Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:8]1=[O:29].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(OCC)(=O)C.CCCCCC>[CH3:36][O:35][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([CH2:12][CH2:13][OH:14])[C:8]1=[O:29]
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3ccccc3)C2=O)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(CCO)(Cc3ccccc3)C2=O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (1.0 g, 1.95 mmol) and tetrahydrofuran (5 mL). Cool to 0° C. using a ice bath. Add a solution of tetrabutylammonium fluoride (3.90 mL, 1 M in THF, 3.90 mmol). After the addition is complete, warm to ambient temperature. After 1.5 hours, add aqueous 1 M hydrochloric acid solution (20 mL). Extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound: Rf=0.27 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[C:9]([C:22]([F:25])([F:24])[F:23])[CH:8]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C.O>[N:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:26](=[O:28])[CH3:27])=[CH:8][C:9]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A solution of isopropylmagnesium chloride (2M in THF, 10 ml, 20.04 mmol) was added drop wise to a solution of the product obtained in step 1 (5.00 g, 13.36 mmol) in THF (30 ml) at −10° C. The mixture was stirred at this temperature for 1 h and then added drop wise to acetic acid anhydride (12.6 ml, 133.60 mmol) at −15° C. The reaction mixture was stirred at 0° C. for 2 h and allowed to warm up slowly to RT. Water (100 ml) was added and the reaction mixture was stirred at 60° C. for 15 min. The mixture was diluted with ethyl acetate at RT, neutralized with aqueous NaHCO3, washed with brine, dried over sodium sulphate and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (2.00 g, 44%).
Reaction SMILES: [F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][NH:4][CH2:3]1.C=O.[CH3:22]C(O)=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:22])[CH2:3]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3F)c2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)C(F)C1
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of compound 131 (0.2 g, 0.765 mmol) in dry methanol (5 mL) was treated with formaldehyde (0.07 mL, 0.918 mmol, 37% in water), AcOH (0.1 mL, 1.913 mmol) and NaBH3CN (0.057 g, 0.918 mmol) at 0° C. The resulting mixture brought to room temperature and stirred for 3 h. The reaction was basified with 1 N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:99 to 1:9) to obtain compound 132 (0.2 g, 95%) as a yellow solid. mp 94-96° C.; 1H NMR (DMSO-d6) δ 2.32 (s, 3H), 2.48-2.63 (m, 1H), 2.78-2.87 (m, 1H), 3.03-3.12 (m, 1H), 3.38-3.48 (m, 1H), 5.45 (d, 1H, J=48.9 Hz), 6.48-6.50 (m, 1H), 7.58 (d, 1H, J=8.7 Hz), 7.75 (s, 1H), 8.03 (dd, 1H, J=2.1, 9.0 Hz), 8.68 (d, 1H, J=2.1 Hz), 11.96 (s, 1H); ESI-MS m/z (%): 276 (MH+, 100).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]([O:39][C:40]([C:42]1([NH2:51])[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])[CH3:38].CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C(Cl)Cl>[CH2:37]([O:39][C:40]([C:42]1([NH:51][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:2]([CH3:1])=[O:3])[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])[CH3:38]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CS(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccccc2S(C)=O)Cc2ccccc2C1

Procedure:
To a 40 mL vial containing a stirring bar, 2-(methylsulfinyl)benzoic acid (0.449 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) is added. The 2-aminoindane-2-carboxylic acid ethyl ester ([500 mg, 2.44 mmol) is added followed by DIPEA (0.95 mL, 8.0 mmol). The reaction is allowed to stir for 94 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.2 g of yellow foam. This material is dissolved in 10 mL of DCM and purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 100% EtOAc over 8 column volumes and then hold for 5 column volumes. 25 mL fractions are collected. Fractions 9 through 18 are combined and evaporated in vacuo to a constant weight to give 0.75 g of amorphous off-white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].[C:23](#N)[CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:24]2[CH:23]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC1CCN(c2c(Cl)cncc2-c2ccccc2)CC1
Yield: 22 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48 (100 mg, 0.39 mmol), phenyllboronic acid (57 mg, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 5 mol %), 0.5 M sodium carbonate (1.1 mL, 0.55 mmol) and acetonitrile (3.5 mL) for 45 min. The crude product was purified by preparative hplc (H2O, MeCN, 90:10-10:90, 30 min) to furnish the title compound (25 mg, 22%), LC-MS (ESI, 3.5 min) Rt 2.24 min, m/z 298 (100%, [M+H]+).
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]([C:18]([O:20]C)=[O:19])[C:14]3=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>ClCCl.CO>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:18]([OH:20])=[O:19])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1CCc2ccc(C3CCCCC3)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(C3CCCCC3)ccc2CC1
Reaction time: 1 h
Yield: 20.4 %

