Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
In a reactor under nitrogen atmosphere, 200 mL of THF was added to 41.2 g of methyltriphenylphosphonium bromide, and the mixture was cooled to −20° C., to which 12.9 g of t-BuOK was added, followed by stirring for 1 hour. A solution containing 15.0 g of 1.4-dioxaspiro[4.5]decan-8-one dissolved in 200 mL of THF was added dropwise thereto, followed by stirring at −20° C. for 1 hour. The temperature of the reaction mixture was increased to room temperature, and 200 mL of water was added to the reaction mixture, followed by extracting three times with 300 mL of toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated to about 200 mL under reduced pressure, and the concentrated solution was placed in 1,000 mL of hexane, followed by removing deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 10.6 g of 8-methylene-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([O:32][CH2:33][C:34]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:6]=2)[CH2:1]1)=[O:35])(=[O:31])[CH3:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COC(C)=O)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A solution of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 1, Step 6, 350 mg, 1.21 mmol) and triethylamine (0.252 mL, 1.81 mmol) in dry CH2Cl2 (6 mL) under N2 is cooled to 0° C. and treated with acetoxyacetyl chloride (0.156 mL, 1.45 mmol). The resulting mixture is stirred at 0° C. for 1 hr and is then warmed to ambient temperature, diluted with CH2Cl2 (20 mL), washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-3/97), and those fractions with an Rf=0.44 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 323 mg (69%) of the title compound as a glassy solid. An analytical sample is prepared by trituration and filtration from Et2O. MS (ESI+) for C19H23N3O6 m/z 390 (M+H)+; Anal. Calcd for C19H23N3O6: C, 58.60; H, 5.95; N, 10.79. Found: C, 58.46; H, 6.06; N, 10.66; [α]25D =−18° (c 0.93, DMSO).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[S:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].ClS([N:27]=[C:28]=[O:29])(=O)=O>C1(C)C=CC=CC=1>[C:28]([N:11]1[C:10](=[O:14])[C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[S:13][CH2:12]1)(=[O:29])[NH2:27]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2SCN(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 69.3 %

Procedure:
5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)thiazolidin-4-one (479 mg, 1.5 mmole) described in Kokai 62-42977 was suspended in dried toluene (3 ml), to which chlorosulfonyl isocyanate (144 μl; 1.65 mmole) was added with stirring under nitrogen atmosphere, to obtain a transparent solution of orange color. Furthermore, the solution was heated at 90° C. for 10 min., from which toluene was evaporated under reduced pressure, then 3.6 ml of mixed solution of acetic acid and water (2:1) was added thereto. The resulting mixture was heated at 90° C. for 10 min. and poured into ice-water, which was subjected to extraction with dichloromethane. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (chloroform:acetone=20:1), whereby 377 mg of the objective compound was obtained, which was recrystallized from ethanol-ether in 53% yield. The physical constants are described on Table 1.
