Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:12]=[C:13]([OH:18])[C:14](=[CH:16][CH:17]=3)[OH:15])[N:10]=[C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=1.CC(O[CH2:24][C:25]1[CH2:34][S:33][C@@H:28]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:27]2[C:26]=1[C:35]([OH:37])=[O:36])=O.S1(CCCC1)(=O)=O.B(F)(F)F.CCOCC>ClCCl>[NH2:32][C@@H:29]1[C:30](=[O:31])[N:27]2[C@@H:28]1[S:33][CH2:34][C:25]([CH2:24][S:1][C:2]1[N:7]3[N:8]=[C:9]([C:11]4[CH:17]=[CH:16][C:14]([OH:15])=[C:13]([OH:18])[CH:12]=4)[N:10]=[C:6]3[N:5]=[C:4]([CH3:19])[CH:3]=1)=[C:26]2[C:35]([OH:37])=[O:36]
Reactant: Cc1cc(S)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
4-(7-Mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)pyrocatechol (1.8 g) and 1.63 g of 7-amino-cephalosporanic acid are suspended in 30 ml of a 1:1 mixture of dichloromethane and sulpholane. 2.63 g of boron trifluoride etherate are added thereto at 3° C. and the solution is left at the same temperature for 11/2 hours. Thereafter, it is diluted dropwise with 60 ml of dichloromethane, the resulting precipitate is filtered off under suction, rinsed with diethyl ether and dissolved immediately in 40 ml of water. Sufficient 20% aqueous sodium hydroxide solution is added while cooling with ice until pH 3.1 has been reached, whereby the product precipitates. This is filtered off under suction, washed with a small amount of water and finally with 20 ml of acetone and dried in a vacuum at 0.1 mmHg. There are obtained 2.17 g of (6R,7R)-7-amino-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7 -yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=CC1CCOCC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)cc1