Procedure:
Methyl 7-cyclohexyl-1-tetralone-2-carboxylate (8.6 g) was dissolved in dichloromethane (40 ml)-methanol (50 ml). To this solution, sodium borohydride (1.13 g) was added in small portions at room temperature. The reaction mixture was poured into water (80 ml) and extracted with dichloromethane. The dichloromethane layer was successively washed with water and brine, and dried (MgSO4), after which the solvent was distilled off. The residual oil was dissolved in methanol (40 ml), followed by dropwise addition of 2N NaOH (45 ml) at room temperature and stirring for 1 hour. The reaction mixture was washed with ether; the aqueous layer was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was successively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off. To the residual oil, dioxane (25 ml) and concentrated hydrochloric acid (4.2 ml) were added, followed by stirring at 90° C. for 40 minutes, after which the mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off, to yield 7-cyclohexyl-3,4-dihydronaphthalene-2-carboxylic acid (1.57 g, 20%), which was then recrystallized from ethanol to yield colorless prisms having a melting point of 179°-180° C.
Reaction SMILES: FC1C=C[CH:5]=[C:4](F)[C:3]=1[NH:9][C:10]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[Cl:27])=[CH:15][CH:16]=1)=[O:11].[CH3:28][C:29]1[CH:30]=[N:31]C=CC=1N.FC1C=CC=C(F)C=1N>>[CH3:28][C:29]1[CH:30]=[N:31][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=2[Cl:27])=[CH:15][CH:16]=1)=[O:11]
Reactant: O=C(Nc1c(F)cccc1F)c1ccc(-c2cc(C(F)(F)F)ccc2Cl)s1
Reactant: Cc1cnccc1N
Agent: Nc1c(F)cccc1F
Product: Cc1cnccc1NC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2Cl)s1

Procedure:
Compound 2 was synthesized in an analogous fashion as described for Compound 1 except that 3-methyl-4 amino pyridine was used in step 2 instead of 2,6-difluoroaniline.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:13][CH:15]1[CH2:16][O:17]1
Reactant: ClCC1CO1
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cccc(OCC2CO2)c1

Procedure:
The title compound was prepared from 3-trifluoromethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1ccc2cnccc2c1

Procedure:
Prepared from 6-aminoisoquinoline (Description 51) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 362 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[CH:36]1([CH2:41][C:42](Cl)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:42](=[O:43])[CH2:41][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC1CCCC1

Procedure:
In 10 ml of dichloromethane are dissolved 0.5 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one and 0.2 ml of N,N-dimethylaniline and, with stirring, 0.3 ml of cyclopentylacetyl chloride is added. The mixture is stirred at room temperature (15°-25° C.) overnight and 150 ml of ethyl acetate is added. The mixture is washed with 10% H3PO4, water, 10% aqueous NaHCO3, water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off and the residue is subjected to column chromatography. Following passage of 80 ml of diisopropyl ether-n-hexane (1:10), elution is carried out with 80 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.1 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:39])[N:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][NH:11][C:12]([CH2:14][C@H:15]([NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:16]([N:18]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:19]2[CH2:21][CH2:20]2)=[O:17])=[O:13])[CH2:5]1.[OH-].[Li+].Cl>C1COCC1>[NH2:39][C:3](=[NH:2])[N:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][NH:11][C:12]([CH2:14][C@H:15]([NH:28][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:16]([N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]2[CH2:20][CH2:21]2)=[O:17])=[O:13])[CH2:5]1
Reactant: CCOC(=O)CN(C(=O)[C@H](CC(=O)NC[C@@H]1CCCN(C(=N)N)C1)NC(=O)OCc1ccccc1)C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N(CC(=O)O)C2CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
1.5 g of ethyl [[(S)-3-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethylcarbamoyl]-2-benzyloxycarbonylamino-propionyl]-cyclopropyl-amino]-acetate hydrochloride (Example 1) are dissolved in 15 ml of THF, treated with 7.9 ml of 1N lithium hydroxide solution and stirred at room temperature for 90 minutes. Then, the solution is treated with 7.9 ml of 1N hydrochloric acid and evaporated. The residue is chromatographed on RP-18 with a water-acetonitrile gradient. 0.63 g of colourless [[(S)-3-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethylcarbamoyl]-2-benzyloxycarbonylamino-propionyl]-cyclopropylamino]-acetic acid, MS (ion spray): 503.5 (M+H)+, is obtained.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:21])[NH:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)O)(C)(C)C>C1COCC1>[F:20][C:15]1[CH:14]=[C:13]([CH:11]2[O:21][C:8](=[O:7])[NH:9][CH2:10]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCC(c2ccc(F)c(F)c2)O1
Yield: 24 %

Procedure:
To a well stirred suspension of 95% NaH (0.55 g, 11.8 mmol) in THF (20 mL) at room temperature was added a solution of [2-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (3.2 g, 23.0 mmol) in THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et2O, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf=0.15, 3:2 hexane-EtOAc) to obtain 5-(3,4-difluoro-phenyl)-oxazolidin-2-one as a white solid (1.1 g, 47%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3F)=[CH:8][CH:9]=2)[N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:3]1.C([O-])(O)=O.[Na+].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[CH3:1][C:2]1([CH3:28])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:40][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:8][CH:9]=2)[N:4]([CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:3]1
Reactant: CN1CCC(N2CC(C)(C)c3ccc(NC(=O)c4cccnc4F)cc32)CC1
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC(N2CC(C)(C)c3ccc(NC(=O)c4cccnc4NCc4ccc(F)cc4)cc32)CC1
Temperature: 85 °C