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH2:6][SiH:7]([Cl:9])[Cl:8])[Cl:5]>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.C1C=CC=CC=1>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH2:6]1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C#C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl[Si]1(Cl)C=C[Si](Cl)(Cl)C1
Yield: 55.2 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)methane in the presence of Pd(PPh3)4. Into the same apparatus as described in Example 1 were placed 10 g of bis(dichlorosilyl)methane, 0.103 g of Pd(PPh3)4, and 20 ml of dried benzene. Acetylene gas was blown into the flask at 90 ml/min for 3 hours. The products were vacuum distilled at 67 Pa to yield a mixture comprising 8.29 g of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene (TCD-GC area 55.2%); 3,3,5,5-tetrachloro-3,5-disilapent-1-ene (TCD-GC area 12.7%); 1,1,3,3-tetrachloro-1,3-disilacyclopentane (TCD-GC area 5.3%); and 1,1,3,3,6,6,8,8-octachloro-1,3,6,8-tetrasilaoctane (TCD-GC area 0.3%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)nccc23)c1
Yield: 16.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-6, 100 mg, 0.329 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 133 mg, 0.493 mmol), oxalyl chloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (129 mg, 1.00 mmol) in CH2Cl2 (5 mL) to afford 31 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.22 (br t, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.98 (d, J=5.7 Hz, 1H), 7.82-7.67 (m, 6H), 7.55 (m, 2H), 7.39 (d, 1H), 4.34-4.32 (d, J=5.7 Hz, 2H), 1.14 (s, 9H); MS [M+H]+: 556.16.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@H:25]4[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2ccc(F)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanone (Intermediate 48; 197 mg; 0.45 mmol) in MeOH (15 mL) was added NaBH4 (34 mg; 0.90 mmol). The reaction mixture was stirred overnight, concentrated, and purified by preparative TLC (DCM/MeOH=20/1) to afford 32 mg (16%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8](=[O:21])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]([CH3:12])[CH3:11].C(OC(=O)C)(=O)C.CO>O1CCCC1>[CH3:12][CH:10]([C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:8](=[O:21])[CH:1]=[CH2:2])[CH3:11]
Reactant: CON(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: C=C[Mg]Br
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C=CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
Vinylmagnesium bromide (1M soln in THF, 34.6 mL, 34.6 mmol) was added to a solution of (R)-tert-butyl 1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (4.5 g, 17.30 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogen at −78° C., dropwise, over 20 min. The reaction was slowly warmed to 0° C. and then stirred for an hour at 0° C. The reaction warmed to room temperature and then stirred for 10 h. Acetic anhydride (10 mL) was added to the reaction mixture at 0° C. After several minutes methanol (10 mL) was added to the reaction. The mixture was allowed to stir for 10 min, and then concentrated to a volume of 25 mL. The reaction mixture was washed with water (100 mL) and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (2×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at less than 40° C. The resulting residue was purified by flash column chromatography on silica gel, eluting with 85:15 hexanes:ethyl acetate to provide (R)-tert-butyl 2-methyl-4-oxohex-5-en-3-ylcarbamate (2.52 g) as a white solid. 1H NMR (CDCl3): 6.50-6.32 (m, 2H), 5.85 (d, 1H), 5.22 (d, 1H), 4.56 (dd, 1H), 2.18 (m, 1H), 1.44 (s, 9H), 1.01 (d, 3H), 0.80 ppm (d, 3H).
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Na+].Cl[CH2:17][C:18](Cl)=[O:19]>O>[C:2]1([N:1]2[CH2:8][CH2:9][O:10][CH2:17][C:18]2=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: OCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1COCCN1c1ccccc1
Temperature: 41 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A 250-mL flask was charged with 2-anilinoethanol (9.17 ml, 73.2 mmol), 9 mL dry EtOH, an overhead stirrer, a calibrated pH probe, and 27 mL water. An addition funnel was charged with 10 N sodium hydroxide solution (45.4 ml, 454 mmol). The solution was heated to 41° C., and treated with chloracetyl chloride (17.5 ml, 220 mmol) via a syringe pump over 1 h. The sodium hydroxide solution was simultaneously added to the stirring solution so that the pH was maintained between 12 and 12.5. After the addition was complete, the solution was cooled to 0° C. and stirred for 1 h. The solids were collected and washed with water (2×60 mL cold water). The solids were dried at 50° C. at 0.2 mm Hg for 36 h to afford 4-phenylmorpholin-3-one (8.10 g, 62.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) 3.75-3.80 (m, 2H) 4.02-4.06 (m, 2H) 4.35 (s, 2H) 7.27-7.36 (m, 3H) 7.39-7.46 (m, 2H). 13C NMR (101 MHz, CHLOROFORM-d) 49.69 (s, 1C) 64.14 (s, 1C) 68.57 (s, 1C) 125.48 (s, 2C) 127.15 (s, 1C) 129.30 (s, 2C) 141.31 (s, 1C) 166.59 (s, 1C).
