Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.FC(F)(F)SCl>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]=2[S:3][C:2]([F:8])([F:7])[F:1])=[CH:14][CH:15]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)[nH]1
Agent: FC(F)(F)SCl
Solvent: ClCCl
Product: COC(=O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 902.7 %

Procedure:
Trifluoromethanesulfonic acid (0.27 g, 0.001795 mol) is added to a solution of methyl 5-(p-chlorophenyl)pyrrole-2-carboxylate (4.23 g, 0.01795 mol) in methylene chloride (70 mL) at -30° C. This mixture is treated with trifluoromethylsulfenyl chloride (4.0 g, 0.0293 mol), stirred for 30 minutes at -15° C., warmed to room temperature with stirring for three hours, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as an off-white solid (5.44 g, mp 133°-137° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:32][CH2:31][C@H:29]2[CH2:28][C@@H:27]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]4=[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)[N:9]=3)[CH2:30]2)=[O:41])=[CH:43][CH:44]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (46.52 g, 105.5 mmol) and 4-nitrobenzoyl chloride (23.55 g, 126.9 mmol) in methylene chloride (260 mL) was added N,N-diisopropylethyl amine (55.17 mL, 316.7 mmol). The mixture was stirred at rt for 15 h. Yellow precipitates were collected by filtration, washed with ethyl acetate, and dried to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.70-2.78 (m, 4H), 2.96-3.02 (m, 1H), 3.81-3.86 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 7.44-7.48 (m, 1H), 7.51-7.55 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.88-7.96 (m, 5H), 8.16-8.19 (m, 2H), 8.26-8.29 (m, 2H), 8.33 (d, J=8.8 Hz, 1H), 8.54 (s, 1H); MS (ES+): m/z 590 [MH+]; HPLC: tR=4.37 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13](=NN)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I:24]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]([I:24])=[CH2:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=NN)C1(C)CN(C(=O)OC(C)(C)C)C1
Reactant: II
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(I)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 3-(1-hydrazono-ethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.076 g, 0.33 mmol) and triethylamine (0.169 g, 1.67 mmol) in THF (3 mL) was added dropwise a solution of iodine (0.127 g, 0.50 mmol) in THF (1 mL). The reaction mixture was stirred for 1 h at ambient temperature then concentrated in vacuo. The residue was dissolved in DCM (10 mL) and washed with aqueous Na2S2O3 (5%, 2 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 20% EtOAc in petroleum ether) to give 3-(1-iodo-vinyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.060 g, 55%), which was unstable and used without further purification. TLC: Rf=0.30 (eluting with 10% EtOAc in petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[CH:29]=[CH2:30].CCN(C(C)C)C(C)C>CO>[C:33]([O:32][C:28](=[O:31])[CH2:29][CH2:30][N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][C:4]3[CH:19]=[CH:20][C:21]([CH:22]4[CH2:27][CH2:26][S:25][CH2:24][CH2:23]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2ccc(C3CCNCC3)cc2)ccc1C1CCSCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCSCC1
Temperature: 60 °C

Procedure:
Crude 4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidine is dissolved in MeOH (8 mL) and treated with t-butyl acrylate (1.777 mmol, 228 mg, 0.26 mL) and DIEA (4.442 mmol, 574 mg, 0.77 mL). The resulting mixture is heated at 60° C. for 45 minutes. After concentration, the residue is partially purified by silica gel chromatography (0 to 10% MeOH in DCM) to give crude 3-(4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid tert-butyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:11]([NH2:13])=O)[O:3]1.[CH3:20][C:21](N)([CH3:24])[CH2:22][NH2:23].C1(C)C=CC=CC=1>O>[OH:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2](=[O:1])[N:23]2[CH2:22][C:21]([CH3:24])([CH3:20])[N:13]=[C:11]12
Reactant: NC(=O)C1(c2ccccc2)OC(=O)c2ccccc21
Reactant: CC(C)(N)CN
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CN2C(=O)c3ccccc3C(O)(c3ccccc3)C2=N1
Temperature: 25 °C

