Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[C:12]([C:22](=[O:28])[CH:23](OCC)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=1>C(O)C>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[C:12]([CH:22]([OH:28])[CH:23]=[N:41][C:38]([CH3:39])([CH3:40])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c2c1OC(C)(C)C(=O)N2
Solvent: CCO
Product: COc1ccc(CC(C)(C)N=CC(O)c2ccc(OCc3ccccc3)c3c2OC(C)(C)C(=O)N3)cc1

Procedure:
10.1 g (26 mmol) 5-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one and 4 g (22 mmol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine are stirred in 100 ml of ethanol for 2 hours at 60 to 70° C. After some of the solvent has been distilled off a solid is precipitated out during cooling, and this is suction filtered and washed with ethanol and diethyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C[Si]([CH2:16][C:17]#[N:18])(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[F-].[F-].[Zn+2].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH2:16][C:17]#[N:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: C[Si](C)(C)CC#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: N#CCc1ccc2ncccc2c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 0.012 mol), tris(dibenzylideneacetone)dipalladium(0) (10.0 g, 0.012 mol), 6-bromoquinoline (120.0 g, 0.577 mol) in DMF (360 mL) in a 3-neck round bottom flask with stirring under an atmosphere of nitrogen was added (trimethylsilyl)acetonitrile (98.7 mL, 0.721 mol), followed by zinc difluoride (42 g, 0.40 mol). The flask was sealed under an atmosphere of nitrogen. The reaction was stirred at 105° C. for 20 h. After cooling the solution to RT, the reaction mixture was quenched with aqueous ammonia solution and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%) to afford the desired product quinolin-6-ylacetonitrile (70 g, 72.1%). Analytical LCMS: (M+H)+=168.9.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=O)[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:64]([N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)([CH3:67])([CH3:66])[CH3:65]>>[C:64]([N:68]1[CH2:73][CH2:72][N:71]([C:22]([C:19]2[N:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:24])[CH2:70][CH2:69]1)([CH3:67])([CH3:66])[CH3:65]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ncc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)N3CCN(C(C)(C)C)CC3)ncc1OCC2
Reaction time: 0.17 h

Procedure:
[2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carboxylic acid (0.140 g, 0.411 mmol) was dissolved in N,N-Dimethylformamide (3.18 mL, 0.0411 mol) at room temperature. N,N-Diisopropylethylamine (0.287 mL, 0.00164 mol) was added followed by N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.172 g, 0.452 mmol). The suspension was stirred for 10 minutes. 1-tert-butylpiperazine (0.0878 g, 0.617 mmol) was added and the reaction mixture was stirred for 1 hour. LCMS shows complete conversion to product. The reaction mixture was concentrated to dryness and was purified by reversed phase HPLC to give 203. 1H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.94 (s, 1H), 5.76 (dt, J=13.2, 6.6 Hz, 1H), 4.64 (s, 4H), 3.56 (br d, J=48.6 Hz, 8H), 1.49 (d, J=6.6 Hz, 6H), 1.02 (s, 9H). LCMS 465.3.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1c(OC)nc2nc(C(=O)O)cn2c1C
Yield: 81505.3 %

