Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.CO[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:29]Br)=O)=[CH:23][CH:22]=1>CCOC(C)=O>[C:24]1([C:27]2[NH:9][C:6]3[C:7]([CH:29]=2)=[CH:8][CH:3]=[CH:4][CH:5]=3)[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2cc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a boiling mixture of in-anisidine (1.56 ml, 20.0 minol) and N,N-dimethylaniline (3.5 ml) was added 2-bromo-4-methoxyacetophenone (1.37 g in EtOAc, 6.00 mmol) slowly by syringe. After addition, the mixture was kept at 170° C. for 1 hour. The reaction mixture was cooled to room temperature and a dark colored solid was formed. EtOAc was added along with HCI (2 N). The aqueous layer was extracted with EtOAc several times. The combined organic layers were washed with brine, and dried over MgSO4. Solvent was removed under the reduced pressure to afford a dark brown colored solid. Purification by recrystallization in EtOH afforded indole 31 as a white crystallinc material.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:20][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6]1(=[O:34])=[O:33])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-].CCOC(C)=O>N1C=CC=CC=1>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6]1(=[O:33])=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(CC(=O)O)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of methyl (3-{3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propoxy}phenyl)acetate (Example 21) (0.087 g, 0.179 mmol) and LiI (0.239 g, 1.788 mmol) in pyridine (2 ml) was heated at 120° C. for 18 h. EtOAc was added and the mixture was washed with 1N HCl, evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 0-12% MeOH (+1% AcOH) in EtOAc as eluent to give the title compound (0.033 g, 39%). 1H NMR (500 MHz CDCl3): δ 7.54-7.46 (m, 2H), 7.45-7.40 (m, 3H), 7.25 (t, 1H), 6.89 (dd, 1H), 6.82-6.75 (m, 2H), 5.73 (t, 1H), 3.87 (t, 2H), 3.63 (s, 2H), 3.10-3.04 (m, 2H), 1.87-1.79 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 176.7, 159.8, 158.7, 135.4, 135.0, 131.8, 129.9, 129.8, 128.8, 125.3, 122.4, 115.7, 113.6, 107.2, 65.9, 61.7, 42.3, 41.2, 29.0, 27.8; Mass Spectrum: M2H+ 472.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[C:11](=[O:16])[O:12][C:13](=O)[NH:14][C:9]=2[CH:8]=[CH:7][CH:6]=1.O>CO>[NH2:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[C:11]([O:12][CH3:13])=[O:16]
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(N)cccc1OC
Temperature: 65 °C
Reaction time: 14.5 h
Yield: 93.7 %

Procedure:
To a stirred solution of sodium hydroxide (0.06 g, 1.5 mM) in methanol (7 mL) under a nitrogen atmosphere was added 5-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (2.90 g, 15.0 mM). The reaction mixture was stirred at 65° C. for 14.5 hr, cooled to room temperature and poured into water. The resulting solution was extracted with ethyl acetate and the combined extracts were dried (Na2 SO4), filtered and concentrated to provide the title compound (2.55 g, 94%) as a tan oil; MS(CI): 182 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:19][CH2:18]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 6-chloro-N-{trans-4-[(dimethylamino)methyl]-cyclohexyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (61 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (63 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (52 mg, 59%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.90 (s, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.90 (dd, J=11.5, 2.2 Hz, 1H), 5.77-5.67 (m, 1H), 3.38 (s, 3H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.51-2.44 (m, 2H), 2.08-1.97 (m, 3H), 1.76-1.64 (m, 2H), 1.46-1.34 (m, 2H). ESI MS m/z 507 [M+H]+; HPLC 99.0% (AUC), tR=9.81 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Br[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][C:3]=1[CH3:10]
Reactant: BrCC1CCCO1
Reactant: Cc1cc(O)cc(C)c1Br
Product: Cc1cc(OCC2CCCO2)cc(C)c1Br

