Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH3:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:37]3[CH:36]=[N:35][C:34]([CH3:33])=[CH:42][CH:41]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: Cc1ccc(C(=O)O)cn1
Product: Cc1ccc(C(=O)N2CCN(c3nc4cc(F)cc(F)c4c(Nc4cncc(N5CCOCC5)c4)c3C)CC2)cn1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and 6-methylnicotinic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(6-methylpyridin-3-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.09 (br s, 3H), 2.50-2.52 (m, 4H), 3.03-3.05 (m, 4H), 3.33-3.40 (m, 3H), 3.55 (br s, 2H), 3.67-3.69 (m, 4H), 3.82 (br s, 2H), 6.49 (s, 1H), 7.14-7.20 (m, 1H), 7.30-7.26 (m, 1H), 7.35-7.37 (m, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.78 (br s, 2H), 8.37 (s, 1H), 8.54 (d, J=2.4 Hz, 1H). Mass Spectrum (ESI) m/e=560.4 (M+1).
Reaction SMILES: [O:1]=[C:2]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[NH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH-].[NH4+:23].Cl>>[O:1]=[C:2]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[NH:8][CH:7]=1)[C:3]([NH2:23])=[O:4]
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccc(Oc3ccccc3)cc12
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NC(=O)C(=O)c1c[nH]c2ccc(Oc3ccccc3)cc12
Yield: 96.4 %

Procedure:
Combine 2-oxo-(5-phenoxy-1H-indol-3-yl)acetyl chloride (2.15 g, 7.18 mmol), and ammonium hydroxide (28-30%, 32 ml, 680 mmol) and stir for 2 hours. Pour the reaction mixture into 10% (aq.) HCl, extract with dichloromethane, combine the organic layers and dry over Na2SO4, evaporate solvent in vacuo to give 1.94 g (96%) of title compound: 1H NMR (300 MHz, CDCl3) 4.87 (s, 2H), 7.51-7.91 (m, 7H), 8.13-8.24 (m, 3H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:23][CH:22]3[CH:24]([CH2:35][OH:36])[O:25][CH:26]([N:27]4[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]4=[O:34])[CH:21]3[O:20]2)=[CH:15][CH:14]=1)C.Cl>O.CO>[O:34]=[C:28]1[NH:29][C:30](=[O:33])[CH:31]=[CH:32][N:27]1[CH:26]1[CH:21]2[CH:22]([O:23][CH:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:18][CH:17]=3)[O:20]2)[CH:24]([CH2:35][OH:36])[O:25]1
Reactant: CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCOc1ccc(C2OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of NaOH (12.6 g, 315 mmol) in H2O (100 mL) was added to a suspension of 6 (50 g, 102 mmol) in MeOH (750 mL) and stirred for 8 h at room temperature. Approximately half of the solvent was removed in vacuo and the remainder was treated dropwise with 1 M aqueous HCl (315 mmol, 315 mL). The white precipitate was filtered, washed with H2O (2×200 mL) and Et2O (3×200 mL) and dried in vacuo to afford a white powder (15, 46.7 g, 100 mmol, 99%) as a mixture of two diastereomers: M.p.: 158-160° C.; 1H-NMR (400 MHz, (CD3)2SO3) δ=11.95 (s, 1H, 1H′), 11.38 (s, 1H, 1H′), 7.85 (d, J=8.0, 1H), 7.77 (d, J=8.0, 1H′), 7.41 (d, J=8.5, 2H), 7.37 (d, J=8.5, 2H′), 6.96 (d, J=8.5, 2H), 6.93 (d, J=8.5, 2H′), 6.04 (s, 1H′), 5.93 (m, 1H, 1H′), 5.90 (s, 1H), 5.64 (d, J=8.0, 1H), 5.63 (d, J=8.0, 1H′), 5.2 (broad, 1H, 1H′), 4.99-4.83 (m, 2H, 2H′), 4.23 (m, 1H), 4.13 (m, 1H′), 3.97 (m, 2H, 2H′), 3.62 (m, 2H, 2H′), 2.20 (m, 2H, 2H′), 1.70 (m, 2H, 2H′, 1.54 (m, 2H, 2H′), 1.41 (m, 2H, 2H′); 13C -NMR (400 MHz, (CD3)2SO3) δ=176.0, 176.0, 164.1, 164.1, 160.6, 160.5, 151.2, 151.2, 143.0, 143.0, 129.3 (2C), 129.3 (2C), 128.9, 128.9, 115.1 (2C), 115.0 (2C), 107.4, 103.4, 102.8, 102.6, 92.2, 91.3, 87.3, 85.1, 84.8, 83.7, 82.6, 80.8, 68.3, 68.3, 62.2, 62.2, 35.1, 35.1, 29.3, 29.3, 26.1, 26.1, 25.4, 25.4; IR (film) ν=3467, 3132, 2938, 1696, 1677, 1245, 1108, 1077, 1046, 1019, 976, 828, 809; HRMS (MALDI-FTMS) m/z 485.1534 (485.1536 calculated for C22H26N2O9Na (M+Na)+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Nc1ccc(B(O)O)cn1
Product: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and 6-aminopyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.963 min, m/z=431.8; 1H NMR (CDCl3) 1.36 (d, 3H), 1.75 (m, 1H), 1.98 (m, 3H), 2.21 (m, 1H), 2.38 (m, 2H), 2.89 (m, 1H), 3.56 (m, 2H), 5.05 (s, 1H), 5.65 (m, 1H), 6.62 (d, 1H), 6.97 (d, 2H), 7.17 (d, 2H), 7.20-7.39 (m, 5H), 7.63 (d, 1H), 8.12 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([CH3:9])=[C:6]([F:8])[CH:7]=1>C(O)C.O.Cl.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[C:4]([NH2:10])[CH:3]=1
Reactant: Cc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(N)cc(Br)cc1F

