Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:30].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccccn3)C2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccn4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 6 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine and (0.24 mmol), (1-(2-ethyloxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.28 mmol), and 3 Å molecular sieves (about 12 g) in methanol (5 mL). After 6 hours, add sodium cyanoborohydride (0.15 g, 2.4 mmol) and stir under an inert atmosphere. After 18 hours, add a solution of 2 M sodium hydroxide and dichloromethane. After 1 hour, filter, separate the layers in the filtrate, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12](O)=[C:9]([O:10][CH3:11])[CH:8]=1.[N+:16]([O-])([OH:18])=[O:17]>>[C:1]([O:4][C:12]1[CH:14]=[CH:15][C:7]([CH:6]=[O:5])=[C:8]([N+:16]([O-:18])=[O:17])[C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C=O)ccc1O
Product: COc1c(OC(C)=O)ccc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 41 %

Procedure:
Fuming nitric acid (2200 mL) under nitrogen was cooled to 0° C. at which time vanillin acetate (528 g, 2.7 mol) was added portionwise, keeping the internal temperature below 10° C. After 2 h the resulting mixture was poured over ice with stirring. The slurry was filtered and the resulting solids were washed with water (3×100 mL) and air-dried. After 2 days the solids were heated in DCM (3000 mL) until complete dissolution. The solution was allowed to cool to room temperature while hexanes (3000 mL) was added dropwise. The solids were filtered, washed with hexanes (500 mL) and air dried to give the desired product (269 g, 41%): 1H NMR, (DMSO-d6) δ: 9.90 (s, 1H), 7.94 (d, 1H), 7.75 (d, 1H), 3.87 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution 0.16 g of (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 2 mL of dichloromethane, 0.14 g of tert-butyl (piperidin-4-yl)carbamate, 41 μL of acetic acid and 0.23 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour 30 minutes. The reaction mixture was charged with chloroform and a saturated aqueous sodium hydrogen carbonate solution and adjusted to pH 8.5, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=19:1 to obtain 0.23 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oily substance.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:36])([F:35])[C:5]1[CH:6]=[C:7]([C@H:15]([O:17][C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:22]([C@H:30]3CCN3C)[CH2:21][CH2:20][O:19]2)[CH3:16])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[N:37]1([C:42]([O-:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.O>O1CCCC1.C(OCC)(=O)C>[F:13][C:11]([F:12])([F:14])[C:9]1[CH:8]=[C:7]([C@H:15]([O:17][C@@H:18]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:22]([CH:30]3[O:43][C:42](=[O:44])[N:37]4[CH2:41][CH2:40][CH2:39][CH:38]34)[CH2:21][CH2:20][O:19]2)[CH3:16])[CH:6]=[C:5]([C:4]([F:36])([F:35])[F:3])[CH:10]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H]([C@H]2CCN2C)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1OCC[C@@H](C2OC(=O)N3CCCC23)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 15 mg, 0.36 mmol) was added to a solution of 1,1-dimethylethyl (2R or S)-2-[(R or S)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate (Example 41, Isomer A; 75 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 15 hours. Water (2 mL) was added slowly, then ethyl acetate (10 mL). The layers were separated and the organic layer was washed with brine (5 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (80:20 increasing to 60:40), to give the title compound (Single diastereoisomer; Stereochemistry unassigned) as a colorless foam (54 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][CH2:13][OH:14].CO.C1C(=O)N(Br)C(=O)C1>ClCCl>[CH3:10][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:14][CH2:13][CH2:12][CH2:11][O:9]1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: OCCCO
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C2(C)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 25 %

