Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])=[CH:4][CH:3]=1.Br.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)[C:9](=[O:19])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: BrCCCN1CCCCC1
Reactant: Cc1cc2ccccc2c(=O)n1-c1ccc(O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
2-(4-hydroxyphenyl)-3-methyl-1(2H)-isoquinolinone (30 mg, 0.12 mmol), 1-(3-bromopropyl)piperidine hydrobromide (51 mg, 0.18 mmol) and potassium carbonate (49 mg, 0.36 mmol) were mixed in dimethylformamide (3 mL) and stirred at 80° C. for 3 hours. The solvent was distilled off under reduced pressure, distilled water was added. and the mixture extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, and the product purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain the title compound (18 mg, 40%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH2:23]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2c(=O)c3c(n2Cc2ccccc2)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 100 °C
Yield: 14 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol), tetrabutylammonium iodide (371 mg, 1.0 mmol) and benzyl bromide (478 μL, 4.0 mmol) in dimethylformamide (10 mL) was heated at ˜100° C. overnight. The solvent was evaporated. Dichloromethane (150 mL) was added and the solution was washed with brine (150 mL), saturated aqueous sodium thiosulfate (150 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (150 mL) and brine (150 mL). The solution was dried (sodium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 0.5-2% methanol/dichloromethane to give a partially purified product that still contained some tetrabutylammonium iodide (according to 1H NMR). The solid was dissolved in dichloromethane, washed with saturated sodium thiosulfate and brine, and then evaporated to dryness. The solid was passed through a plug of silica, eluting with 0-5% methanol/dichloromethane, to give (4S,7R)-1-Benzyl-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (54.5 mg, 14%). APCI(+)-MS (M+H) 389.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@@H]3CCOC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide (150 mg, 0.49 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (120 mg, 0.49 mmol), bromotris(triphenylphosphine)copper (92 mg, 0.10 mmol) and caesium carbonate (484 mg, 1.48 mmol) in acetonitrile (7 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The solid was filtered off, the solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue. The organic phase was washed with water (10 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the title compound as a white solid (86 mg). 1H NMR δ (CDCl3): 2.10-2.17 (m, 1H), 2.19-2.25 (m, 1H), 2.32-2.38 (m, 2H), 3.76 (s, 3H), 3.87-3.92 (m, 1H), 3.95-4.01 (m, 3H), 4.24 (t, 2H), 4.71 (t, 2H), 4.97 (t, 1H), 6.73 (t, 1H), 6.81 (s, 1H), 7.11 (s, 1H), 7.24 (s, 1H), 7.27-7.30 (m, 1H), 7.36-7.39 (m, 1H), 8.12 (d, 1H), 8.31 (d, 1H), 8.72 (s, 1H); m/z 464 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:33][C:32](=O)[CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:33][C:32](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a cooled (-70° C.) and stirred solution of trimethyl phosphonoacetate (1.5 g) in anhydrous tetrahydrofuran (40 ml) was added potassium bis(trimethylsilyl)amide (0.5M in toluene; 15.07 ml) at such a rate as to maintain the internal temperature below -62° C. (ca 8 min). After 15 minutes of stirring at -70° C., a solution of 3-(tert-butyloxycarbonylamino)cyclobutan-1-one (1.27 g) in anhydrous tetrahydrofuran (10 ml) was added over 9 minutes, under a nitrogen atmosphere. The mixture was then allowed to warm to room temperature and it was stirred for 1 hour before it was quenched with saturated aqueous ammonium chloride (40 ml). Products were extracted with ethyl acetate (2×50 ml) and the combined organic solutions were washed with brine (1×40 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, hexane-ethyl acetate, 75:25) gave 1.61 g (97%) the title compound as a white solid; mp 79°-82° C. δ (250 MHz, CDCl3) 5.70 (1H, m, --CH--), 4.81 (1H, br s, --NH--), 4.32-4.13 (1H, m, --CH--), 3.69 (3H, s, --OMe), 3.64-3.50 (1H, m, --CH2 --), 3.26-3.10 (1H, m, --CH2 --), 3.00-2.86 (1H, m, --CH2 --), 2.80-2.68 (1H, m, --CH2 --), 1.45 (9H, s, t--Bu); m/z (CI) 240 (M- -1). (Found: C, 60.28; H, 7.87; N, 5.76. C12H19NO4 ×0.03 C6H14 requires: C, 59.99; H, 8.02; N, 5.75%.)
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH2:18]([NH:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)[CH3:19]
Reactant: CCNc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CCNc1ccc2c(c1)CNC2
Reaction time: 168 h
Yield: 68.1 %

