Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:12])[F:25])=[CH:19][CH:18]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(C(F)(F)F)cc2)c1C

Procedure:
3-Methyl-4-[2-(4-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (100) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 96%. 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, 3H), 2.61 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.37 (m, 2H), 7.51 (d, 1H), 7.58 (m, 2H), 9.29 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.71, 14.41, 46.90, 60.78, 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00, 161.98, 193.49 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.71, 14.41; CH2 carbons: 46.90, 60.78; CH carbons: 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00 ppm. LC/MS: 73.23%, n/z=339.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16](O)=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C[N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([NH2:28])=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(C(N)=O)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
To a round bottom flask was added 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (1.1 g, 2.8 mmol), DCM (35 mL), TBTU (3.6 g, 11.3 mmol), and TEA (3.0 mL, 21.5 mmol). The mixture was allowed to stir for 5 min at rt and then ammonia (0.5M in dioxane, 32 mL) was added. The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was washed with water to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxamide (0.96 g, 92%). LCMS (FA): m/z=371.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[C:6]1[CH2:10][O:9][C:8](=[O:11])[CH:7]=1.[I-:20].[Na+]>C(#N)C>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:5]([CH2:4][CH2:3][CH2:2][I:20])[C:6]2[CH2:10][O:9][C:8](=[O:11])[CH:7]=2)=[CH:18][CH:17]=1
Reactant: O=C1C=C(N(CCCCl)Cc2ccc(Cl)nc2)CO1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1C=C(N(CCCI)Cc2ccc(Cl)nc2)CO1
Yield: 87.9 %

Procedure:
27.50 g (91.3 mmol) of 4-[(3-chloropropyl)[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one (I-2) and 51.60 g (344.2 mmol) of sodium iodide in 1.2 l of acetonitrile are heated under reflux for 4 hours. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 31.5 g of 4-[[(6-chloropyridin-3-yl)methyl](3-iodopropyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9]C(=O)O[C:12](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH3:16]>CN(C=O)C>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[C:12]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH:15]([CH2:17][CH3:18])[CH3:16])=[CH:20][CH:21]=1)=[O:13]
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2cccc(OC)c2N)cc1

Procedure:
A solution of 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (0.50 g, 2.6 mmol) and 4-sec-butylaniline (0.42 g, 2.8 mmol) in DMF (4.0 mL) were stirred at 110° C. under N2 for 24 hours. The mixture was concentrated to dryness then purified by column chromatography on silica gel using ½ EtOAc/hexane as eluent to afford 2-amino-N-(4-sec-butyl-phenyl)-3-methoxy-benzamide as white solid. Yield: 0.533 g (69%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=[O:9])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.CI.[H-].[Na+].[C:27](OCC)(=O)C>O1CCCC1.O>[S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH3:27])[C:8]([OH:10])=[O:9])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1csc2ccccc12)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1csc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(2R)-3-(Benzo[b]thiophen-3-yl)-2-tert-butoxycarbonylamino-propionic acid (2.65 g; 8.25 mmol) was dissolved in dry tetrahydrofuran. Methyl iodide was added and the reaction mixture was cooled to 0° C. Sodium hydride (60% in mineral oil, 0.80 g, 24.8 mmol) was added. The reaction mixture was stirred for 48 hours at room temperature. Ethyl acetate (25 mL) and water (10 mL) were added dropwise. The solvent was removed in vacuo and the residue was dissolved in ether (1 5 mL) and water (15 mL). The organic phase was washed with an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL). To the aqueous phase was added citric acid (5%) until pH 3 and extracted with ethyl acetate (4×20 mL). The combined organic phases were washed with water (2×30 mL), an aqueous solution of sodium thiosulfate (5%; 30 mL) and water (30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was dissolved in ether (10 mL). Dicyclohexylamine (5 mL) was added. The precipitated crystals were filtered off, washed with ether (2×10 mL) and dissolved in water (30 mL). An aqueous solution of sodium hydrogen sulfate (10%; 20 mL) and ethyl acetate (40 mL) were added. The aqueous phase was extrated with ethylacetate (4×30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 3.75 g of (2R)-3-(benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonyl methylamino)propionic acid.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(O)(=O)C.[CH3:34][NH2:35].C1COCC1>ClCCCl>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH:35][CH3:34])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CN
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CNC)C1=O
Reaction time: 48 h

Procedure:
To a solution of 1.67 g (3.88 mmol) of (S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (Example 126, Step C) and acetic acid (6.60 mL, 116 mmol) in DCE (40 mL) was added 2 M methylamine in THF (19.40 mL, 38.8 mmol) and sodium triacetoxy hydroborate (3.29 g, 15.52 mmol) at room temperature. The reaction was stirred for 2 days. The reaction was quenched with sat aq. NaHCO3, extracted with EtOAc, and the combined organic layers were washed with 1N NaOH and sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as a pale yellow oil, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>ClCCl>[CH2:1]([C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[N:5]=[C:19]=[S:20])[CH3:2]
Reactant: CCc1cc(OC)ccc1N
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(OC)ccc1N=C=S
Temperature: 0 °C
Yield: 83.3 %