Procedure:
To a stirred mixture of 4-methylacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-1,3-dioxane (22) as a colourless oil (480 mg, 24%). 1H nmr (200 MHz, CDCl3) 1.50 (s, 3H, CH3), 1.96-2.25 (m, 2H, OCH2CH2CH2O), 2.37 (s, 3H, ArCH3), 3.70-4.00 (m, 4H, OCH2CH2CH2O), 7.23 (d, J=8.3 Hz, 2H, 2×ArH), 7.33 (d, J=8.3 Hz, 2H, 2×ArH).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH:21]1[CH3:27].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:19][N:20]1[CH:21]([CH3:27])[CH2:22][C:23]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[C:24]=2[CH2:25]1
Reactant: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Reactant: CC1CC(=O)CCN1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(C)N(C)C1
Temperature: 85 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
To a solution of N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine (200 mg, 0.829 mmol) in dioxane (7 mL) was added 1,2-dimethyl-piperidin-4-one (137 mg, 1.078 mmol) in dioxane (3 mL) at RT. To this mixture was added sulfuric acid (0.1 mL) at RT. After complete addition the mixture was stirred at 85° C. for 1 h. The reaction was monitored by TLC. After completion of reaction, the mixture was basified with NaHCO3 solution and extracted with EtOAc (300 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum and purified by HPLC to obtain 28.5 mg of desired compound as the TFA salt. 1HNMR (CD3OD, TFA salt) d (ppm): 8.20 (s, 1H), 8.05 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 4.70 (m, 1H), 4.45 (t, 2H), 4.36 (m, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 3.20 (m, 2H), 3.0 (m, 3H), 2.90 (m, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[Si:15]([O:6][CH2:5][C:2]1([NH2:1])[CH2:4][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC1(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(N)CC1
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a stirring solution of (1-aminocyclopropyl)methanol (9.69 mmol), 4-(dimethylamino)pyridine (0.484 mmol), and triethylamine (21.32 mmol) in anhydrous dichloromethane (25 mL) was added chloro(1,1-dimethylethyl)dimethylsilane (10.66 mmol). After stirring 20 h, the reaction was quenched with saturated aq ammonium chloride and extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to afford the crude title compound (1.70 g, 78% yield) as a colorless liquid. MS(ES)+ m/e 202.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH:20](CC(N)=O)[CH2:19]1)[C:13]([CH3:28])=[CH:12]2)[CH3:2].C1(N2C3C(=CC(O)=CC=3)C([CH2:46][C:47]([NH2:49])=[O:48])=C2C)CCCCC1.[H-].[Na+].BrCCCC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([CH3:28])=[C:12]2[CH2:46][C:47]([NH2:49])=[O:48])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)cc(C)n2C1CCCC(CC(N)=O)C1
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1C1CCCCC1
Agent: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2C1CCCCC1
Yield: 46 %

Procedure:
[4-[[3-(2-Amino-2-oxoethyl)-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester. 1-Cyclohexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (300 mg, 1.0 mmol) was reacted with 40 mg (1.0 mmol) of 60% NaH/mineral oil and then 0.143 mL (1.0 mmol) of ethyl 4-bromobutyrate as described in Example 50, Part D to give a product that was chromatographed on silica gel (eluted with 2% MeOH/methylene chloride) to give 190 mg (46% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 92°-94° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li][CH2:17][CH2:18][CH2:19][CH3:20].[Br:21][C:22]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[C:31]3[CH:30]=[C:29]4[C:37]5[C:42]([C:43]([CH3:45])([CH3:44])[C:28]4=[CH:27][C:26]=3[C:25](=[O:46])[C:24]=2[CH:23]=1)=[CH:41][CH:40]=[CH:39][CH:38]=5>C1COCC1>[Br:21][C:22]1[CH:35]=[CH:34][C:33]2[C:32]([C:2]3[C:3]4[C:8]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[CH:15]=3)=[CH:7][CH:6]=[CH:5][CH:4]=4)([OH:36])[C:31]3[CH:30]=[C:29]4[C:37]5[C:42]([C:43]([CH3:44])([CH3:45])[C:28]4=[CH:27][C:26]=3[C:25]([C:18]3[C:19]4[C:20]([C:2]6[CH:15]=[CH:14][CH:9]=[CH:8][C:3]=6[CH:17]=3)=[CH:7][CH:6]=[CH:5][CH:4]=4)([OH:46])[C:24]=2[CH:23]=1)=[CH:41][CH:40]=[CH:39][CH:38]=5
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(=O)c1cc(Br)ccc1C3=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2cc3c(cc21)C(O)(c1cc2ccccc2c2ccccc12)c1cc(Br)ccc1C3(O)c1cc2ccccc2c2ccccc12
Reaction time: 1 h
Yield: 64.2 %

Procedure:
9-bromophenanthrene (13.88 g, 0.054 mol) was placed in a flask, and THF (200 ml) was added thereto. After dissolution, n-BuLi (38.4 ml, 0.06 mol) was gradually added at −780, and the reaction mixture was stirred for one hour at a maintained temperature. Then, 9-bromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (9.67 g, 0.024 mol) was added and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, the reaction solution was washed with distilled water, extracted with ethyl acetate, and purified by column chromatography to give 9-bromo-13,13-dimethyl-6,11-di(phenanthren-9-yl)-11,13-dihydro6H-indeno[1,2-b]anthracene-6,11-diol (11.7 g, yield=64%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:36]=1[C:37]([OH:39])=[O:38]>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([NH:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:36]=1[C:37]([OH:39])=[O:38])=[O:18])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(NC(=O)[C@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.5 h
Yield: 33 %