Procedure:
400 mg of 10% palladium on carbon was added to 2.17 g of 2-benzyl-5-ethylaminoisoindoline prepared above in 30 ml of methanol and catalytic hydrogenation was carried out at 45° C. for 7 days. After removing the catalyst by filtration, the filtrate was concentrated and purified by vacuume distillation (bath temperature: 160°-200° C., pressure: 0.1 mmHg) to obtain 950 mg of 5-ethylaminoisoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:12][C:37](=[O:38])[C:36]([S:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:40]([OH:41])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: COc1ccc(C(C)=O)cc1Cl
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1Cl

Procedure:
The title compound was prepared by Method A using 3'-chloro-4'-methoxy acetophenone (0.979 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)-thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 171° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.93 (s, 3 H), 3.99 (s, 2 H), 6.68 (s, 1 H), 7.32 (m, 6 H), 7.77 (d, 1 H), 7.83 (d, 1 H).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=O.CC(C)([O-])C.[K+].C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:10][C:8]1[C:7]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:6][C:5]2[NH:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[C:4]=2[CH:9]=1
Reactant: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(OC(F)(F)F)c(C)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1OC(F)(F)F)NCCCC2=O
Temperature: 100 °C
Yield: 45 %

Procedure:
Add a solution of 2-[tert-Butoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-5-methyl-4-trifluoromethoxy-benzoic acid methyl ester (1.1 g, 2.4 mmol), in toluene (25 mL) to a solution of potassium t-butoxide (0.51 g, 4.9 mmol) in toluene (75 mL) at 100° C. over 30 min. After heating for 1 h cool the reaction to room temperature and quench the reaction with acetic acid (5.0 mmol). Dilute the reaction with ethyl acetate (100 mL) and wash with water (2×200 mL) followed by brine (200 mL). Dry the organics over sodium sulfate and remove solvent under vacuum. Dissolve the residue in acetic acid (25 mL) and dilute with concentrated HCl (15 mL) and water (10 mL). Heat the mixture at 100° C. for 2 h then cool to room temperature. While cooling in an ice bath neutralize the reaction with 5 N NaOH. Extract the organics with ethyl acetate (200 mL) and wash the organic with brine (100 mL). Remove solvent under vacuum and chromatograph the crude product over silica gel using ethyl acetate/hexane (5-20%) to elute. This provides the title compound (0.28 g, 44%) as an oil that crystallizes upon standing: H NMR (CDCl3, 400 MHz) δ 2.11-2.18 (m, 5H), 2.81 (t, J=6.8 Hz, 2H), 3.24 (t, J=6.8 Hz, 2H), 6.61 (m, 1H), 7.59 (s, 1H). MS (ES+): 260 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]12([NH2:27])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>>[C:17]12([NH:27][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NC12CC3CC(CC(C3)C1)C2

Procedure:
The title compound is prepared from N-benzyloxycarbonyl-D-alanine and 1-adamantanamine using the usual DCC-HOBt procedure described above.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[CH3:30][C:31]1[CH:36]=[C:35]([NH:37][NH2:38])[CH:34]=[C:33]([CH3:39])[N:32]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:37]([C:35]2[CH:34]=[C:33]([CH3:39])[N:32]=[C:31]([CH3:30])[CH:36]=2)[N:38]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: Cc1cc(NN)cc(C)n1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cc(C)nc(C)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with (2,6-dimethyl-pyridin-4-yl)-hydrazine hydrochloride (CAS Reg. No. 1187853-32-2) to give the title compound as brown oil. MS (ESI): m/z=523.2 [M+H]
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[O:3]1.[CH3:17][C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[N:29]3)[N:19]=1.ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:23][C:21]3[N:20]([C:24]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:25]=4[CH:26]=[CH:27][CH:28]=[N:29]5)[N:19]=[C:18]([CH3:17])[CH:22]=3)(=[O:14])=[O:13])[CH:8]=2)[O:3]1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc3c(c2)CCC(C)(C)O3)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 10 %

Procedure:
A stirring mixture of 2,2-dimethylchroman-6-sulfonyl chloride (0.050 g, 0.22 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.068 g, 0.26 mmol) in pyridine (1.0 mL) was heated at 80° C. for 15 h. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous saturated bisulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.010 g, 0.022 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=4.8 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.66 (dd, J=4.8, 8.8 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.40-7.38 (m, 2H), 6.72 (d, J=9.2 Hz, 1H), 6.09 (s, 1H), 2.71 (t, J=6.4 Hz, 2H), 2.34 (s, 3H), 1.83 (t, J=6.4 Hz, 2H), 1.36 (s, 6H); MS: (ES) m/z calculated for C24H25N4O3S [M+H]+ 449.2. found 449.1
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]([F:15])=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7]=1[F:16])(=O)C.[OH-].[K+].O.C(OCC)(=O)C>CO>[OH:4][CH2:5][C:6]1[C:14]([F:15])=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7]=1[F:16]
Reactant: CC(=O)OCc1c(F)cc2sccc2c1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: OCc1c(F)cc2sccc2c1F
Reaction time: 0.5 h

