH]3)cc2Br)S(=O)(=O)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C[C@H](NS(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)[nH]2)ccc1C1CC(=O)NS1(=O)=O
Yield: 60 %

Procedure:
A solution of N-[(1S)-2-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-1-(5-phenyl-1H-imidazol-2-yl)ethyl]benzenesulfonamide trifluoroacetate (3.5 mg, 4.8 μmol), zinc cyanide (1.7 mg, 14 μmol), tetrakis(triphenylphosphine)palladium(0) (1.11 mg, 960 nmol) and N,N-dimethylformamide (1.5 mL) was heated at 175° C. for 4 min in the microwave. The reaction filtered, concentrated in vacuo and purified by preparative LCMS to yield the desired product (2.0 mg, 60%). 1H NMR (400 MHz, CD3OD): δ 7.8–7.3 (m, 13H), 5.3–5.0 (m, 2H), 3.5–3.4 (m, 2H), 3.3–3.2 (m, 2H); MF=C29H24F3N5O7S2; LCMS found for C27H24N5O5S2(M+H)+: m/z=562.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[CH:11][N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:19]1([C:16]2[N:15]=[CH:14][C:13]([C:12]3[NH:8][C:9]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:10][CH:11]=3)=[CH:18][N:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(Cn2c(-c3cnc(-c4ccccc4)nc3)cnc2-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(-c2ncc(-c3cnc(-c4ccccc4)[nH]3)cn2)cc1
Temperature: 70 °C
Yield: 57.5 %

Procedure:
To a solution consisting of 5-(1-benzyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine (0.495 g, 1.27 mmol) in methanol (100 mL) was added ammonium formate (Aldrich, 0.804 g, 12.7 mmol) and 10% palladium on carbon (Alfa Aesar, 0.500 g). The reaction mixture was brought to reflux at 70° C. for 16 hours. After cooling the solution to room temperature, the crude reaction mixture was filtered over a bed of Celite, which was rinsed with additional methanol (300 mL). Concentration of the filtrate afforded an off-white solid. The product was purified by flash silica column chromatography. Elution through a 40-g Silicycle® flash silica cartridge with gradient of 100% dichloromethane to 5% methanol in dichloromethane afforded the title compound as a white solid (0.218 g, 57% yield); Rf 0.56 with 95:5 v/v dichloromethane-methanol; melting point 253° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.3 (s, 2H), 8.4 (m, 2H), 8.05 (m, 3H), 7.55-7.35 (m, 6H); MS (ESI+) m/z 299.1 (M+1); H-PGDS FPBA IC50: 0.25 μM; H-PGDS inhibitor EIA IC50: 0.012 μM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]([OH:19])=O)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:17](=[O:19])[NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A solution of the mixture of 4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester and 4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester (24.2 mg, 0.08 mmol) in methylene chloride (0.87 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.05 mL, 0.10 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (19.3 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.21 mmol) in tetrahydrofuran (0.44 mL). The reaction mixture was stirred at 25° C. for 4 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid methyl ester (18.1 mg, 57.6%) as an off-white solid: mp 54–56° C.; EI-HRMS m/e calcd for C19H22N2O3S (M+) 358.1351, found 358.1346.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.CC(C)(C)C=[N:13][CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([NH2:13])([CH3:20])[CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)[CH3:19]
Reactant: CCOC(=O)C(C)N=CC(C)(C)C
Reactant: BrCc1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(N)Cc1cccc(I)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-Iodobenzyl bromide (14.4 g, 48.6 mmol) was added to a RT solution of rac-ethyl 2-((2,2-dimethylpropylidene)amino)propanoate (10 g, 48.6 mmol) from above in toluene (100 mL) under argon and the resulting mixture was cooled to −10° C. before KOtBu (10.9 g, 97.2 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 4 h before being quenched with water. The toluene was evaporated in vacuo and the remaining aqueous phase was extracted with EtOAC (3×). The combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuo. The residue was stirred in 1M aq. HCl overnight after which LCMS showed the desired product. EtOAc was added and the mixture was stirred for 30 min before the layers were separated. The organic phase was discarded and the aqueous phase was basified with 2M aq. NaOH and re-extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuo to give the title compound that was used further without purification. LC-MS D: tR=0.88 min; [M+H+MeCN]+=375.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18].NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(F)=CC=3)=CC=2Cl)=O)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18]
Reactant: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Product: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 405, using compound 429 (8.46 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:8 followed by 3:7 as the eluent to afford the title compound as solid.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C@H:4]([OH:22])[CH2:5][C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([OH:21])[CH2:12][CH2:11]2)[CH2:8][CH:7]=3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C[O-].[Na+].CO>[CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The 1β,2β-methylene-5-androstene-3β,17β-diol prepared in this manner is dissolved in acetone and Jones Reagent added until a persistent yellow-orange color appears. After stirring at room temperature for 10 minutes the mixture is poured onto ice-water and the precipitate is dissolved in a solution of sodium methoxide in methanol and stirred about 30 minutes at room temperature. The methanol is removed and the residue triturated with water. The filtered solid is crystallized from acetone to yield 1β,2β-methylene-4-androstene-3,17-dione.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][C@H:59]([C:63](O)=[O:64])[CH:60]([CH3:62])[CH3:61])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][C@H:59]([C:63]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:64])[CH:60]([CH3:62])[CH3:61])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-L-valine.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1ccccc1