Procedure:
After a tetrahydrofuran solution (40 ml) of N-benzyloxycarbonyl-D-valine (5.08 g) was cooled to -15° C., N-methylmorpholine (2.23 ml) and isobutyl chloroformate (2.61 ml) were added to the solution, and the mixture was stirred for 0.5 hour. An N,N-dimethylformamide solution (25 ml) containing 2-amino-6-methylbenzoic acid (2.04 g) and N-methylmorpholine (1.79 ml) was added dropwise to the above reaction mixture, and the resultant mixture was stirred at -15° C. for 0.5 hour and then at room temperature for two hours. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 2-(N-benzyloxycarbonyl-D-valyl)amino-6-methylbenzoic acid (1.71 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:12]=1>>[CH3:32][O:31][C:21]1[CH:20]=[C:19]([NH:18][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[CH:16]=[C:15]([CH3:17])[N:14]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: N#Cc1cccc(O)c1
Product: COc1cc(Nc2nc(C)cc(Oc3cccc(C#N)c3)n2)ccc1-n1cnc(C)c1
Yield: 75 %

Procedure:
The title compound was prepared in analogous manners as described in example 9) from 3-hydroxy-benzonitrile and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 75% yield as a pale-brown solid. MS ISP (m/e): 413.4 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:37]([C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:38].C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:42]2[CH:43]=[N:44][C:39]([CH:37]=[O:38])=[CH:40][CH:41]=2)[CH:3]=1)=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)cn1
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: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (0.5 g, 0.892 mmol), (6-formylpyridin-3-yl)boronic acid (0.31 g, 1.33 mmol) and Pd(PPh3)4 (0.103 g, 0.082 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (0.34 g, 3.21 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (0.40 g, 87.9%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:16][C@@H:14]1[CH2:15][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([CH2:10][OH:11])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-Boc-cis-4-fluoro-L-proline (2 g, 8.575 mmol) was dissolved in tetrahydrofuran (20 ml), the solution was cooled and boron hydride-tetrahydrofuran complex (1 mol/l, 12.86 ml) was added slowly at 0° C. The reaction mixture warmed slowly to room temperature, after stirring for 3 h it was cooled again to 0° C., water (5 ml) was slowly added dropwise, potassium carbonate (2 g, 14.477 mmol) was added and the mixture was stirred for 30 min. After separation of the phases, the aqueous phase was extracted with diethyl ether (3×20 ml) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with diethyl ether/hexane (4:1). Yield: 1.73 g, 92%
Reaction SMILES: [O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C@@H:18]2[OH:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([O:21][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:22])[C:20]3[C@:2]4([O:1][C:19]1=3)[O:24][C@H:3]4[C@@H:4]1[C@@H:14]2[CH2:13][CH2:12][C@@:11]2([CH3:23])[C@H:5]1[CH2:6][CH2:7][C@@H:8]2[CH2:9][CH3:10])(=[O:33])[CH3:32]
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a mixture of 0.084 g (0.189 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-ol, 0.5 ml (6.18 mmoles) of dry pyridine and 5 ml of methylene chloride was gradually added 0.1 ml (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the solution was stirred at room temperature for 8 hours. The reaction mixture thus obtained was diluted with methylene chloride and washed with saturated aqueous copper (II) sulfate solution. The aqueous layer (washings) was extracted with methylene chloride and the extract was combined with the organic layer. The resulting mixture was washed with water and aqueous sodium chloride solution in that order and dired over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane: 1:10, v/v) to recover 0.083 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-yl acetate (yield: 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2)([O-:31])=[O:30].FC(F)(F)C([O-])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([N:36]1[CH2:35][C:34]2[C:38](=[CH:39][CH:40]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=2)[CH2:37]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (505 mg; 1.3 mmol) (Preparation B5), 5-nitroisoindoline, trifluoroacetate (360 mg; 1 equiv.), EDAC (300 mg; 1.2 equiv.), HOBt (210 mg; 1.2 equiv.) and NEt3 (270 μl; 1.5 equiv.) in DMF (10 ml) was stirred at room temperature overnight then evaporated in vacuo. The residue was partitioned between EtOAc and 2M HCl, the EtOAc layer was separated, washed with saturated NaHCO3, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:4 then 1:2 then 1:1 EtOAc/P.E. as eluant) gave 460 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl)methanone. MS: [M+H]+ 523.
Reaction SMILES: [CH2:1]1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]=[CH2:2].[N:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)=[N:11][CH:12]=1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)ncn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=C
Product: O=C1CCN(c2ccncn2)CC1

Procedure:
A solution of 1-(6-chloropyrimidin-4-yl)-4-piperidone ethylene ketal (2 g, 8.87 mmol) in ethanol (25 ml) and ethyl acetate (25 ml) was hydrogenated at 60 psi for 1 hr over 10% Pd/C (0.25 g). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through celite. The filtrate was concentrated in vacuo to give 1-(pyrimidin-4-yl)-4-piperidone ethylene as a white solid (112-115° C.).