Procedure:
The title compound is prepared from 4-bromo-3,5-dimethylphenol and 2-(bromomethyl)tetrahydrofuran following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 1): tR=1.37 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4](Cl)=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][C:3]1[C:4]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ncncc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(c2ncncc2Br)CC1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-4-chloropyrimidine hydrochloride 21 (0.10 g, 0.36 mmol) in DMF (2 mL) was added triethylamine (0.51 mL, 3.6 mmol). After stirring for 30 min, a solution of isonipecotamide (0.14 g, 1.1 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (60 mg, 58%), m.p. 188-190° C.; umax (CHCl3)/cm−1 3012, 2853, 1682, 1566, 1447, 1359, 1144, 1017, 950; m/z (ESI) C10H14BrN4O requires 285.0346, found [M+H]+ 285.0344.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][CH2:26]O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][CH2:26][N:30]3[C:31](=[O:33])[CH2:32][S:28][C:29]3=[O:34])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCCO
Reactant: O=C1CSC(=O)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCCN1C(=O)CSC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-1-ol (0.5 g, 1.4 mmol, 1 eq.), thiazolidine-2,4-dione (0.20 g, 1.7 mmol, 1.2 eq.), triphenylphosphine (1.1 g, 4.2 mmol, 3.0 eq.) in THF (25 mL) in ice/water bath was added DIAD (0.85 mmol, 4.2 mmol, 3.0 eq.) dropwise. The resulting solution was stirred at this temperature for 0.5 h and then stirred at room temperature for another 2 h. The volatile phase was removed off under reduced pressure. The residue was applied on silica gel and eluted to give 3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)thiazolidine-2,4-dione (0.4 g, 62%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1>C(#N)C.O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(CCl)cn1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COc2ccc(CNC(=O)OC(C)(C)C)cc2OC)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.2 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (22.44 g, 88.59 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methoxypyridine hydrochloride (18.33 g, 94.46 mmol). The resulting mixture was heated to reflux and stirred. After 23 h, the light green suspension was allowed to cool to room temperature and was diluted with water (600 mL), resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water. The moist solids were dissolved in dichloromethane (300 mL), and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 31.92 g (96%) of tert-butyl 3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate as an off-white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:3][CH2:2]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(CC(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
Benzyl 1-piperazinecarboxylate (2.0 g, 9.08 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.5 g, 10.8 mmol) and triethylamine (1.9 mL, 13.8 mmol) were dissolved in 50 mL of tetrahydrofuran, and the reaction mixture was stirred at 60° C. for two hours. After cooling to room temperature, the reaction mixture was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were sequentially washed with water and brine in this order. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate:hexane=50:50) to give 4-(2,2,2-trifluoroethyl)piperazin-1-carboxylic acid benzyl ester (3.1 g) as a colorless oil.
Reaction SMILES: CC(O)C.[ClH:5].[C:6]([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[O:20][N:19]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].[BH4-].[Na+]>CO>[ClH:5].[F:27][C:25]1[CH:24]=[CH:23][C:22]2[C:18]([CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][C:9]([CH:6]([OH:8])[CH3:7])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:14][CH2:13]3)=[N:19][O:20][C:21]=2[CH:26]=1
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CC(O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a mixture of 50 ml of 2-propanol and 10 ml of methanol, was added 2.8 g of 4-acetyl-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-phenylpiperidine hydrochloride and 0.76 g of sodium borohydride. After stirring at ambient temperature for twenty hrs, the mixture was evaporated. The residue was stirred with 100 ml of water for ten mins and then extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the ether solution was acidified to pH 1 with ethereal hydrogen chloride. The resultant precipitate was collected and dried to give 2.3 g (78%) of product, mp 80° C. Recrystallization from ethyl acetate/methanol (9:1) gave the analytical sample, mp 143°-147° C.
Reaction SMILES: [OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].[C:26](OC(=O)C)(=[O:28])[CH3:27].O>CCOCC>[C:26]([O:1][CH:2]([CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(O)CN1CCN(C)CC1
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of 7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxyquinazolin-4-one (1.2 g, 3.3 mmol) and acetic anhydride (670 μl) in ether (2 ml) was stirred 10 minutes at ambient temperature. Ether (2 ml) was further added, followed by acetic anhydride (670 μl). After stirring 1 hour at ambient temperature, water (305 μl) was added and stirring was continued for 1.5 hours. The mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with methylene chloride. The organic layers were combined, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-[2-acetoxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxyquinazolin-4-one (0.93 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Cl:11][C:12]1[C:13]([F:20])=[C:14](/[CH:15]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)\[C:9]#[N:10])[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(F)cc1
Yield: 79.5 %

Procedure:
In a manner similar to the method described in Example 1b, 4-fluorophenylacetonitrile (Aldrich) (3.5 g, 26 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.3 g, 34 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (200 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-fluoro-phenyl)-acrylonitrile as a white powder (5.7 g, 80%).
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.I[C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[OH-].[K+]>O1CCOCC1.O>[C:1]1([C:17]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C2=CCCCC2)c(C(=O)O)c1

