Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)COc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
To a stirred solution of 2-bromo-4-chlorophenol (3.38 g, 16.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (25 ml) under an atmosphere of nitrogen, was added cesium carbonate (8.0 g, 24.4 mmol). The mixture was cooled to 0° C. before addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.78 g, 16.3 mmol) drop-wise over 2 minutes. The reaction was allowed to warm to room temperature and stirred for 14 hours. To encourage complete reaction the reaction mixture was warmed to 120° C. for 3 hours. The reaction mixture was cooled to room temperature then water (50 ml) was added. The layers were separated and the aqueous was extracted with heptane (3×50 ml). All organic extracts were combined then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (4.20 g, 89%). Material was taken on without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36])[CH3:39]
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]([O:37][CH3:38])=[O:36])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]([O:37][CH3:38])=[O:36])([CH3:34])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 97 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 104b (0.7 g, 1.23 mmol) was reacted trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.75 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[N:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]N(C)C=O.S(OC)(OC)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[N:18][N:17]([CH3:23])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(n3cn[nH]c3=O)CC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1ccc(N2CCN(n3cnn(C)c3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 4.5 parts of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-3H-1,2,4-triazol-3-one, 0.8 parts of sodium hydride dispersion 78% and 27 parts of N,N-dimethylformamide is stirred for one hour at room temperature. Then there are added 2.5 parts of dimethyl sulfate and stirring at room temperature is continued for another hour. Water is added to the reaction mixture and the product is extracted twice with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 3.3 parts (71%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-methyl-3H-1,2,4-triazol-3-one; mp. 178.2° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([C:22]2([CH3:27])[CH2:26][CH2:25][NH:24][CH2:23]2)[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:3]1=[O:28].[CH:29]1([CH:33]=O)[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:29]1([CH2:33][N:24]2[CH2:25][CH2:26][C:22]([N:13]([CH2:12][C:4]3[C:3](=[O:28])[N:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])([CH3:27])[CH2:23]2)[CH2:32][CH2:31][CH2:30]1
Reactant: O=CC1CCC1
Reactant: Cn1c(=O)c(CN(C(=O)C2CCCCC2)C2(C)CCNC2)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)c(CN(C(=O)C2CCCCC2)C2(C)CCN(CC3CCC3)C2)cc2ccccc21
Reaction time: 2.5 h

Procedure:
N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(3-methylpyrrolidin-3-yl)cyclohexanecarboxamide (300 mg, 0.786 mmol), cyclobutanecarbaldehyde (99 mg, 1.180 mmol), and acetic acid (0.090 ml, 1.573 mmol) were combined in CH2Cl2 (70 ml). Sodium triacetoxyborohydride (333 mg, 1.573 mmol) was added and the reaction stirred for 2.5 hours. The reaction mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was purified in two batches by reversed phase chromatography (15-95% ACN in water (with 0.5 ml/l NH4OH) over 20 min at 50 ml/min, 30×100 mm Phenomenex Gemini C18 column). Desired fractions were combined and concentrated in vacuo. HRMS [M+H]1+ 450.3099. 1H NMR (400 MHz, CDCl3): δ 7.62-7.55 (m, 3 H); 7.42 (d, J=8.5 Hz, 1 H); 7.29 (t, J=7.6 Hz, 1 H); 4.44 (s, 2 H); 3.80 (s, 3 H); 2.99 (d, J=10.0 Hz, 1 H); 2.85 (d, J=10.2 Hz, 1 H); 2.53 (t, J=7.9 Hz, 1 H); 2.47-2.35 (m, 4 H); 2.09-1.92 (m, 5 H); 1.92-1.64 (m, 14 H); 1.28-0.99 (m, 3 H). 210 mg, 59%.
Reaction SMILES: [Li]CCCC.BrC1C=CC2OCOC=2C=1.C([Cu])#N.[S:19]([N:29]1CC1)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].B(F)(F)F.CCOCC.[NH4+].[Cl-]>C1COCC1>[CH3:26][C:25]1[CH:24]=[CH:23][C:22]([S:19]([NH2:29])(=[O:21])=[O:20])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC2)cc1
Agent: N#C[Cu]
Agent: Brc1ccc2c(c1)OCO2
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
n-BuLi (1.94 M in hexane, 10 mL) was added to a solution of 6-bromo-1,3-benzodioxol (16.6 mmol) in THF (65 mL) at -78° C. The reaction mixture was stirred for 40 min at -78° C. and CuCN (744 mg, 8.3 mmol) was added. After stirring at -78° C. for 1 h, a solution of aziridine 3 (1.27g, 3.95 mmol) in THF (10 mL) was added, followed by BF3.Et2O (0.40 mL). The reaction mixture was allowed to warm slowly to room temperature while stirring. After addition of saturated aqueous NH4Cl solution (10 mL), the organic layer was separated and the aqueous phase was extracted with ethyl acetate (4×10 mL). The combined organic layers were dried over Na2 SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2 /acetone, 12:1) to give tosylamide 5 (552 mg, 32%) as a white solid: mp 75°-76° C.; [α]D22 +44.6° (c 1.16, CHCl3); 1H NMR (200 NMz, CHCl3) δ 7.43 (d, J=8.2 Hz, 2H), 7.09 (d, J=8.2 Hz, 2H), 6.49 (m, 3H), 5.95 (m,3H), 5.76 (dd, J=9.9, 1.6 Hz, 1H), 5.34 (d, J=8.5 Hz, 1H), 4.61 (t, J=4.46 Hz, 1H), 4.13 (dd, j=9.1, 6.0 Hz, 1H), 3.51 (q, J=9.2 Hz, 1H), 3.13 (bd, J=9.8 Hz, 1H), 2.38 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H); 13C NMR (50 MHz, C6D6) δ 147.9 (C), 146,9 (C), 141.6 (C), 140.6 (C), 135.1 (CH), 135.0 (C), 129.0 (CH), 126.9 (CH), 124.3 (CH), 122.3 (CH), 109.9 (C), 109.2 (CH), 108.4 (CH), 100.7 (CH2), 78.2 (CH), 72.7 (CH), 59.6 (CH) 47.5 (CH), 28.3 (CH3), 26.3 (CH3), 21.1 (CH3); HRMS: calculated for C23H25 O6NS 443.1403, found 443.1416.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(CO)cc3)cc2o1
Temperature: 82.5 °C

