Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[C:30](OCC)(OCC)(OCC)[CH3:31].CS(O)(=O)=O.O1CCCC1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]3[O:27][C:30]([CH3:31])=[N:29][N:28]=3)=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)NN)cc2)c1-c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nnc(Cc2ccc(NC(=O)/C=C/c3cnn(C)c3-c3ccc(F)cc3)cc2)o1
Yield: 47.1 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(2-hydrazino-2-oxoethyl)phenyl]acrylamide (0.50 g), triethyl orthoacetate (0.63 g), methanesulfonic acid (0.025 g), and tetrahydrofuran (10 mL) was heated under reflux for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(5-methyl-1,3,4-oxadiazol-2-yl) methyl]phenyl}acrylamide as pale-yellow crystals (0.25 g, yield 46%) from a fraction eluted with ethyl acetate-methanol (100:0-20:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 151-152° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH2:21])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:31])[NH2:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Solvent: Cc1ccccc1
Product: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.5 %

Procedure:
A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (prepared from 7-methoxyindole as described in Example 1; 5.10 g, 17.8 mmol), Lawesson's reagent (7.92 g, 19.6 mmol), and toluene (150 ml) was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with dichloromethane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (3.58 g). A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0.99 mmol), and ethanol (2.0 ml) was stirred at 60° C. for 1 h. The reaction mixture was concentrated in vacuo, and the obtained residue was mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture was extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 25% (v/v) ethyl acetate in n-heptane to give 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3)nccc12
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Yield: 79.9 %

Procedure:
To 100 ml of carbon tetrachloride was added 14 g of 1-(4-chlorophenyl)-5-methylisoquinoline. While the solution was heated under reflux and light was irradiated on it, 7.5 g of N-chlorosuccinimide was added. The mixture was heated with stirring. After the reaction, the reaction mixture was cooled. The insoluble matter was removed by filtration. The filtrate was washed in water, and dried, followed by distilling off the solvent. Recrystallization of the residue from ether-hexane afforded 12.7 g of 1-(4-chlorophenyl)-5-chloromethylisoquinoline as light yellow prisms having a melting point of 101° to 102.5° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1)#[N:2]>CCOC(C)=O.CC(O)=O.[Fe]>[NH2:11][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: COc1cc([N+](=O)[O-])cnc1C#N
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(N)cnc1C#N
Temperature: 65 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
2-Cyano-3-methoxy-5-nitropyridine (1.0 g, 5.6 mmol) was dissolved in 1:1 EtOAc/AcOH (10 mL) and heated to 65° C. Iron powder (1.61 g, 28 mmol, 325 mesh) was added and the mixture stirred for two h. The mixture was filtered though Celite and the filtrate concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by SiO2 Prep-TLC using CH2Cl2 as the eluent to give the compound 762D (0.805 g, 97%) as an off-white solid. HPLC: 100% at 1.31 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 149.90 [M+H]+.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.II.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: II
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
In 500 ml of dichloromethane were dissolved 58.8 g of benzophenone hydrazone, 42 ml of 1,1,3,3-tetramethylguanidine and 150 mg of iodine, and after the mixed solution was cooled to 0° C. to -5° C., 74 g of m-chloroperbenzoic acid (with a purity of 70%) was added, followed by stirring at 0° C. for 40 minutes. The reaction solution was washed with water and dried over sodium sulfate, and the solvent was distilled off to give diphenyldiazomethane.
Reaction SMILES: [H-].[Na+].COCCOC.COP([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:17])(=O)OC.[CH2:31]([O:33][C:34](=[O:49])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C@@H:42]1[CH:47]=O)[CH3:32]>C(OCC)(=O)C>[CH2:31]([O:33][C:34](=[O:49])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C@@H:42]1/[CH:47]=[CH:15]/[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)[OH:17])[CH3:32]
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)c1cccc(Cc2ccccc2)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.1 %

Procedure:
To 60% sodium hydride in mineral oil (20 mg, 0.51 mmol) was added a DME solution (5 mL) of [2-(3-benzyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (164 mg, 0.51 mmol). After 1.5 h a DME solution (5 mL) of 7-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester (126 mg, 0.47 mmol) was added. The reaction mixture was stirred for 45 min. at room temperature then diluted with ethyl acetate and washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to column chromatography (2.5 ethyl acetate: 1 hexanes) to provide 7-{(R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxy-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (112 mg, 0.24 mmol) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]>C(Cl)Cl.O=[Mn]=O>[CH:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11]
Reactant: OCc1cc2ccccc2[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cc2ccccc2[nH]1

