Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].COCCOC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1sccc1-c1ccc(Cl)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromothiophene-2-carbaldehyde (10 g, 52.34 mmol, 1.00 equiv), ethylene glycol dimethyl ether (120 mL), (4-chlorophenyl)boronic acid (9 g, 57.55 mmol, 1.10 equiv), Pd(PPh3)4 (3 g, 2.60 mmol, 0.05 equiv), sodium carbonate (16.4 g, 154.73 mmol, 2.96 equiv), water (40 mL). The resulting solution was heated to reflux for 4 h. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (30/1). This resulted in 12 g (93%) of 3-(4-chlorophenyl)thiophene-2-carbaldehyde as a light yellow solid.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](O)[C:32]([CH3:43])([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[O:45][CH3:46])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[O:45][CH3:46])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(C(O)C(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of Et3SiH (8.67 mL, 54.3 mmol) in CH2Cl2 (45 mL) was treated with BF3.Et2O (6.8 mL, 54.3 mmol). 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionic acid (7.39 g, 18.1 mmol) in CH2Cl2 (90.5 mL) was then added dropwise via addition funnel, maintaining temperature below −7° C. After the addition was complete, the reaction was stirred for 1.5 h at −10° C., then quenched with 1 M NaOH (18.1 mL) and diluted with H2O (12 mL). 1N HCl was used to adjust pH to 4, followed by separation of layers. The aqueous layer was extracted with CH2Cl2 (2×15 mL), and combined organic layers were washed first with 1N HCl (15 mL), then H2O (15 mL), followed by drying over Na2SO4 and concentration to a gummy orange solid (6.86 g, 97%): MS (EI) 410.2 (M+NH4)+, 391.3 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]([F:33])([F:32])[O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[ClH:67]>C1COCC1.O1CCOCC1>[ClH:67].[F:15][C:16]([F:32])([F:33])[O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidinecarboxylate (0.40 g, 1.99 mmol) in anhydrous THF (8 mL) was added 4-(4-Trifluoromethoxy-phenoxy)-phenol (0.58 g, 2.65 mmol) and triphenylphosphine (0.63 g, 2.40 mmol). The resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (0.47 mL, 2.43 mmol) was added portionwise over a ten minute period. The reaction mixture was warmed to ambient temperature for an hour and then heated to 60° C. for 48 h. The solvent was removed in vacuo. The crude residue was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give a yellow oil. To the oil was added 4 M HCl in dioxane (7 mL). The resulting mixture was stirred at ambient temperature 2 h. The solvent was removed under reduced pressure to obtain crude product. The residue was triturated with ether to afford the title compound (98 mg, 14%); 1H NMR (400 MHz, DMSO-d6); δ 1.85 (m, 2H), 2.10 (m, 2H), 3.06 (m, 2H), 3.23 (m, 2H), 4.61 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 7.06 (s, 3H), 7.35 (d, J=8.8 Hz, 2H), 8.92 (br s, 2H); MS (m/z) 354.4 (M+1); LC (97.5%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=[CH:28][C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[F:56]C1C=C(S(Cl)(=O)=O)C=CC=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:56])[CH:27]=3)(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 100 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.0 mmol) and 3-fluorobenzenesulfonyl chloride (0.60 mL, 4.5 mmol) the title compound of Step A was obtained (1.46 g, 2.99 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.48-7.65 (m, 4H), 7.37 (t, J=7.7 Hz, 1H), 7.20-7.28 (m, 3H), 6.97 (d, J=5.1 Hz, 1H), 3.30-3.37 (m, 1H), 1.38 (d, J=7.0 Hz, 6H). MS (ESI): 489.1 [M+H]+.
Reaction SMILES: [Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([CH2:29][S:30][CH3:31])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].Cl.C([OH:41])C>O.CCOCC>[Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)([CH2:29][S:30]([CH3:31])=[O:41])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CS(=O)CC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (3R,4R)-1-tert-butyl-3-({3-cyclohexyl-3-[(methylthio)methyl]-8-azabicyclo[3.2.1]oct-8-yl}carbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-7) (0.150 g, 0.0270 mmol) in ethanol (6.0 mL) was added a solution of NaIO4 (0.174 g, 0.813 mmol) in 6.0 mL of water. The mixture was stirred at room temperature for 50 min. The solid was filtered and filtrate was concentrated, diluted with methylene chloride, washed with a saturated aqueous solution of Na2SO3. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated, followed by the addition of one equivalent HCl in ether to afford (3-8) as white solid (m,z (ES) 534 (MH+)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[OH:42][C:35]1[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])=[CH:14][CH:13]=2)=[C:39]([CH3:40])[CH:38]=[C:37]([CH3:41])[N:36]=1
Reactant: CC(CCO)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A mixture of 4-(4-hydroxybutan-2-yl)benzoic acid (290 mg, 1.5 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (432 mg, 2.25 mmol), N-hydroxybenzotriazole (3.4 mg, 2.25 mmol) and triethylamine (455 mg, 4.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (228 mg, 1.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloro methane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (41 mg, 8.3%). LRMS (M+H+) m/z: calcd 328.18 found 328; 1H. NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.11 (s, 1H), 4.49 (s, 2H), 3.44-3.42 (m, 2H), 2.94 (q, J=7.2 Hz, 1H), 2.36 (s, 3H), 2.42 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.26 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=O)([O-])[O-].[K+].[K+].C=O.O>CN1CCCC1=O>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccccc1
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C(C(=O)OCC)c1ccccc1
Yield: 53.5 %