Procedure:
A mixture of 120 g (0.456 mmol) of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate and 120 g of potassium carbonate in 1200 ml of methanol and 600 ml of water was heated at reflux for 2 hours and the methanol was then evaporated. 150 ml of more water were added, and the resulting solution was acidified to a pH of 1 with concentrated HCl. The solid obtained was filtered and was washed with water, then dried under vacuum over P2O5 at 80° C. to obtain 87.43 g (82% yield) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13]C)=[C:9]([CH:12]=1)[CH:10]=[O:11].B(Br)(Br)Br.C(OCC)(=O)C.O>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2Cl)cc1C=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(C=O)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a cooled (−78° C.), stirred solution of 5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-methoxy-benzaldehyde (10 g) in dichloromethane (300 mL) was added boron tribromide (23.3 g) dropwise. The reaction was allowed to warm to ambient temperature, stirred for 1.5 h, ice was added to quench the reaction and work up was done with ethyl acetate/water. The organic layer was dried over sodium sulfate, concentrated in vacuo and the resulting oil filtered through a plug of silica gel (eluting with chloroform) to afford 5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-hydroxy-benzaldehyde (8.65 g) as an off-white solid.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[N:4]([CH3:13])[C:3]2=[O:14].N[C@H](C(O)=O)C[SeH].[Li]CCCC.C1CCCCC1.[C:33](=[O:35])=[O:34]>C1COCC1>[CH3:13][N:4]1[C:3](=[O:14])[C@@:2]2([CH3:1])[C:9]([CH3:10])([CH3:11])[C@:6]([C:33]([OH:35])=[O:34])([CH2:7][CH2:8]2)[C:5]1=[O:12]
Reactant: CN1C(=O)C2CC[C@@](C)(C1=O)C2(C)C
Reactant: O=C=O
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN1C(=O)[C@@]2(C(=O)O)CC[C@@](C)(C1=O)C2(C)C
Temperature: -95 °C
Reaction time: 0.25 h

Procedure:
To a solution of step 2 intermediate (2 g, 10.2 mmol) in THF maintained at −95° C. under N2 atmosphere, 1.2N Sec.BuLi in cyclohexane (9.5 mL, 13.3 mmol) was added. After stirring for 15 min at −95° C., small pieces of dry ice (2 g) were added and the reaction mixture was kept at this temperature for 1 h before quenching with water (3 mL). The reaction mixture was allowed to warm to room temperature. To this 5% NaHCO3 solution (100 mL) and diethyl ether (50 mL) was added, the aqueous layer was separated and acidified with KHSO4 to pH 2. This was extracted again with diethyl ether, washed with brine, dried with anhydrous Na2SO4 and concentrated. (1.85 g). 1H NMR (400 MHz, CDCl3) δ ppm: 1.0 (s, 3H), 1.1 (s, 3H), 1.26 (s, 3H), 1.88-1.98 (m, 2H), 2.64-2.72 (m, 1H), 2.8 (m, 1H), 3.13 (s, 3H). m/z (M−H): 238.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.O.C(=O)(O)[O-].[K+]>CCOCC>[CH3:1][O:2][C:3]([C:5]1([CH2:8][N:9]([C:18]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(CNC2CCCC2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of 4.88 g (0.0247 mole) of 1-cyclopentylaminomethyl-cyclopropanecarboxylic acid methyl ester and 4.48 g (0.0231 mole) of 2,4-dichloro-5-nitro-pyrimidine in 100 mL of ether was added 50 mL of water and 4.62 g (0.0462 mole) of potassium bicarbonate. The mixture was stirred at ambient temperature for 5 hours. The resulting two-layer mixture was separated and the aqueous layer was extracted with ether. The combined ether extracts were washed successively with aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7.80 g of 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (IV-53) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.[H-].[Na+].Cl[C:21]1[N:22]=[C:23]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:24]2[S:29][C:28]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)=[CH:27][C:25]=2[N:26]=1>CN(C=O)C.O.[Cl-].[Na+].C(O)C.ClCCl.[Pd]>[CH3:38][N:37]([CH3:39])[CH:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:28]2[S:29][C:24]3[C:23]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[N:22][C:21]([N:14]4[C:15]5[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=5)[CH:12]=[CH:13]4)=[N:26][C:25]=3[CH:27]=2)[CH2:32][CH2:33]1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [Pd]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5cc(O)ccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 2.4 %

