Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:27]I.CCOC(C)=O>C1COCC1>[I:27][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=1
Reactant: CCOC(=O)c1ncoc1-c1ccccc1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(I)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 29, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium bis(trimethylsilyl)amide in THF (1M, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes: EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes: EtOAc=6:1), retention time (LC-MS)=3.01 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 77.6 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and morpholine (41.1 mg, 472 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(6-fluoro-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (54.9 mg, 77.5%) as white solid. MS: m/z=451.0 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+]([O-])=O)[C:20]=1[C:21]#[N:22])([O-:18])=[O:17].C(OC(C)(C)C)=O>>[C:21]([C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=[CH:24][C:23]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 58 %

Procedure:
Prepared as in Example 197c from tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate and 2,6-dinitrobenzonitrile in 58% yield. MS 263 [M+H-Boc]+.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)=[N:16]2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)=[N:16]2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1CCCC(O)C1
Yield: 97.7 %

Procedure:
A solution of 3-[2-{3-(tert-butyldimethylsilyloxy)cyclohexyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (570 mg) and 70% aqueous tetrabutylammonium fluoride (4.3 g) in tetrahydrofuran (10 ml) was stirred for overnight at room temperature. A reaction mixture was diluted with ethyl acetate (100 ml), which was washed in turn with water (50 ml×4) and saturated sodium chloride in water (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (40 ml) eluting in turn with 30%, 50% ethyl acetate in dichloromethane and ethyl acetate. Fractions containing desired product were concentrated under reduced pressure to give residue, which was recrystallized from ethanol to give 3-[2-(3-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (430 mg).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: COC(=O)C1CNCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(C)=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (10 g, 51.65 mmol) was dissolved in dichloromethane (130 mL). Triethylamine (7.20 mL, 51.65 mmol) was added followed by acetic anhydride (4.87 mL, 51.65 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to give methyl 1-acetyl-4-oxopiperidine-3-carboxylate (6.10 g, 59.3%), which was used in the next step as such.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](OC)(=[O:23])[CH:21]=[CH2:22].N1C=CC=CC=1>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]3[NH:1][C:20](=[O:23])[CH2:21][CH2:22][N:6]3[N:5]=2)=[CH:8][CH:9]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: C=CC(=O)OC
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.016 g), methyl acrylate (10 ml), pyridine (20 ml) and water (5 ml) was refluxed for 8 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in a mixture of acetic acid (10 ml) and concentrated hydrochloric acid (1.5 ml). The solution was refluxed for 2 hours, cooled and neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (750 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])=[O:22]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
5-Chloro-2-nitroaniline (1 g; 5.8 mmol) and pyridine (0.64 ml; 8.1 mmol) were dissolved in dichloromethane (10 ml) and cooled to 0° C. This was added drop wise over 5 minutes to a solution of 2-chloro-5-nitrobenzoyl chloride (1.34 g; 6.1 mmol) in dichloromethane (5 ml). The reaction was stirred at room temperature for 72 hours before adding further acid chloride (1.34 g) and pyridine (0.64 ml). After 30 minutes, the solvent was evaporated and the bisacylated residue treated with 1:1 concentrated ammonia/acetonitrile (10 ml). All the solvent was removed after 5 minutes and the residue crystallised from 1:1 chloroform/heptane (30 ml) to give 2-chloro-N-(5-chloro-2-nitro-phenyl)-5-nitro-benzamide (1.78 g, 86%)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: O=Cc1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Yield: 81 %

