Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C@@H:10]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.C([O+](CC)CC)C.C1C2[C:45](=[CH:46][CH:47]=[CH:48]C=2)[CH:44]=[C:43](N)N=1>C(Cl)Cl>[C:23]([O:22][C:20]([N:18]([CH3:19])[C@H:10]([CH2:9][O:8][C:6](=[O:7])[NH:1][C:2]1[N:3]=[CH:4][C:5]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: Nc1cc2ccccc2cn1
Reactant: COC(=O)CCC[C@@H](COC(=O)n1ccnc1)N(C)C(=O)OC(C)(C)C
Agent: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl(methyl)amino)-6-methoxy-6-oxohexyl 1H-imidazole-1-carboxylate (2 g, 5.4 mmol) in DCM (10 mL) was added a solution of triethyloxonium hexafluorophosphate (1.61 g, 6.5 mmol, 1.2 equiv.) in DCM (5 mL) dropwise at 0° C. The solution was warmed up to RT and stirred for 15 min. A solution of isoquinolin-3-amine (0.94 g, 6.5 mmol, 1.2 equiv.) in DCM (5 mL) was added. The solution was stirred for overnight. DCM was removed and the residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoate (1.4 g, 58%). LRMS (M+H+) m/z 446.2.
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.[CH3:47][O:48][CH2:49][CH2:50]NC>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[C:20](=[O:21])[CH2:19][CH2:18][CH:17]4[CH3:22])=[CH:15][C:10]=3[C:9]([N:8]([CH2:50][CH2:49][O:48][CH3:47])[CH3:6])=[O:39])=[O:24])[CH2:26][CH2:27]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: CNCCOC
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: COCCN(C)C(=O)c1cc(N2C(=O)CCC2C)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 837 and (2-methoxyethyl)(methyl)amine (49 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (28 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Mg].II.C[Mg]Br.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOCC>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1cc(C)ccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Mg]Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cc1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
A solution of 2-bromo-5-methylanisole (3.8 g) [obtained as described in J. Gen. Chem. U.S.S.R., 1932, 2, 455 (Chemical Abstracts, 1933, 27, 962)] in THF (50 ml) was added to magnesium turnings (0.47 g) and a catalytic amount of iodine under an atmosphere of argon. A catalytic volume of 1M methyl magnesium bromide in ether was added and the mixture was heated 50° C. for 1 hour, and then cooled to 0° C. Tributyltin chloride (5.6 g) was added dropwise over 5 minutes and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue partitioned between ether (50 ml) and saturated ammonium chloride solution (50 ml). The organic phase was separated and washed with saturated ammonium chloride solution (2×20 ml). The ether layer was separated, diluted with ethyl acetate (50 ml), and washed with water (25 ml), followed by saturated sodium chloride solution (50 ml). Volatile material was removed by evaporation and the residue purified by distillation to give (2-methoxy-4-methylphenyl)tributyl tin (B) (4.8 g), as an oil, b.p. 190° C. at 0.05 torr; NMR: 0.75-1.7 (complex m,27H), 2.4(s,3H), 3.8(s,3H), 6.6(t,1H), 6.8(d,1H), 7.2(d,1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 3 h

Procedure:
A solution of 4-nitrophenyl chloroformate, 5.04 g (25 mMole) in 25 ml of dry ethyl acetate was added dropwise to an ice bath cooled, stirred solution of N-methylpiperazine, 5.55 ml (50 mMole), and N,N-diisopropylethylamine, 5.23 ml (30 mMole), in 50 ml of dry ethyl acetate. The ice bath was removed and stirring was continued at 22° C. for three hours. The thick reaction mixture was diluted with ethyl acetate, extracted with aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The solid residue was recrystallized from methylene chloride hexane furnishing 3.67 g of 1-(4-nitro-phenoxycarbonyl)-4-methylpiperazine, m.p. 134°-135° C., which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=C[C:17](C#N)=[C:16](N)[CH:15]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[N:29][CH:28]=[N:27][CH:26]=1.C(O)(=O)C>C(O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:26]3[C:17]([C:30]([NH2:25])=[N:29][CH:28]=[N:27]3)=[CH:16][CH:15]=2)[C:9]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C#N)c(N)c2)C1=O
Reactant: c1ncncn1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 8 h
Yield: 520.4 %