Procedure:
A solution of 5-benzyloxyindole (0.245 g) in DMF (5 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 30 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature and diluted with water and saturated aqueous sodium chloride solution. The solid separated was filtered and then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane). The residue obtained was dissolved in ethanol (30 mL) and dichloromethane (20 mL). Palladium on carbon (10%, 40 mg) was added. The mixture was degassed and was purged with hydrogen, and continued under a hydrogen balloon overnight. The reaction mixture was filtered through solka floc. The filtrate was concentrated and purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 132 (0.012 g, 15%) as a white solid. MS m/e 493 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.7-1.8 (m, 2H), 2.0-2.1 (d, 2H), 2.3 (m, 3H), 2.7 (s, 6H), 2.95 (d, 2H), 3.2 (m, 2H), 3.89-4.04 (m, 10H), 6.5 (d, 1H), 6.75 (d, 1H), 6.95 (d, 1H), 7.2 (br. s, 1H), 7.4 (s, 1H), 8.2 (d, 1H), 8.5 (d, 1H).
Reaction SMILES: [CH:1](=O)[CH3:2].[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][C:29]([O:35][CH3:36])=[CH:30][CH:31]=5)[N:26]=4)[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1>>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]([CH2:1][CH3:2])[CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][S:24][C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][C:29]([O:35][CH3:36])=[CH:30][CH:31]=5)[N:26]=4)[CH2:20][CH2:21]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)nc2c1
Reactant: CC=O
Product: CCN(Cc1ccc2c(c1)OCCO2)C1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1

Procedure:
The title compound is prepared as a yellow solid (67 mg, 20% yield) following Scheme 3 and in analogy to Example 40 using acetaldehyde (181 μg, 3.21 mmol 5.0 eq) and (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine (300 mg, 0.64 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][SH:2].F[C:4]1[CH:18]=[CH:17][C:7]([C:8]([C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]=2[CH3:16])=[O:9])=[CH:6][CH:5]=1>C(O)C>[CH3:16][C:11]1[NH:12][C:13](=[O:15])[S:14][C:10]=1[C:8](=[O:9])[C:7]1[CH:17]=[CH:18][C:4]([S:2][CH3:1])=[CH:5][CH:6]=1
Reactant: Cc1[nH]c(=O)sc1C(=O)c1ccc(F)cc1
Reactant: CS
Solvent: CCO
Product: CSc1ccc(C(=O)c2sc(=O)[nH]c2C)cc1
Temperature: 25 °C

Procedure:
Gaseous methylmercaptan is added to a solution of 5(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone (4.7 g) in ethanol (200 ml) to saturation. The mixture is heated at 120° C. in a sealed stainless steel container for 16 hours. After cooling to ambient temperature, the mixture is evaporated to dryness. The residue is recrystallized twice from ethanol to give the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:52])[CH2:7][CH:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH2:39][CH:38]4[CH:36]([CH:37]4[C:40]([O:42]CC)=[O:41])[CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1.[OH-].[Na+].Cl.O>O1CCOCC1>[O:52]=[S:2]1(=[O:1])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:32])([CH3:33])[C:21]([C:34]2[CH2:39][CH:38]4[CH:36]([CH:37]4[C:40]([OH:42])=[O:41])[CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4CC3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C