Procedure:
A mixture of 5-bromo-1-fluoro-2-methyl-3-nitro-benzene (9.96 g) and iron powder (11.9 g) in ethanol (100 ml), water (20 ml) and concentrated hydrochloric acid (2 ml) was heated at reflux for one hour. After cooling, the reaction mixture was filtered through hyflo (calcined diatomaceous earth) and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:9 to 1:4). Yield: 7.06 g of 5-bromo-3-fluoro-2-methyl-phenylamine as an oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.[C:40]1([N:46]=[C:47]=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:21][C:20]1[N:15]2[C:14](=[O:22])[N:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH:4]([NH:3][C:47]([NH:46][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH2:17][C:16]2=[CH:18][N:19]=1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccccc3)c3ccccc3)CC1)C2
Yield: 60.1 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) and DBU (0.15 g) were dissolved in acetonitrile (10 ml). Phenyl isocyanate (66 mg) was added thereto, and mixed at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) and solidified with ethyl acetate and diethyl ether to obtain the title compound (0.14 g, 59%) as colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([CH2:11][C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[C:7](=[O:18])[C:6]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: O=c1c2cc(Br)ccc2nnn1Cc1cccnc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2nnn1Cc1cccnc1
Yield: 49.4 %

Procedure:
A mixture of 10.0 g of 6-bromo-3-(3-pyridylmethyl)-1,2,3-benzotriazin-4 (3H)-one, 6.1 g of 4-chlorophenol, 9.4 g of cupric oxide, 13.1 g of potassium carbonate and 100 ml of pyridine was refluxed under heating for 9 hours. After finishing the reaction, the insoluble material was filtered off, and the filtrate was concentrated in vacuo. The resulting residue was chromatographed on a column of silica gel, developing with ethyl acetate/hexane=1:1 and then recrystallized from hexane-methylene chloride to give 5.68 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([NH2:14])[CH3:13]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:14][CH2:12][CH3:13])=[S:10])[CH:7]=1
Reactant: CCN
Reactant: Cc1ccc(F)cc1N=C=S
Product: CCNC(=S)Nc1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Fluoro-2-methylphenyl isothiocyanate (16.7 g; 0.1 mol) was added dropwise to aqueous ethylamine (120 mL of 70% solution). The mixture was stirred for 2 hour at ambient temperature. Excess ethylamine was removed under a stream of nitrogen. The residue was diluted with water. The solids were collected by filtration, washed with water and dried. The solid was dissolved in ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate then evaporated to dryness to give N-(5-fluoro-2-methylphenyl)-N′-ethylthiourea (18.5 g), m.p. 93–95° C. Mass spectrum; (El, M.+) m/z 212. 1H-NMR (DMSO-d6; 300 MHz): δ 9.01 (br s, 1H), 7.66 (br s, 1H), 7.25–7.18 (m, 2H), 6.96 (m, 1H), 3.45 (m, 2H), 2.13 (s, 3H), and 1.09 ppm (t, 3H).
Reaction SMILES: C([NH:8][C@H:9]([C:17]([CH:19]1[C:26]2([NH2:28])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:29][C:20]1([C:30]([O:32][CH3:33])=[O:31])[CH2:21]3)[CH2:25]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][C@H:9]([C:17]([CH:19]1[C:26]2([NH2:28])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:29][C:20]1([C:30]([O:32][CH3:33])=[O:31])[CH2:21]3)[CH2:25]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@@H](N)Cc1ccccc1)C2
Reaction time: 0.17 h