Procedure:
A mixture of 130 mg (0.86 mmol) of 4-(hydroxymethyl)phenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol-/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 55 mg (23% of theory) of the title compound are isolated.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=O)[CH:14]=[C:9]12)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl.[CH2:26]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)[CH3:27].C([O-])(O)=O.[Na+]>ClCCCl.O>[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:31]3[CH:32]=[C:28]([CH2:26][CH3:27])[N:29]=[CH:30]3)[CH:14]=[C:9]12)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: CCc1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(C(C)=O)cccc4C3=C2)cn1
Temperature: 110 °C
Yield: 128.2 %

Procedure:
115-1. A mixture of 9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione [example 100-1] (128 mg, 0.47 mmol) in DCE (4 mL) was treated with POCl3 (0.053 mL, 0.57 mmol) and heated to 110° C. for 1 h. The mixture was then allowed to cool to RT and then poured onto cooled H2O. The mixture was extracted with DCM and the combined org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (4 mL) and 4-ethyl-1H-imidazole (182 mg, 1.89 mmol) was added. The mixture was heated to 110° C. for 1 h, then allowed to cool to rt and poured onto a saturated aq. solution of NaHCO3. The mixture was extracted with DCM and the combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (210 mg) that was used as it is in the next step. UPLC-MS: MS 349.2 (M+H+); UPLC rt 0.71 min.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[N:13]1[CH:14]=[C:15]2[N:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=13)[S:18][C:17]([C:25]([OH:27])=O)=[CH:16]2.ON1C(=O)CCC1=O.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][C:41]1=[O:53].C(N(CC)CC)C>C(#N)C>[C:49]([O:48][C:46]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:25]([C:17]2[S:18][C:19]3[N:24]4[C:15](=[CH:14][N:13]=[C:23]4[CH:22]=[CH:21][CH:20]=3)[CH:16]=2)=[O:27])[C:41](=[O:53])[CH2:42]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)C(=O)C1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCNC(=O)C2=Cc3cnc4cccc(n34)S2)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.4 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.22 g, 22.0 mmol) was added to a stirred suspension of 5-thia-1,8b-diazaacenaphtylene-4-carboxylic acid (2.40 g, 11.0 mmol) and N-hydroxysuccinimide (2.53 g, 22.0 mmol) in acetonotrile (30 ml) at room temperature and the mixture was stirred at room temperature for 1.5 hours. A solution of 1-(3-aminopropan-1-yl)-4-tert-butoxycarbonyl-2-oxopiperazine (3.67 g, 14.3 mmol) and triethylamine (4.45 g, 44.0 mmol) in acetonitrile (15 ml) was added to the mixture. After stirring at room temperature for 19 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with Ethyl acetate-Methanol (10:1) to give N-[3-(4-tert-butoxycarbonyl-2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder(1.53 g, 30%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[C:20]([CH3:22])[S:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[S:19][C:20]([CH3:22])=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1csc(C)c1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2sc(C)cc2c1
Yield: 41.7 %

Procedure:
Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-thienyl)but-3-enoic acid (30 g, 0.12 mol) in 300 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 14 g (50 mmol, 42%) as a solid.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[C:18]([NH:28][C@@H:29]([C:34]([OH:36])=[O:35])[CH2:30][C:31]([OH:33])=[O:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[C:18]([NH:28][C@@H:29]([C:34]([OH:36])=[O:35])[CH2:30][C:31]([OH:33])=[O:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@H](Cc1ccccc1)C(=O)O