Procedure:
{circle around (1)} 100 g (0.676 mol) of 2,3-dichloropyridine, 101.4 g (0.676 mol) of (4-formylphenyl)boronic acid and 86 g (0.811 mol) of sodium carbonate were dissolved in 500 mL of 1,2-dimethoxyethane and 500 mL of distilled water, and 78 g (0.0676 mol) of Pd(PPh3)4 was added. The mixture was heated to reflux for 18 hours so that it was allowed to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove 1,2-dimethoxyethane, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 81% yield.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>O>[C:26]([O:25][C:23]([CH2:22][O:21][N:20]=[C:14]([C:12]1[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=1)[C:15]([OH:17])=[O:16])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
Sodium bicarbonate (4.2 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (10 g.) in water (500 ml.) to prepare a solution. t-Butyl 2-aminooxyacetate hydrochloride (8.1 g.) was added to the solution and stirred at ambient temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (11.3 g.), mp. 117° C. (dec.).
Reaction SMILES: C(=O)=O.C(#N)C.[C:7]([C:9]1[N:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)#[N:8].[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(#N)C.CCOC(C)=O>[Br:22][C:12]1[CH:13]=[C:9]([C:7]#[N:8])[N:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nn1cccc1C#N
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple and thermocontroller, and dry-ice acetonitrile cooling. 2-Cyano-pyrrol-1-yl-carbamic acid, tert-butyl ester (20 g, 96.5 mmol) was added and dissolved in 350 mL acetonitrile and cooled to below −30° C. 1,3-Dibromo-5,5-dimethylhydantoin (13.79 g, 48.26 mmol) was added as a solid, and the reaction was allowed to warm to rt over 2 h. Analysis by RP-HPLC at 2 h indicated that about 10% starting material remained. The reaction was cooled again to below −30° C. and treated with additional 1,3-dibromo-5,5-dimethylhydantoin (1.3 g, 4.8 mmol). The reaction was allowed to warm slowly to rt over 3 h. The reaction was diluted with 500 mL EtOAc and transferred to a separatory funnel. The organic layer was washed with 1N aq sodium carbonate, water and brine and then dried with sodium sulfate. Filtration of the organic layer through silica gel removed much of the colored impurities. Evaporation of the solvent under vacuum provided reddish oil, which provided orange-brown crystals of the desired product upon seeding (27.16 g, 98%). 1H-NMR (DMSO): δ 10.95 (bs, 1H), 7.61 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2 Hz), 1.44 (s, 9H, J=4.4, 1.7 Hz). MS: LC/MS (+esi), m/z=[M+H].
Reaction SMILES: [C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)#[N:2]>C(O)C.CC(C)=O.[C].[Pd]>[C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)CC1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of Compound 10 (0.55 g, 1.5 mmol) obtained in Example 10 in ethanol (5.5 mL) and acetone (8.0 m) was added 10% palladium-carbon (containing 50% of water) (0.11 g), and the mixture was subjected to a hydrogenation reaction at room temperature and ordinary pressure for 3 hours. After removal of the catalyst, the solvent was evaporated in vacuo from the filtrate to give Compound 20 (0.54 g, 100%) as a mixture of isomers in a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH3:36])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2N)C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(F)cc1NC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-amino-5-fluorophenylamino)azetidine-1-carboxylic acid tert-butyl ester (15.5 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (3.81 g, 17.1 mmol), HOAt (2.32 g, 17.1 mmol), 4-methylmorpholine (3.75 mL, 34.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.27 g, 17.1 mmol) in DCM (53 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow oil (quantitative). LCMS (Method B): RT 3.63 min [M+H]+ 487.3.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15]C(N)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH3:24][N:25]([CH:27]=[O:28])[CH3:26]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][C:27]([N:25]4[CH2:26][C:20]5[C:2](=[CH:3][CH:4]=[CH:5][CH:19]=5)[CH2:24]4)=[O:28])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Reaction time: 16 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65 C for 3 hours. αα-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70 C for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184-185° C.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1ccccc1Br
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1Br

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.00 mL, 34.9 mmol), pyridine (3.76 mL, 46.5 mmol) and 2-bromoaniline (4.00 g, 23.3 mmol). The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexane) to give ethyl 3-(2-bromophenylamino)-2-methyl-3-oxopropanoate as a yellow solid. Mass Spectrum (ESI) m/e=300.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, 1.4 g (8.0 mmol) of N-methoxycarbonyl-(L)-valine, 2.87 g (15 mmol) of EDC and 1.35 g (10 mmol) of HOBT are dissolved in 22 ml of DMF. After 45 min, 4.2 ml (30 mmol) of TEA are added and then a solution of 2.34 g (5.0 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 45 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is concentrated by evaporation; the residue is taken up in methylene chloride and washed with water, sat. NaHCO3 solution, water and brine. The aqueous phases are extracted 2× with methylene chloride; the combined organic phases are dried (Na2 SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/ethyl acetate 2:1) and crystallisation from ethyl acetate/ether yield the title compound: m.p: 178°-179° C.; HPLC20-100 : tRet =15.8.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Br)c1O
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask vanillin (Aldrich, 33.3 g, 0.22 moles) was dissolved in glacial acetic acid (100 mL) with stirring. A solution of bromine (Baker, 35.0 g, 0.43 mol, 11.2 mL) in glacial acetic acid (100 mL) was added to the solution of vanillin. After 5 min a precipitate formed but the reaction was allowed to stir for an additional 15 min. The solid was collected by filtration giving 18.2 g, 35%. The filtrate was then slowly added to water (300 mL) and allowed to stand overnight. The resulting solid was filtered and dried under vacuum giving additional product (18.4 g, 35%, total yield 36.6 g, 70%), mp 159°-163° C. (lit, 163°-164° C.), 1H NMR (CDCl3) δ3.99 (s, 3H), 6.61 (bs, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 9.79 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(S(=O)(=O)c3ccccc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(S(=O)(=O)c5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 18 h
Yield: 23 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(phenylsulfonyl)piperazin-1-yl)pyridin-2-amine (40 mg, 0.090 mmol), DMF (1 mL), 1M Na2S2O4 (3 eq, 0.27 mmol, 0.27 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.099 mmol, 15 mg). After 18 h, the reaction was quenched with NH4OH and extracted with EtOAc (5×5 mL). The organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the product (11 mg, 23%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.01 (s, 6H, N(CH3)2), 3.17-3.27 (m, 4H, piperazine N(CH2)2), 3.65 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 6.82 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 7.68-7.70 (m, 2H, phenyl H-3 & H-5), 7.73-7.76 (m, 1H, phenyl H-4), 7.81 (dd, J=7.1, 1.5 Hz, 2H, phenyl H-2 & H-6), 7.99 (d, J=9.0, 2H, N,N-dimethylaminophenyl), 8.14 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.21 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH2:28][OH:29])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:30])[CH2:11]1>CO.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH2:28][OH:29])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:30])[CH2:11]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O

Procedure:
A solution of 3β,19-dihydroxyandrost-5-en-17-one diacetate in methanol is hydrogenated with a 10% Palladium-on-charcoal catalyst at atmospheric pressure for 8 hours. The catalyst is removed by filtration and the filtrate concentrated to a small volume, cooled, and filtered to yield the desired 3β,19-dihydroxy-5α-androstan-17-one diacetate. Recrystallization from hexane results in pure material.