Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:5]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[O:7][N:6]=1)=O)[CH3:2].Cl.[OH:21][NH2:22]>CO>[OH:21][N:22]=[C:3]([C:5]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[O:7][N:6]=1)[CH2:1][CH3:2]
Reactant: NO
Reactant: CCC(=O)c1noc(COc2ccc(Cl)cc2Cl)n1
Agent: Cl
Solvent: CO
Product: CCC(=NO)c1noc(COc2ccc(Cl)cc2Cl)n1
Yield: 84.7 %

Procedure:
0.9 g of 3-ethylcarbonyl-5-[(2,4-dichlorophenoxy)methyl]-1,2,4-oxadiazole and 0.21 g of hydroxyamine hydrochloride were added to 10 ml of methanol. The mixture was heated to reflux for 4 hours. After evaporation of methanol, water was added to the residue. The aqueous solution was extracted with ethylacetate. After evaporation of ethylacetate, the residue was purified by column chromatography(benzene:ether=1.1) to provide 0.80 g of the desired product(yield: 85.0%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[C:18]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:26]1([C:25]2[C:18]3[C:17]([NH:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:22][CH:21]=[N:20][C:19]=3[O:23][C:24]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2oc3ncnc(NCCN4CCNCC4)c3c2-c2ccccc2)cc1

Procedure:
A mixture of 69 (0.2 g, 0.57 mmol), 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 1.13 mmol) and DIEA (0.20 mL, 1.14 mmol) in 1-butanol (5 mL) was heated to 120° C. for 1.5 h. After concentration, the residue was purified by silica gel chromatography using 2-5% MeOH/DCM, to give 4-[2-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-ylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester 71 (0.20 g). Compound 71 was subjected to 20 mL of 20% TFA/DCM at rt for 2 h, then the reaction was concentrated almost to dryness under reduced pressure, and purified by silica gel column chromatography using 0.1% MeOH/DCM containing 1 mL ammonium hydroxide, to give 72 (0.15 g). MS: 400.2(M+1). 1HNMR (DMSO-d6) ppm 8.36 (s, 1H), 7.61-7.33 (m, 10H), 5.49 (t, 1H, J=4.48 Hz), 3.45 (dd, 2H, J1=5.10 Hz, J2=5.84 Hz), 2.33 (t, 2H, J=5.80 Hz), 2.13 (br, 4H), 1.95 (br, 1H) (note: some peaks overlapped with water peak in DMSO-d6). 1HNMR (CCl3-d) ppm 8.43 (s, 1H), 7.60-7.50 (m, 6H), 7.50-7.26 (m, 4H), 5.39 (t, 1H), 3.54 (dd, 2H, J1=5.05 Hz, J2=6.20 Hz), 2.73 (t, 4H, J=4.71 Hz), 2.44 (t 2H, J=5.91 Hz), 2.28 (br, 4H), 1,87 (br, 1H).
Reaction SMILES: [B:1]([O-:7])([O-:6])[O:2][CH:3]([CH3:5])[CH3:4].O[C:9]([C:12](O)([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[CH:3]([O:2][B:1]1[O:7][C:12]([CH3:14])([CH3:13])[C:9]([CH3:11])([CH3:10])[O:6]1)([CH3:5])[CH3:4]
Reactant: CC(C)(O)C(C)(C)O
Reactant: CC(C)OB([O-])[O-]
Product: CC(C)OB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A 5 L 4-neck flask equipped with a reflux condenser, mechanical stirrer, N2 inlet, and thermowell was flushed well with N2 and charged with isopropyl borate (2.673 L, 11.5 mol, 1.15 equiv) and pinacol (1.179 kg, 10 mol). The resulting mixture was heated at reflux (80-85°) for overnight. The mixture was then cooled to room temperature, transferred to a 5 L 4-neck flask equipped with a 24 inch Vigreux column, magnetic stirrer, and thermowell. The mixture was distilled at atmospheric pressure under nitrogen. After the low boiling fraction (bp 90-180°) which contained predominately 2-propanol and isopropyl borate (GC analysis) was removed, the completed distillation afforded 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (10, 1.628 kg, 1.86 Kg theoretical, 87.5%) as a colorless liquid (bp 180-185° C. with GC purity >97.5%). This material was stored in Sure/Seal bottles to minimize hydrolysis.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:7])#[N:3].[N:17]([O-])=O.[Na+]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:7][NH2:17])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])#[N:3]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)COc1ccc(NN)cc1C#N
Yield: 88.9 %