Procedure:
The title compound, light pink solid, m.p. 116° C. and MS: m/e=287 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-phenyl-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH3:26][O:27][CH:28]([CH2:31][O:32][CH3:33])[CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:29][CH:28]([O:27][CH3:26])[CH2:31][O:32][CH3:33]
Reactant: COCC(C=O)OC
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Product: COCC(C=NOCCC1=C(C)/C(=C/c2ccc(S(C)=O)cc2)c2ccc(F)cc21)OC

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2,3-dimethoxypropanal by the method of Example 1.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=2)[N:16]([CH3:27])[N:15]=1)=[O:13])[CH3:10].[O:28]1[C:32](B(O)O)=[CH:31][C:30]2[CH:36]=[CH:37][CH:38]=[CH:39][C:29]1=2>>[CH2:9]([O:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:32]2[O:28][C:29]3[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=3[CH:31]=2)[N:16]([CH3:27])[N:15]=1)=[O:13])[CH3:10]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCOC(=O)c1nn(C)c(-c2cccc(Br)c2)c1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1nn(C)c(-c2ccccc2-c2cc3ccccc3o2)c1C
Yield: 73 %

Procedure:
In analogy to the procedure described in Example 14C] but with 2.8 eq of K3PO4, 5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester and benzo[b]furan-2-boronic acid gave 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 73% yield as light brown foam. MS: 361.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[F:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.C[O-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:18](\[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)/[C:19]#[N:20])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1C
Reactant: N#CCc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(/C=C(/C#N)c2cccc(F)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution of 3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6 mmol) and 3-fluoro-benzeneacetonitrile (CAS 501-00-8) (4.35 g, 29.6 mmol) in absolute EtOH, 30 mL, was added NaOMe (0.1 equiv), then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with cold EtOH and gave (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile as a white solid (6.20 g, 78%). NaBH4 (1.8 g, 47 mmol) was added slowly to a solution of (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile (6.17 g, 23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70° C. for 16 h. The solution was cooled to room temperature and quenched with water. The reaction mixture was diluted with 100 mL water and acidified with 6M HCl (aq.). After extraction with ether (3×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated and gave 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile as a white solid (6 g, 96%). DIBAL-H (1.0 M in toluene, 14 mL, 14 mmol) was added dropwise to a solution of 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile (2.93 g, 11.72 mmol) in Toluene (40 mL) at −78° C. under argon. The mixture was stirred at −78° C. to −20° C. for 3 h and then quenched by slow addition of saturated NH4Cl solution (2 mL) followed by Celite (2 g) at −20° C. The mixture was diluted with Et2O (50 mL), warmed slowly to room temperature, and stirred till all aluminum precipitated. The solid was filtered and washed with ether (3×50 mL), the combined organic layers were dried over MgSO4, filtered, concentrated and gave Intermediate 5 (2.34 g, 74%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([CH3:11])=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:14]=1
Reactant: Cc1ccc(N)cc1C(F)(F)F
Reactant: Clc1nc2ccccc2[nH]1
Product: Cc1ccc(Nc2nc3ccccc3[nH]2)cc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-methyl-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp>265° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][N:4]2[NH:3]1.[CH3:12]I>O1CCCC1>[CH3:12][S:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: O=c1[nH]c(=S)[nH]n2cccc12
Reactant: CI
Solvent: C1CCOC1
Product: CSc1nn2cccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a Round bottom flask, 2-Thioxo-2,3-dihydro-1H-pyrrolo[2,1-f][1,2,4]triazin-4-one (29.22 g, 0.1748 mol), Tetrahydrofuran (800 mL) and Methyl iodide (14.0 mL, 0.225 mol) were added, respectively. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum to give a solid. The combined solid was washed with water (500 mL) and saturated NaHCO3 (500 mL). The mixture was stirred for 30 minutes. The solid was filtered and washed with water to give 2-Methylsulfanyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as a white solid which was allowed to dry under vacuum overnight, affording 23.23 grams. 1H NMR (400 MHz, DMSO, d6) δ 12.02 (s, 1H), 7.52 (m, 1H), 6.84 (m, 1H), 6.47 (m, 1H), 2.53 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)cc(C(=O)OC)n3)C[C@H]2OC)nc1Cl
Yield: 49.5 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (90.9 mg, 0.28 mmol), methyl 2-chloro-6-methylpyrimidine 4-carboxylate (50 mg, 0.27 mmol) and diisopropylethylamine (104 mg, 0.8 mmol), to obtain 58.4 mg of the title compound as a yellow brown oily substance (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 24 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(4-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.