Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:54][C:55]1[N:60]=[C:59]([CH3:61])[C:58]([S:62](Cl)(=[O:64])=[O:63])=[CH:57][CH:56]=1.Cl>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:58]1[C:59]([CH3:61])=[N:60][C:55]([Cl:54])=[CH:56][CH:57]=1)(=[O:64])=[O:63])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Cc1nc(Cl)ccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(Cl)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 79.8 %

Procedure:
(S)-2-({(S)-7-(6-Chloro-2-methyl-pyridine-3-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (80 mg) was prepared from (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (80 mg) and 6-Chloro-2-methyl-pyridine-3-sulfonyl chloride (29 mg) according to General Procedure E (except that the 1 N HCl wash was omitted). LCMS (m/z) 937.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: COc1ccccc1Br
Product: CCCCCCNc1ccccc1OC
Yield: 88.8 %

Procedure:
Using the general procedure, 2-bromoanisole (125 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol) at 100° C. for 22 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (30:1) as eluent afforded the desired product as a colorless liquid (184 mg, 89% yield). Rf=0.4 (hexane/ethyl acetate=20:1).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH2:9][CH3:10])([CH2:7][OH:8])[N:6]=1.[C:11](O)(=[O:15])[CH2:12][CH2:13][CH3:14]>>[CH3:1][C:2]1[O:3][CH2:4][C:5]([CH2:9][CH3:10])([CH2:7][O:8][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CCC1(CO)COC(C)=N1
Reactant: CCCC(=O)O
Product: CCCC(=O)OCC1(CC)COC(C)=N1

Procedure:
The 2-methyl-4-ethyl-4-hydroxymethyl-2-oxazoline is reacted with butyric acid in a 1:1 molar ratio following the method of Purcell to produce 2-methyl-4-ethyl-4-butyryloxymethyl-2-oxazoline.
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:26]([O-])=O)=[N:9][CH:10]=[C:11]([CH:25]=1)[C:12](OCC1C(C)=CC=CC=1CC)=[O:13])[CH3:2].[NH3:34]>CO>[NH2:26][C:8]1[C:7]([O:6][CH2:5][C:4]2[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:3]=2[CH2:1][CH3:2])=[CH:25][C:11]([C:12]([NH2:34])=[O:13])=[CH:10][N:9]=1
Reactant: CCc1cccc(C)c1COC(=O)c1cnc([N+](=O)[O-])c(OCc2c(C)cccc2CC)c1
Reactant: N
Solvent: CO
Product: CCc1cccc(C)c1COc1cc(C(N)=O)cnc1N
Temperature: 35 °C
Reaction time: 96 h
Yield: 31 %

Procedure:
2-ethyl-6-methylbenzyl 5-(2-ethyl-6-methylbenzyloxy)-6-nitronicotinate (0.7 g, 2 mmol) was added to a solution of ammonia in methanol (5-10%)(40 ml) and the mixture was stirred at 35° C. for 96 h. The solvent was evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel using ethylacetate:methylene chloride (1:1) and methanol:methylene chloride (1:9) as eluent gave 0.14 g (31%) of the title compound.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A mixture of 500 mg (0.90 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)] in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature and under an atmosphere of nitrogen for 30 minutes, and then the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and then the solvent was removed by distillation under reduced pressure. The same operation was repeated in total three times. The resulting residue was dried by evaporation under reduced pressure for 8 hours, and then the residue was suspended in 10 ml of anhydrous tetrahydrofuran. 275 mg (0.92 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension, and then 0.15 ml (0.99 mmoles) of diethyl cyanophosphate and 0.42 ml (3.01 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure and the residue was purified by silica gel thin layer chromatography (using an 8:1 by volume mixture of methylene chloride and methanol as the developing solvent) and then recrystallization of the product from ethyl acetate, to give 500 mg (yield 78%) of the title compound as white crystals, melting at 150°-152° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:27][CH:28]([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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(O)C>[F:27][CH:28]([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:17]2[C:16]([CH3:19])=[N:15][N:14]3[C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[CH:10][C:11]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][OH:26])=[N:12][C:13]=23)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(C(F)F)cc1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
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: CCO
Solvent: Cc1ccccc1
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
(S)-(1-(7-(3,5-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (55 mg), 4-(difluoromethyl)phenylboronic acid (34 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred at 85° C. for 4 hours under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (51 mg).
Reaction SMILES: C(O[C:9]([N:11]([CH:13]([CH:31]([CH3:33])[CH3:32])[C:14]([NH:16][CH:17]([CH3:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15])C)=O)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:26]([C:21]1[CH:20]=[C:19]([CH2:18][CH:17]([NH:16][C:14](=[O:15])[CH:13]([NH:11][CH3:9])[CH:31]([CH3:32])[CH3:33])[CH3:30])[CH:24]=[CH:23][C:22]=1[OH:25])([CH3:27])([CH3:29])[CH3:28]
Reactant: [H][H]
Reactant: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC(C(=O)NC(C)Cc1ccc(O)c(C(C)(C)C)c1)C(C)C