Procedure:
5.48 g of methyl Boc-phenylalanyl-3-amino-1-adamantanecarboxylate is dissolved in 15 ml of dioxane and 20 ml of a 5.9 M solution of hydrogen chloride in dioxane is added. After standing for 10 minutes at room temperature the solvent is removed under reduced pressure and the residue is stirred with diethyl ether. The crystalline product is collected by filtration, washed with diethyl ether and dried in a vacuum oven for 16 hours at 50° C. and 0.1 mm pressure to give methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR24##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22].Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1cscn1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(thiazol-4-yl)propanoic acid (Compound SP726) (800 mg, 2.94 mmol) in tetrahydrofuran (20 ml) was added dropwise to a suspension of sodium hydride (470 mg, 11.8 mmol, 60%) in tetrahydrofuran (30 ml) under a nitrogen atmosphere. Subsequently, iodomethane (1.67 g, 11.8 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was adjusted to pH 4 with 6 mol/1 aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and then concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate) to afford (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(thiazol-4-yl)propanoic acid (Compound SP727) (560 mg, 67%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1.CO>C(OCC)(=O)C.[C].[Pd]>[NH2:26][C:25]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][C:9]=1[OH:8]
Reactant: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2ccc(N)c(O)c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
To a solution of methyl 3-[3-(benzyloxy)-4-nitrophenoxy]benzoate (19.1 g, 50.4 mmol) in ethyl acetate (50 mL) were added methanol (80 mL) and 10% palladium-carbon (2.31 g), and the mixture was vigorously stirred at room temperature for 20 hr under a hydrogen atmosphere. 10% Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (13.1 g) as a brown syrup.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH-].[K+]>CO>[F:1][CH:2]([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(F)F)cc1
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Dissolve methyl 4-(difluoromethyl)benzoate (2.855 g, 15.336 mmol) in MeOH (30 mL). Add potassium hydroxide (8.41 mL 2 equivalents, 30.7 mmol), and stir the mixture for 16 hours. Concentrate the reaction mixture under reduced pressure, and add EtOAc (100 mL) and 1 N HCl (50 mL). Stir for 30 minutes. Separate the layers. Dry the organics over Na2SO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the titled compound as a white solid (2.541 g, 96% yield). 1H NMR (399.83 MHz, d6-DMSO) δ 13.29-13.28 (m, 1H), 8.04 (d, J=7.8 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.24-6.97 (t, J=55.6, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)[C:7]([Cl:19])=[CH:6][C:3]=1[CH:4]=O.[C:20]1(C)C=CC=CC=1>>[Br:1][C:2]1[CH:9]=[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)[C:7]([Cl:19])=[CH:6][C:3]=1[CH:4]=[CH2:20]
Reactant: Cc1ccccc1
Reactant: CCc1ccc(Cc2cc(Br)c(C=O)cc2Cl)cc1
Product: C=Cc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Reaction time: 1 h

Procedure:
To a suspension of Ph3PCH3I (3.151 g, 7.8 mmol) in 22 mL of dry toluene, was added dropwise with KN(TMS)2 (15.64 mL, 7.8 mmol, 0.5 M in toluene) under argon. After it was stirred for 1 h, a solution of 2-bromo-5-chloro-4-(4-ethylbenzyl)benzaldehyde (1.76 g, 5.2 mmol) in 17 mL of toluene was added. This reaction mixture was stirred at room temperature and monitored by TLC (PE, Rf=0.8). After being stirred for 4 h, the reaction mixture was quenched by addition of 5 mL of saturated NaHCO3. The organic layer was washed 2× with H2O, 2× with brine, dried over anhydrous Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by column chromatography on silica gel (PE), to give the title compound as a colorless oil. Yield: 3.0 g (96%). 1H NMR (CDCl3, 300 MHz) δ 7.54 (s, 1H), 7.33 (s, 1H), 7.14 (d, J=2.1 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.92 (dd, J=11.0, 17.6 Hz, 1H), 5.68 (dd, J=17.6, 0.9 Hz, 1H), 5.37 (dd, J=11.0, 0.9 Hz, 1H), 4.02 (s, 2H), 2.63 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].Br[C:36]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C(OCC)(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:36]4([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OC3(C(=O)OCC)CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 42 %