Reaction SMILES: C(C1C=CC=CC=1O)#N.[C:10]([C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][O:19][C:18](C)([CH3:21])[O:17]1)#[N:11].CCO.[BrH:30]>C(O)(=O)C>[C:10]([C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[O:14][CH2:15][C@@H:16]([O:17][C:18](=[O:19])[CH3:21])[CH2:20][Br:30])#[N:11]
Reactant: CC1(C)OC[C@@H](COc2ccccc2C#N)O1
Reactant: Br
Agent: N#Cc1ccccc1O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)O[C@@H](CBr)COc1ccccc1C#N

Procedure:
In the same way as in [H] but reacting 2-cyanophenol (7.1 g, 59.7 mmoles) with (S)-(+)-2,2-dimethyl-4-toxyloxymethyl-1,3-dioxolane (J. Org. Chem. 42, 1006 (1977)) (17.1 g, 59.7 mmoles) the (R)-(-)-4-(2-cyanophenoxymethyl)-2,2-dimethyl-1,3-dioxolane with [α]D (C=1, EtOH)=-30.18°, was obtained. The reaction of this compound (13.9 g, 59.6 mmoles) with 40% hydrobromic acid in acetic acid yields (R)-(-)-3-(2-cyanophenoxy)-2-acetoxy-1-bromopropane with [α]D (C=1, EtOH)=-15.9°.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=O)[CH:7]=[N:8][CH:9]=1.[OH:12][C:13]([CH3:18])([CH3:17])[C:14](=[O:16])[CH3:15]>CO.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:15]/[C:14](=[O:16])[C:13]([OH:12])([CH3:18])[CH3:17])[CH:7]=[N:8][CH:9]=1
Reactant: CC(=O)C(C)(C)O
Reactant: O=Cc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(O)C(=O)/C=C/c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (1.1 eq, 29.6 mmol, 29.6 ml) in MeOH (100 ml) under an inert atmosphere of nitrogen is cooled at 0° C. and treated with 5-bromo-pyridine-3-carbaldehyde (1 eq, 26.9 mmol, 5 g). After 1 h at 0° C., 3-hydroxy-3-methyl-butan-2-one (1 eq, 26.9 mmol, 2.75 g) is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is dissolved in EtOAc and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (0-50% EtOAc in iso-hexane) to afford the title compound; [M+H]+ 270/272.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.BrC1C=CC(C(OC)=O)=C(CBr)C=1.Cl.COC(=O)[C@H](C)N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: COC(=O)[C@H](C)N
Agent: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Product: COC(=O)[C@H](C)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 365 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and alanine methyl ester hydrochloride.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1)(=[O:7])[O:5][CH3:6]
Reactant: COC(=O)CCCCc1ccc2c(n1)NCCC2
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Reaction time: 0.75 h

Procedure:
A solution of dimethyl methylphosphonate (13.20 g, 106.5 mmol) in anhydrous THF (165 mL) was cooled to −78° and treated dropwise with 2.5 M n-BuLi (42.3 mL). After stirring at −78° for 45 min, a solution of ester 1-5 (6.6 g, 26.6 mmol) in THF (35 mL) was added dropwise and the resulting solution stirred for 30 min −78°, quenched with sat. NH4Cl (100 mL), then extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to afford a yellow oil. Chromatography on silica gel (5% MeOH/CH2Cl2) afforded 15-1 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([CH:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1)#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:33]([CH:30]3[CH2:31][CH2:32][CH:27]([C:25]#[N:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#CC1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(C#N)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(4-cyano-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 4-cyano-cyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 484.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([OH:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[C:27](Cl)(=O)C.C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([O:26][CH3:27])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CC(OC)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxyphenyl)-2-hydroxy-7-methyl-pyrrolo[2,3-h]chroman (5 mg; 0.012 mmol ) in methanol (0.5 ml) at 0° C. was added acetyl chloride (10 μl). The mixture was warmed to room temperature and stirred at this temperature for 3 h. Saturated sodium bicarbonate solution was added and the reaction mixture was extracted with dichloromethane. The extract was washed with saturated sodium chloride solution, dried and evaporated. The crude product was passed through bond-elute (hexane:ethyl acetate=9:1 as eluent), giving the title compound (3 mg; 58%). 