Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1-c1cnc2c(c1)NCCO2
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To 3 ml of tetrahydrofuran/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 2-trifluoromethyl-phenyl boronic acid (78 mg, 0.41 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (21 mg, 0.02 mmol) were added and then stirred at 800 for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=50:1. The fractions containing the product were collected and evaporated to obtain 7-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (67 mg, 64%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F-].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:52][OH:53]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12]([O:53][CH3:52])=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 110 °C
Yield: 72.1 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.35 g, 0.59 mmol), Cu(I)I (113 mg, 0.59 mmol), KF on Al2O3 (40%) (241 mg, 4.15 mmol), 1,10-phenanthroline (107 mg, 0.59 mmol) and MeOH (1.2026 mL, 29.688 mmol) were placed in toluene (3 mL), degassed under argon, and then heated to 110° C. overnight. The reaction was then cooled to room temperature. EtOAc was added, and the reaction was filtered through celite and washed with EtOAc. The filtrate was then concentrated, and the resulting residue was purified by column chromatography (1:1 hexanes:EtOAc) to give the product tert-butyl 4-(5-cyclopropyl-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.21 g, 71% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Br)=[CH:15][CH:14]=1.Br>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][C:13]([CH3:12])=[CH:14][CH:15]=3)=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: Br
Solvent: CC#N
Product: Cc1ccc(C(=O)Cn2cccc3c(C)c(C)nc2-3)cc1

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (0.16 g, 1.1 mmol) and p-methylphenacyl bromide (0.26 g, 1.2 mmol) in 4.5 ml CH3CN was warmed to reflux which was enough to initiate crystallisation of the product as a light yellow solid. The precipitate was isolated as described in example 27 furnishing 0.29 g (74%) pure hydrobromide.
Reaction SMILES: [NH2:1][C@:2]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=2)[CH2:3]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C@:2]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: [H][H]
Reactant: COCCCCCC#Cc1ccc([C@H]2CC[C@](N)(C(=O)OC)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COCCCCCCCc1ccc([C@H]2CC[C@](N)(C(=O)OC)C2)cc1
Reaction time: 15 h

Procedure:
(1R,3S)-methyl 1-amino-3-(4-(7-methoxyhept-1-ynyl)phenyl)cyclopentanecarboxylate was taken up in ethanol (14.94 ml). To this was added Pearlman's Catalyst (0.052 g, 0.075 mmol) and the mixture was stirred at ambient temperature under the atmosphere of hydrogen. After about 15 hours, the reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to yield (1R,3S)-methyl 1-amino-3-(4-(7-methoxyheptyl)phenyl)cyclopentanecarboxylate (0.48 g, 1.38 mmol) as dark green oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:43])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[C:23]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:22]=1>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:43])=[O:17])=[CH:22][C:23]=3[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)O)c1
Product: CCCc1c(OCCCCCOc2ccc(CCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 4-[5-(methylsulfonyl)oxypentyloxy]-1,3-benzenedipropanoic acid methyl ester from the preceding exapmle, followed by saponification, in 8% overall yield. The product was a colorless solid, mp 108°-109° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][CH2:30][CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]2=[O:27])=[O:13])[N:10]=1)=O.[Na+:32].C(=S)(SC)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][CH2:30][CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:24])=[O:25])[C:16]2=[O:27])=[O:13])[N:10]=1.[Na+:32]
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 110 mg of sodium cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-ethoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) in 8 ml of water is added ice-cooling 30 mg of sodium monomethyl dithiocarbamate. The mixture is stirred at room temperature for one hour, then another 10 mg of sodium monomethyl dithiocarbamate is added thereto. After the mixture is stirred for further one hour, the resulting reaction mixture is subjected to filtration, and the filtrate is washed with ether. The aqueous layer is purified by column chromatography on Amberlite XAD-II and then lyophilized to give sodium cis-3-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[C:24]1([P:30](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][P:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:31])[CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: O=P(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 70 mg of 3-styryl-1H-indazol-5-ol, 300 mg of imidazole and of 273 μl of diphenylphosphinyl chloride in 15 ml of dichloromethane is stirred at ambient temperature. After stirring for approximately 90 minutes, the medium is treated with 30 ml of distilled water. The aqueous phase is extracted twice with 30 ml of dichloromethane and the organic phases are then dried over magnesium sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude is taken up with ethyl acetate. The solid is filtered through sintered glass, and rinsed with ethyl ether. The filtrate is concentrated under reduced pressure in a rotary evaporator, and purified by flash chromatography on silica 35-70 μm. Eluent: cyclohexane/ethyl acetate gradient of 80:20 to 70:30. 143 mg of a yellow solid are collected. This compound is purified by preparative LC/MS to obtain 47.3 mg of diphenylphosphinic acid 3-((E)-styryl)-1H-indazol-5-yl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18](Cl)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([O:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Reactant: OCc1ccncc1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 33 mmol), pyridin-4-yl-methanol (6.9 g, 63 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (60.0 mL, 60 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product is purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 7.1 g (57%) of 4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.65 (d, 2H), 7.32 (d, 2H), 5.49 (s, 2H), 3.55 (m, 8H) 1.48 (s, 9H) ppm. LC-MS (MH+)=378.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[OH-].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:34]([N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCCI
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(c1ccccn1)c1ccccn1
Reaction time: 1 h

