Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:14]=1)[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A DMF (4 mL) solution containing Na2CO3 (60 mg, 0.57 mmol), 4-chloro-2-fluoro-1-nitrobenzene (100 mg, 0.57 mmol) and methyl 4-hydroxybenzoate (87 mg, 0.57 mmol) was stirred at room temperature for 8 hours. HPLC analysis indicated ca. 85% product. The reaction solution was stirred for an additional 2 hours at 40° C. The solution was then diluted with ethyl acetate and washed with 1N NaOH. The organic phase was washed with water (3×), brine and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J=8.1 Hz, 2H); 8.01 (d, J=8.2 Hz, 1H); 7.31-7.27 (m, 1H); 7.11-7.07 (m, 3H); 3.95 (s, 3H). LCMS1 3.66 min. (M+H)=308.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[C:13](Cl)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 85.8 %

Procedure:
To 600 mL of toluene in a Morton reaction flask was added 100 g (0.598 mol) of 2-methyl-3-nitrophenylmethanol with stirring. The solution was heated to reflux, and 100 mL of toluene was removed by distillation into a Dean Stark trap. The solution was cooled, and 48.3 mL of pyridine was added. After further cooling with an ice-water bath, 51.6 g (0.658 mol) of acetyl chloride was added dropwise. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature, and was stirred for 16 hours. The reaction mixture was heated under reflux for 3.5 hours, cooled to ambient temperature, then poured over 1 L of ice. When the ice had melted, the organic layer was separated, and the aqueous layer washed with three portions of 300 mL each of toluene. The toluene wash was combined with the organic layer, and the whole was washed with two portions of 250 mL each of aqueous 2 N hydrochloric acid, 250 mL of saturated aqueous solution of sodium chloride, two portions of 250 mL each of an aqueous 2 N solution of sodium hydroxide, and finally, 250 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to distillation using a Kugelrohr distilling system to give 107.3 g of 2-methyl-3-nitrophenylmethyl acetate, b.p. 120° C./0.25 mm.
Reaction SMILES: [CH:1]([N:4]1[C:28](=[O:29])[C:27]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:20]=4[C:11]3=[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[C:35]([N:7]1[CH2:8][C:9]2[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([O:21][CH:22]([CH3:23])[CH3:24])[C:17]([O:25][CH3:26])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:27]=2[C:28](=[O:29])[N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]1)(=[O:37])[CH3:36]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Reaction time: 0.5 h

Procedure:
A solution of 35 mg of 14e in 250 μl of pyridine was treated with 30 μl of acetic anhydride and a catalytic amount of DMAP. After stirring ½ hr the reaction mixture was diluted with 400 μl of water and stirred for an additional 1 h. The precipitate was filtered, washed with water and dried to give 31 mg of crystalline white 14f;
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>O1CCOCC1>[C:10]([O:9][C:7]([N:4]1[CH2:3][C:2](=[O:1])[C:6](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:5]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: C1COCCO1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Yield: 46.4 %

Procedure:
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours. The dioxane was removed in vacuo. The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered. The solid was rinsed with hexanes (2×80 mL) and air dried. Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH:14]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[OH-].[NH4+].[CH2:28](O)[CH3:29]>>[CH2:28]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH:14]=1)=[O:3])[CH3:29]
Reactant: CCO
Reactant: CN1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 42 %

Procedure:
A solution of 0.513 gm (2 mMol) 5-carboxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole in 5.1 mL ethanol was cooled in an ice bath while 0.51 mL sulfuric acid was added dropwise. The resulting mixture was heated at reflux for 5 hours. The now homogeneous solution was poured into 50 mL cold water and was then made basic with saturated ammonium hydroxide. The light yellow precipitate was collected by filtration and then recrystallized from ethanol to provide 0.24 gm (42%) of the desired compound as light yellow crystals.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1>CN(C=O)C>[F:12][C:7]1[CH:6]=[C:5]([C:2]#[N:3])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: Cc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1F
Temperature: 150 °C
Yield: 58 %

Procedure:
Copper(I) cyanide (Aldrich, 3.6 g, 40 mmol) was added to a solution of 4-bromo-2-fluorotoluene (Aldrich, 5 g, 27 mmol) in DMF (60 ml). The reaction mixture was heated at 150° C. for 11 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc (500 ml each). The organic layer was dried (MgSO4), and solvent was removed under vacuum to give the title compound (2.08, 58%). 1H NMR (CDCl3) δ 2.36 (s, 3H), 7.30 (m, 3H), 7.35 (d, 1H, J=8.1 Hz).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH2:15]>C1COCC1.O>[CH3:14][NH:15][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc2ccc([N+](=O)[O-])cc2s1
Yield: 88 %