Procedure:
[1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (890 mg, 2.69 mmol) and 1,3,5-triazine (650 mmol, 8 mmol) are combined in ethanol (40 mL), and acetic acid (480 mg, 8 mmol) added. The reaction mixture is refluxed under nitrogen overnight, cooled and presorbed directly onto silica. The product is purified by column chromatography on silica with 5-20% methanol/dichloromethane (containing 0.5% of 28% aqueous ammonium hydroxide). The product factions are combined and concentrated, and the residue left under high vacuum overnight. The product is isolated as a pale yellow powder (0.50 g, 14 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCC1.Cl[Si](C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:36][C:37]([CH3:40])([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH3:38])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCCC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCC1
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
To a mixture of (S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (285 mg, 0.60 mmol), 2-methyl-2-pyrrolidin-1-yl-propanal (719 mg, 5.1 mmol) and pyrrolidine (0.23 mL, 2.8 mmol) in DCM (6 mL) at room temperature was added chloro(trimethyl)silane (0.23 mL, 1.8 mmol). After stirring 90 min, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 g column:0%-15% iPrOH/DCM) to obtain 270 mg of (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-enenitrile. MS (pos. ion) m/z: 595 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH:3]([C@H:16]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:18]([CH2:25][C:26]2[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(B(CC)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)C.[OH-].[K+].C(=O)([O-])O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.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>[ClH:1].[ClH:1].[ClH:1].[CH:3]([C@H:16]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:18]([CH2:25][C:26]2[CH:31]=[C:30]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: COc1ccc(Br)cc1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cccnc2)cc1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of (4R,8aS)-4-benzhydryl-2-(5-bromo-2-methoxybenzyl)octahydropyrrolo[1,2-a]pyrazine dihydrochloride (100 mg), diethyl-3-pyridylboran (39.1 mg), tetrakis(triphenylphosphine)palladium (20.5 mg), powdered potassium hydroxide (29.8 mg) and tetrabutylammonium bromide (17.1 mg) in tetrahydrofuran (2 ml) were stirred for 8 hours at 70° C. After being cooled to room temperature, the reaction mixture was poured into aqueous saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative TLC (0.5 mm) with a mixture of dichloromethane and methanol (10:1) as an eluent. The resulting residue was treated with 4N hydrogen chloride in ethyl acetate to give (4R,8aS)-4-benzhydryl-2-[2-methoxy-5-(3-pyridyl)benzyl]octahydropyrrolo[1,2-a]pyrazine trihydrochloride (25.9 mg).
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[CH2:9]([NH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH3:3][C:2]1[C:1](=[O:8])[N:18]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5](=[O:6])[CH:4]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: CCCCCCCCCN
Solvent: c1ccncc1
Product: CCCCCCCCCN1C(=O)C=C(C)C1=O
Temperature: 90 °C

Procedure:
A solution of citraconic anhydride (0.1 M) in pyridine (20 ml)was treated with nonylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: O1CCN[C:2]1=O.[C:7]([NH:17][CH2:18][C:19]([OH:21])=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:7]([N:17]([CH2:18][C:19]([OH:21])=[O:20])[CH3:2])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=C1NCCO1
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
The oxazolidinone from Cbz-glycine (221 mg, 1.0 mmole) was dissolved in 10 ml of CHCl3 and triethylsilane (193 ∥l=174 mg, 1.5 mmoles) and trifluoroacetic acid (770 μl, 10 mmoles) were added. The solution was stirred at room temperature for 2 hrs. and concentrated in vacuo. CHCl3 was added and the solution was reconcentrated to a colorless oil. Silica gel chromatography gave 107 mg (48%) of Cbz-sarcosine, identified by NMR (N-Me, 2.98 ppm) and amino acid analysis.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:46]([CH3:48])[CH3:47]>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:46]([CH3:48])[CH3:47])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: CC(C)I
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 2-iodopropane (226 μl, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (287 mg, 66%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH2:12])=[O:11]>S(=O)(=O)(O)O.O>[C:1]([NH:12][C:10](=[O:11])[CH:9]([Cl:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NC(=O)C(Cl)c1ccccc1