Procedure:
To a flask were added 1.0 g 2,2′-dipyridylamine, 1.0 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 2.2 g of 1-iodooctadecane were added. The mixture was allowed to warm to 22 C and stirred for 16 hours, then heated to 40 C for 2 hours. After quenching with 25 ml water and cooling to 22 C, the product was filtered and washed with water. The product was dissolved in 25 ml hot ethanol with 100 mg activated carbon, stirred for 30 minutes and filtered through celite. After adding 25 ml water and cooling to 5 C, the product was filtered, washed with water and dried leaving 2.1 g light yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-Furoyl chloride (118 μL, 1.2 mmol) was added to a stirred solution of Compound 26 (287 mg, 0.8 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried and recrystallized by hexane and ether to yield 340 mg (90%) of white solids. M.P. 146° C. 1H NMR (DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.97 (m, 4H), 5.47 (s, 2H), 6.66 (t, J=2.5 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.23 (d, J=7.4 Hz, 1H), 7.29–7.33 (m, 3H), 7.44 (d, J=1.3, 8.7 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 1H). EIMS m/z 475 (M+23). Anal. (C27H24N4O3) C, H, N.
Reaction SMILES: O1CCOC1.C(OP([CH2:14][CH:15]=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=[O:20])(OCC)=O)C.CC([O-])(C)C.[K+].[CH3:28][C:29]1[CH2:34][CH2:33][CH2:32][C:31]([CH3:36])([CH3:35])[C:30]=1/[CH:37]=[CH:38]/[C:39]([CH3:41])=O>C1COCC1>[CH3:28][C:29]1[CH2:34][CH2:33][CH2:32][C:31]([CH3:35])([CH3:36])[C:30]=1/[CH:37]=[CH:38]/[C:39](/[CH3:41])=[CH:14]/[CH:15]=[CH:16]/[C:17](/[CH3:21])=[CH:18]/[CH:19]=[O:20]
Reactant: CCOP(=O)(CC=CC(C)=CC=O)OCC
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCO1
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reaction time: 1.5 h

Procedure:
Phosphonate (I) (0.5 g, 1.72 mmol) in solution in THF (10 ml) was introduced under argon into a 25-ml two-necked flask. Potassium tert-butylate (0.275 g, 2.22 mmol) was added in small portions at -70° C. Stirring was continued at -70° C. for 90 minutes. β-ionone (0.34 g, 1.8 mmol) in solution in THF (1 ml) was then added. The solution was kept at -70° C. for 15 minutes and then at -20° C. for 1 hour.
Reaction SMILES: C(O[C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([O:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:37])[C@@H:18]4[CH2:36][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:28]([O:27][C@H:23]1[CH2:24][C@@:25]2([CH3:26])[C@@H:11]([CH2:10][CH:9]=[C:5]2[C:6](=[O:8])[CH3:7])[C@H:12]2[C@H:22]1[C@:20]1([CH3:21])[C:15]([CH:14]=[CH:13]2)=[CH:16][C:17](=[O:37])[C@@H:18]2[CH2:36][C@H:19]12)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](OC(=O)c3ccccc3)C[C@@]21C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](OC(=O)c3ccccc3)C[C@]12C
Yield: 79.5 %