Procedure:
To a solution of ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S)2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate (28 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was added sodium hydroxide (1N) (0.149 mL, 0.149 mmol). The mixture was warmed to 70° C. After heating the mixture for 16 h, it was cooled to rt and was acidified by adding 1 mL of 1N HCl. Then water was added until solids formed. The solids were collected by filtration, dissolved in 1,4-dioxane and methanol and purified by prep HPLC (method 12) to afford 3-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-((2-((1R,4R)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylic acid as two different isomers (isomer 1, 16.5% and isomer 2, 11.5%)
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CO>[ClH:26].[CH2:1]([C:8]1[S:12][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(Cc3ccccc3)s2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(Cc2cnc(C3CCNCC3)s2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 37 mg of 4-(5-benzyl-thiazol-2-yl)-1-t-butyloxycarbonyl-piperidine (from Step B) was added 4 ml of a saturated solution of hydrochloric acid in methanol. The reaction was stirred for 3.5 hours at room temperature. The methanol was evaporated under reduced pressure to give 24 mg of the title compound. ESI-MS 259 (M+H); HPLC A: 2.00 min.
Reaction SMILES: [CH3:1][N:2]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:2]([CH3:1])[C:3]2([C:6]([NH:46][CH2:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([C:36]4[CH:37]=[CH:38][C:33]([O:32][C:31]([F:30])([F:47])[F:48])=[CH:34][CH:35]=4)[CH:40]=3)=[O:8])[CH2:4][CH2:5]2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CN(C1(C(=O)NCc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Acid 15A (350 mg, 1.28 mmol) was dissolved in 5 ml of THF and at rt DEPC (0.25 mL, 1.3 mol eq) and [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.376 g, 1.1 mol eq) were added to the solution. The mixture was stirred at rt overnight then evaporated. he residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded 100 mg of a white solid. Yield=15% 1HNMR (DMSO, 200 MHz) δ 1.09 (2H, bs), 1.34 (2H, bs), 3.00 (3H, s), 4.35 (2H, d, J=5.8 Hz), 7.43 (8H, m), 7.81 (4H, m), 8.17 (1H, bt); [M+1] 523.9 (C25H22F4N2O4S requires 522.51).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21]CC=C)=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH2:5][CH2:4]1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH2:4][CH2:5]1)#[N:2]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C2(C#N)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2cccc(C3(C#N)CC3)c2)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (375 mg, 0.98 mmol) and morpholine (0.8 mL, 9.2 mmol) in THF (8 mL) was degassed and then Pd(PPh3)4 (117 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH 4. The precipitate was collected and washed with water to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:30])[N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([Mg]Cl)([CH3:35])([CH3:34])[CH3:33].[Cl-].[NH4+]>C1COCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:3](=[O:2])[C:4]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: COC(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a solution of 0.16 g (0.38 mmol) of 5 in anhydrous THF (2 mL) was added dropwise at −78° C. a 2.0M solution of 0.21 mL (0.42 mmol) of tert-butyl magnesium chloride in THF, and the mixture was stirred for 3 hours at −78° C. The solution was poured over saturated ammonium chloride (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:4) to yield 0.13 g (76.5%) of 6 as a clear oil. TLC Rf=0.62 (EtOAc/Hexanes, 1:4) 1H NMR (CDCl3, 300 MHz): δ 1.40 (s, 9H); 1.36–2.29 (m, 9H); 2.62–2.82 (m, 4H); 3.39–3.52 (m, 2H); 5.18 (m, 1H); 5.31 (d, 1H, J=6.2); 5.42 (d, 1H, J=5.2); 7.42–7.26 (m, 10H); Anal. (C29H37NO3) C, H, N.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:12](C(O)=O)[C:11]2=[O:25].C1(P([N:40]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.O1CCOCC1>C(O)(C)(C)C>[NH2:40][C:12]1[C:11](=[O:25])[C:10]2[C:15](=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][CH:9]=2)[O:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCOCc1cccc2c(=O)c(C(=O)O)c(-c3ccccc3)oc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Nc1c(-c2ccccc2)oc2c(CO)cccc2c1=O

Procedure:
8-Methoxymethoxymethylflavone-3-carboxylic acid was reacted with diphenylphosphoryl azide and then with t-butanol. The resultant product was hydrolyzed with aqueous hydrochloric acid-dioxane to give 3-aminoflavone-8-methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCBr)cc1
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Compound 13-1 (690 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.33 g) and N-bromosuccinimide (899 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (830 mg) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:13][Mg+].[Br-]>CCOCC>[OH:1][C:2]1([CH3:13])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCOC(=O)N1CCC(C)(O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
At −30° C. and under N2 atmosphere, to a solution of ethyl 4-oxopiperidine-1-carboxylate (282) (6.0 g, 35.1 mmol) in anhydrous Et2O (100 mL) was added MeMgBr (3.0 M, 14 mL, 42.1 mmol). The resulting mixture was stirred at 0° C. for 2 hours before being quenched with aqueous NH4Cl solution. The mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo and subjected to silica flash column chromatography using 0 to 50% EtOAc in PE (petroleum ether) to isolate ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (4 g, 61%) as an oil.