Procedure:
In analogy to a procedure described by Masuda et al. [M. Murata, T. Oyama, S. Watanabe, Y. Masuda, Synthesis 2000, 778] a stirred mixture of 1 eq. 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, 0.8 eq. 2-iodo-5-methanesulfonyl-benzoic acid, 2 eq. aqueous 3M KOH solution and 0.03 eq PdCl2 (dppf)2-CHCl3 in dioxane (0.2 ml per mmol) were heated to 80° C. for 5 h. Then the reaction mixture is diluted with water, extracted with AcOEt, the aqueous phase acidified with 2N H2SO4, extracted with AcOEt and the pooled organic extracts dried over Na2SO4, filtered and evaporated. The crude product is purified by flash-chromatography on silica gel with heptane/AcOEt as eluent to yield the title compound; MS (ISN): 279.8 M−H−.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:6][CH2:5]1)=[O:3].[CH3:17]C1C(C)=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:17])[C:11]=2[CH3:16])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(N2CCN(C(=O)Cl)CC2)c1C
Yield: 78 %

Procedure:
1-chlorocarbonyl-4-(2,3-dimethylphenyl)piperazine Compound 40A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(2,3-dimethylphenyl)piperazine (3.94 g, 20.7 mmol); triphosgene (2.05 g, 6.9 mmol); pyridine (1.68 ml, 21 mmol); dichloromethane (150 ml).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]1.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:22][C:23]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.6 %

Procedure:
An aqueous solution (20 mL) of sodium carbonate (6.90 g, 65.1 mmol) was added to 3-piperidinylmethanol (5.00 g, 43.4 mmol) in tetrahydrofuran (20 mL). While the mixture was chilled in an ice bath, benzyloxycarbonyl chloride (9.36 g, 52.1 mmol) was added and the mixture was stirred for 1 hour and subsequently 7 hours at room temperature. The solvent was then evaporated and ethyl acetate was added to the residue. The mixture was then washed sequentially with water, 0.1 mol/L hydrochloric acid and brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 9.15 g (85%) of the desired compound as a colorless powder.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (84 mg, 87%), MS (ISP) m/z=386.4 [(M+H)+], mp 239° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13](Br)[CH:14]=1)#[N:2].[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([CH:24]=[CH:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:14]=1)#[N:2]
Reactant: C=Cc1ccccn1
Reactant: N#Cc1ccccc1-c1cc(Br)cn(-c2ccccc2)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(C=Cc2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixed liquid of 100 mg of 3-(2-cyanophenyl)-1-phenyl-5-bromo-1,2-dihydropyridin-2-one, 100 mg of 2-vinylpyridine, 6 mg of palladium acetate, 17 mg of tri-(o-tolyl)phosphine and 3 ml of triethylamine was stirred at 130° C. for 2 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 16 mg of the title compound as a white powder.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:43]CC)C.CCCCCC>CC(C)=O>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:43])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:22][C:23]=1[CH3:35]
Reactant: CCOCC
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl} ethanone of Step D (2.0 g, 3.6 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.9 mL, 7.25 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.0 mL, 8.0 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether-hexane provided 1.4 g of the desired product as a white solid, m.p. 174-184° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>CO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:16][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C=C[N+](=O)[O-])cc1
Temperature: 3 °C
Reaction time: 2 h

Procedure:
A mixture of 4-methylsulphonylbenzaldehyde (22.08 g, 120 mmol) and nitromethane (12.5 ml, 14.2 g, 233 mmol) in MeOH (1 l) is cooled to 3° C. in an ice bath; sodium hydroxide solution (32%, 420 ml, 567 g, 135 g of NaOH, 3.36 mol) is then added dropwise, a clear solution being formed after addition of 30 ml (time needed 1 h). The mixture is stirred at 10° C. for 2 h and then added dropwise at 10° C. to initially introduce HCl (20%, 1080 ml, 216 g of HCl, 5.9 mol) (time needed 40 min). The HCl-acidic mixture is stirred until formation of the precipitate is complete (30 min). The nitrostyrene crystallizate is filtered off with suction, washed with ice water until the wash phase gives a neutral reaction and dried over P2O5 in an evacuated desiccator. The yield of crystallizate is 16.03 g after drying.