Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:16]C(=O)C)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=O)C.Br[CH2:21][C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])(O)=O.[Na+]>O1CCCC1.[Zn].C1(C=CC(O)=CC=1)O>[CH3:27][C:26]1([CH2:16][O:15][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[NH:6][C:5](=[O:4])[CH:14]=[CH:13]3)[CH2:21][C:22](=[CH2:28])[C:23](=[O:24])[O:25]1
Reactant: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Reactant: C=C(CBr)C(=O)OCC
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CC(C)(COc2cccc3ccc(=O)[nH]c23)OC1=O
Temperature: 0 °C
Yield: 68.9 %

Procedure:
To a solution of 5c (0.78 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.26 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was refluxed under nitrogen atmosphere for 6 h (monitored by TLC). After cooling, it was poured into an ice-cold 5% HCl solution (300 ml), neutralized with 1.0N NaHCO3, and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with water, dried over Na2SO4, and then evaporated to give a residual oil which was purified by column chromatography on silica gel using CH2Cl2 as the eluent to afford the title compound (0.59 g, 60%). UV λmax (log ε): 258 (4.70) (0.1N HCl in MeOH), 246 (4.69) (MeOH), 261 (4.59) (0.1N NaOH in MeOH); 1H-NMR (CDCl3): δ1.61 (s, 3H, 2'-CH3), 2.78 (dt, 1H, 3'-H), 3.17 (dt, 1H, 3'-H), 4.50 (s, 2H, OCH2), 5.65 (t, 1H, vinylic H), 6.29 (t, 1H, vinylic H), 6.91 (d, 1H, 3-H), 7.18-7.41 (m, 3H, Ar--H), 8.02 (d, 1H, 4-H). Anal Calcd for C16H15NO4 : C, 67.36; H, 5.30; N, 4.91. Found: C, 67.38; H, 5.32; N, 5.00.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([OH:6])=O.[CH2:16]1[CH:20]2[CH2:21][NH:22][CH2:23][CH:19]2[CH2:18][N:17]1[C:24]1[N:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[N:25]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([N:22]1[CH2:21][CH:20]2[CH2:16][N:17]([C:24]3[N:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[N:25]=3)[CH2:18][CH:19]2[CH2:23]1)=[O:6]
Reactant: Cc1cc(C#N)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Product: Cc1cc(C#N)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 12 and Intermediate 49. MS (ESI): mass calculated for C21H19F2N8O, 418.44; m/z found 419.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.91-7.80 (m, 2H), 7.75 (s, 1H), 7.55-7.42 (m, 1H), 7.15 (ddd, J=8.4, 6.6, 4.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.07-3.46 (m, 7H), 3.35-3.20 (m, 1H), 3.19-2.94 (m, 2H), 2.40 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH2:33][NH:34][CH3:35])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:56][S:57](Cl)(=[O:59])=[O:58].C(=O)([O-])O.[Na+]>ClCCl>[F:48][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:35])[S:57]([CH3:56])(=[O:59])=[O:58])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of 65 mg (95 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[(methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 58, in 0.2 ml of dichloromethane, 30 μl (0.19 mmol) of triethylamine and 8 μl (0.1 mmol) of methanesulfonyl chloride were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-40/60 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 37 mg of the title compound as a white solid (yield: 52%).
Reaction SMILES: C(Cl)(Cl)=O.[CH3:5][O:6][C:7](=[O:19])[C@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:9][CH:10]=O.CN1CCOCC1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:19])[CH:8]([N+:9]#[C-:10])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC=O
Agent: O=C(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: [C-]#[N+]C(Cc1ccccc1)C(=O)OC