Procedure:
To a solution of one drop of concentrated sulfuric acid in 5 ml. of acetic anhydride was added 2 g. of the amide of Step A above, and the reaction mixture was heated on a steam bath for 1.5 hours. The resulting yellow solution was stirred with ice and water and 2.1 g. of precipitate was soon collected. The precipitate was dissolved in about 15 ml. of dichloromethane, after which petroleum ether was carefully added to near the cloud point. Short white needles of precipitate formed to give a yield of 1.9 g. having an m.p. of 101°-102° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[C:18]1([NH:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH:20]2[CH2:23][NH:22][CH2:21]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH:32]1[CH2:34][O:33]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C.O>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH:32]([OH:33])[CH2:34][N:22]1[CH2:23][CH:20]([CH2:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:21]1
Reactant: Fc1ccc(C2CO2)c(F)c1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=S(=O)(CC1CN(CC(O)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Triethylamine (210 μL, 1.52 mmol) was added to a stirred suspension of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4, 270 mg, 1.02 mmol) in acetonitrile (3 mL) under nitrogen. 2-(2,4-Difluorophenyl)oxirane (WO 99/23083; 1:1 mixture of enantiomers, 238 mg, 1.52 mmol) was added followed by lithium perchlorate (110 mg, 1.03 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane (x3). The combined organic layers were washed with water (x3) and brine, dried over MgSO4 and evaporated in vacuo. The residue was triturated with diethyl ether/isohexane then with 5% methanol/ethyl acetate to give 1-(2,4-difluorophenyl)-2-(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)ethanol (134 mg, 34%). 1H NMR (500 MHz, CD3OD) δ 7.96–7.92 (2H, m), 7.50–7.46 (1H, m), 7.39–7.33 (2H, m), 6.93–6.91 (1H, m), 6.88–6.84 (1H, m), 3.48 (2H, d, J=7.3 Hz), 3.44–3.38 (2H, m), 2.96–2.88 (2H, m), 2.83–2.75 (1H, m), 2.67–2.61 (2H, m); m/z (ES+) 386 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16].[Cl:21][C:22]1[CH:23]=[C:24]([C:32](O)=O)[CH:25]=[N:26][C:27]=1[O:28][CH:29]([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:32]2[O:1][N:2]=[C:3]([C:4]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:5]=3[CH:6]=[CH:7][N:8]4[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:20]=2)[CH:25]=[N:26][C:27]=1[O:28][CH:29]([CH3:30])[CH3:31]
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3ccn4CCC(=O)O)no2)cc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
Ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg) in DMF (2.5 ml) was added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D61) (118 mg), HOBT (81 mg) and EDCI (114 mg) which had been stirring at RT for 10 minutes in DMF (2.5 ml). The resultant mixture was stirred at RT for 2 hours then heated at 80° C. for three days. The reaction mixture was evaporated to dryness and extracted from H2O (25 ml) with EtOAc (2×25 ml). The combined organics were evaporated and the residue stirred in EtOH/2 M aq. NaOH (1:1 mixture, 20 ml) at 50° C. for 2 hours. The EtOH was evaporated and the precipitate removed by filtration. This was acidified then purified by MDAP to give the title compound (48 mg) as an off white solid. δH (d6-DMSO, 400 MHz): 1.40 (6H, d), 2.80 (2H, t), 4.50 (2H, t), 5.46 (1H, septet), 7.08 (1H, d), 7.36 (1H, apparent t), 7.60 (1H, d), 7.82 (1H, d), 7.95 (1H, d), 8.60 (1H, d), 8.97 (1H, d). MS (ES−): C21H1935ClN4O4 requires 426; found 425 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]4[OH:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.N.NC1C=CC=CC=1.[Li].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 31.8 %

Procedure:
Add dl-3-methoxyestra-1,3,5(10),8-tetraen-17β-ol (37.5 g) in tetrahydrofuran (350 ml) to a stirred solution of liquid ammonia (1 liter) and aniline (45 ml). Add lithium (2 g), stir for 30 minutes, and then add ammonium chloride (20 g) followed by water. Extract with ether-benzene (1:1) and wash the organic solution with water, excess 3N hydrochloric acid, water and dry. Evaporate the solvent and recrystallize the residue from ethyl acetate-hexane to obtain dl-3-methoxyestra-1,3,5(10)-trien-17β-ol (12 g), m.p. 121°-124°; ultraviolet absorption peak at 278 mμ (ε1,810); infrared maxima at 3.0 μ, 6.2 μ, 6.75 μ.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[Na+].[Na+].ClCCl.N#N>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:26]([F:25])[CH:27]=4)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)cc1F
Temperature: 95 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.15 mmol, chiral pure, first peak from Example 20, Step 2), [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (from Combi-Blocks, 0.041 g, 0.20 mmol), sodium carbonate (36 mg, 0.34 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (6 mg, 0.007 mmol) in acetonitrile (1.2 mL)/water (0.3 mL) was vacuumed and then refilled with N2. The reaction was stirred at 95° C. for 2 hours. Then solvent was removed and the crude mixture was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2, to give the desired product (54 mg, 75%). LCMS calculated for C24H24ClFN5O3 (M+H)+: m/z=484.2; Found: 484.1