Procedure:
One gram of 17α-acetoxy-11β-benzoyloxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione is dissolved in 10 ml of "Dowtherm" (filtered over A12O3). The solution is heated under a stream of nitrogen gas for 30 minutes to 285° C. After cooling, the mixture is diluted with hexane, introduced into a silica gel column, and the "Dowtherm" is eluted with hexane. The thus-prepared compound is now eluted with methylene chloride and a gradually increasing proportion of chloroform. The individual fractions are tested for content and purity by thin-layer chromatography. The fractions having the desired compound are combined, concentrated, and the residue is recrystallized from benzene, thus obtaining 700 mg of 11β-benzoyloxy-1α,2α-methylene-4,6,16-pregnatriene-3,20-dione (79% of theory), m.p. 227°-229° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=[N:16][C:17]2[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Br:24])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH2:15][NH:16][C:17]2[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Br:24])[C:6]=1[OH:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C=Nc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(CNc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a suspension of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)imino]methyl]phenol (0.91 g, 2.41 mmol) in methanol (20 ml) was added NaBH4 (1.2 g), in small portions. The yellow suspension was stirred for 2 hours during which the yellow solution turned clear. Water (10 ml) was then slowly added, the organic phase separated and the aqueous phase extracted with dichloromethane (3×10 ml). The organic fractions were combined, dried (NaSO4), and the solvent removed under reduced pressure. The crude product was purified by recrystallisation from hot hexane to afford the product as large colourless crystals. Yield 0.48 g, 95%.
Reaction SMILES: CS(O[CH2:6][C:7]([N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[N:11]1)([CH3:9])[CH3:8])(=O)=O.[I-].[Na+].[CH3:25][S:26]([O-:28])=[O:27].[Na+].O>CN(C)C=O>[C:19]([O:18][C:16](=[O:17])[NH:15][C:13]1[CH:12]=[N:11][N:10]([C:7]([CH3:9])([CH3:8])[CH2:6][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)COS(C)(=O)=O)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CS(C)(=O)=O)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of the crude 2-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)-2-methylpropyl methanesulfonate (1.1 g) obtained in Step B of Example 114 in N,N-dimethylformamide (10 mL) were added sodium iodide (740 mg) and sodium methanesulfinate (1.0 g), and the mixture was stirred overnight at 140° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (250 mg).
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[N:20]=[C:19]([NH:21][C@H:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH3:23])[N:18]=[C:17]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:16]=2)=[N:11]1)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C@@H:22]([NH:21][C:19]2[N:18]=[C:17]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:16]=[C:15]([C:12]3[N:11]=[N:10][NH:14][N:13]=3)[N:20]=2)[CH3:23])=[CH:29][CH:28]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2nnn(COCc3ccccc3)n2)n1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2nn[nH]n2)n1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
50 mg of (S)-6-[2-(Benzyloxymethyl)-2H-tetrazol-5-yl]-N2-[1-(4-fluoro phenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 1.5 ml of methanol, and 1.5 ml of 10% hydrochloric acid was added thereto, and the mixture was stirred at 80° C. for hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate, and the pH of the mixture was adjusted to 4 by using saturated sodium bicarbonate aqueous solution. The organic layer was subjected to extraction, and washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with methanol and filtered and dried under reduced pressure to obtain 15 mg of the objective compound as white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:13])[CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:14].[CH:15]1C(O)=CC=CC=1C.C[C@@H](CC)C(Cl)=O>>[CH3:15][C:7]1[CH:2]=[C:3]([OH:14])[CH:4]=[CH:5][C:6]=1[C:8](=[O:13])[CH:9]([CH3:12])[CH2:10][CH3:11]
Reactant: Cc1cccc(O)c1
Reactant: CCC(C)C(=O)c1ccc(O)c(Cl)c1
Agent: CC[C@H](C)C(=O)Cl
Product: CCC(C)C(=O)c1ccc(O)cc1C

Procedure:
Generally following to the procedure as described in paragraph (1) of Preparation Example 1, m-cresol and (S)-(+)-2-methylbutanoic acid chloride were reacted to obtain 3-methyl-4-(1-oxo-2-methylbutyl)phenol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:29]([NH2:28])=[O:30])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc(CN(CCCCN)[C@@H](C)c2ccccn2)c(C)c1
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCCNC(N)=O)[C@@H](C)c2ccccn2)c(C)c1
Yield: 41.5 %

Procedure:
To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-butane-1,4-diamine (63 mg, 0.21 mmol) in 2-propanol (1 mL) was added trimethylsilyl-isocyanate (40 μL, 0.30 mmol). The resultant solution was stirred at room temperature for 6 hours then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 31 mg (41%) of the free base of the title compound as a white foam. Using General Procedure D: Conversion to the HBr salt gave COMPOUND 148 (43 mg, 72%) as a white solid. 1H NMR (D2O) δ 1.29 (br s, 4H), 1.59 (d, 3H, J=6.6 Hz), 2.42 (s, 3H), 2.47 (s, 3H), 2.51-2.68 (m, 2H), 2.92 (br s, 2H), 4.24 (s, 2H), 4.57 (q, 1H, J=6.6 Hz), 7.97-8.02 (m, 1H), 8.11-8.18 (m, 2H), 8.41 (s, 1H), 8.56-8.62 (m, 1H), 8.77 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 14.63, 16.78, 17.50, 24.06, 27.15, 39.52, 51.05, 52.94, 60.19, 126.67, 126.74, 136.16, 137.31, 137.65, 142.10, 147.93, 148.95, 149.33, 156.40, 161.76; ES-MS m/z 356 (M+H). Anal. Calcd. For C20H29N5O.3.3HBr.2.5H2O: C, 35.99; H, 5.63; N, 10.49; Br, 39.50. Found: C, 36.26; H, 5.38; N, 10.10; Br, 39.78.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Yield: 95 %

Procedure:
A stirred mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (23.8 g, 70.5 mmol), 1-BOC-4-aminopiperidine (15.5 g, 77.5 mmol) and diisopropylethylamine (17.0 mL, 98.7 mmol) in propan-2-ol (250 mL) was heated to reflux for approximately 2 hours. After cooling, the resulting suspension was filtered and the solid washed with propan-2-ol and diethyl ether, then air dried to afford 33.6 g (95%) of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.12 (br d, 1H), 9.09 (s, 1H), 8.21 (m, 2H), 7.66 (m, 2H), 7.53 (t, 2H), 6.69 (d, 1H), 4.14 (m, 1H), 4.01 (d, 2H), 3.12 (t, 2H), 2.11-2.08 (m, 2H), 1.65-1.64 (m, 2H), 1.48 (s, 9H).