Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:12](Br)[C:13]#[CH:14].[C:16](=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CN(C=O)C.C(OCC)C>[CH2:12]([O:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[C:14][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)cc1OC
Reactant: C#CCBr
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC#CCOc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 3,4-dimethoxy phenol (15.4 g, 0.1 mol) in DMF (100 mL) is added propargyl bromide (14.15 g, 0.12 mol) and potassium carbonate (11.88 g, 0.12 mol). The reaction is stirred at room temperature for 12 h, sat. NH4Cl and diethyl ether are added. The organic layers are washed with water, brine and dried over Na2SO4. The crude material is filtered trough a pad of silica (1:1 hexanes:dichloromethane) to afford 4-but-2-ynyloxy-1,2-dimethoxybenzene as a yellow oil.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[O:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[CH3:1][S:2][C:5]1[C:6]2[O:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: C[S-]
Reactant: Clc1ncnc2ccoc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CSc1ncnc2ccoc12
Temperature: 90 °C
Yield: 85.2 %

Procedure:
Sodium thiomethoxide (1.2 g) was added to a solution of 4-chlorofuro[3,2-d]pyrimidine (Intermediate 84) (1.32 g) in MeCN (100 mL). The mixture was heated to 90° C. for 60 minutes, cooled, and added to 50% sodium carbonate solution (100 ml). The resulting mixture was extracted into EtOAc (3×100 mL). The combined organics were dried (MgSO4) and the solvent removed to afford the title compound as a pale orange solid (1.21 g, 85%);
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][Si](CC=[N+]=[N-])(C)C>CO.ClCCl>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][CH:18]([CH2:20][CH3:21])[N:17]([CH3:23])[N:16]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC=[N+]=[N-]
Reactant: CCc1nnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Solvent: CO
Solvent: ClCCl
Product: CCC1NC(c2cc(C(=O)OC)c(C)cc2C2CCC2)=NN1C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Methyl 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (compound 164.1, 87 mg, 0.29 mmol) was dissolved in methanol and dichloromethane (1:1 v/v) (6 ml). ((Trimethylsilyl)methyl)diazomethane (2.0 M in ether) (220 ul, 0.44 mmol) was added. The mixture was stiffed for 16 hours and quenched with HOAc (300 ul). The volatiles were removed in vacuo to afford an oil (85 mg). The residue was carried as crude onto the next step without further purification. m/z (ES+) 314 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21]>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CCOCCCCCCBr
Product: O=[N+]([O-])c1ccc(C#CCOCCCCCCBr)nc1

Procedure:
2-Bromo-5-nitropyridine (6.4 g) and 1-bromo-6-[(2-propynyl)oxy]hexane (6.39 g) were treated as in Intermediate 20 to give, after FCC eluting with hexane-ether (2:1), the title compound as a brown oil (7 g), t.l.c. (hexane-ether 5:1) Rf 0.22.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C([NH2:11])C.O.[BH4-].[Na+].[CH2:15](O)[CH3:16]>C1CCCCC1>[CH2:15]([N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:11])=[CH:3][CH2:2]1)[CH3:16]
Reactant: CCN
Reactant: O=Cc1ccncc1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: CCN1C=CC(CN)=CC1
Reaction time: 0.33 h