Procedure:
Place 2-chloro-6-nitro-benzothiazole (5.82 g, 27.1 mmol) in THF (130 mL). Add 40% methylamine in water (7 mL) and stir until the product precipitates out. Concentrate in vacuo and then triturate with methanol. Filter off the product and wash with methanol, Dry thoroughly to yield 4.99 g (88%) of the title compound: mass spectrum (ion-spray): (m/z)=210.0 (M+1).
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:3]2[NH:2][C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:5]([CH3:13])[N:4]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(-c2nc(C)c(-c3cccnc3)n2O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: COc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)cc1OC
Yield: 60.5 %

Procedure:
To a suspension of 1-hydroxy-2-(3,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.68 g) in methylene chloride (9 ml) was added phosphorus trichloride (0.76 ml) at ambient temperature. The mixture was refluxed for 1 hour, and cooled. The mixture was adjusted to pH 7.8 with aqueous sodium carbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was triturated with diisopropyl ether to give 2-(3,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.39 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH:5][CH:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>>[N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH:5][CH:4]=1)=[N+:17]=[N-:18]
Reactant: CO[Si](OC)(OC)c1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CO[Si](OC)(OC)c1ccc(CN=[N+]=[N-])cc1
Temperature: 150 °C

Procedure:
1.0 mole of p-chloromethylphenyltrimethoxysilane and 1.1 moles of sodium azide were heated in the presence of 5 mole percent of the catalyst described in Example 1 (a) for three hours under stirring at 150° C. Then the salt formed was separated and the subsequent distillation under reduced pressure gave the p-azidomethylphenyltrimethoxysilane in a yield of 89 weight percent with the following characteristics:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([O:9]CC)=O>C(O)C>[C:12]1([CH:6]2[NH:4][CH2:1][CH2:2][NH:3][C:7]2=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCN
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCO
Product: O=C1NCCNC1c1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a stirred solution of 1928 g (32.1 mol) of ethylenediamine in 2 liters of absolute ethanol was added a solution of 3130 g (12.8 mol) of ethyl α-bromophenylacetate in 4 liters of absolute ethanol at such a rate so as to maintain reflux (~45 minutes addition time). The mixture was allowed to cool to ambient temperature and then concentrated to a thick yellow slurry. The slurry was stirred with 2 liters of chloroform, filtered, and the solid washed thoroughly with chloroform (total of 8 liters). The filtrate was concentrated to near dryness and the resulting residue stirred for a short time with 2 liters of isopropanol. The solid was collected by filtration, washed with 4 liters of isopropanol, and dried to give 1224 g (54%) of 3-phenyl-2-piperazinone. This material was used as such in the next step. [Pure material could be obtained by recrystallization from benzene and then from acetone to give a white solid (mp. 139.0°-139.5° C. ).]
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH:19]1([C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH2:21][CH2:20]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:19]1([C:22]([C:23]2[C:24]([CH3:25])=[N:1][C:2]3[S:10][C:5]4[CH2:6][O:7][CH2:8][CH2:9][C:4]=4[C:3]=3[C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:21][CH2:20]1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCOC2
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCOC3
Temperature: 70 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a stirred solution of 100 mg (0.38 mmol) (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-phenyl-methanone in 5 ml acetic acid was added 73 mg (0.57 mmol) of 1-cyclopropyl-butane-1,3-dione (prep. described in the patent DE 94-4404059) and one drop of sulfuric acid. The mixture was then stirred at 70° C. for 2 hours and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 3:1) afforded 50 mg (37%) cyclopropyl-(2-methyl-4-phenyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-methanone as a yellow solid. ES-MS m/e (%): 350 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 75.5 %