Procedure:
A mixture of 3-oxo-1-phenyl-1,3-dihydro-2-benzofuran-1-carboxamide (10 g), 2-methyl-1,2-diaminopropane (15 mL), and toluene (100 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (57.3 g), m.p. 186-188° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:34][C:31]3[CH:32]=[CH:33][C:28]([C:25]4[O:26][CH:27]=[C:23]([CH2:21][CH3:22])[N:24]=4)=[CH:29][C:30]=3[O:35][CH3:36])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5]
Reactant: CCc1coc(-c2ccc(O)c(OC)c2)n1
Reactant: COC(=O)C(C)n1ccc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[5-(3-Bromo-propoxy)-indol-1-yl]-propionic acid methyl ester (Example 48, 170.20 mg, 0.50 mmol) and 4-(4-ethyl-oxazol-2-yl)-2-methoxy-phenol (Example 39, 109.68 mg, 0.50 mmol) were dissolved in DMF (2 mL) at rt. Cesium carbonate (244.5 mg, 0.75 mmol) was added to the solution, followed by three drops of water. The mixture was stirred at rt for 17 h. The crude reaction mixture was filtered and purified by HPLC. The desired product was isolated as a white solid (143.8 mg, 60.1%). LC/MS m/z 479.3 (M+H)+; RT 3.59 min. 1H NMR (400 MHz, CD2Cl2) δ 7.58 (d, 1H), 7.56 (s, 1H), 7.41 (m, 1H), 7.24 (d, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 7.00 (d, 1H), 6.88 (dd, 1H), 6.46 (d, 1H), 5.11 (q, 1H), 4.28 (t, 2H), 4.22 (t, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 2.61 (q, 2H), 2.34 (m, 2H), 1.82 (d, 3H), 1.29 (t, 3H).
Reaction SMILES: I[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>O1CCCC1.[Pd+2].[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:13]([C:9]1[CH:8]=[C:7]([C:3]2[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:6][NH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
415 mg (1.32 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in 15 ml of dry tetrahydrofuran and 494 μL (3.42 mmol) of triethylamine, 80 mg (0.106 mmol) of palladium(II)-bis(triphenylphosphine) dichloride, 26 mg (0.166 mmol) of cuprous iodide and 406 μL (2.9 mmol) of trimethylsilylacetylene were added consecutively in a nitrogen atmosphere. The reaction was refluxed under stirring for 4 hours. The solvent was then removed in vacuo and the residue re-dissolved with dichloromethane and washed with water. The organic phase was dried over sodium sulphate and evaporated, affording, after trituration with diisopropylether, 300 mg (80%) of the title compound, that was employed for the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:27]1([CH2:37]Cl)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Reactant: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC(c2ccc(F)cc2)C(Cc2ccc(C(F)(F)F)cc2)N1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1 g, 2.95 mmol) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (142 mg, 3.54 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added 1-naphthylmethyl chloride (480 ml, 3.25 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from diisopropyl ether-hexane gave (4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1.23 g, 87%).
Reaction SMILES: [C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][OH:33])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:38].O>C1COCC1>[C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][O:33][CH3:38])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CO)c(C(=O)N(C)C(C)(C)C)n1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1c(-c2cccs2)c2n(c1C(=O)N(C)C(C)(C)C)CCc1cc(OC)c(OC(C)C)cc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product of example 40 (20 mg), sodium hydride (3.3 mg, 60% dispersion in oil) and iodomethane (13 μl) in THF (2.5 ml) was stirred for 18 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→1/1 (v/v)] as eluent.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]([O:15]C(C)(C)C)=O)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:31][NH:32][CH3:33].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH3:33][N:32]([CH2:31][C:23]1[N:22]([CH3:21])[C:30]2[C:25]([CH:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH2:4][C:3](=[O:20])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1)=[O:15]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2NCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN1Cc2cc(C(=O)N(C)Cc3cc4ccccc4n3C)ccc2NCC1=O
Yield: 91.8 %

Procedure:
According to the procedure of Example 8, except using tert-butyl 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.60 g, 2.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.35 g, 2.2 mmole), Et3N (0.62 mL, 4,4 mmole), HOBt.H2O (0.30 g, 2.2 mmole), and EDC.HCl (0.42 g, 2.2 mmole), the title compound (0.76 g, 92%) was prepared as an off-white solid following flash chromatography on silica gel (5% MeOH/CHCl3): MS (ES) m/e 377.0 (M+H)+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C1(=O)[N:27]([C:28]([N:45]2C(=O)C3=CC=CC=C3C2=O)([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:29][O:30][O:31][O:32][OH:33])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:45][C:28]([NH2:27])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:29][O:30][O:31][O:32][OH:33]
Reactant: CCCCCCCCCCCC(OOOOO)(N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCC(N)(N)OOOOO
Temperature: 25 °C
Reaction time: 3 h
Yield: 173.6 %