Procedure:
A solution of phosgene (5.2 g, 0.052 mole) in dry methylene chloride (45 ml) is added dropwise to a stirred solution of N-formylphenylalanine methyl ester (10.0 g, 0.048 mole) and 1-methylmorpholine (13 g, 0.125 mole) in dry methylene chloride (25 ml) at -30° C. After completion of the addition the filtrate is concentrated under reduced pressure at room temperature. Benzene is added to the residue followed by filtration and concentration of the resulting solution. The residue is distilled to afford the title compound as a yellow oil, b.p. 97° C/0.3 mm, νmaxCHCl3 2150, 1746, 1595, 1578, 1489, 694 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.O1CCCC1.B>O1CCCC1>[OH:9][CH2:8][CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)COc1ccc(O)cc1
Agent: B
Solvent: C1CCOC1
Product: OCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 4-hydroxyphenoxyacetic acid (4.9 g, 29 mmol) (Aldrich) in anhydrous tetrahydrofuran (30 mL) at 0° C. was added borane tetrahydrofuran (1 M, 90 mL, 90 mmol) dropwise. The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give title compound as a yellow oil (4.2 g, 94%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:20][O-].[Na+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:20])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: C[O-]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of compound 1 was dissolved in 30 ml of dimethylformamide and the solution was stirred at room temperature. 258 mg of sodium methoxide was added to the solution, followed by stirring for 30 minutes. Then,678 mg of methyl iodide was added dropwise to the solution and the reaction was continued for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, followed by addition of ethyl acetate and washing with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The obtained crude product was recrystallized from ethanol to give 3-(p-methoxybenzoyl)-N-methylindole (compound 8) in the form of white platy crystals. (Yield: 94%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:12]2[CH:25]=[C:24]3[C:15]([O:16][CH2:17][CH2:18][N:19]4[C:23]3=[N:22][C:21]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][N:27]=3)=[CH:20]4)=[CH:14][CH:13]=2)[CH3:11])[CH2:7]1)(=O)=O.[CH3:34][NH:35][CH3:36]>O1CCOCC1>[CH:31]([N:30]1[C:26]([C:21]2[N:22]=[C:23]3[C:24]4[CH:25]=[C:12]([CH:10]([N:8]5[CH2:7][CH:6]([N:35]([CH3:36])[CH3:34])[CH2:9]5)[CH3:11])[CH:13]=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:27][CH:28]=[N:29]1)([CH3:32])[CH3:33]
Reactant: CNC
Reactant: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(OS(C)(=O)=O)C1
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(N(C)C)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl)azetidin-3-yl methanesulfonate from Example 162 (70 mg, 0.15 mmol) and dimethylamine (68 mg, 1.5 mmol) in 1,4-dioxane (4 mL) was stirred at 80° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 168. The enantiomers were separated by chiral HPLC (OJ-H column, 2% EtOH (0.1% DEA) in n-hexane isocratic) to give: 9 mg of one enantiomer and 5 mg of the other (23% total yield).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1COCC1>[CH3:11][O:10][C:3]1[C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: COc1ncnc(OC)c1Br
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ncnc(OC)c1-c1ccncc1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A mixture of 5-bromo-4,6-dimethoxypyrimidine (2.18 g, 10 mmol), pyridine-4-boronic acid (1.85 g, 15 mmol), K2CO3 (2.76 g, 20 mmol), and PXPd (539 mg, 1.0 mmol) in ethanol/THF (1:1, 25 mL) under argon was heated at 70° C. for 3 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, the solvent mixture was removed under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (1.79 g) as a white solid. 1H NMR (CDCl3): δ 3.97 (s, 6H), 7.36 (d, 2H), 8.47 (s, 1H), 8.64 (d, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]([OH:18])=O)[N:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:32][NH:33][CH:34]([CH2:36][CH3:37])[CH3:35]>C(Cl)(Cl)Cl>[CH3:32][N:33]([CH:34]([CH3:35])[CH2:36][CH3:37])[C:16]([C:8]1[N:7]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:18]
Reactant: CCC(C)NC
Reactant: O=C(O)c1cc2ccccc2c(-c2cccs2)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2cccs2)n1
Yield: 65.6 %