Procedure:
A total of 1.76 g of 2-indolemethanol was dissolved in dry CH2Cl2 (20 mL) at room temperature and stirred overnight with MnO2 (2.1 g, 24 mmol). The mixture was filtered through Celite, the filtrate was evaporated under reduced pressure, and the product was purified by flash chromatography (CH2Cl2). Yield: 1.31 g (75%), 1H NMR (CDCl3): δ7.1-7.5 (m, 4H), 7.76 (d, 1H, J=7.8 Hz), 9.41 (br s, 1H), 9.86 (s, 1H).MS EI): m/z 145 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[CH:74]=[CH:73][N:72]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:71]1=[O:82]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([NH:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[CH:74]=[CH:73][N:72]([C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[C:71]1=[O:82])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)n1ccn(C[C@H]2NC(=O)[C@H]2N)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ccn(C(=O)OC(C)(C)C)c2=O)cs1
Yield: 87.7 %

Procedure:
Prepared in analogous manner to example 4 step 4, using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (117 mg, 0.276 mmol), HATU (105 mg, 0.276 mmol), DIPEA (36 mg, 0.28 mmol), tert-butyl 3-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-carboxylate (65 mg, 0.23 mmol) and DMF (5 mL). The crude residue was purified via silica gel chromatography (MeOH-DCM, 3%), affording the title compound (140 mg, 88%). LCMS: m/z=694.0 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:20]C1C=C2C(=CC=1)NC=C2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Product: Clc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 96 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-chloroindole (5 g, 33 mmol)) to afford 9.14 g (96%) of the title compound as a white solid: mp 178-181° C.; MS EI m/e 273 (M+).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[F:31])[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[C:28]([F:31])[CH:27]=[CH:26][CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Reactant: CC1Cc2c(F)cccc2N1
Agent: [Na+]
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 42.5 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 133 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 75 mg of (−)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (reference example 5a). After silica column purification: eluent 98/02 dichloromethane/methanol, 78 mg of 5-fluoro-2-[2-((+)-4-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>>[Br:1][C:2]1[C:3]([O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(Cl)ncc2Br)C1

Procedure:
Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidine was reacted with (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 4.10 (m, 2H), 3.62-3.17 (m, 5H), 2.72-2.69 (m, 1H), 2.10-2.05 (m, 2H), 1.80-1.75 (m, 1H), 1.44 (s, 9H); MS (ESI) m/z: Calc: 392.68 (M). Found. 337.9 (M+-(CH3)3C).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[CH:26][C:27]([O-:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>O1CCCC1.O>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2cnc(C=CC(=O)[O-])nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2cnc(C=CC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
10 mg (242.5 μmol, 2.5 eq) of sodium hydroxide pellets are added to a solution of 37.6 mg (97 μmol, 1 eq) of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidine-2-acrylate in 2 ml of tetrahydrofuran and 4 drops of water. The reaction mixture is stirred for 8 hours at room temperature. The reaction medium is concentrated and then diluted with 10 ml of water and washed with twice 10 ml of dichloromethane. The aqueous phase is acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on a preparative silica plate (95/5/0.5% dichloromethane/methanol/aqueous ammonia). 7.9 mg of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}acrylic acid are obtained in the form of beige-colored crystals. Yield=22%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@@H:12]1[OH:25])[CH3:2].[CH3:27][Mg]Br>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18]([OH:24])([CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@@H:12]1[OH:25])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCCCCC(=O)CC=C1CC[C@H](O)[C@@H]1CCCCCCC(=O)OCC
Product: CCCCCC(C)(O)CC=C1CC[C@H](O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
Following the procedure of Example 16, 9α-hydroxy-15-oxo-12-prostenoic acid ethyl ester is reacted with methyl magnesium bromide to produce 9α,15-dihydroxy-15-methyl-12-prostenoic acid ethyl ester as a mixture of the 15-epimers, Rf = 0.29.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[C:24]1([S:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30]([N:33]2[CH:37]=[C:36]([C:2]3[CH:3]=[CH:4][C:5]4[O:14][CH2:13][CH2:12][C:11]5[S:10][C:9]([C:15]6[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=6)=[N:8][C:7]=5[C:6]=4[CH:23]=3)[CH:35]=[N:34]2)(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2cnn(S(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cnn(S(=O)(=O)c4ccccc4)c3)cc1-2
Yield: 39 %