Procedure:
A mixture of pyridine-4-carboxaldehyde (26.78 g, 0.25 mole) and ethyl amine (32.2 g of a 70% water solution, 0.5 mole) were stirred for 20 min. Cyclohexane (250 ml) was added and the mixture was refluxed for 3 hrs under a Dean-Stark trap. The mixture was then concentrated in vacuo. Ethanol (250 ml) and sodium borohydride (thirteen 0.4 g tablets, 0.13 mole) were then added to the residue and mixture was stirred for 18 hrs. The mixture was concentrated in vacuo and the residue was dissolved in methylene chloride (250 ml) and filtered. The filtrate was concentrated in vacuo to give the product, N-ethyl-4-aminomethylpyridine (26.92 g, 79% which was taken on without purification.
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:13]([O:24][CH2:25][CH2:26][CH3:27])(=[O:23])[C:14]1[CH:22]=[C:20]([OH:21])[C:18]([OH:19])=[C:16]([OH:17])[CH:15]=1>C(O)C>[CH2:25]([O:24][C:13]([C:14]1[C:15]([CH2:1][N:6]2[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]2)=[C:16]([OH:17])[C:18]([OH:19])=[C:20]([OH:21])[CH:22]=1)=[O:23])[CH2:26][CH3:27]
Reactant: C=O
Reactant: CSC(=S)N1CCNCC1
Reactant: CCCOC(=O)c1cc(O)c(O)c(O)c1
Solvent: CCO
Product: CCCOC(=O)c1cc(O)c(O)c(O)c1CN1CCN(C(=S)SC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
In 10 ml of ethanol was dissolved 0.86 g (10 mmol.) of 35% formalin. To thesolution placed in an ice bath was further added a solution of 1.94 g (10 mmol., purity 90.7%) of methyl 1-piperazinecarbodithioate in 4 ml of ethanol. The resulting mixture was then stirred for 30 min. at room temperature. To the mixture placed in an ice bath was dropwise added a solution of 2.12 g (10 mmol.) of propyl gallate in 4 ml of ethanol. The mixture was stirred overnight at room temperature and subsequently refluxed under heating for 4 hours. The mixture was cooled to room temperature. Precipitated crystals were collected by filtration and washedwith ethanol to give 1.848 g of the desired compound as a grayish powder, m.p. 142°-144° C. (decomp.), yield 31.3%.
Reaction SMILES: [C:1]([Br:4])(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([N+]([O-])=[O:14])[CH:9]=[CH:8][N+:7]=1[O-:16].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[C:1]([O-:3])(=[O:14])[CH3:2].[Br:4][C:10]1[CH:9]=[CH:8][N+:7]([OH:16])=[C:6]([CH3:5])[C:11]=1[CH3:12]
Reactant: CC(=O)Br
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: Cc1c(Br)cc[n+](O)c1C
Temperature: 80 °C
Yield: 72 %

Procedure:
To a stirred solution of acetyl bromide (67.45 mL, 912.28 mmol) in acetic acid (140 mL) was added 2,3-dimethyl-4-nitro-1-oxido-pyridin-1-ium [TCl](15.34 g, 91.23 mmol) portionwise under nitrogen. The reaction was then warmed to 80° C. for 3 hours. The reaction was cooled and poured into a beaker of ice, and then basified with K2CO3 [caution]. The aqueous was then extracted with EtOAc (600 mL) and the organics were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. This gave 4-bromo-1-hydroxy-2,3-dimethyl-pyridin-1-ium acetate (D5)(18.12 g, 65.677 mmol, 72% yield);
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: C=CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[C:15]1[N:16]=[C:17]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]2)[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.[ClH:33]>>[ClH:33].[CH2:11]([C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[N:16]=[C:17]([N:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH2:30]3)[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][N:6]=1)=[O:10])[CH2:12][CH3:13]
Reactant: CCCC(=O)Nc1ccc(Br)cn1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: Cl
Product: CCCC(=O)Nc1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cn1