Procedure:
A mixture of 2.01 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.95 g of 2-(dimethylamino)ethyl chloride hydrochloride, 2.49 g of powdered potassium carbonate, 60 ml of acetone and 0.6 ml of water is refluxed for 23 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent. The residue is digested with isopropyl ether and the resultant crystals are collected by filtration and recrystallized from ethyl acetate. 1.84 g of (±)-cis-2-(4-methoxypheny)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained. Yield: 75.4%
Reaction SMILES: [CH:1]1([C:5]2[C:10]([OH:11])=[C:9]([F:12])[C:8]([C:13]3[CH:22]=[N:21][C:20]4[NH:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]1([C:5]2[C:10]([O:11][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=3)=[C:9]([F:12])[C:8]([C:13]3[CH:22]=[N:21][C:20]4[NH:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=3)=[CH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Oc1c(C2CCC2)ccc(-c2cnc3c(c2)OCCN3)c1F
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(COc2c(C3CCC3)ccc(-c3cnc4c(c3)OCCN4)c2F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
A solution of 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol (50 mg, 0.17 mmol) and 2-(4-(bromomethyl)phenyl)acetic acid (38 mg, 0.17 mmol) in DMSO (1 mL) was treated with potassium tert-butoxide (38 mg, 0.33 mmol) and stirred for 16 hours at 80° Celsius. The reaction was then cooled to rt, filtered, and the filtrate subjected directly to HPLC purification to give (4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid (8 mg, 9%). MS (ESI): mass calcd. for C26H25FN2O4, 448.18; m/z found, 449.2 [M+H]+. 1H NMR (600 MHz, CD3OD) δ 7.72 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=8.1, 2H), 7.31 (d, J=8.1, 2H), 7.19 (d, J=6.0, 2H), 5.04 (s, 2H), 4.38-4.32 (m, 2H), 3.78-3.72 (m, 1H), 3.71-3.67 (m, 2H), 3.63 (s, 2H), 2.29-2.22 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.97 (m, 1H), 1.84 (t, J=9.6, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH:26]6[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]6)[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[NH:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)[CH:22]=[N:23]2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2ccc(Cn3nnc4ccc(-c5cnn(C6CCNCC6)c5)nc43)cc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.6 %

Procedure:
To a solution of example 156 (0.063 g, 0.123 mmol) in dichloromethane (1 ml) was cooled to 0° C., TFA (0.356 g, 2.47 mmol) was added and warmed to RT. After 12 h, the reaction mixture was poured in ice water and pH was adjusted to 10-11 with 10% NaOH solution and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as an off-white solid (0.021 g, 42%). M.P.: 188-191° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.55 (s, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 8.01 (m, 2H), 7.82 (m, 2H), 7.53 (q, J=4.2 Hz, 1H), 6.11 (s, 2H), 4.29 (m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 1.99 (m, 2H), 1.86 (m, 2H). MS (m/z): 411.28 (M++1).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@H:7]3[C@H:10]4[C@H:20]([CH2:21][CH2:22][C@:5]23[CH3:6])[C@:18]2([CH3:19])[C:13]([CH2:14][C@@H:15]([CH3:23])[CH2:16][CH2:17]2)=[CH:12][CH2:11]4)[O:3]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:23][C@H:15]1[CH2:16][CH2:17][C@@:18]2([CH3:19])[C:13](=[CH:12][CH2:11][C@@H:10]3[C@@H:20]2[CH2:21][CH2:22][C@@:5]2([CH3:6])[C@H:7]3[CH2:8][CH2:9][C:4]2=[O:3])[CH2:14]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1

Procedure:
The 3β-methylandrost-5-en-17-one 17-ethylene ketal (13) (2.20 g 6.7 mmol) was dissolved in acetone (100 ml). p-Toluenesulfonic acid (100 mg) and H2O (20 ml) were added and the solution was refluxed for 2 hours. The solution was evaporated, taken up in ether (30 ml), washed with saturated NaHCO3, H2O, and then dried over MgSO4. The solution was filtered and evaporated to give a colorless solid which was recrystallized from methanol to give 3β-methylandrost-5-en-17-one (14) as colorless plates, 1.17 g (61%) mp 148°-150° C.; IR(KBr) 3010, 2910, 1740, 1455, 1430, 1365 cm-1 ; 1H NMR (CDCl3) δ5.41 (brd, J=6Hz, 1H, H-6), 1.11 (s, 3H, C-19 Me), 0.99 (s, 3H, C-18 Me), 1.07 (d, 3H, C-3 Me); MS (m/e) 286 (M+, 58), 271 (51), 229 (31), 159 (36), 105 (72), 9- (95), 79 (89), 55 (9), 41 (100).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:17])[C:4]2[C:9]([C:10]=1[C:11]([NH:13][CH3:14])=[O:12])=[CH:8][CH:7]=[C:6]([O:15]C)[CH:5]=2.B(Br)(Br)Br.C(Cl)Cl>>[CH3:14][NH:13][C:11]([C:10]1[C:9]2[C:4](=[CH:5][C:6]([OH:15])=[CH:7][CH:8]=2)[N:3]([CH3:17])[C:2]=1[Cl:1])=[O:12]
Reactant: CNC(=O)c1c(Cl)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)c1c(Cl)n(C)c2cc(O)ccc12
Yield: 58.4 %