Procedure:
94 g of ethyl phenylacetate (methyl ester content 0.01%) were stirred in 300 ml of N-methylpyrrolidone with 120 g of potassium carbonate and 25 g of paraformaldehyde at 75 to 80° C. for 1.5 h. After cooling, 150 ml of water were added, and the aqueous phase was separated off. The N-methylpyrrolidone phase was extracted twice with 75 ml of diisopropyl ether each time. The combined diisopropyl ether phases were washed with 50 ml of water and concentrated in vacuo. 58 g of product were obtained, corresponding to 54 g of ethyl atropate (53% of theory) with a methyl atropate content of 0.03%.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:3]=12.[CH3:23][NH2:24]>>[CH2:11]([N:10]1[C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17](=[O:18])[C:3]3=[C:2]([NH:24][CH3:23])[C:7]=2[CH:8]=[N:9]1)[CH3:12]
Reactant: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Reactant: CN
Product: CCn1ncc2c(NC)c3c(nc21)CCc1ccccc1C3=O
Reaction time: 5 h

Procedure:
8.4 g. of 4-chloro-1ethyl-10,11-dihydrobenzo [4,5]cyclohepta [1,2-b ]pyrazolo [4,3-e ]pyridin-5(1H)one (0.027 mol.) dissolved in 90 ml. of an alcoholic methylamine solution (270 g/1) are allowed to stand at room temperature for five hours. After this time, 7.1 g. of precipitated 1-ethyl-10,11-dihydro-4-(methylamino)benzo [4,5]cyclohepta [1,2-b ]pyrazolo-[4,3-e ]pyridin-5(1H)one are collected, m.p. 148°-150°. A sample recrystallized from absolute ethanol melts at 149°-150°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:37][CH2:38][O:39][CH3:40])=[C:13]([CH:36]=1)[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15].Cl.Cl.[CH2:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH2:44][CH3:45]>CC(C)=O>[CH3:40][O:39][CH2:38][O:37][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:49]2[CH2:50][CH2:51][N:46]([CH2:43][CH2:44][CH3:45])[CH2:47][CH2:48]2)=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:15]
Reactant: CCCN1CCNCC1
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1CCN(Cc2ccc(OCOC)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Under ice-cooling, potassium carbonate (0.19 g) and tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.12 g) were sequentially added to an acetone (1.8 mL) suspension of 1-propylpiperazine dihydrochloride (0.13 g), followed by stirring at room temperature for 5 hours and 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.088 g of tert-butyl 2-(2-(methoxymethoxy)-5-((4-propylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:14])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(2-methylprop-1-en-1-yl)benzyl alcohol (0.60 g) and carbon tetrabromide (1.2 g) in dichloromethane (12 mL) was added triphenylphosphine (0.97 g) at 0° C., and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane) to give 4-(2-methylprop-1-en-1-yl)benzyl bromide. To a solution of methyl acetoacetate (0.44 mL) in tetrahydrofuran (17 mL) was added sodium hydride (60%, 0.18 g) at 0° C., and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of 4-(2-methylprop-1-en-1-yl)benzyl bromide in tetrahydrofuran (3 mL), and the mixture was heated under reflux for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in toluene (8 mL). To the solution was added hydrazine monohydrate (0.54 mL), and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to 0° C., and the resulting precipitates were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 5-methyl-4-{[4-(2-methylprop-1-en-1-yl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-pyrazol-3-one (0.31 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: COc1ccccc1-c1ccnc(F)c1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1ccnc(Nc2ccccc2)c1
Temperature: 150 °C

Procedure:
A mixture of A3 (80 mg, 0.39 mmol) and aniline (102 mg, 1.1 mmol) was heated for 20 minutes at 150° C. in a microwave oven. The title compound B1 was obtained from the residue by preparative HPLC (water/ACN gradient) as an amorphous solid (20 mg, 19%). MS (ES) C18H16N2O requires: 276. found: 277 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[N+]=[N-])=[CH2:3].[Cl:7][CH2:8][C:9](=[O:34])[C@:10]1([OH:33])[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@:24]([F:30])([C@@H:25]([OH:29])[CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:31])[CH:20]=[CH:21]2)[CH2:16][CH2:15]3)[CH2:12][C@H:11]1[OH:32]>CCOCC.CO>[Cl:7][CH2:8][C:9](=[O:34])[C@:10]1([OH:33])[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@:24]([F:30])([C@@H:25]([OH:29])[CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:31])[CH:20]=[CH:21]2)[CH2:16][CH2:15]3)[CH2:12][C@H:11]1[O:32][CH2:3][C:2]([CH3:4])=[CH2:1]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: C=C(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Temperature: 0 °C