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted under palladium Suzuki conditions to give 301 (39% yield). LC/MS (ESI+): m/z 519 (M+H). 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.62 (d, J=2.1, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 8.03 (d, J=7.6, 2H), 7.81 (t, J=7.5, 1H), 7.75-7.60 (m, 3H), 7.12 (d, J=8.4, 1H), 5.82 (dt, J=13.0, 6.6, 1H), 4.39 (t, J=4.8, 2H), 3.46 (t, J=4.9, 2H), 1.59 (d, J=6.6, 6H)
Reaction SMILES: [CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Si]([N:24]=[N+:25]=[N-:26])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CO>[NH:17]1[C:16]([CH2:15][NH:14][CH2:13][C:12]2[CH:18]=[CH:19][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[N:26][N:25]=[N:24]1
Reactant: CCCCCCCCc1ccc(CNCC#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCc1ccc(CNCc2nnn[nH]2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of the product of Step B (0.07 g; 0.271 mmol) and Me3SiN3 (0.36 ml; 2.71 mmol) and 1M TBAF in THF (0.27 ml; 0.271 mmol) was stirred at 75±5° C. for 8 h in sealed flask. After cooling to room temperature, the mixture was diluted to 1 ml with MeOH, refluxed for 30 min under N2 and left overnight in refrigerator. The precipitate formed was filtered off, washed with Et2O and dried to give a title compound (0.069 g; 84%) as colourless solid. 1H-NMR (CD3OD) 7.32 (d, 2H, J=8.0 Hz); 7.21 (d, 2H, J=8.0 Hz); 4.72 (s, CD3OH); 4.34 (s, 2H); 4.16 (s, 2H); 2.59 (t, 2H, J=7.76 Hz); 1.57 (t, 2H, J=7.19 Hz); 1.25 (m, 10H); 0.84 (t, 3H, J=6.93 Hz);
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]2[C:13](=[CH:14][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=2)[CH:12]=1
Reactant: Cc1cc(Cl)cc2cn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1cc(Cl)cc2cn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-chloro-7-methyl-2H-indazol-2-yl)propionitrile (58 mg, described in Example 101) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (77 mg, 73%). MS (ES): M/Z [M+H]=453. 1H NMR: (400 MHz, DMSO-d6): 1.69 (s, 3H), 2.38 (s, 3H), 5.05 (d, 1H), 5.21 (d, 1H), 7.03 (s, 1H), 7.66 (s, 1H), 7.87 (d, 2H), 7.94 (d, 2H), 8.37 (s, 1H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: C(#N)C.[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:10]([O:18]OC(C)(C)C)(=[O:17])[C:11]1C=CC=CC=1>[Cu].C(O)(=O)C>[C:10]([O:18][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:17])[CH3:11]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: C1=CCCCC1
Agent: [Cu]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of 1.100 g of the copper complex of N-salicylidene-3-amino-3-deoxy-1,2-O-isopropylidene-5-O-triphenylmethyl-α-D-ribofuranose, 0.70 g of copper powder, 15 ml of acetonitrile, 5 ml of acetic acid, 15 ml of cyclohexene and 5 of t-butyl peroxybenzoate was stirred at room temperature for 9 hours in a nitrogen atmosphere. After filtering the reaction solution, the filtrate was treated in the same manner as in Example 1 to obtain 1.80 g of 2-cyclohexenyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([OH:22])=O.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([Cl:25])=[O:22]
Reactant: CC1(C2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(CC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
To a solution of (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid (21.8 g., 0.0623 mole) in chloroform (150 ml) and dimethylformamide (1 drop) is added thionyl chloride (25 ml). The reaction mixture is heated at reflux for 3 hours, cooled and concentrated at reduced pressure. The crude (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetyl chloride, thus obtained, is dissolved in methylene chloride (75 ml) and added over 0.5 hour to a mixture of ether (100) ml) and methylene chloride (75 ml) which has been saturated with ammonia.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][N:7]1[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[NH:9][C:8]1=[O:15]>C(Cl)Cl>[Cl:3][CH2:6][N:7]1[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[NH:9][C:8]1=[O:15]
Reactant: CC1(C)C(=O)NC(=O)N1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.69 ml Thionyl chloride was added to a solution of 500 mg 1-Hydroxymethyl-5,5-dimethyl-imidazolidine-2,4-dione in 5 ml DCM at 0° C. for 30 minutes, then left to stir at 25° C. for 16 hours. The mixture was evaporated to dryness and used crude in the synthesis of example 23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12](=O)[NH:13][CH:14]=[CH:15][C:16]=2[N:17]=1.P(Br)(Br)([Br:21])=O>CC#N>[Br:21][C:12]1[C:11]2[S:10][C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[N:17][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]ccc2nc(-c3c(Cl)cccc3Cl)sc12
Solvent: CC#N
Product: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.32 g, 1.1 mmol) in CH3CN (50 ml) was added POBr3 (0.918 g, 3.21 mmol). The mixture was heated at 100° C. for 2 hours. The mixture was cooled to room temperature, quenched with ice (200 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with a 0-10% gradient of EtOAc/petroleum ether to give the desired product as a white solid (0.22 g, 56% yield). 1H NMR (500 MHz DMSO-d6): δ 8.59 (d, J=5.5 Hz, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.76-7.74 (m, 2H), 7.71-7.68 (m, 1H). LCMS (ESI) m/z: 359.1 [M+H+].