Procedure:
This material was prepared by reaction of 2-chloro-6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75b (0.38 g, 1.4 mmole) with 1.0 M BBr3 in CH2Cl2 (4.19 ml, 4.19 mmole) in a manner as previously described for example 1d to give an off-white solid (0.195 g, 85%). 1NMR (300 MHz, CD3OD) δ7.61 (1H, d, J=8.3 Hz), 6.65 (1H, s), 6.62 (1H, d, J=2.1 Hz), 3.56 (3H, s) 2.85 (3H, s); ESIMS (MH+): 239.00.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][SH:11])[C:5]([F:16])=[CH:4][N:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:10][S:11][CH3:17])[C:5]([F:16])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[C@@H](CS)Nc1nc(Cl)ncc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 70 °C

Procedure:
To a suspension of (S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutane-1-thiol, 77a, (0.85 g, 3.60 mmol) and K2CO3 (2.26 g, 16.35 mmol) in acetone was added iodomethane (0.82 mL, 13.08 mmol). The suspension was heated at 70° C. for 1.30 hours and then cooled to room temperature. The solid was filtered and the solution was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-10% EtOAc/Hexanes gradient) to afford 310 mg of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 278.29 (M+H) RT=1.35 minutes.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:8]=2)[NH:3]1.[NH:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>C(O)C.N1CCCCC1>[O:1]=[C:2]1[C:10](=[CH:25][C:21]2[NH:20][CH:24]=[CH:23][CH:22]=2)[C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccc(NC(=O)c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(NC(=O)c3ccccc3)ccc2C1=Cc1ccc[nH]1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 6-amino-1,3-dihydro-indol-2-one (0.15 g, 1.0 mmol) in 2:1 CH2Cl2-1,4-dioxane mixture (30 ml) is added triethylamine (0.30 g, 3.0 mmol) and benzoyl chloride (0.14 g, 1.0 mmol). The reaction is stirred for 2 hours at room temperature, and then a saturated aqueous solution of NH4Cl is added. The precipitate is collected and washed with water to give crude N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide. To a solution of this benzamide (20 mg, 0.079 mmol) and 1H-pyrrole-2-carbaldehyde (7.6 mg, 0.079 mmol) in ethanol (2 ml) is added 2 drops of piperidine. It is stirred at 80° C. for 4 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol and purified by HPLC(C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give the desired compound as an orange solid: 1H NMR (DMSO-d6) δ 6.34 (s, 1H), 6.80 (s, 1H), 7.33 (s, 1H), 7.39 (d, 1H, J=8.4 Hz), 7.53 (t, 2H, J=7.8 Hz), 7.57 (s, 1H), 7.59 (s, 1H), 7.61 (s, 1H), 7.64 (s, 1H), 7.96 (d, 2H, J=7.8 Hz), 10.29 (s, 1H), 10.94 (s, 1H), 13.23 (s, 1H); LC-MS: 330.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12](=O)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:12]1[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([CH3:1])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2cc(C)[nH]c(=O)c2n1
Product: CSc1ncc2cc(C)nc(Cl)c2n1
Yield: 52 %

Procedure:
A solution of 6-methyl-2-(methythio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 51, 100 mg, 0.483 mmol) in POCl3 (5 mL) was heated to 70° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and washed with water (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in cyclohexane to give the title compound (28.4 mg, 52%).
Reaction SMILES: [C:1]([CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[CH2:6][C:7](O)=[O:8])(=[O:3])[NH2:2].B#B.O1CCCC1>C(Cl)Cl>[OH:8][CH2:7][CH2:6][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:17])([F:18])[F:19])[CH2:4][C:1]([NH2:2])=[O:3]
Reactant: NC(=O)CC(CC(=O)O)c1ccccc1C(F)(F)F
Agent: B#B
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)CC(CCO)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
4-Carbamoyl-3-(2-trifluoromethylphenyl)butanoic acid (646 mg) was dissolved in methylene chloride (32 mL), and a diborane-tetrahydrofuran solution (7.12 mL) was added at 0° C. After stirring at room temperature for two hours, the reaction solution was cooled to 0° C. The reaction was terminated with 1 N hydrochloric acid, followed by dilution with ethyl acetate. The organic layer was washed with 1 N sodium hydroxide and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a crude product (388 mg) which was used for the next reaction without purification.