Procedure:
To an aqueous solution (33 ml) of 3-cyano-4-neopentyloxyaniline hydrochloride (21 g) were added sodium nitrite (6.7 g), stannous chloride dihydrate (59.5 g) and con. hydrochloric add (100 ml) with stirring under ice-cooling. After the completion of the reaction, precipitated crystals were collected by filtration The crystals were added to water, and the mixture was neutralized with aqueous sodium hydroxide solution, extracted with a mixed solvent of toluene and tert-butanol, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 17 g of 3-cyano-4-neopentyloxy-phenylhydrazine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:5]2[CH2:6][CH2:7][NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1.CC(C)([O-])C.[Na+].Br[C:19]1[CH:24]=[N:23][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:21][N:20]=1.O>CS(C)=O>[CH:25]1([C:22]2[N:23]=[CH:24][C:19]([O:1][CH:2]3[CH2:11][N:5]4[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]4[CH2:3]3)=[N:20][CH:21]=2)[CH2:27][CH2:26]1
Reactant: O=C1NCCN2C[C@H](O)C[C@@H]12
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Temperature: 25 °C
Reaction time: 0.4 h
Yield: 23.7 %

Procedure:
In a 4 mL vial were combined (7R,8aS)-7-hydroxyhexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (180 mg, 1.152 mmol) from Step 2 and sodium tert-butoxide (188 mg, 1.959 mmol) in dimethyl sulfoxide (1 mL). The mixture was stirred at room temperature for 0.4 hours followed by the addition of 2-bromo-5-cyclopropyl-pyrazine (229 mg, 1.152 mmol). After stirring at room temperature for 8 hours, water was added, and the solution was extracted with ethyl acetate. The extract was concentrated in vacuo, and the resulting solid was purified using an Agilent Technologies SuperFlash SF-15-12 g cartridge eluted with a gradient of 0-8% methanol/dichloromethane over 20 minutes to give 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (75 mg, 0.273 mmol, 23.72% yield) as an oil in a 3:1 (7R,8aS: 7R,8aR) diastereomer ratio. 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=32.4 Hz, 1H), 8.19 (dd, J=14.4, 0.9 Hz, 1H), 8.12-8.05 (m, 1H), 5.54-5.41 (m, 1H), 3.77 (t, J=8.0 Hz, 0.5H), 3.54 (dddd, J=12.4, 10.1, 8.1, 4.0 Hz, 1H), 3.49-3.35 (m, 1H), 3.30-3.19 (m, 1.5H), 3.02 (ddd, J=16.9, 9.2, 4.7 Hz, 1H), 2.91 (dt, J=7.7, 4.2 Hz, 1H), 2.89-2.80 (m, 1H), 2.80-2.66 (m, 1H), 2.60-2.51 (m, 1H), 2.00 (qt, J=9.5, 4.8 Hz, 1H), 1.12-1.02 (m, 2H), 0.96-0.86 (m, 2H); MS (ESI+) m/z 275 (M+H)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:6][C:7](=[O:27])[N:8]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[C:17]=1[N+:24]([O-:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]>CO.C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:27])[N:8]([C:16]1[CH:21]=[C:20]([S:2][CH3:1])[N:19]=[C:18]([NH2:23])[C:17]=1[N+:24]([O-:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(SC)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Sodium methanethiolate (180 mg) was added portion-wise to a stirred suspension of (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (300 mg) in methanol:THF (3:1, 4 ml). The mixture was sealed in a ReactiVial then left to stir at room temperature for 2 hours. The reaction mixture was diluted with methanol then pre-absorbed directly onto silica gel. The crude was columned on Isco Companion on a silica column (12 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 30:70 to 50:50 over 6 column volumes. The desired fractions were combined and evaporated to provide the title compound (297 mg) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[C:7]([Si:8]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])(OCC)[O:9][CH2:10][CH3:11])=[C:6]([F:26])[C:5]([F:27])=[C:4]([F:28])[C:3]=1[F:29].S(Cl)([Cl:32])=O.Cl.[NH+]1C=CC=CC=1>>[F:1][C:2]1[C:7]([SiH:8]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[O:9][CH2:10][CH2:11][Cl:32])=[C:6]([F:26])[C:5]([F:27])=[C:4]([F:28])[C:3]=1[F:29]
Reactant: O=S(Cl)Cl
Reactant: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Fc1c(F)c(F)c([SiH](OCCCl)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reaction time: 16 h