Procedure:
Operations are carried out as for Example 7, starting from 3 g of 1-(2-thienyl) isoquinoline 3-carboxylic acid, 1.73 g of triethylamine, 1.86 g of ethyl chloroformate and 1.69 g of N-methyl 2-butanamine in 150 ml of chloroform. 2.5 g of N-methyl N-(1-methyl propyl) 1-(2-thienyl) isoquinoline 3-carboxamide, melting at 146° C. are obtained.
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>C(Cl)(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][NH:34][CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(F)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Solvent: ClC(Cl)Cl
Product: Fc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Yield: 91.8 %

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 37a and running the reaction in chloroform. The crude brownish oily residue was used without further purification in the next reaction step. Yield: 91.8%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OC(C)C)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=S(=O)(c1ccc(I)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 g of 4-iodobenzenesulphonyl chloride (0.165 mol) in 500 ml of CH2Cl2 there are added 46 ml of triethylamine (0.33 mol) and then, dropwise, 17 ml of morpholine (0.198 mol). Because the reaction is exothermic, the flask is placed in an ice bath until it has returned to ambient temperature. The reaction mixture is stirred for 1 hour at ambient temperature. After washing the reaction mixture with about 100 ml of 1N HCl and then 100 ml of water, the organic phase is dried (MgSO4) and evaporated under reduced pressure. The solid residue thereby obtained is re-suspended in a small amount of isopropyl ether to yield the title product after filtration and drying in vacuo.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=S)[S-:19])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C([NH+](CC)CC)C.ClC(OC)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=2)=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(-c2ccc(NC(=S)[S-])cc2)nc1
Agent: CC[NH+](CC)CC
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1cnc(-c2ccc(N=C=S)cc2)nc1
Temperature: 0 °C
Yield: 81 %

Procedure:
6.77 g of triethylammonium p-(5-butyl-2-pyrimidinyl)-phenyldithiocarbamate were largely dissolved in 60 ml of chloroform and 2.5 ml of triethylamine. The mixture was subsequently treated dropwise with 2.00 ml of methyl chloroformate within 5 minutes while stirring and cooling with an ice bath The ice bath was removed after 10 minutes. After a further 60 minutes the yellowish solution was washed once with 20 ml of 0.5 N hydrochloric acid and three times with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on 60 g of silica gel with hexane/ethyl acetate (vol. 95:5) gave 3.65 g of p-(5-butyl-2-pyrimidinyl)phenyl isothiocyanate which was recrystallized twice from hexane for further purification. Yield 3.17 g; m.p. (C-S) 60.8° C., cl.p. (S-I) 77.8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15].CCCCCC.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OCCNCCO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)c(F)c1
Temperature: 140 °C
Yield: 90.4 %

Procedure:
In 4 ml of DMSO, 5.0 g (31.4 mmol) of 3,4-difluoronitrobenzene and 8.3 g (78.5 mmol) of diethanolamine were dissolved, followed by stirring under heat at 140° C. for one hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated. To the reddish brown syrup so obtained, n-hexane/ethyl acetate was added for crystallization, whereby 6.93 g of the title compound were obtained as yellow powder (yield: 90%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([C:27](=[O:29])[CH3:28])=[C:25]([Cl:30])[N:24]=[C:23]3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:27]([C:26]1[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][CH:17]=2)[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:24][C:25]=1[Cl:30])(=[O:29])[CH3:28]
Reactant: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 24 h
Yield: 97.5 %

