Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:5][CH2:3][CH:2]([NH2:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCC(N)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC(N)CN
Yield: 69 %

Procedure:
To a slurry of 2-aminoeicosanamide prepared as in Example 28C (57.5 g, 0.176 mol) in anhydrous THF (1.0 l) under a dry argon atmosphere was added a solution of lithium aluminum hydride (880 ml-1.0M in THF, 0.880 mol) over a 30 min period. The mixture was refluxed for 17.5 h and then quenched by the dropwise addition of H2O (100 ml) while cooling in an ice bath. The solid was filtered, washed with hot THF (2×1 l) and then hot methanol (1 l). The solids were then refluxed with THF (1 l) for 15 min and filtered again. The filtrates and washings were combined and the solvent was removed in vacuo. The crude product was dissolved in THF and solid impurities were removed by filtration. The solvent was again removed in vacuo and the procedure was continued using CH2Cl2. The crude product was recrystallized from CH2Cl2 -hexane to give 37.9 g (69% yield) of the product as: mp 98°-101° C.; 1H NMR (CDCl3) δ 0.91 (t, J=6.5 Hz, 3 H), 1.33 (m, 34 H), 1.96 (br s, 4 H), 2.52 (m, 1 H), 2.78 (m, 2 H).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][CH2:31][N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:28])=[O:27]
Reactant: COCCCBr
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: COCCCN1C(c2cn(CC(=O)O)c3ccc(C)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 3-bromo-1-methoxy propane. 1H NMR (DMSO-d6) 7.95-7.92 (m, 1H), 7.60 (d, J=3.6 Hz, 1H), 7.58 (s, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.79 (t, J=7.5 Hz, 1H), 5.89 (s, 1H), 4.57 (s, 2H), 3.44-3.03 (m, 4H), 3.01 (s, 3H), 2.45 (s, 3H), 1.71 (quint., J=6.6 Hz, 2H); MS: ESI (negative): 427 (M−H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>C(OCC)C>[O:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([C:19]([F:20])([F:22])[F:21])([OH:23])[CH2:4][OH:3])[C:18]=2[O:17][CH2:16]1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cccc2c1OCO2)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CC(O)(CO)C(F)(F)F)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
12.5 g (36.03 mmol) of 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanoic acid ethyl ester is introduced into 430 ml of diethyl ether and mixed in portions with 2.05 g (54.1 mmol) of lithium aluminum hydride at 0° C. After stirring overnight at room temperature, the batch is carefully added to sodium bicarbonate solution. It is filtered by means of diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. Chromatography of the residue on silica gel (mobile solvent ethyl acetate/hexane) yields 6.7 g (61%) of the desired alcohol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCOCC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to morpholine via General Procedure B. The product was purified via reverse phase HPLC to give 8.7 mg of 252. MS (Q1) 450.8 (M)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:6]4[CH2:5][CH2:4][O:3][C:2]4=[O:1])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(CN2CCOC2=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCOC4=O)cc3)CC2)c(C)c1
Yield: 86.9 %

Procedure:
Using 4-(2-oxooxazolidin-3-ylmethyl)benzoic acid (133 mg) described in Preparation Example 62 and 1-(3,5-dimethylpyridin-2-yl)piperazine (115 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (206 mg) was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[N:2]=1.[N+:15]([O-])([O-:17])=[O:16].[K+].[NH4+].[OH-]>OS(O)(=O)=O>[N+:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[N:2]=[CH:1]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1cc2ccccc2cn1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CC(=O)Nc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-(isoquinolin-3-yl)acetamide (3.89 g, 20.9 mmol) in concentrated H2SO4 (40 mL) was cooled to 0° C. and solid potassium nitrate (2.53 g, 25.1 mmol) was added slowly in portions over 10 min. After stiffing for 1 h at 0° C., the reaction mixture was poured over ice (50 g), and neutralized with concentrated NH4OH solution. The resulting yellow solid was collected by vacuum filtration, washed with water, and dried in the vacuum oven at ambient temperature for 48 hours. This material was triturated with 1:1 CH3OH—CH2Cl2, collected by filtration, washed with CH2Cl2, and dried under vacuum. This provided 4.14 g of the title compound as a yellow solid in approximately 60% purity. MS (ESI+) m/z 232 (M+H)+.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.C(Cl)(=O)C.O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([C:2](=[O:4])[CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)Cl
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.25 g (3.5 mmol) of acetyl chloride is then added and the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is washed with water to neutrality. The solution is dried over magnesium sulfate and then concentrated. A honey-like product is obtained which is purified by chromatography on a silica column. The purified product crystallizes from diisopropyl ether. 0.25 g of Compound 23 is obtained in the form of a white powder melting at 132° C.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]([F:21])([F:20])[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)(=[O:10])=[O:9].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]3[CH2:40][O:39]3)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>O1CCOCC1.C(OCC)(=O)C.N.CO>[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]([OH:39])[CH2:40][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[S:8]([C:7]([F:20])([F:6])[F:21])(=[O:9])=[O:10])[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: COc1cccc(NS(=O)(=O)C(F)(F)F)c1
Agent: N
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
N-butyllithium (2.5 M in hexanes, 48 ml) was added dropwise to an ice-cooled solution of 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (22.07 g, 86.5 mmol) in dry dioxane (145 ml) over a 40 minute period. The solution was then stirred at rt for 15 minutes before addition of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (25.05 g, 65.7 mmol), followed by heating at 90° C. for an hour. These conditions were optimized to maximize conversion while minimizing formation of an aziridene by-product. The reaction was allowed to cool to rt then diluted with 1.2 L ethyl acetate and washed several times with water and finally brine. The organic layer was dried over MgSO4, filtered and condensed to give an orange viscous mixture. To this mixture was added 150 ml of 60% methylene chloride/hexanes, and the solution was then concentrated to generate a yellow foam (presumably this procedure helps remove residual ethyl acetate and/or dioxane). A further 150 ml of 60% methylene chloride/hexanes was added and stirred overnight. The mixture was filtered and washed several times with 60% methylene chloride/hexanes until the solid was white giving 20.1 g of 99% purity. A second crop gave 2.98 g in 91% purity. Filtrates and washings were combined and found to contain a 2:2.6:1 mixture of SM: product: aziridene by-product. This mixture was subjected to amination conditions by heating the mixture (24 g in approximately 2 equal portions) in ammonia in methanol (7N, 11 and 8 ml, respectively) at 100° C. in sealed pressure tubes overnight. Epoxide SM is converted to β-hydroxy amine (MacMillan et al., J. Am. Chem. Soc. 2011, 133, 1428), which aids chromatographic purification. Column chromatography in 80% DCM/hexanes gave a further 9.7 g of product with an overall yield of 32.78 g and 78%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:17].[C:11]1([CH:9]([O:8][C:7]2[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH3:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: CC(Oc1cccnc1N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(Oc1cccnc1NC(=N)Cc1ccccc1)c1ccccc1
Yield: 14.3 %