Procedure:
4-Aminobenzenesulfonamide (6.80 g), tetrahydropyran-4-carboxaldehyde (4.96 g), and sodium triacetoxyborohydride (16.74 g) in tetrahydrofuran (300 mL) and acetic acid (15 mL) were stirred at room temperature for 24 hours. The reaction was concentrated and taken up in ethyl acetate. The resulting solution was washed with water and brine, concentrated, and chromatographed on silica gel with 50% ethyl acetate/hexanes.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:20][CH2:21][O:22][CH3:23]>O1CCCC1>[CH3:23][O:22][CH2:21][CH2:20][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COCCBr
Reactant: COC(=O)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of lithium diisopropylamide (2.0 M, 20 mL) in tetrahydrofuran (20 mL) was added methyl cyclohexanecarboxylate (5.0 g) in tetrahydrofuran (30 mL). The mixture was stirred at −78° C. for 30 minutes and a solution of 1-bromo-2-methoxyethane (5.86 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred overnight and the temperature was allowed to warm up to room temperature. The mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate (200 mL) and washed with water (3×), brine and dried over Na2SO4. Filtration and evaporation of solvent gave crude product which was used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@@H:12]([CH:14]=[O:15])[CH3:13])=[CH:3]1.[BH4-].[Na+]>C(O)C>[OH:15][CH2:14][C@@H:12]([CH3:13])[C@@H:11]1[C@:16]2([CH3:24])[C@H:8]([C@H:7]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C:4](=[CH:3][C:2](=[O:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -10 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
i)—A solution of (20S)-3-oxopregn-4-ene-20-carboxaldehyde (2) (125 g) in dry ethanol (1250 ml) was cooled to −10° C., whereupon a solution of sodium borohydride (4.4 g) in dry ethanol (80 ml) was added in 30 min. After stirring the mixture for 2 h at −10° C., the reaction was quenched by adding a 50% aqueous solution of acetic acid. The reaction mixture was concentrated under reduced pressure to 25% of its original volume and then poured into ice-water (5 l). The resulting suspension was stirred overnight and filtered. The residue was washed with water and dried to give (20S)-21-hydroxy-20-methylpregn-4-en-3-one (3) (124 g) which was used in the following step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:25])[C:12]=2[NH:13][C:14](=[O:24])[O:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[CH2:33][CH:32]1CC)=[O:30])[CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:37]=[C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:9]=[N:10][N:11]([CH3:25])[C:12]=4[NH:13][C:14]([O:15][C@@H:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:17])=[O:24])=[CH:4][CH:3]=3)[CH:39]=[CH:40][CH:41]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1CC
Reactant: C[C@@H](OC(=O)Nc1c(-c2ccc(Br)cc2)nnn1C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2cccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mixture of (R)-1-phenylethyl 4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazol-5-ylcarbamate (120 mg, 0.3 mmol), ethyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylic acid ethyl ester (142 mg, 0.449 mmol), palladium(II) acetate (10.1 mg, 0.05 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (36.8 mg, 0.1 mmol), and potassium phosphate tribasic (190 mg, 0.9 mmol) in a vial were added toluene (2.25 mL) and water (0.5 mL) at room temperature under nitrogen atmosphere. The resulting light brown suspension was disconnected from the nitrogen line and the reaction mixture was heated to 105° C. and the progress of the reaction was followed by TLC analysis and it was completed after 1 h at this temperature. Then, it was cooled to room temperature and diluted with water and ethyl acetate. The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude compound which was purified using an ISCO (40 g) column chromatography eluting with 0-70% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain (R)-1-(4′-(1-methyl-5-((1-phenylethoxy)-carbonylamino)-1H-1,2,3-triazol-4-yl)biphenyl-3-yl)cyclopropanecarboxylic acid ethyl ester as a white solid (94 mg, 61% yield). LC/MS calcd. for C30H30N4O4 (m/e) 510.0, obsd. 511.1 (M+H, ES+).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH2:19][C@H:20]([NH:32]C(OC(C)(C)C)=O)[C:21]([O:23][C@H:24]([CH3:31])[C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:22])[CH:10]=[CH:11][C:12]=1[O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:32][C@@H:20]([CH2:19][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)[C:21]([O:23][C@H:24]([CH3:31])[C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:22]
Reactant: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)[C@@H](C)OC(C)=O)cc1OC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)[C@@H](C)OC(C)=O)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
(1R,2R)-2-Acetyloxy-1-methylpropyl(2S)-3-[3,4-bis(ethoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (35) (0.6 g, 1.1 mmol) was dissolved in 10 mL of 4M HCl in 1,4-dioxane. The mixture was stirred at room temperature for 60 min. Dioxane was evaporated under reduced pressure. The colorless oil was further dried under vacuum to give 0.6 g (96% yield) of the title compound (31). 1H NMR (400 MHz, CD3OD): δ 1.16 (d, J=7.8 Hz, 3H), 1.18 (d, J=7.8 Hz, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 2.03 (s, 3H), 3.23 (dd, J=14.0, 6.8 Hz, 1H), 3.27 (dd, J=14.0, 6.8 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H), 4.40 (t, J=6.8 Hz, 1H), 4.94 (m, 1H), 5.05 (m, 1H), 7.26 (dd, J=8.0, 2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H). MS (ESI) m/z 456.2 (M+H)+ and 454.0 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([CH3:33])([CH3:32])[C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCO.C(OCC)C>CCO>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[C:16]([CH3:33])([CH3:32])[C:17]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C(C)(C)C(=O)N3Cc2cccc(F)c2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)C(=O)N(Cc2cccc(F)c2)c2cccc(N3CCNCC3)c21

Procedure:
4-[1-(3-Fluoro-benzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (260 mg) was dissolved in 3 mL of EtOH and 0.5 mL of 2.0 N HCl/EtOH was added. After heating for 30 minutes at reflux, the solution was cooled and diethyl ether was added to precipitate out 1-(3-Fluoro-benzyl)-3,3-dimethyl-4-piperazin-1-yl-1,3-dihydro-indol-2-one as a hydrochloride salt (121 mg). MS: 354 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH2:4][C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)[NH2:2].[CH:22](OCC)(OCC)OCC.S(=O)(=O)(O)O>>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]3[CH:22]=[N:2][N:1]=[C:3]3[CH2:4][C:5](=[O:21])[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:13]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Agent: O=S(=O)(O)O
Product: O=C1Cc2nncn2-c2ccc(Cl)cc2N1c1ccccc1
Reaction time: 0.5 h