Procedure:
1.0 g of 4′-(5-acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid tert-butylamide and 230 μl of anisole are dissolved in 5 ml of trifluoroacetic acid and allowed to stand at RT for 24 h. The volatile constituents are then removed in vacuo and the residue is digested with 50 ml of heptane. 870 mg of an amorphous solid are obtained.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>CC(O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc2c(c1)OCO2)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,4-methylenedioxybenzaldehyde (15.013 g, 0.1 mol), benzyl acetoacetate (20.18 g, 0.105 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (500 mL) was stirred at room temperature for 48 hours. The white solid, benzyl 2-{(3,4-methylenedioxyphenyl)methylene}-3-oxobutyrate, formed was filtered, washed with 2-propanol (2×50 mL) and dried (29.84 g, 92%); m.p. 137-138° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH2:10][CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][C:17]([CH3:23])([CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(CO)cn2)cc1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of ethyl 2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (500 mg; 0.94 mmol) in 7 ml of methanol was cooled in an ice bath and treated with sodium borohydride (65 mg; 1.7 mmol) in small portions. After 30 minutes, the reaction mixture was concentrated and the residue partitioned between ethyl acetate and saturated brine. The organic phase was washed with water and the combined aqueous phases reextracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (5–50% gradient) afforded ethyl 2-[4-(2-{[5-(hydroxymethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (450 mg; 85% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:14]2[N:15]=[CH:16][C:17]3[N:23]([CH3:24])[C:22](=[O:25])[CH:21]([CH3:26])[CH2:20][N:19]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:18]=3[N:33]=2)[CH3:13])=[C:8]([O:34][CH3:35])[CH:7]=1.O1CCCC1>CO>[CH:27]1([N:19]2[CH2:20][CH:21]([CH3:26])[C:22](=[O:25])[N:23]([CH3:24])[C:17]3[CH:16]=[N:15][C:14]([N:12]([CH3:13])[C:9]4[CH:10]=[CH:11][C:6]([C:5]([OH:36])=[O:4])=[CH:7][C:8]=4[O:34][CH3:35])=[N:33][C:18]2=3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc(N(C)c2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1N(C)c1ncc2c(n1)N(C1CCCCC1)CC(C)C(=O)N2C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
An aqueous solution of sodium hydroxide (2N, 1.0 mL, 2 mmol) was added A mixture of 0.170 g (0.00036 mole) of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid methyl ester, 6 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of 2M sodium hydroxide was heated at 75 degrees for 4 hours. The mixture was concentrated under reduced pressure and then azeotroped with toluene and concentrated under reduced pressure, The solid residue was triturated with ethyl acetate. The solid was then suspended in water and treated with 1M hydrochloric acid to pH=4. After stirring 30 minutes, the solid was collected, washed with water and dried to give 0.080 g of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:11][CH:10]=2)#[N:13]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(F)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(F)c3)c2c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 28.1 %

Procedure:
Dissolved 1.00 g (3.37 mmol) 6-amino-4-[(3,4-difluorophenyl)amino]-3-quinolinecarbonitrile in 2 ml DMF, added 12 ml THF, and chilled to 0° C. under N2. Added 517 μl (3.71 mmol) triethylamine and 310 μl (3.72 mmol) acryloyl chloride. Removed ice bath a 15 minutes. At 3.5 hours stripped solvent and slurried residue with dilute sodium bicarbonate. Collected solids, washed with water, and air dried. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 332 mg of yellow solid: mass spectrum (electrospray m/e): M+H=351.1.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[BH4-].[Na+]>>[CH:24]1([CH2:30][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)=[CH:22][CH:23]=3)[CH2:3]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(CC4CCCCC4)C3)cc2)nc1
Yield: 18.6 %

Procedure:
Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.96 mL of 0.12 M stock solution in methanol, 0.0344 g, 0.116 mmol) and cyclohexanecarboxaldehyde (0.021 mL, 0.173 mmol), and stir overnight. Add sodium borohydride (0.0108 g, 0.285 mmol), stir for 4.5 h, then concentrate and purify by silica gel chromatography (20:1→10:1 ethyl acetate:methanol) to provide 0.0085 g (19%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H32N3O2 394.2495, found 394.2488; 1H NMR (CDCl3): 8.58 (s, 1H), 8.14 (d, 1H, J=7.8 Hz), 7.27 (d, 2H, J=8.3 Hz), 7.05 (d, 2H, J=7.8 Hz), 6.93 (d, 1H, J=8.8 Hz), 5.89 (s br, 2H), 2.99-2.77 (m, 3H), 2.16-2.06 (m, 2H), 1.97-1.83 (m, 3H), 1.80-1.59 (m, 7H), 1.54-1.34 (m, 2H), 1.29-1.03 (m, 5H), 0.93-0.77 (m, 3H).