Procedure:
A solution of diphthalimide (Step 4:60 g), hydrazine hydrate (15 g) and ethanol (500 mL) is heated at 100° C. with stirring for 3 hrs. The reaction mixture is cooled to room temperature and filtered. The solid is washed with cold ethanol. The combined filtrate is concentrated under vacuum in a rotary evaporator to afford 33 g of yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)CC=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
A mixture of diphenylacetaldehyde (19.6 g), malonic acid (10.9 g) and piperidine (0.4 mL) in pyridine (20 mL) was heated at reflux until the evolution of gas had subsided (1.25 h). The solution was cooled and poured into a stirred mixture of ice (100 g) and 2N hydrochloric acid (150 mL). The resulting solid was recovered by filtration, washed with water and dried to provide 23.1 g of 4,4-diphenyl-3-butenoic acid, mp 109°-111° C. A portion was crystallized from ethyl acetate-hexane to give the pure acid of 4,4-diphenyl-3-butenoic acid, mp 112.5°-114° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]1[C:16]([O:23][CH3:24])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:18]([C:17]1[C:16]([O:23][CH3:24])=[C:15]([CH:22]=[CH:21][CH:20]=1)[O:14][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:19]
Reactant: COc1c(O)cccc1C=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cccc1Oc1cc(C(F)(F)F)ccc1C#N
Yield: 91.1 %

Procedure:
2-Fluoro-4-trifluoromethyl-benzonitrile (0.56 mL, 0.76 g, 4 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.61 g, 4 mmol) and cesium carbonate (1.3 g, 4 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (2×), 10% sodium carbonate solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-2-methoxy-phenoxy)-4-trifluoromethyl-benzonitrile (1.17 g, 91%) as a brown solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]1=2)=[O:11].Cl.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](O)=[O:38])=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:27].[Cl:27][C:25]1[CH:24]=[CH:23][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH2:18][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:37](=[O:38])[CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[C:13]=2[CH:26]=1
Reactant: O=C(O)CCc1ccncc1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccncc1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (0.8 mL) was added to a stirred mixture of 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (0.77 gram) and 4-pyridinepropanoic acid, monohydrochloride (0.50 gram) in dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere. After 5 minutes, the mixture was cooled to 5° C. in an ice bath, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (0.56 gram) was added. The reaction was stirred at room temperature under a nitrogen atmosphere for 60 hours, partitioned between saturated aqueous sodium bicarbonate (100 mL) and ethyl acetate (75 mL), and filtered. The layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The ethyl acetate extracts were combined, washed with aqueous saturated sodium bicarbonate (2×100 mL), water (100 mL), and brine (100 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 9:1 ethyl acetate:ethanol. The purified product was taken up in ethyl acetate and treated with 9.5 M HCl in ethanol to pH 1. The precipitated product was collected by filtration and dried in vacuo at 80° C. Yield: 0.233 gram (19%). Analysis calculated for C23H20ClN3O3 ×1 HCl: C, 60.27; H, 4.62; N, 9.17; Cl, 15.47. Found: C, 59.88; H, 4.66; N, 8.99; Cl, 15.58.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].N1C=CN=C1>O1CCCC1>[C:7]1([C:5]2[N:6]=[C:2]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:3]([CH3:19])[C:4]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -20 °C

Procedure:
A solution of 2-chloro-4,5-diphenyl-1-methylimidazole (1.46 g, 5.4 mmol) from Step B in tetrahydrofuran (THF) (20 mL) under nitrogen was cooled to −70° C. in a dry ice/acetone bath. n-Butyl lithium (1.6 N in hexanes, 10.2 mL, 16.3 mmol) was added via syringe. The reaction was allowed to warm to −20° C. for 2 hr. In a separate round-bottomed flask, a solution of benzyl chloroformate (CBZ-Cl) (4.3 mL, 16.3 mmol) in THF (10 mL) was cooled to −20° C. The above imidazole reaction was added via a double-tipped needle to the solution of CBZ-Cl and after 20 min the reaction was allowed to warm to rt for 30 min. The reaction was then quenched into an aqueous sodium bicarbonate solution and was then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (5% methylene chloride and 15% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.O>CN(C=O)C>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)=[O:40])[CH2:9][CH2:10]1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(C(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
17α-Hydroxy-21-(1-piperazinyl)pregna-4,9(11) -diene-3,20-dione (EXAMPLE 6A, 5.00 g) is treated in DMF (20 ml) with m-chlorophenyliso-cyanate (1.84 g) for 3 days. The mixture is poured into water (200 ml). After 1 hr, the liquid is decanted. The solid is dissolved in methylene chloride and is extracted with aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (3% methanol in methylene chloride to 4%) to give the title compound which is crystallized from hot ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH2:31][CH3:32]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH2:31][CH3:32])[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.4 %

Procedure:
To a solution of 0.600 gm (2.05 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 35 mL acetonitrile were added 0.283 gm (2.05 mMol) potassium carbonate followed by 240 μL (2.46 mMol) iodopropane and the reaction mixture was stirred at room temperature for 2.5 days. Additional iodopropane was added and the reaction stirred at room temperature until all of the starting material had been consumed. The reaction mixture was then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the combined organic phases were then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 96.5:3:0.5 dichloromethane:isopropanol:ammonium hydroxide. Fractions shown to contain the desired compound were concentrated under reduced pressure to give 0.270 gm (39%) of the desired compound.