Procedure:
In the same manners sequentially as in Examples 161-2 and 20, the free compound of the title compound (338 mg, yield; 40%) from 5-bromo-2-propylcarbonylaminopyridine (3.11 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (514 mg). The resulting free compound was converted into a hydrochloride in a conventional manner, to give the hydrochloride of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#C.BrCC#[N:21].CN(C=O)C>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#[N:21])=[CH:11][N:12]=1
Reactant: N#CCBr
Reactant: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(CC#N)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 154, on a 0.31 mmol scale, utilising bromoacetonitrile (Aldrich; 33 μL, 0.47 mmol), as an amber gum containing 0.6 equivalents of DMF (97 mg, 100%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C([BH3-])#N.[Na+]>CO>[CH:31]1([N:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]4[NH:9][CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)=[CH:17][N:16]=3)[CH2:19][CH2:20]2)[CH2:33][CH2:32]1
Reactant: c1ccc(-c2cnc(-c3ccc(N4CCNCC4)nc3)[nH]2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(-c2c[nH]c(-c3ccc(N4CCN(C5CC5)CC4)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
(Reference: Tetrahedron Lett. 1995, 36 (41), 7399) To a solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (99 mg, 0.32 mmol) in anhydrous methanol (5 ml) under nitrogen atmosphere was added 3A molecular sieves (50 mg). This solution was stirred for 5 min, then glacial acetic acid (0.19 ml, 200 mg, 3.3 mmol, 10 equiv), (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.32 ml, 281 mg, 1.62 mmol, 5 equiv), and sodium cyanoborohydride (81 mg, 1.29 mmol, 4.0 equiv) were added. The reaction was heated at reflux overnight, then cooled to room temperature. The mixture was filtered, then diluted with an aqueous solution of 1 N NaOH and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired product (74 mg, 66%).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCOCC1>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:2][C:3]2[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(CBr)o1
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(C=O)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of 0.20 g (1.1 mmol) of 5-(bromomethyl)furan-2-carboxaldehyde in anhydrous dioxane (10 ml) are added 261 μL (0.24 g, 2.3 mmol) of 1-methylpiperazine. The mixture is stirred at room temperature for 30 min. The precipitate formed is filtered and rinsed with dioxane. The filtrate is concentrated, dissolved in dichloromethane, and washed in water. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue obtained is purified by chromatography on silica (eluent: 7N NH4OH in MeOH/CH2Cl2, 5:95) to yield 0.12 g (55%) of 5-((4-methylpiperazine-1-yl)methyl)furan-2-carboxaldehyde in the form of an orange solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CO[CH:8]([O:27]C)[C:9](=O)[CH2:10][CH2:11][CH:12]=[C:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].[C:29]([OH:32])(=[O:31])[CH3:30]>O1CCCC1>[O:31]1[CH2:10][CH2:9][CH2:8][CH2:30][CH:29]1[O:32][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:11][CH2:12][CH:13]=[C:9]([CH:8]=[O:27])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23]
Reactant: COC(OC)C(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: [Li]CCCC
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C=O)=CCCC(C)=CCOC1CCCCO1

Procedure:
Following the procedure stated in Example 2-(1), 5.8 g of (E)-4-methyl-6-(2'-tetrahydropyranyloxy)-4-hexen-1-yltriphenylphosphonium iodide was treated with n-butyllithium in 30 ml of anhydrous tetrahydrofuran. Then, the resultant was treated with 3.2 g of 1,1-dimethoxy-6,10,14-trimethyl-5,9,13-pentadecatrien-2-one prepared by the process stated in Referential example 7. The resulting oil was treated with 40 ml of 50% acetic acid to yield 4.2 g of 7-formyl-3,11,15,19-tetramethyl-2,6,10,14,18-eicosapentaen-1-ol tetrahydropyranyl ether. The product was reduced with 150 mg of sodium borohydride and treated with p-toluenesulfonic acid in methanol in the same manner as stated earlier, and purified by the silica gel column chromatography to yield 1.6 g of the desired product. This was a mixture of the (E,E,E,E), (E,Z,Z,E), (E,Z,E,E) and (E,E,Z,E) isomers.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
After dissolving 6-methoxycarbonyl-7-methoxy-4-(indol-5-yloxy)quinoline (400 mg) in tetrahydrofuran (5 ml), a 1.5N aqueous lithium hydroxide solution (2.5 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 4 with IN aqueous hydrochloric acid, and the precipitated crystals were filtered out and washed with ethyl acetate to obtain the title compound (280 mg).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14](O)=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])(C)(C)C.[CH2:17]([N:24]1C[C@H]2[C@H](N)CC[C@H]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:34]1[CH:39]=CC=C[CH:35]=1>>[CH2:17]([N:24]1[CH2:25][C@H:10]2[C@H:9]([NH:8][C:6](=[O:7])[CH2:33][CH:34]([CH3:39])[CH3:35])[CH2:14][CH2:12][C@H:11]2[CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: CC(C)CC(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21