Procedure:
A solution of 2-methyl-3-diazo-1-propene in 150 ml of ether (prepared from 0.1 mole of N-(2-methyl-2-propenyl)-ethyl carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem., Soc., 91, 711 (1969)) is diluted with 50 ml of methanol and cooled to 0°C. A total of 7 g of 21-chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g -silica gel column. Elution with chloroform gives TLC pure material which crystallizes from acetone-hexane to give 5.4 g of 21-chloro-9-fluoro-11β,17 -dihydroxy-16α-[(2-methyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione, melting point 238°-240°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10](Cl)(=[O:12])=[O:11])=[CH:2]1.[NH3:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:2]1
Reactant: O=S(=O)(Cl)c1coc2ccccc12
Reactant: N
Product: NS(=O)(=O)c1coc2ccccc12
Temperature: 50 °C

Procedure:
To the above prepared benzofuran-3-sulfonyl chloride (0.104 g, 0.480 mmol) was added ammonia (6 eq., 0.5 M in dioxane) and the mixture stirred for one night at 50° C. Evaporation of the solvent, followed by flash chromatography (SiO2, heptane/AcOEt=7/3) and direct crystallization from heptane/AcOEt, generated 0.036 g of the title compound as off-white crystals. Extensive nOE measurements and 13C-NMR NMR corroborated the structure.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10])(=[O:5])=[O:4].[NH2:17][NH2:18]>CO>[NH:17]([C:9]([C:8]1[CH:7]=[C:6]([S:3]([N:2]([CH3:16])[CH3:1])(=[O:5])=[O:4])[CH:15]=[CH:14][CH:13]=1)=[O:10])[NH2:18]
Reactant: NN
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 65 °C
Yield: 40 %

Procedure:
Methyl 3-(N,N-dimethylsulfamoyl)benzoate (150 mg, 0.617 mmol) was added to hydrazine (29.6 mg, 0.925 mmol) in methanol (10 mL) and refluxed for 8 h at 65° C. Following cooling, the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (60 mg). 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.01 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.65 (t, 1H, J=8.0 Hz), 2.73 (s, 6H). ESI-MS: 244.0 [M+H]+.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1C(=O)C2=CC=CC=[C:14]2[C:13]1=[S:22])C.C1(=O)NC(=O)C2=CC=CC=C12>C1C=CC=CC=1>[C:3]1([CH2:2][CH2:1][S:9][S:22][CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCCc1ccccc1
Reactant: CCN1C(=O)c2ccccc2C1=S
Agent: O=C1NC(=O)c2ccccc21
Solvent: c1ccccc1
Product: CCSSCCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 111.3 %

Procedure:
8 g (0.058 mol) of phenethylmercaptan are added with intensive stirring to a suspension of 12 g (0.058 mol) of N-ethylthiophthalimide in 70 ml of benzene. After a few minutes, a homogeneous solution forms and the phthalimide slowly begins to precipitate out therefrom. After stirring for 48 hours at room temperature, the mixture is filtered through a paper filter, the filtrate is concentrated in a vacuum and the crude 2-phenylethyl-ethyl-disulphide (12.8 g) obtained is distilled through a Vigreux column. There are thus obtained 10.5 g of pure product (91% of theory) which has a purity of 99% (gas-chromatographic estimation). Boiling point 87-88 mm Hg/0.04 mm Hg; nD20 = 1.5742. IR (liquid): bands inter alia at 3020, 1610, 1505, 1460, 1260, 710 cm-1.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:25])[F:27])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ncc3n2)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[1,2-a]pyrazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0516 g, 0.13 mmol), 2-fluorophenylboronic acid (Combi-Blocks, 32 mg, 0.26 mmol), Na2CO3 (0.0413 g, 0.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.009 g, 0.01 mmol), and isopropanol-water (1 mL, 3:1). The mixture is stirred at 70° C. for 16 hr. The reaction mixture is concentrated, taken up into EtOAc and CH2Cl2 (1:1) and purified by preparative plate TLC (1:1 Hexanes:EtoAc) to give the title compound (6 mg, 10% yield). LCMS m/z=457.5 [M+H]+, tR=3.06 min. (compound same as Example 86)
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1ncccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methylnicotinic acid (500 mg, 3.6 mmol) in DCM (30 mL) is added oxalyl chloride (0.93 mL, 10.9 mmol) dropwise followed by DMF (1 drop). The reaction mixture is stirred at room temperature for 1 h and then concentrated in vacuo to give methylnicotinoyl chloride in a quantitative yield. A solution of I-83.1 (250 mg, 0.93 mmol) and methylnicotinoyl chloride (159.0 mg, 1.02 mmol) in DCM is stirred at room temperature for 1 h with the addition of more methylnicotinoyl chloride (28.9 mg, 0.19 mmol). The reaction mixture is then diluted with saturated aqueous NaHCO3 and the combined organics are dried over Na2SO4, The solvent is removed in vacuo to give I-110 (360 mg, quantitative).