Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.C([Li])CCC.[C:24]([CH2:26][CH2:27][N:28]=[C:29]=[O:30])#[N:25].[Cl-].[NH4+]>COC(C)(C)C>[C:24]([CH2:26][CH2:27][NH:28][C:29](=[O:30])[C:14]#[C:13][C:10]([CH2:11][F:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][F:16])#[N:25]
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reactant: N#CCCN=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: N#CCCNC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
An amount (61 mg) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69 M n-butyllithium (0.148 ml) was added at −70° C. under a nitrogen atmosphere and the mixture was stirred for 10 minutes. To the reaction mixture, 2-cyanoethyl isocyanate (28 mg) was added and the resulting mixture was stirred at −70° C. for 10 minutes. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane/ethyl acetate (1/1); the resulting organic layers were washed with a 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried with anhydrous sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=3/2) to give the titled compound (45 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.C(O[C:15](=O)[CH2:16][CH2:17][C:18]1[N:19]([CH:31]2[CH2:33][CH2:32]2)[C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1)C.CC(C)([O-])C.[Na+].CCO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:15]([CH2:16][CH2:17][C:18]3[N:19]([CH:31]4[CH2:33][CH2:32]4)[C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[O:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCc1cnc(-c2ccc(OC)cc2)n1C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ncc(CCc3nc(-c4cccc(Cl)c4)no3)n2C2CC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
3-chloro-N′-hydroxybenzenecarboximidamide (54.3 mg, 0.32 mmol), 3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-propionic acidethyl ester (100 mg, 0.32 mmol) and sodium-tert-butoxide (30.6 mg, 0.32 mmol) were mixed with EtOH (1 ml) and toluene (1 ml), followed by stirring at 100° C. for 24 h. The mixture was then concentrated, in-vacuo, and the residue was purified via column chromatography using 50% EA in hex. and then triturated with Et2O to isolate the title compound (27 mg). 1H-NMR: 8.1 (m, 1H), 7.97 (dd, 1H), 7.64 (d, 2H), 7.47 (m, 2H), 6.96 (d, 2H), 6.88 (s, 1H), 3.87 (s, 3H), 3.37 (m, 4H), 3.24 (m, 1H), 1.06 (m 2H), 0.68 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:12]([CH:13]=O)=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26]>ClCCl>[CH3:23][O:24][C:25](=[O:26])/[CH:27]=[CH:13]/[C:12]1[C:3]([N:2]([CH3:22])[CH3:1])=[N:4][C:5]2[C:10]([C:11]=1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Solvent: ClCCl
Product: COC(=O)/C=C/c1c(N(C)C)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
2-(Dimethylamino)-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde (4.20 g) is dissolved in 100 ml of dichloromethane and (5.25 g, 1.1 equivalents) of methyl (triphenylphosphoranylidene) acetate is added in one portion. The reaction is stirred at room temperature for three days, evaporated, and the residue eluted through a 3-inch silica column to give 4.60 g of (E)-methyl-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propenoate as an orange solid; 1H NMR (chloroform-d): δ 7.78-6.87 (m, 9H), 5.98 (d, 1H), 3.60 (s, 3H), 2.95 (s, 6H) ppm.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[CH:12]=1.O>O1CCOCC1>[CH2:20]([CH:19]1[C:13]2[CH:12]=[C:11]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[CH:15][C:14]=2[C:17](=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[NH:24][C:23]2=[O:32])[O:18]1)[CH3:21]
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)cc21
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (177 mg, 1.51 mmol) in 3 mL of dioxane is treated with 3-(6-Chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.30 mmol) in one portion. The reaction mixture is heated at 100° C. until no starting material remained. The reaction mixture is treated with water (10 mL) and heating is continued for 1 hr. The precipitate which formed is collected by filtration and washed with small amounts of water, EtOAc and ether. The solid obtained is dried under vacuum to give the title compound as a yellow solid (18 mg, 14%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[SH:13].[OH-].[Na+].[CH3:16]I>O>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:10])([CH3:12])[CH3:11])=[N:5][N:4]=[C:3]1[S:13][CH3:16]
Reactant: CI
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1N
Yield: 80.6 %

Procedure:
41.2 g (0.206 mol) of 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (VI) were introduced into a mixture of 200 g of 45% strength sodium hydroxide solution and 135 g of water, while stirring. After all of the product had dissolved, 34.0 g of methyl iodide were added in a manner such that the internal temperature did not rise above 30° C. When the addition had ended, the reaction mixture was stirred for a further 2 hours at room temperature. The reaction product which had precipitated was then filtered off, washed with 200 ml of water and dried. 35.6 g (81% of theory) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one (I) of melting point 123°-125° C. were obtained.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[CH2:22]([O:26][CH:27]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:24][CH3:25]>>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][CH:27]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:39][CH:38]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Product: CCCCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OCC
Yield: 54.2 %