Procedure:
A suspension of 0.54 g (1.19 mmol) of 2-[N-(benzyloxycarbonyl)-N-methylamino]-N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methylbutanamide and 0.10 g of a 20% palladium hydroxide on carbon catalyst in methanol (8 ml) was stirred in a hydrogen atmosphere for 2 hours. After filtering off the catalyst, the solvent was distilled off under reduced pressure to give N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methyl-2-(methylamino)butanamide in the amount of 0.36 g (95%).
Reaction SMILES: [C:1]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[C:1]([NH:20][CH2:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C1(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
Tritylamine (180 mg, 0.00068 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.170 g, 0.000568 mol, this was prepared by using procedures analogous to that described for the synthesis of example 1, steps 1-2) in 1,2-dichloroethane (4.0 mL, 0.051 mol) and followed by sodium triacetoxyborohydride (0.36 g, 0.0017 mol) and the mixture was stirred overnight. The mixture was poured into pre-cooled water, and extracted with ethyl acetate. The organic layer was separated, dried (NaSO4), and concentrated in-vacuo. The product was purified by CombiFlash eluting with hexane/EtOAc (max EtOAc 20%). LC-MS: 543.3 (M+H)+; 243.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:37]2[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=2)[CH2:40]Cl)[CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([C:29]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH:38]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(C(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (689 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(N)nc3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.30 g, 0.75 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.248 g, 1.13 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.040 g, 11%). MS (ISP) 413.2 [(M+H)+]; mp 191° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.[CH2:15]([S:22][CH2:23][C@@H:24]1[CH2:28][C@@H:27]([S:29]CC2C=CC(OC)=CC=2)[CH2:26][N:25]1[S:39]([CH3:42])(=[O:41])=[O:40])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:15]([S:22][CH2:23][C@H:24]1[N:25]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:26][C@H:27]([SH:29])[CH2:28]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CSCc3ccccc3)N(S(C)(=O)=O)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1CSCc1ccccc1
Temperature: 80 °C
Yield: 20.5 %

Procedure:
(TFA/triethylsilane for not labile methoxy-benzylsulfanyl, Method 2): 100 mg (0.23 mmol) of (2S,4R)-2-benzylsulfanylmethyl-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine was dissolved in 8.2 ml TFA and treated at 0° C. with 0.35 ml (2.38 mmol) triethylsilane. The reaction was warmed up over night, heated 2.5 min at 80° C. and evaporated. Flash silica gel column (CH2Cl2/EtOAc 99:1) gave 15 mg (21%) of (3R,5S)-5-benzylsulfanylmethyl-1-methanesulfonyl-pyrrolidine-3-thiol, mp 101.5-103.5° C., MS: 318 (MH+).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[O:30][CH3:31])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@:18]12[CH2:19][C:20](=[O:52])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]/[C:17]/2=[N:29]\[O:30][CH3:31]
Reactant: CO/N=C1\C[C@H]2[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCCC[C@]12O
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CO/N=C1\C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Yield: 80 %