Procedure:
A solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.4 g), ethyl 1-bromocyclobutanecarboxylate (1.5 mL) and cesium carbonate (3 g) in dimethylacetamide (14 mL) was stirred at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.76 g, 42%) as a pale-yellow liquid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)=O.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27].CN(C)C=O>CS(C)=O>[N+:26]([CH:29]=[CH:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)([O-:28])=[O:27]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2ccc(-c3ccc4[nH]cnc4c3)cc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])C=Cc1c[nH]c2ccc(-c3ccc4[nH]cnc4c3)cc12
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 5-(3-formylindol-5-yl)-1H-benzimidazole (0.40 g, 1.53 mmol) and ammonium acetate (50 mg) in a solution of nitromethane (10 mL), N,N-dimethylformamide (5 mL), and dimethyl sulfoxide (1 mL) was heated at reflux under nitrogen for 4 hours. The resulting reaction mixture was cooled to room temperature and filtered to afford the title compound (0.40 g, 86%) as a yellow solid: mp >280° C.; 13C NMR (DMSO-d6) δ 146.9, 145.3, 144.3, 137.4, 136.6, 135.5, 134.2, 132.1, 129.8, 127.8, 125.0, 119.9, 118.7, 115.9, 113.4, 108.7. Anal. calcd for C16H11N5O2.0.125 H2O: C, 62.49; H, 3.69; N, 22.77. Found: C, 62.34; H, 3.51; N, 22.45.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:53]=[C:54]([F:56])[CH:55]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34][C:35](=[O:52])[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:38][C:37]=1[N+:49]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:49][C:37]1[CH:38]=[C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH:40]=[CH:41][C:36]=1[C:35]([NH:34][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]3[CH:53]=[C:54]([F:56])[CH:55]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[N:11]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)=[O:52]
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (170 mg, 0.236 mmol), 10% Pd—C (10 mg) and ammonium formate (25 mg, 0.4 mmol) in methanol (5 mL) was stirred for 18 hours at room temperature. The catalyst was filtered off and the solution was concentrated. The residue was dissolved in dichloromethane, washed with aqueous solution of NaHCO3, dried and concentrated to yield title compound (145 mg, 87%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1)[CH2:14][CH3:15])=O.[CH3:29][S:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=1>>[CH3:29][S:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[N:38][C:37]([NH:40][CH2:1][C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=2[N:13]([CH2:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:22]2)[CH2:14][CH3:15])=[N:36][CH:35]=1
Reactant: CSCCOc1cnc(N)nc1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2C=O)CC1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CNc2ncc(OCCSC)cn2)CC1

Procedure:
By using ethyl trans-[4-({[2-(formyl)-4-(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetate instead of 2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)benzaldehyde, the reaction with 5-[2-(methylthio)ethoxy]pyrimidin-2-amine and treatments were performed in the same manner as those of Step 4 of Example 1 to obtain ethyl trans-{4-[({2-[({5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetate as a pale yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
To a biphasic mixture of 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (40 mg, 0.118 mmol) in DCM (1.5 mL) and saturated aqueous NaHCO3 (1.5 mL) was added piperidine (25 μL, 0.253 mmol). The reaction was stirred at room temperature for 16 hours. TLC analysis of the reaction mixture indicated consumption of starting material. The biphasic mixture was extracted with DCM (1.5 mL) (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-90% EtOAc to provide (1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone (32.5 mg, 0.081 mmol, 68.9% yield) as a white solid. LCMS (+ESI) m/z=388.1 [M+H]+; 1H-NMR (CDCl3) δ 8.25. (d, 1H), 8.14 (d, 1H), 7.66 (m, 2H), 7.61 (tt, 1H), 7.49 (m, 2H), 3.93 (m, 2H), 3.85 (m, 2H), 3.69 (br s, 2H), 3.45 (br s, 2H), 1.75-1.55 (m, 6H).