Procedure:
The title compound (0.25 g, 53%) was prepared as a colorless liquid from 2-(phenoxazin-10-yl)ethyl methanesulfonate (0.3 g, 0.98 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoate (0.26 g, 0.97 mmol) obtained in preparation 6 by an analogous procedure to that described in example 6 (Method B).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:3].Cl.[CH:15]([O:17][CH2:18][CH3:19])=[CH2:16]>>[CH2:15]([O:17][CH:18]([O:3][CH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH3:19])[CH3:16]
Reactant: C=COCC
Reactant: CCOC(=O)CC(O)C(=O)OCC
Agent: Cl
Product: CCOC(=O)CC(OC(C)OCC)C(=O)OCC

Procedure:
A mixture of 19 g. diethyl malate and 0.1 g. of 36% hydrochloric acid was added to a 50 ml. round-bottom flask equipped with an addition funnel, static nitrogen head, condensor, heating mantle, thermometer, and magnetic stirrer. Ethyl vinyl ether was then added, dropwise, at 41° to 43° C. over a one-hour period and quenched with 0.4 g. of solid sodium carbonate. Distillation was performed directly on the mixture (short path column):
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](O)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(C2CC2)n1
Product: Clc1ccnc(C2CC2)n1
Reaction time: 3 h

Procedure:
2-Cyclopropylpyrimidin-4-ol (1.0 g, 7.34 mmol) was suspended in phosphorous oxychloride (5.0 mL, 53.6 mmol) and over the course of about one hour, the solid went into solution. After three hours, the solution was concentrated, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:11]1[C:12]([NH2:14])=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:10]=1
Reactant: BrBr
Reactant: Nc1cnc(-c2ccncc2)c(-c2cccc(F)c2)n1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.5 %

Procedure:
To a solution of 6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-ylamine (Example 1, 70 mg, 0.26 mmol) in chloroform (4 mL) at 0° C. was added pyridine (22 μL, 0.27 mmol) and bromine (14 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 24 h, chloroform (20 mL) was added, the organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol 95:5) to provide the title compound as a red solid (22 mg, 24%).
Reaction SMILES: [CH3:1][C@:2]1([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:11]2=[O:22])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[ClH:23].O>CO.[Pd]>[ClH:23].[NH2:21][CH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:22])[N:10]([C@@:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:18]2=[O:19]
Reactant: C[C@]1(N2C(=O)c3ccc(C#N)cc3C2=O)CCC(=O)NC1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of 2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (4.70 g, 15.8 mmol), 4N HCl (21 mL), and 10% Pd—C (1.88 g) in CH3OH (200 mL) was hydrogenated under 50 psi of H2 for 16 hours. Water (24 mL) was added, and the reaction mixture was filtered through Celite. The filter was washed with additional methanol (50 mL). The filtrate was concentrated and dried to give 3.5 g of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride, in 66% yield; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 1.00 (97.70%); 1H NMR (DMSO-d6) δ 1.91 (s, 3H), 2.03-2.10 (m, 1H), 2.49-2.61 (m, 2H), 2.66-2.75 (m, 1H), 4.23 (s, 2H), 7.89-8.03 (m, 3H), 8.68 (br, 3H), 11.04 (s, 1H); 13C NMR (DMSO-d6) δ 20.9, 28.6, 29.0, 41.6, 58.9, 123.2, 123.5, 130.8, 131.4, 135.3, 141.2, 167.5, 167.6, 172.1, 172.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
Add 2,5-dichloropyridine (6.0 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc dust (116 mg, 1.8 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.98 mmol) to a flask containing DMF (40 mL). Heat the mixture to reflux for 5 h, then cool to ambient temperature. Dilute the mixture with EtOAc (300 mL) and wash with 10% aqueous NaCl (3×75 mL). Collect the organic layer, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (2.6 g, 46%).
Reaction SMILES: [CH:1]1([C:4]2[CH:27]=[CH:26][C:7]([C:8]([N:10]([C@@H:12]3[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]3[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:28]1([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)=[O:32])[CH2:30][CH2:29]1>>[CH:1]1([C:4]2[CH:27]=[CH:26][C:7]([C:8]([N:10]([C@@H:12]3[CH2:17][CH2:16][N:15]([C:39]([CH:36]4[CH2:35][CH2:34][N:33]([C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:38][CH2:37]4)=[O:40])[CH2:14][C@H:13]3[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C(=O)c1ccc(C2CC2)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Product: CN(C(=O)c1ccc(C2CC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 649, step 1 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[C:15]1([NH:21][CH2:22][CH2:23][C:24]#[N:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:21]([CH2:22][CH2:23][C:24]#[N:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N#CCCNc1ccccc1
Product: CCOC(=O)c1cnc(SC)nc1N(CCC#N)c1ccccc1