Procedure:
To a solution of 0.14 g of 5-acetoxymethyl-4,6-difluorobenzo[b]thiophene in 5 ml of methanol is added 0.03 g of potassium hydroxide at room temperature, and thereafter, the resulting mixture is stirred at the same temperature for 30 minutes. After the reaction, 10 ml of water and 10 ml of ethyl acetate are added to the thus stirred reaction mixture. The resulting organic layer is separated, washed successively with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure to obtain 0.12 g of colorless, oily 5-hydroxymethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]4=O)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:40])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4[Cl:40])=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3[nH]c(-c4ccccc4)cc(=O)c3c1)n2C1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Temperature: 100 °C

Procedure:
1-Cyclohexyl-2-(4-oxo-2-phenyl-1,4-dihydro-quinolin-6-yl)-1H-benzoimidazole-5-carboxylic acid ethyl ester acid (4 g, 8.14 mmol) was dissolved in phosphorous oxy chloride and heated at 100° C. overnight. After evaporation of the solvent the product was recrystallized from methanol/water to give 3.96 g of crude product. Silica gel purification of the title compound proved to be unsatisfactory due to degradation of the product on the column. MS: 510.22 (M+H+).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].C([O-])([O-])=O.[K+].[K+]>O>[CH3:5][C:4]1[CH:3]=[C:2]([CH3:1])[NH:13][C:11](=[O:12])[C:10]=1[C:8]#[N:9]
Reactant: N#CCC(N)=O
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)c(C#N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
To a solution of pentane-2,4-dione (100 g, 1.0 mol) in H2O (2 L) were added 2-cyanoacetamide (84 g, 1.0 mol) and K2CO3 (13.8 g, 0.1 mol). Then the mixture was stirred at room temperature for 16 hr. The reaction solution was filtrated to give crude product. The crude was washed with water and concentrated to give 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (138 g, 93%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]2[C:24]([F:27])([F:26])[F:25])=[CH:5][C:4]=1[O:28][CH3:29])#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:29][O:28][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]2[C:24]([F:26])([F:27])[F:25])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2C(F)(F)F)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CCN2CCNCC2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate (116 mg, 0.282 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to provide 2-methoxy-4-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}benzonitrile. LC-MS (IE, m/z): 314.4 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH2:34][CH3:35])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH2:34][CH3:35])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1CC
Yield: 108.6 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.98 g, 3.2 mmol), butyl 3-bromo-2-oxopentanoate obtained in Example (110a) (5 g, 19.9 mmol), sodium bicarbonate (0.63 g, 7.5 mmol) and THF (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1, 4/1) to obtain 1.5 g of the title compound as a yellow solid (100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: COc1ccc([C@@H](C)N)cc1
Product: COc1ccc(C(N[C@H](C)c2ccc(OC)cc2)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Following a similar procedure to that described in Example (1a), 6.00 g of 4-methoxyphenyl 3-nitrophenyl ketone and 5.32 g of (R)-1-(4-methoxyphenyl)ethylamine were reacted, to obtain 8.83 of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:18](I)=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(I)n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (229 mg), 3-hydroxy-2-iodo-6-methylpyridine (486 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give the title compound (186 mg, yield 61%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH2:14])[NH:10][CH:11]=2)=[CH:3][CH:2]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>ClCCCl>[CH2:21]([NH:25][C:26]([NH:14][CH2:13][CH2:12][C:9]1[NH:10][CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:2][CH:3]=2)[N:8]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: NCCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reactant: CCCCN=C=O
Solvent: ClCCCl
Product: CCCCNC(=O)NCCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Temperature: 60 °C
Yield: 66 %

Procedure:
A mixture containing 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine (obtained in Stage 32.2 of Example 32; 660 mg; 0.0025 mol) and n-butyl isocyanate (341 mg; 0.0025 mol) in 20 ml of 1,2-dichloroethane is stirred for fifteen minutes at 60° C. The suspension is stirred for sixteen hours at 23° C. and filtered. The solid obtained is washed with 1,2-dichloroethane and with ether. A white-coloured powder is obtained with a yield of 66%. Melting point: 178° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(#N)C>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: NCc1ccc(F)cc1F
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)c(F)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,4-difluorobenzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=95%, [M+H]+=401.