Procedure:
A mixture of 2-amino-3-(1-phenylethoxy)pyridine (4.28 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave a residue which was purified by chromatography (silica, chloroform/methanol) to obtain the product (1.05 g), m.p. 75°-80° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=1)#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:59]=1)#[N:51]
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4C#N)c3)c(=O)oc12
Temperature: 25 °C
Yield: 85.2 %

Procedure:
DIEA (0.015 mL, 0.085 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.017 g, 0.077 mmol) and HATU (0.032 g, 0.085 mmol) in 0.45 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-cyano-biphenyl-3-ylamine (0.015 g, 0.077 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.026 g of product in 85% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:32]([O:34]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:38][NH2:39]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:32](=[O:34])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(F)(F)F)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.30 mmol) and hydrazine monohydrate (0.5 mL) in methanol (10 mL) was stirred at 30° C. overnight. The mixture was concentrated under reduced pressure to give crude product, which was purified by flash chromatography to give the title compound (60 mg, yield 34.5%) as a white solid. LC-MS (ESI) m/z: 465 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.64 (s, 3H), 2.65 (s, 3H), 4.19-4.20 (d, J=4.0 Hz, 2H), 4.53-4.55 (d, J=9.2 Hz, 1H), 4.88-4.90 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.35-7.46 (m, 7H), 7.50 (s, 1H), 7.56-7.63 (m, 3H), 9.69-9.71 (br s, 1H), 12.20 (s, 1H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.Br[C:31]1[N:32]=[CH:33][CH:34]=[N:35][CH:36]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:5]1[CH:6]=[C:2]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[N:3]=[CH:4]1
Reactant: Brc1cnccn1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1cnc(-c2c[nH]cn2)cn1
Reaction time: 1.5 h

Procedure:
To a solution of 4-Iodo-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine) palladium (10%) and 5-bromopyrazine (1.3 eq) were added to the reaction mixture. Subsequent reaction conditions and work up are as described previously in Example 73, the resulting solid 2-(1H-Imidazol-4-yl)-pyrazine (37%) was collected by filtration. MH+(147).
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[CH:15]1)[CH3:10])C1C=CC=CC=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[Cl:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][N:14]2[CH2:13][CH2:12][C@@H:11]([N:24]2[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]2)[C@@H:9]([OH:8])[CH3:10])=[CH:18][CH:19]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCn1ccc2ccc(Cl)cc21)n1cnc(C(N)=O)c1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: C[C@H](O)[C@@H](CCn1ccc2ccc(Cl)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 52.7 %

Procedure:
To an ice cooled solution of 1-[(2S,3R)-2-benzyloxy-5-(6-chloroindol-1-yl)-3-pentyl]imidazole-4-carboxamide (47.9 mg, 0.110 mmol) in chloroform (5 ml) was added trimethylsilyl iodide (42.6 mg, 0.213 mmol). After 3 minutes, the ice bath was removed, and then stirred at room temperature for 3 hours. The reaction was quenched by addition of methanol. This mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (1.5 g) chromatography eluting with chloroform/methanol (50:1 to 10:1) to give 1-[(2S,3R)-5-(6-chloroindol-1-yl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (20.1 mg, 52.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19]Cl)[CH:3]=1.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>C(Cl)Cl>[CH2:21]([N:24]([CH2:19][CH2:18][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]
Reactant: CCCNCCC
Reactant: ClCCCc1cc(Cl)ccc1OCCc1ccccc1
Solvent: ClCCl
Product: CCCN(CCC)CCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 120 °C
Reaction time: 39 h