Procedure:
Eight grams of DL-phenylalanine and 1.2 g of sulfuric acid was suspended in 100 ml of water at 40° C. Ten grams of N-carbobenzoxy-D-aspartic acid was added to the solution over five hours, while this solution was continuously stirred. The resulting crystal was separated, washed with 10 ml of water and dried to give 5.2 g of a D-phenylalanine N-carbobenzoxy-D-aspartic acid. Analysis revealed that the optical purity of the D-phenylalnine was 98%.
Reaction SMILES: [Br-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[C@H:23]([CH2:24][CH2:25][C:26](=[O:30])[CH:27]=2)[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:31])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]>C(#N)C.[Cu](Br)Br>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:31])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Br[Cu]Br
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
17.8 g of lithium bromide and 92.83 g of copper(II) bromide are added to a solution of 82.3 g of 7α-(5-acetoxypentyl)-estr-4-ene-3,17-dione in 936 ml of acetonitrile at a bath temperature of 80° C. After 10 minutes at a bath temperature of 80° C., the reaction solution is cooled, extracted three times with ethyl acetate, washed with water and sodium bicarbonate solution and dried. The residue that is obtained after the concentration by evaporation is chromatographed on silica gel, and 60.4 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(OCC)(=O)C.C1COCC1.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-fluoropyridine-2-carbaldehyde (18.49 g, 148 mmol) in ethyl acetate (850 mL), THF (250 mL) and hexanes (300 mL) were added (R)-(+)-2-methyl-2-propanesulfinamide (19.71 g, 163 mmol) and anhydrous copper(II) sulfate (59.0 g, 370 mmol). The mixture was stirred at ambient temperature. After 18 h, the mixture was filtered through Celite. The filtered cake was washed with ethyl acetate and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→98% dichloromethane/methanol) gave the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[C:6]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC1C=C(C2C3C(=CC=C(OC)C=3)C(=O)C=2C2C=NC=CC=2)C=C(F)C=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[C:6]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccc(C)cc1)C2=O
Agent: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(c1cccnc1)C2=O
Product: Cc1ccc(C2=C(c3ccccc3)c3cc(O)ccc3C2=O)cc1
Yield: 90 %

Procedure:
The procedure of Step 5 of Example 128 was repeated except for using 5-methoxy-3-phenyl-2-(p-tolyl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 3-(3,5-difluorophenyl)-5-methoxy-2-(pyridin-3-yl)-1H-inden-1-one to obtain the title compound (90%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:31][CH:30]=1)[NH:24][CH2:23][CH2:22]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C1COCC1>[C:1]1([S:7]([N:24]2[CH2:23][CH2:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:20]=3)[CH:25]2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:31][CH:30]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 168 %

Procedure:
Benzenesulfonyl chloride (0.016 g, 0.09 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.040 g, 0.09 mmol) and Et3N (0.026 ml, 0.19 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 18 hr, then evaporated in vacuo to give 0.086 g of yellow residue. Purification by flash chromatography, eluting with EtOAc:MeOH (6:4) gave 0.045 g (85% yield) of white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:5]([CH:4]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: BrCCCC1CCCCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)C(CCCC1CCCCC1)C(C)=O

Procedure:
Analogously to Example 28A, 10 g (72.4 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate and 0.4 g (2.41 mmol) of potassium iodide are reacted with 14.9 g (72.4 mmol) of (3-bromopropyl)cyclohexane to give methyl 2-acetyl-5-cyclohexylpentanoate.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C@H:15]3[C@@H:19]([CH2:20]Br)[O:18][C:17]([CH3:23])([CH3:22])[O:16]3)=[O:14])[CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[NH:3]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][C:17]1([CH3:23])[O:18][C@@H:19]2[CH2:20][N:12]([C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])[NH:3][C:2]4=[O:1])=[CH:7][CH:8]=3)[C:13](=[O:14])[C@@H:15]2[O:16]1
Reactant: CC1(C)O[C@H](CBr)[C@H](C(=O)Nc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2CN(c3ccc4cc(-c5ccccc5C(F)(F)F)[nH]c(=O)c4c3)C(=O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
The (4R,5S)-5-bromomethyl-2,2-dimethyl-[1,3]dioxolan-4-carboxylic acid [1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]amide (3.0 g, 5.71 mmol) obtained in step B was dissolved in anhydrous DMF (50 ml), and potassium carbonate (3.95 g, 28.6 mmol) was then added thereto. The obtained mixture was stirred at a room temperature for 2 hours. Thereafter, the solvent was distilled away. Water and ethyl acetate were added to the obtained residue. An organic layer was separated, and a water layer was extracted with ethyl acetate. The organic layer was mixed with the extract. The obtained mixture was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=70:1 to 20:1), so as to obtain 640 mg of 7-((3aR,6aR)-2,2-dimethyl-4-oxotetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (25%).