Procedure:
2-Hydrazino-7-chloro-4,5-dihydro-5-phenyl-3H-1,5-benzodiazepin-4-one is heated with triethyl orthoformate and concentrated sulfuric acid. The mixture is stirred for 30 minutes to give 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepine-5(6H)-one.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][CH2:8][C:9]1[O:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[CH:41]=[CH:40][C:19]([C:20]([N:22]([CH3:39])[C@:23]([CH3:38])([C:28]([NH:30][O:31]C3CCCCO3)=[O:29])[C:24]([NH:26][CH3:27])=[O:25])=[O:21])=[CH:18][CH:17]=2)[CH:10]=1.C(=O)([O-])O.[Na+].[Cl-].[Na+]>O.C(OCC)(=O)C.O1CCOCC1>[OH:31][NH:30][C:28](=[O:29])[C@:23]([N:22]([C:20]([C:19]1[CH:40]=[CH:41][C:16]([C:15]#[C:14][C:11]2[CH:10]=[C:9]([CH2:8][O:7][CH3:6])[O:13][CH:12]=2)=[CH:17][CH:18]=1)=[O:21])[CH3:39])([CH3:38])[C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2coc(COC)c2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@](C)(C(=O)NO)N(C)C(=O)c1ccc(C#Cc2coc(COC)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
A 1 mol/L sulfuric acid aqueous solution (2.6 mL) was added dropwise, under water cooling, to a 1,4-dioxane (4.0 mL) solution of (2S)-2-[(4-{[5-(methoxymethyl)furan-3-yl]ethynyl}benzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.43 g) as obtained in Example 18-(4), and the mixture was stirred for 3 hours and 45 minutes at room temperature. Ethyl acetate and water were added, and the mixture was adjusted to pH 6 with a saturated aqueous solution of sodium hydrogen carbonate. Then, sodium chloride was added, and the organic layer was isolated. The extract was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=100/0→80/20) to obtain (2S)-N-hydroxy-2-{[(4-{[5-(methoxymethyl)furan-3-yl]ethynyl}phenyl)carbonyl](methyl)amino}-N′,2-dimethylpropanediamide (Compound 550, white solid) (0.25 g, 68%).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[CH3:9][O:10][C:11]1[C:22]([O:23]C)=[CH:21][C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:13]=2[C:12]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NC(C(O)=O)CCSC.CS(O)(=O)=O>>[OH:23][C:22]1[C:11]([O:10][CH3:9])=[C:12]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15][C:14]=2[CH:21]=1
Reactant: COc1cc2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Agent: O=C(O)/C=C/C(=O)O
Product: COc1c(O)cc2c(c1Sc1ccccc1)CCN(C)CC2
Yield: 87 %

Procedure:
A mixture of 2.6 g. (0.008 mole) of 7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 3) and 1.26 g. (0.0085 mole) of dl-methionine in 35 ml. of methanesulfonic acid was stirred at room temperature for 3.5 hours. The reaction mixture was quenched with ice/water, made basic with 10% sodium hydroxide solution to pH 8.5 and extracted with chloroform. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give 2.18 g. (87% yield) of 8-hydroxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 161°-162° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH:37][CH3:38]>>[CH3:36][N:37]([CH3:38])[C:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)[N:24]=1)=[O:26]
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CNC
Product: C[C@@H](c1ccc(-c2cccc(C(=O)N(C)C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=502 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](Cl)=[N:10][N:9]=1>CO>[CH3:6][O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[N:10][N:9]=1
Reactant: COc1nnc(Cl)c2c1CCCC2
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OC)c2c1CCCC2

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.99 g(0.01 mol) of 1-methoxy-4-chloro-5,6,7,8-tetrahydro-phthalazine obtained from Preparation 6. The reaction solution was refluxed for one hour and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[C:20]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(P(N(C)C)(N(C)C)=O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:28][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)c1ccccc1

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [4.0 g; prepared as hereinbefore described in Example 1(iv)] and benzoylmethylenetriphenylphosphorane (5.6 g; prepared according to the method of F. Ramirez and S. Dershowitz, J. Org. Chem. 1957, 22, 41) in hexamethylphosphotriamide (35 ml.) was heated on a steam bath under dry nitrogen for 48 hours then poured into water (200 ml.). The mixture was extracted with diethyl ether and the ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether, allowed to stand at 0° C., then filtered to remove triphenylphosphine oxide. The filtrate was evaporated to give 6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane (5.5 g.) (νmax 950 cm-1, 985 cm-1, 1615 cm-1, 1660 cm-1, 3380 cm-1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[F:17])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>CN(C)C=O>[CH3:25][Si:26]([CH3:28])([CH3:27])[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[F:17])[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 70 °C
Yield: 86 %