Procedure:
The title compound was prepared from ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (3.7 g, 15.8 mmol) and 3-phenylamino-propionitrile (2.3 g, 15.8 mmol) according to the procedure outlined in Example 1 (B). The product was purified chromatographically (silica, EtOAc/hexanes 1:20-1:2, v/v). A white solid was obtained (3.5 g, 65%). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.32 (s, 1H), 7.34(m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 4.32 (t, J=7.1 Hz, 2H), 3.56 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[N:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][N:21]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:24]3[C:20]([CH3:19])=[N:21][CH:22]=[N:23]3)=[CH:33][CH:32]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.30 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [CH:1]1(SC2C=CC(C(C3C=CC(C(F)(F)F)=C(OC)N=3)=O)=CC=2)CC1.[Si]([O:42][CH2:43][C@@H:44]([CH3:60])[CH2:45][S:46]([C:49]1[N:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=[N:51][N:50]=1)(=[O:48])=[O:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:54]1([N:53]2[C:49]([S:46]([CH2:45][CH:44]3[CH2:60][CH2:1][O:42][CH2:43]3)(=[O:47])=[O:48])=[N:50][N:51]=[N:52]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CS(=O)(=O)c1nnnn1-c1ccccc1
Reactant: COc1nc(C(=O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Product: O=S(=O)(CC1CCOC1)c1nnnn1-c1ccccc1

Procedure:
The title compound was obtained as a white solid (22 mg, 4% (three steps)) by performing substantially the same reaction as in Examples 1-47(1), 1-2 and 1-1(2) sequentially except for using [4-(cyclopropylsulfanyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanone obtained in Reference Example 1-68 and using 5-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl]sulfonyl}-1-phenyl-1H-tetrazole obtained in Reference Example 3-14 in place of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH:11]([CH3:1])[CH2:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C=Cc1c(C)cccc1C
Reactant: [Li]C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CC(C)c1c(C)cccc1C
Reaction time: 2 h

Procedure:
To a mixture containing 20 g of CuI and 50 ml of tetrahydrofuran (THF) are added 105 ml of methyllithium dropwise during with agitation in a nitrogen atmosphere at a temperature of 0° C. or lower until the yellow precipitate barely dissolves. Then 8,7 g of 4-(2,6-dimethylphenyl)-3-buten-2-one in 50 ml of THF are added slowly at 0° C. The stirring is continued for an additional 2 h with a gradual increase of the temperature to +25° C. The reaction mixture obtained is hydrolysed with 300 ml of a solution of NH4Cl. The ether layer is removed, dried and evaporated to give the crude product.
Reaction SMILES: [C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Cl:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O.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>[C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Cl:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 90 °C

Procedure:
A mixture of 65 mg of 19e, 25 mg of 3-pyridine-boronic acid, 45 mg of K2CO3 and 12 mg of Pd(PPh3)4 in 3 ml of degassed 90% aq. dimethoxyethane was heated under a nitrogen atmosphere for 16 h at 90° C. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated. The residues were purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent. The material thus obtained was triturated with pentane, to provide 45 mg of white crystalline 19f; Mp: 190-192° C. MS-ESI: [M+1] 464.17, 465.17 and 466.17. NMR (CDCl3) δ 1.58 (s, 3, tertC4H9), 1.62-1.77 (bm, 2, CH2), 1.80-2.05 (bm, 2, CH2), 2.60-2.77 (bm, 2, CH2), 2.970-3.18 (bm, 2, CH2), 3.50 bm, 1, CH), 3.76-3.92 (bm, 2, CH2), 3.86 (s, 3, OCH3), 4.50 (bm, 1, CH), 6.87 (s, 1, ArH), 8.20 (s, 1, ArH), 7.36, 7.89, 8.57, 8.83 (4×m, 4, pyridine-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:5]=2[O:9]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1-c1cc(F)cc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CNC(=O)OCc1ccccc1)C2

Procedure:
Treatment of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.11 g, 12.1 mmol) with diisopropylethylamine (2.34 g, 18.1 mmol) and benzyl chloroformate (2.27 g, 13.3 mmol) generally according to the procedure described for Intermediate 12 gave 4.35 (92%) of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.83 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C24H22FO3.0.2H2O: C, 72.97; H, 5.72; N, 3.55. Found: C, 72.8; H, 5.72; N, 3.48. Chiral HPLC separation of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 8:2) provided two fractions. Fraction 1 (Rt=7.269 min, Chiralcel OD, hexane:isopropanol 8:2); Fraction 2 (Rt=8.449 min, Chiralcel OD, hexane:isopropanol 8:2).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1([CH2:43]O)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:43][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: OCc1cccc2ccccc12
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (1.0 g, 5.7 mmol) in dry THF (80 mL) are added triphenylphosphine (1.8 g, 6.9 mmol) and naphthalen-1-yl-methanol (1.1 g, 6.9 mmol). Then diisopropyl azodicarboxylate (1.4 mL, 6.9 mmol) is added drop wise into the above solution at room temperature. The mixture is stirred for 16 hrs and then the solvent is removed under vacuum. The residue is purified by flash column chromatography using 10% EtOAc in hexanes to give 1.6 g (89%) of 1-isopropenyl-3-naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one.