Procedure:
180.93 g (0.400 mol) di(pentafluorophenyl)diethoxysilane, 29 mL (0.400 mol, 47.6 g) thionylchloride and 4.92 g (0.0426 mol) pyridinium hydrochloride are refluxed and stirred for 16 h. Unreacted SOCl2 is evaporated and di(pentafluorophenyl)chloroethoxysilane isolated by vacuum distillation.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[C:6](OC)([O:8]C)[CH3:7].Cl.[CH2:15]([NH:17][C:18]([NH2:20])=[NH:19])[CH3:16].[O-]CC.[Na+]>>[CH2:15]([NH:17][C:18]1[N:20]=[C:5]([C:6](=[O:8])[CH3:7])[CH:4]=[CH:3][N:19]=1)[CH3:16]
Reactant: COC(C)(OC)C(=O)C=CN(C)C
Reactant: CCNC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCNc1nccc(C(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6 g of 1-dimethylamino-4,4-dimethoxypent-1-en-3-one, 3.96 g of N-ethylguanidine hydrochloride and 26 ml of 20% strength ethanolic sodium ethoxide solution is heated under reflux for 2 hours. After cooling, the solid is filtered off with suction, and the filtrate is concentrated in vacuo and mixed with 20 ml of trifluoroacetic acid and 2 ml of water and stirred at room temperature overnight. Then 50 ml of water are added, the pH is adjusted to 10 with sodium carbonate, and the mixture is extracted twice with 25 ml of ethyl acetate each time. The organic phase is dried over sodium sulfate and concentrated. The resulting oily residue is purified by column chromatography (silica gel, mobile phase: methylene chloride:methanol=98:2).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37]>>[Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:34]4[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3Cl)c2)S1
Reactant: O=C1CNCCN1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=C4SC(N5CCNC(=O)C5)=NC4=O)ccc32)c(Cl)c1

Procedure:
4-{5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one was prepared from 5-[1-(2-chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazin-2-one following General Procedure C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1
Product: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ0.61 (s, 3H), 7.11-7.23 (m, 4H), 7.26 (m, 1H), 7.45-7.62 (m, 2H), 8.38 (m, 1H), 9.80 (s, 1H), 11.33 (br s, 1H). LC MS (m/e)=358 (MH+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[S:22](Cl)(=[O:24])=[O:23])[C:18](=[O:26])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:16]=[C:15]3[Cl:36])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH3:37]>C1COCC1>[Cl:36][C:15]1[C:14]2[C:19](=[CH:20][C:21]([S:22](=[O:24])(=[O:23])[NH2:37])=[C:12]([O:11][C@@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[C:18](=[O:26])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:16]=1
Reactant: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(S(=O)(=O)Cl)cc3c2=O)cc1
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(S(N)(=O)=O)cc3c2=O)cc1

Procedure:
To a solution of 29 mg of 6-(4-acetylamino-cis-cyclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-7-sulfonyl chloride (129, crude product) in 2 ml of THF 2 ml of 33% aqueous ammonia solution were added. After 1 h at room temperature the solvent was removed under reduced pressure and the crude product was used without further purification. Rt=1.22 min (Method C). Detected mass: 534.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][C:23]=2[CH3:24])=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[C:23]([CH3:24])=[CH:22][N:21]([CH2:30][O:31][CH3:32])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Reactant: COCBr
Product: COCn1cc(C)c(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, with the compound from Example 131, 3-(4-chlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and bromomethyl methyl ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH:16]=[CH:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][OH:9].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>N1C=CC=CC=1>[S:32]([O:1][CH2:2][CH2:3][O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH:16]=[CH:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][OH:9])([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCO)[C@]2(O)C(=O)CO
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOS(C)(=O)=O)[C@]2(O)C(=O)CO