1H NMR (acetone-d6): 7.14 (d, J=2.7 Hz) and 7.13 (d, J=2.9 Hz) (1H), 6.94-7.02 (m, 2H), 6.89 and 6.88 (d each, J=8.5 Hz, 1H), 6.50-6.57 (m, 2H), 5.32 (t, J=2.6 Hz) and 5.27 (dd, J=2.3, 7.6 Hz) (1H), 4.34 (dd, J=6.6, 9.5 Hz) and 4.27 (dd, J=6.0, 11.3 Hz) (1H), 3.85, 3.82, 3.81, 3.80, 3.79, 3.78 (s each, 9H), 3.59 and 3.50 (s each, 3H), 2.43 (ddd, J=2.3, 6.6, 13.3 Hz) and 2.12-2.30 (m) (2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.ClC1C=CC=C(C(OO)=O)C=1.[CH2:29]([N:31](CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(#N)C.CO>[CH3:1][C:2]1([CH3:17])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][C:11]([C:29]#[N:31])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1
Reactant: CCN(CC)CC
Reactant: Cc1ccnc2cc3c(cc12)OC(C)(C)C=C3
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C#N)nc2cc3c(cc12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (4.36 g, 19.3 mmol) in chloroform (43.6 mL), a solution of m-chloroperbenzoic acid (7.35 g, 42.6 mmol) in chloroform (17.4 mL)-methanol (4.36 mL) was added dropwise at room temperature and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, the reaction solution was extracted with sodium thiosulfate aqueous solution and the resulting organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, acetonitrile (19.3 mL), trimethylsilylnitrile (7.27 mL, 57.9 mmol) and triethylamine (5.38 mL, 38.6 mmol) were added to the residue at room temperature, and the resulting solution was stirred at 70° C. for 3.5 hours. Upon the completion of the reaction, sodium hydrogencarbonate aqueous solution was added to the reaction solution, and it was extracted with chloroform and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H](C2C=CC(OC)=CC=2)C)[CH:7]=1.[C:23](O)([C:25](F)(F)F)=O>>[NH:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6]1[CH:7]=[C:2]([C:2]2[C:23]3[C:25](=[CH:5][CH:6]=[CH:8][CH:12]=3)[NH:4][CH:3]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Reactant: O=C(O)C(F)(F)F
Product: c1ccc2c(-c3cncc([C@@H]4CCCN4)c3)c[nH]c2c1

Procedure:
A solution of 3-Bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine 3 (3.64 g, 10.0 mmole) in 5 mL of TFA was heated at 120° C. in a microwave reactor for 30 minutes. The resulting solution was concentrated to remove TFA. The residue was dissolved in 150 mL of CH2Cl2 and basicfied by 5 mL of saturated NaHCO3. The solution was washed by 2×10 mL of water, dried over Na2SO4 and concentrated to give 3-((S)-5-Pyrrolidin-2-yl-pyridin-3-yl)-1H-indole 4 (2.4 g, crude) as deep brown gum without further purification for the next step reaction.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([N:20]=[C:21]=[O:22])=[CH:14][C:13]=2[O:12]1>C1C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:21]([NH:20][C:15]3[CH:16]=[CH:17][C:18]4[O:19][CH2:11][O:12][C:13]=4[CH:14]=3)=[O:22])=[CH:4][C:3]=2[O:2]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: Nc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyaniline (0.35 g) and 3,4-methylenedioxyphenyl isocyanate (0.4 g) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0076B (0.697 g, 95%) as a pale brown solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>C(O)(C)(C)C.O.[C].[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O

Procedure:
A solution of 15.0 g of Z-Asn-Leu-OMe in 400 ml of tertiary butanol+water (9:1) is hydrogenated in the presence of 2 g of palladium carbon (10% Pd). On completion of the hydrogenation the catalyst is suctioned off and the filtrate evaporated at 40° C. The residue is further used as it is.