Procedure:
To solution of 2-ethyl-4-methoxyaniline (4.5 g, 30 mmol) and triethylamine (6.0 g, 60 mmol) in dichloromethane (31 mL) was added thiophosgene (3.4 g, 30 mmol) was added drop wise at 0° C. over the period of 1 hour. After completion, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3×200 mL) and washed with ice water (2×100 mL), followed by brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by flash column chromatography using 0-10% ethyl acetate/hexanes as eluent provided 2-ethyl-1-isothiocyanato-4-methoxybenzene as yellow oil (4.9 g, 25 mmol), which was taken onto the next step immediately.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[O:22]=[C:23]1[C:28]2=[CH:29][NH:30][C:31]([CH:32]=O)=[C:27]2[CH2:26][CH2:25][O:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:32][C:31]2[NH:30][CH:29]=[C:28]3[C:23](=[O:22])[O:24][CH2:25][CH2:26][C:27]=23)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]1=[O:24].Cl[C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:32][C:31]1[C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([N:16]4[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]4=[O:24])=[C:2]([F:1])[CH:7]=3)=[O:9])[CH2:11][CH2:12]2)=[N:27][CH:28]=[C:29]([Cl:33])[CH:30]=1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1F
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1F
Temperature: 100 °C
Yield: 48.8 %

Procedure:
(R)-3-[2-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (343 mg) described in Preparation Example 94 was dissolve in N,N-dimethylformamide (2 mL), 2,3,5-trichloropyridine (275 mg) and potassium carbonate (562 mg) were added and the mixture was stirred at 100° C. To the reaction mixture was added ethyl acetate under ice-cooling and insoluble materials were filtered off. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (240 mg).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:1]([C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)=[O:12])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc4c(c3)OCO4)nc12

Procedure:
From piperonylic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. []D20=+25.7° (c=0.86, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[CH2:25][CH2:24][N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][C:21]=4[C:20]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[N:19]3)[CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C[Si]([N:45]=[C:46]=[O:47])(C)C.CO.[CH2:50](Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[CH2:25][CH2:24][N:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:22][C:21]=4[C:20]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)=[N:19]3)[CH2:11][CH2:10]2)=[C:4]([NH:8][C:46]([NH:45][CH3:50])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Reactant: ClCCl
Reactant: C[Si](C)(C)N=C=O
Solvent: CO
Product: CNC(=O)Nc1cccc(Cl)c1N1CCN(CCCn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(C)(=O)=O)C3)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
To a stirred solution of 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine (0.062 g, 0.104 mmol) in CH2Cl2 (0.52 mL) was added trimethylsilyl isocyanate (0.017 mL, 0.125 mmol). The reaction mixture was allowed to stir for 48 h at room temperature. The reaction had not gone to completion, so an additional 0.017 mL (0.125 mmol) of trimethylsilyl isocyanate was added and the reaction was heated to 45° C. for 10 h. Column chromatography (silica, 3-10% MeOH/CH2Cl2) afforded 1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-urea (0.015 g, 22%). MS (electrospray): exact mass calculated for C28H33ClF3N7O3S, 639.2; m/z found, 640.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.26 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.09 (t, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 4.65 (s, 2H), 4.55 (s, 2H), 4.15 (t, J=6.7 Hz, 2H), 3.65-3.73 (m, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.87-2.92 (m, 2H), 2.91 (s, 3H), 2.70 (d, J=11.4 Hz, 2H), 2.40 (t, J=6.7 Hz, 2H), 2.09-2.22 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])([OH:8])[CH2:4][CH2:3]1.[C:24]([Cl:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC>[ClH:32].[C:24]([O:8][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(Cc2ccccc2C2(O)CCN(C)CC2)c(F)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(Cc2ccccc2C2(OC(=O)c3ccccc3)CCN(C)CC2)c(F)c1
Product: Cl

Procedure:
1.5 g of 1-methyl-4-[α-(2-fluoro-4-methylphenyl)-2-tolyl]-4-piperidinol, Example 4, is treated carefully with 7 ml of benzoyl chloride with stirring and cooling. The reaction mixture is stirred for 16 hours at ambient temperature and then diluted with 15 ml of ether. The resulting precipitate is filtered, washed with ether, converted to the free base which is column chromatographed on an alumina column using ether as the eluant. The free base is converted to its hydrogen chloride salt which is recrystallized from a methanol-acetone-ether mixture to give a white powder, mp 218°-219° C. of 4-benzoyloxy-4-[α-(2-fluoro-4-methylphenyl)-2-tolyl]-1-methylpiperidine hydrochloride.
Reaction SMILES: CI.[C:3]1([S:9][C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[CH3:22][N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:10]([S:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:11]1[C:19]([NH2:21])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: c1ccncc1
Product: Cn1c(C(N)=O)c(Sc2ccccc2)c2ncccc21
Yield: 38.8 %