Procedure:
The title compound was prepared by substituting 3-methylbutanoic acid for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step E of Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.30-8.17 (m, 1H), 7.43 (dd, J=11.2, 4.2, 2H), 7.37 (t, J=7.5, 2H), 7.27 (t, J=7.3, 1H), 4.49-4.39 (m, 1H), 3.60 (d, J=13.1, 1H), 3.45 (d, J=13.1, 1H), 2.89-2.78 (m, 1H), 2.55-2.49 (m, 2H), 2.45 (dd, J=10.4, 5.3, 1H), 2.36-2.24 (m, 3H), 2.21 (d, J=7.1, 2H), 2.17-2.08 (m, 1H), 1.90-1.79 (m, 1H), 1.62 (ddd, J=15.1, 12.3, 7.2, 1H), 1.40 (dtd, J=9.2, 8.2, 6.1, 1H), 0.95 (d, J=6.6, 6H); MS (ESI+) m/z 301 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH3:28])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[N:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.CN([CH:37]=[O:38])C1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl.O>[C:6]1([CH3:28])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[N:14]1[C:27]2[CH:26]=[CH:25][C:24]([CH:37]=[O:38])=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: CN(C=O)c1ccccc1
Reactant: Cc1cc(C)c(N2c3ccccc3Sc3ccccc32)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(N2c3ccccc3Sc3cc(C=O)ccc32)c(C)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
3.66 g (23.6 mmol) of 99% phosphorus oxychloride were added dropwise at 20° C. with stirring and ice cooling to a solution of 5.00 g (15.8 mmol) of 10-mesitylphenothiazine and 3.23 g (23.6 mmol) of 99% N-methylformanilide in 5 ml of o-dichlorobenzene within 15 min. After stirring at 20° C. for 30 min, the reaction solution was heated to 70° C. and kept at this temperature for 4 hours. The reaction solution was admixed with a solution of 16 g of sodium acetate in 35 ml of water within 5 min. After stirring at 70° C. for 1 hour, N-methylformanilide and o-dichlorobenzene were removed with a steam distillation. 250 ml of methylene chloride were added to the distillation bottoms. The organic phase was removed and filtered through silica gel. The filtrate was concentrated and dried at 40° C. under reduced pressure. 5.05 g (93% of theory) of analytically pure greenish powder having a melting point of 136-140° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>O1CCCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Yield: 46.7 %

Procedure:
In a manner similar to the method described in Example 38b, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (85 mg, 0.14 mmol) was reacted with acetyl chloride (13 mg, 0.17 mmol), triethylamine in tetrahydrofuran to give the title compound as a white solid (Yield: 43 mg).
Reaction SMILES: F[C:2]1[C:3]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O[C@H]1CCC[C@@H](c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CCC[C@@H](O)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 180 °C

Procedure:
A mixture of (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol (140 mg, 0.713 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (340 mg, 1.427 mmol), and cesium carbonate (465 mg, 1.427 mmol) in NMP (1.8 ml) was heated in a Biotage™ microwave reactor at 180° C. for 45 min. The mixture was partitioned between H2O(10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone as a brown foam. MS (ESI, pos. ion) m/z: 415.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[BH4-].[Na+].C[OH:23]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:5]([CH:4]([OH:23])[CH3:3])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the ester from Example 1, step C, (1.50 g, 5.88 mmol), in methanol (20 ml) at 0° C., was added sodium borohydride (1.0 g, 26.3 mmol) portionwise over 5 minutes. The reaction was stirred at 0° C. for 1 hr and then at room temperature for an additional 1 hr. The reaction was quenched by the addition of sat.NH4Cl solution and the methanol was evaporated in vacuo. The residue was partitioned between EtOAc and sat NaHCO3 solution and the organic extracts dried (MgSO4), and evaporated in vacuo. The residue was purified by chromatography (SiO2, 4 to 10% methanol in methylene chloride, gradient elution) to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:37]1([CH2:36][O:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]3[CH3:34])=[CH:3][C:2]=2[F:1])[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and (bromomethyl)cyclopropane (0.64 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 48 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.95 g, 85%).