Procedure:
A solution of 3.0 g of 16α-(2-hydroxyethoxy)-11β,-17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate in 15 ml of pyridine is stirred with 0.75 ml of methane sulfonyl chloride at 0°C for 150 minutes. The mixture is poured into 1.5 liter of cold 1N hydrochloric acid, stirred for a short time, and filtered. The resulting solid is dissolved in chloroform, washed with water, dried, and evaporated in vacuo to give 4.0 g of crude 16α-(2-mesyloxyethoxy)-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 800 mg, 4.1 mmol) in DMF (40 mL) was added glycine ethyl ester hydrochloride (625 mg, 4.5 mmol), HOBt (0.55 g, 4.1 mmol) and DIPEA (2.13 mL, 12.2 mmol). After 5 min, EDCI (1.01 g, 5.3 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (100 mL) and ethyl acetate (3×80 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (4:96) to give the title compound as a yellow solid. δH (CD3OD): 1.28 (3H, t), 4.14 (2H, s), 4.23 (2H, q), 7.10 (1H, s), 7.68 (1H, s), 8.59 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[N:6][N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19]C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10][NH:9][C:8]=12)(=[O:3])[NH2:2]>C(Cl)Cl.CO.[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:7]2[N:6]=[C:5]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:32][CH:31]=3)[C:4]([C:1]([NH2:2])=[O:3])=[C:8]2[NH:9][CH2:10][CH2:11]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of benzyl 2-(3-carbamoyl-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate (100 mg, 0.17 mmol) in 5 mL of DCM and 5 mL of CH3OH was added 10% w/w Pd/C (50 mg). After stirring at RT under H2 for 16 hr, the mixture was filtered and the cake was washed with DCM/CH3OH (1/1, 50 mL). The filtrate was concentrated and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 10 mg (13%) of 7-(2-aminophenyl)-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ 7.39 (d, J=8.8 Hz, 2H), 7.02-6.91 (m, 7H), 6.66 (d, J=7.6 Hz, 1H), 6.53 (t, J=7.6 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 5.54-5.50 (m, 1H), 3.30-3.24 (m, 1H), 3.12-3.06 (m, 1H) and 2.31-2.20 (m, 2H). MS (ESI) m/e [M+1]+ 443.9.
Reaction SMILES: C(OC([N:6]1[CH2:19][CH2:18][C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C.CO>C(Cl)(Cl)Cl>[CH2:12]1[C:11]2[C:10]3[CH2:18][CH2:19][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)CCC3
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1cc2c(c3c1CCC3)CCNCC2
Temperature: 60 °C
Yield: 63.6 %

Procedure:
Into a glass vial, the product from step (a) (0.126 mmol) in CHCl3 (3 ml) was placed. To this stirred solution, TMSI (172 μL, 1.26 mmol) was added. The reaction mixture was heated to 60° C. for 3 h. The reaction mixture was allowed to cool to room temperature and methanol (1 ml) was added to quench. The solvent was evaporated in vacuo to give the crude product as a yellow residue. The crude product was purified by semi-prep RP-HPLC to give the title compound as light yellow oil (15 mg). Recovered as acetate salt: 1H NMR (CDCl3) δ 7.18 (bs, 2H), 7.02 (d, J=7.2 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 3.15-3.05 (m, 8H), 2.94-2.84 (m, 4H), 2.12-2.02 (m, 2H) 1.98 (s, 3H); MS: ESI (positive): 188 (M+H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17]>C(O)C>[CH3:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(N)cc1C
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1C
Yield: 86.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3,4-dimethylaniline (0.540 g; 4.36 mmol) in ethanol (3 mL). 1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.292 g (86%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](Cl)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:27]([Zn+])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.Cl>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(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([C:14](=[O:15])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)Cl)cc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)Cc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride, benzylzinc bromide (0.5 mol/L, tetrahydrofuran solution, 4.4 mL), dichlorobis-(triphenylphosphine)palladium(II) (153 mg) and toluene (6 mL) was stirred at room temperature under an argon atmosphere for 5 hours. Ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5%-20% ethyl acetate/hexane, gradient elution) to give the title compound (307 mg).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH3:31])[N:15]=[C:14]2OC)=[O:12])=CC=1)([O-])=O.Cl.[CH2:35]([NH:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(CC)CC>CC#N>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[N:13]2[C:11](=[O:12])[N:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:43]=[C:14]2[NH:15][C:16]=1[CH3:31])=[O:28]
Reactant: NNCc1ccccc1
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(C#N)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)Nc2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
Intermediate 5 (250 mg, 0.55 mmol) and benzyl hydrazine hydrochloride (120 mg, 0.61 mmol) were suspended in CH3CN (10 mL) at 0° C., and Et3N (85 μl, 0.61 mmol) was added. The reaction mixture was stirred at 0° C. for 30 mins and then allowed to reach RT and stirred for a further 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% to yield the title compound as a yellow solid (100 mg).