Procedure:
Add methyl iodide (20 mg, 0.14 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid amide (Ia-1, 27 mg, 0.1 mmol), Cs2CO3 (43 mg, 0.13 mmol) in pyridine (0.5 ml). Heat the reaction at 80° C. in a sealed vessel for 15 minutes. Cool the mixture cooled and extract into ethyl acetate from water. Separate the organic solution and evaporate. Purify the residue (33 mg) by flash chromatography (silica gel, 3 gm, elute with MeOH 0-4% in dichloromethane) to provide the title compound (11 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=283) are consistent for the title compound structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[O:13][C:12]([CH3:17])(C)O[C:10]1=O)=[O:8].OCC[C:22]#[N:23].C(=O)=O.[N+:27]([C:30]1[CH:37]=[CH:36][C:33](C=O)=[CH:32][CH:31]=1)([O-:29])=[O:28].N1CCCCC1.C(O)(=O)C>CC(O)C>[C:22]([CH2:17][CH2:12][O:13][C:14](=[O:15])[C:9](=[CH:10][C:33]1[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])#[N:23]
Reactant: N#CCCO
Reactant: COCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COCCCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-(5-Methoxypentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was heated with 3-hydroxypropionitrile (2.79 g, 39.2 mmol) at 80° C. until no more CO2 was released. After cooling to room temperature, the mixture was diluted with 50 ml of 2-propanol and 4-nitrobenzaldehyde (5.40 g, 35.6 mmol), piperidine (150 mg, 1.78 mmol) and acetic acid (110 mg, 1.78 mmol) was added, the mixture was stirred at room temperature for 48 hrs. After evaporation of solvent, the product was purified by chromatography (SiO2, MeOH:CHCl2=5:95). 7-Methoxy-2-[(4-nitrophenyl)methylene]-3-oxoheptanoic acid 2-cyanoethyl ester was obtained as a pale-yellow oil (7.75 g, 60% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[Cl:16]C1C=CC=CC=1C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:16]
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccccc1Cl

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 2-chlorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48]([C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[C:53](Cl)=[O:54])#[N:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:53](=[O:54])[C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([C:48]#[N:49])[CH:51]=2)[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 14 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-cyanobenzoyl chloride as starting materials in 14% yield. LCMS for C32H30ClN8O2 (M+H)+: m/z=593.2.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=1>ClC1C=CC=CC=1>[CH3:14][O:15][C:16]1[N:17]=[CH:18][C:19]([NH:22][CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:20][CH:21]=1
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Solvent: Clc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(C)=O
Temperature: 135 °C
Yield: 84.1 %

Procedure:
A mixture of ethyl 2-(ethoxymethylene)-3-oxobutanoate (100 g, 0.54 mol) and 2-methoxy-5-aminopyridine (67 g, 0.54 mol) in chlorobenzene (500 mL) was heated at 135° C. for 4 h in a round bottomed flask that was equipped with a distillation apparatus to collect the ethanol generated during the reaction. The reaction mixture was cooled and concentrated and the residue was triturated in diethylether and filtered to obtain the desired product (120 g, 84%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 12.74 (d, 12.3 Hz, 1H), 8.35 (d, J=13.0 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.55 (d, J=8.8, 2.9 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.33 (t, J=7.1 Hz, 1H); ESI MS m/z 265 [M+H]+.
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)[C:4](=[NH:7])SC)#N.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N:30]1C=CC=C[CH:31]=1>>[CH2:22]([NH:29][C:4](=[N:7][C:31]#[N:30])[NH:3][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSC(=N)N(C#N)c1ccc(C2=NNC(=O)CC2C)cc1
Reactant: NCc1ccccc1
Reactant: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=NC#N)NCc2ccccc2)cc1

Procedure:
A stirred mixture of 6-(4-(N-cyano-S-methylisothioureido)phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2 g), benzylamine (2 ml) and pyridine (100 ml) was heated under reflux for 2 hours. The residue after evaporation was triturated with ethanol and the resultant solid (1.6 g) was purified by flash chromatography (silica gel, chloroform:methanol mixtures) to give the title compound (0.85 g), m.p. 228°-229° C.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6]N2C3C(=CC(C(F)(F)F)=CC=3)C3(C(=O)NC(=O)N3)C2=O)=[C:4]([F:29])[CH:3]=1.[Br:30]C1C=CC(C[N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)[C:38](=[O:49])[C:37]2=[O:50])=C(F)C=1>>[F:48][C:45]([F:46])([F:47])[C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[NH:36][C:37](=[O:50])[C:38]2=[O:49].[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][Br:30])=[C:4]([F:29])[CH:3]=1
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Br)cc1F)c1ccc(C(F)(F)F)cc12
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2F)c2ccc(C(F)(F)F)cc21
Product: Fc1cc(Br)ccc1CBr
Product: O=C1Nc2ccc(C(F)(F)F)cc2C1=O

Procedure:
(Example 3): 1'-(4-bromo-2-fluorobenzyl)-5'-trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, as a solid, m.p. 231°-232° C., starting from 1-(4-bromo-2-fluorobenzyl)-5-trifluoromethylindoline-2,3-dione (itself obtained as a syrup, of satisfctory purity by NMR, by reaction of 5-trifluoromethylindoline-2,3-dione and 4-bromo-2-fluorobenzyl bromide in an analogous manner to that described for the starting material in Example 1);