Procedure:
The title compound II-bn was prepared in 80% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone/CH2Cl2 60/20/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 5.47 (s, 1H), 3.75 (s, 3H), 3.02 (dd, 1H), 2.79 (d, 1H), 2.45-1.13 (m, 17H), 0.95 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:15]([C:16]1[C:17]([CH3:19])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)COc1cccc(N)c1C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)C)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 2-amino-6-isobutoxybenzonitrile (Example 41b, 16.4 g, 86.32 mmol) and ethyl acetoacetate (10.9 mL, 86.32 mmol) in anhydrous toluene (200 mL) was added SnCl4 (19.9 mL, 172.63 mmol) over a period of 15 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 3.5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜110 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a white solid (18.0 g, 69%). MS 303 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)[N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[CH:6][N:7]=1.NN.C(Cl)Cl>CCO>[Cl:1][C:2]1[C:3]([CH:8]([NH2:9])[C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl

Procedure:
A solution of 2-[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-isoindole-1,3-dione (1.536 g, 3.22 mmol) and anhydrous hydrazine (335 μL, 342 mg, 10.7 mmol) in EtOH (2 mL)/CH2Cl2 (12 mL) is stirred at rt overnight. The white precipitate formed is filtered off and washed with CH2Cl2. The combined filtrate and washings are concentrated in vacuo, the residue is suspended in CDCl3 and filtered (0.45 μM pore size), and the filtrate is concentrated in vacuo to obtain the title compound as yellow foam, which is used for the next step without further purification; 1H NMR (CDCl3, 400 MHz): δ2.4 (brs, 2H), 5.79 (s, 1H), 7.43-7.55 (m, 3H), 7.61 (dd, J=1.8, 8.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 8.10-8.15 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H); MS (ES+):m/z347.0/349.0(30/10) [MH+], 330.0/332.0 (18/6) [MH+-NH3]; HPLC: tR=2.1 min (MicromassZQ, polar—5 min).
Reaction SMILES: [OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH3:29].[OH-].[Na+]>CO.O1CCCC1>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[C:3]([NH2:29])=[O:4]
Reactant: N
Reactant: COC(=O)C(O)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
Methyl 2-hydroxy-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (754 mg, 1.98 mmol) obtained in Example 35 was dissolved in methanol-tetrahydrofuran (1:1, 6 ml). 28% Aqueous ammonia (3 ml) was added and the mixture was stirred at room temperature for 2 days. Thereto was added 1N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred for 1 hr. The reaction mixture was partitioned between tetrahydrofuran-ethyl acetate (1:1, 30 ml) and water (10 ml). The organic layer was washed with saturated brine (10 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (700 mg, yield 96%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:13]=1.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:8]=3[C:7]=2[CH:13]=1
Reactant: CCCNCCC(=O)OC
Reactant: COc1ccc2c(c1)CC(=O)CO2
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CCC(=O)C2=C1COc1ccc(OC)cc12

Procedure:
A mixture of 8.9 g of 6-methoxy-2H-[1]-benzopyran-3-one, 7.46 g of methyl 3-(propylamino)-propionate, 0.8 ml of trifluoroacetic acid in 80 ml toluene is refluxed for 7 hours in a Dean Stark apparatus; additional 0.8 ml portions of trifluoroacetic acid are added at 2, 4 and 6 hours. The reaction mixture is cooled and the solvent is removed in vacuo. The residue is crystallized from ether/methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-1-one, m.p. 97°-100°.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:27]([N:34]1[CH2:38][CH:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH:36]([CH:47]=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:35][CH:36]([CH:47]=[CH2:2])[CH:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of methyltriphenylphosphonium iodide (5.53 g, 0.0136 mol) in THF (50 mL) was added n-BuLi (1.6N in heptane, 6.5 mL, 0.0104 mol) dropwise at 0° C. and stirred for one hour. To this reaction mixture was added a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbaldehyde 2.68 g (0.008 mol) in THF (15 mL) dropwise at 0° C. and stirred for another one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dried on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (4: 1) yielding 2.12 g (80%) of the title compound as a light yellow oil. ES-MS m/e: 332.1 (M+H+).