Procedure:
To 604 mg of the crude 4-chloro-2-(3-chloropropyl)-1-(2-phenylethoxy)benzene, was added 5 ml of di-n-propylamine and the resulting mixture was stirred at 120° C. for 39 hours. After diluting with methylene chloride, the mixture was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:n-hexane =1:5) to give 0.50 g of N,N-di-n-propyl-3-[5-chloro-2-(2-phenylethoxy)phenyl]propylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:40])C=1Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)=[CH:11][C:12]2[C:13](=[O:40])[CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C(O)c1ccc(CCCc2cc3c(cc2OCc2ccccc2)CCCC3)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(CCCc2cc3c(cc2OCc2ccccc2)CCCC3=O)cc1
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-[3-(3-benzyloxy-5,6,7,8-tetrahydro-2-naphthyl) propyl]benzoic acid (1.6 g) in ethyl acetate (50 ml) was added water (1 ml) and 2,3-dichloro-5,6-dicyanobenzoquinone (1.9 g). The mixture was stirred for 2 hours, the solvent evaporated and the residue subjected to chromatography on silica gel, eluting with 0.1% formic acid in EtOAc. The residue was purified by trituration with diethyl ether to give the title compound (0.3 g) mpt. 155°-160° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O1CCN(C2C(N)=CC(N3CCOCC3)=CN=2)CC1.[O:54]1[CH2:59][CH2:58][N:57]([C:60]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[CH:63][C:61]=2[NH2:62])[CH2:56][CH2:55]1.Cl[C:74]1[C:83]2[C:78](=[C:79]([CH3:85])[CH:80]=[CH:81][C:82]=2[F:84])[N:77]=[C:76]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][N:87]=2)[C:75]=1[CH3:92].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:57]1([C:60]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:68][CH2:69][O:70][CH2:71][CH2:72]3)=[CH:63][C:61]=2[NH:62][C:74]2[C:83]3[C:78](=[C:79]([CH3:85])[CH:80]=[CH:81][C:82]=3[F:84])[N:77]=[C:76]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][N:87]=3)[C:75]=2[CH3:92])[CH2:58][CH2:59][O:54][CH2:55][CH2:56]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(C)ccc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(C)ccc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (27.0 mg, 0.056 mmol), 2,5-dimorpholinopyridin-3-amine (37.0 mg, 0.140 mmol), 2,5-dimorpholinoaniline (55.0 mg, 0.21 mmol), 4-chloro-5-fluoro-3,8-dimethyl-2-(pyridin-2-yl)quinoline (100.0 mg, 0.35 mmol) and Pd2dba3 (13.0 mg, 0.014 mmol) in toluene (3.5 mL) was added sodium t-butoxide (84.0 mg, 0.87 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (3×10 mL) and DCM (1×10 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 to 100% EtOAc in DCM) to give the desired products N-(2,5-di-4-morpholinylphenyl)-5-fluoro-3,8-dimethyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (1H, br. m.), 8.22 (1H br m), 8.02-8.12 (1H, m), 7.89 (1H, br. m.), 7.40 (2H, m), 7.28 (1H, m), 6.98-7.15 (2H, m), 6.24 (1H, br. s.), 3.87-4.00 (4H, br m), 3.80 (4H, br m), 3.09 (8H, br. m.), 2.77 (3H, s), 2.32 (3H, s); Mass Spectrum (ESI) m/e=514.3 (M+1). Further elution gave N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3,8-dimethyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.68 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.08 (1H, d, J=7.8 Hz), 7.90 (1H, m), 7.82 (1H, br d), 7.60 (1H, d, J=2.5 Hz), 7.40-7.48 (1H, m), 7.37 (1H, m), 7.07 (1H, dd, J=13.6, 7.9 Hz), 6.47 (1H, br. s.), 3.88-4.00 (4H, m), 3.75-3.85 (4H, m), 3.23 (4H, br. s.), 3.03-3.13 (4H, m), 2.78 (3H, s), 2.31 (3H, s); Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cccc(C(=O)OC)c2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1[nH]c2c(C(=O)OC)cccc2c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(n-butyl)indole-7-carboxylate (P) (0.3 g) in 6 ml of dimethylformamide at room temperature was added N-chlorosuccinimide (0.17 g). The solution was stirred at room temperature for 16 hours, then water was added, and the mixture extracted with ether. The extract was separated and solvent evaporated under reduced pressure, to give methyl 2-(n-butyl)-3-chloroindole-7-carboxylate, a compound of Formula (Q) where X is chloro, as an oil.