Procedure:
The mixture of 4-(4-oxo-piperidin-1-yl)-3-fluoronitrobenzene (0.250 mol), triethylamine (1.250 mol), trimethylsilylchloride (0.750 mol) in dimethylformamide was heated at 70° C. for 24 h. The solvent was removed under vacuum and to the residual mass was extracted with the ethyl acetate water mixture. The combined organic layer was dried and after removal of the solvent afforded title compound as a solid in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[C:9]([Cl:22])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[Cl:22][C:9]1[CH:10]=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([F:40])([F:39])[F:41])[CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:29]=2)[CH:12]=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7]
Reactant: O=C(c1ccc(Br)cc1)N1CCC(C(F)(F)F)CC1
Reactant: CC(=O)OCc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: CC(=O)OCc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Dissolve 18.5 g (1 eq.) of Acetic acid 2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester and 19.9 g (1.1 eq.) of (4-Bromo-phenyl)-(4-trifluoromethyl-piperidin-1-yl)-methanone in 190 mL of dimethoxyethane. Add 8.9 g of potassium carbonate, 95 mL of water, 0.24 g (0.02 eq.) of palladium acetate and 0.85 g (0.06 eq.) of triphenylphosphine. Heat the mixture at 80° C. for 2.5 hours. Stir the reaction mixture at room temperature overnight to afford a suspension. Add 7.4 g of potassium carbonate, 100 mL of water and 100 mL of methanol and stir the mixture at room temperature for 3 hours. Collect the solid by filtration and dry in a vacuum oven at 50° C. to afford 20.8 g (82% yield) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=O)=[CH:5]2.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:25][C@@H:24]3[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@@H:23]3[CH2:22]2)=[N:19][CH:20]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][NH:29][C@@H:26]1[C@@H:24]3[C@@H:23]([CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([C:14]([F:31])([F:30])[F:13])=[CH:20][N:19]=4)[CH2:25]3)[CH2:28][CH2:27]1)=[CH:5]2
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc2[nH]c(CN[C@H]3CC[C@@H]4CN(c5ccc(C(F)(F)F)cn5)C[C@@H]43)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared by combining 5-fluoro-1H-indole-2-carbaldehyde (30.1 mg, 0.184 mmol) and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine (50 mg, 0.184 mmol) from Example 262 Step B in dichloromethane (0.2 mL) to give a colorless solution. 0.2 mL of acetic acid was added. The reaction was stirred at ambient temperature for 30 minutes, then PS-cyanoborohydride (166 mg, 0.369 mmol) was added. After 18 hours, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified using a 12 g silica gel cartridge eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 12.14 (s, 1H), 8.64 (dd, J=1.5, 0.7, 1H), 7.69 (dd, J=8.9, 2.5, 1H), 7.54-7.46 (m, 2H), 7.14-7.07 (m, 1H), 6.61 (d, J=1.2, 1H), 6.36 (d, J=8.9, 1H), 4.12-4.00 (m, 2H), 3.56 (ddd, J=21.0, 9.4, 3.4, 2H), 3.48-3.40 (m, 1H), 3.28 (ddd, J=3.7, 2.1, 0.9, 1H), 3.04 (dd, J=11.0, 5.8, 1H), 2.78-2.68 (m, 1H), 2.57-2.50 (m, 1H), 2.31-2.04 (m, 1H), 2.02-1.91 (m, 2H), 1.55-1.44 (m, 1H), 1.38-1.28 (m, 1H); MS (ESI+) m/z 419 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:19])[C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13].[CH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])=[O:21]>O1CCCC1>[CH3:9][O:10][C:11](=[O:19])[CH:12]([NH:13][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH:20]=[O:21])[CH:23]=1)[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)c1cccc(C=O)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.4 %

Procedure:
A mixture of 30 ml of tetrahydrofuran, 12 ml of triethylamine and 4.11 g of aspartic acid dimethyl ester hydrochloride was added dropwise to a solution of 3.50 g of 3-formylbenzoic acid chloride in 30 ml of tetrahydrofuran at 10° C. After stirred at room temperature for 6 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3.01 g of oily 2-[3-formyl-(benzoylamino)]succinic acid dimethyl ester [Compound No. (p)].