Procedure:
A solution of N-[3,3-dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide (500 mg), 4-fluorobenzylamine (240 μL) and NaHCO3 (359 mg) was dissolved in IpOH (5 mL) and heated to 85° C. overnight. After cooling to RT, the mixture was dried under N2. The residue was partitioned between EtOAc and H2O, the organic layer was separated, washed with brine, dried over Na2SO4 and filtered. Silica was added to the filtrate and concentrated to a residue. It was purified by flash chromatography (10% MeOH/EtOAc) to yield a fluffy yellow solid. M+H 488.4. Calc'd for C29H34FN5O: 487.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:20])[CH2:13][S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:21]1[CH:26]=[C:25]([CH:27]=[O:28])[C:24]([CH:29]=O)=[CH:23][CH:22]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:20]2[CH2:29][C:24]3[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=3)[C:27]2=[O:28])[CH2:13][S:14]([N:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(=O)(=O)N(C)C)ccc1OC
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(=O)(=O)N(C)C)N2Cc3ccccc3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethyl]isoindolin-1-one was prepared by the procedure of Example 3 from 1-(3-ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethylamine (150 mg, 0.49 mmol) and 1,2-phthalic dicarboxaldehyde (67 mg, 0.49 mmol) in acetic acid (2 mL). The product was obtained as a solid (142 mg, 69% yield): mp, 165.0-167.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J=7 Hz, 3H, CH3), 2.86 (s, 6H, N(CH3)2), 3.58 (dd, J=4.7, 14.4 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.30 (d, J=16.5 Hz, 1H, NCHH), 4.33 (dd, J=9, 14.4 Hz, 1H, CHH), 4.49 (d, J=16.5 Hz, 1H, NCHH), 5.60 (dd, J=4.7, 9.5 Hz, 1H, NCH), 6.83 (d, J=8.3 Hz, 1H, Ar), 6.98 (dd, J=2, 8.3 Hz, 1H, Ar), 7.06 (d, J=2 Hz, 1H, Ar), 7.37-7.56 (m, 3H, Ar), 7.84 (d, J=7 Hz, 1H, Ar), 13C NMR (CDCl3) δ 14.69, 37.31, 48.64, 49.73, 52.91, 52.95, 64.54, 111.31, 112.46, 119.29, 122.76, 123.72, 128.03, 130.67, 131.55, 132.75, 141.26, 148.73, 149.39, 168.63; Anal Calcd for C21H26NO5S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.04; H, 6,10: N, 6.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[CH:12][C:13]#[N:14])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Co]>[NH2:14][CH2:13]/[CH:12]=[C:9]1\[CH2:8][CH2:7][C:6]2[C:10]\1=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: COc1ccc2c(c1)C(=CC#N)CC2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)/C(=C/CN)CC2
Reaction time: 32 h
Yield: 85.6 %

Procedure:
To a solution of (6-methoxyindan-1-ylidene) acetonitrile (1.60 g, 8.64 mmol) in ethanol (80 ml) were added a 2M ammonia/ethanol solution (40 ml) and Raney cobalt (1.6 g). The mixture was stirred, under hydrogen atmosphere (4 kgf/cm2), for 32 hours at 40° C., and for further 8 hours at 70° C. The Raney cobalt was filtered off, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=9:1 to chloroform:methanol:triethylamine=90:8:2) to give the above-titled compound (yield 1.40 g, 86%, oily).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:17][C:18](N)=[O:19].O>C(O)(=O)C>[F:15][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][C:12](=[O:14])[NH:17][C:18]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCNc1cccc(C(F)(F)F)c1
Reactant: NC(N)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 67.7 %

Procedure:
A solution of 3-(3-trifluoromethylphenylamino)propanoic acid (2.0 g) (prepared in Reference Example 95) and urea (1.0 g) in acetic acid (20.0 ml) was stirred with heating under reflux for seven hours. To the reaction mixture was water (50 ml) and the resulting mixture was extracted with ethyl acetate (30 ml×3). The organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (1.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:24]#[N:25].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:24]#[N:25])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl chloride (0.66 g) in N,N-dimethylformamide (20 mL) was added potassium cyanide (0.40 g), and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to ambient temperature, and water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1–3/1) to give [4-(2-benzyloxybenzyl)phenyl]acetonitrile (0.54 g).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 4-fluorobenzonitrile (303 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was used in the next step without further purification. Isolated 642 mg (2.13 mmol, 85% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:7]=1.C(O)=[O:18]>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[O:8][C:5]1[N:4]=[N:3][C:2]([OH:18])=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: Clc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1
Product: Oc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1

Procedure:
A solution of 3-chloro-6-(3,4-dichloro-phenoxy)-pyridazine (1.74 g, 6.32 mmol) in formic acid (25 mL) was heated at 100° C. for 3 hours. The solvent was removed by evaporation in vacuo yielding the title compound, which was used without further purification.