Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][C:41](Cl)=[O:42]>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:42]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: COc1ccc(CC(=O)Cl)c(OC)c1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)CN3C(=O)C(c4ccccc4)(c4ccccc4)N=C3C)cc2)c(OC)c1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and (2,4-dimethoxy-phenyl)-acetyl chloride to yield 2-(2,4-dimethoxy-phenyl)-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide (55 mg, 0.098 mmol) which is dissolved 5 mL dry ethanol. Subsequently LiBH4 (22.5 mg, 0.98 mmol) is added and the reaction mixture is stirred for 4 hour at reflux temperature. The reaction is then diluted with 5 mL water and the solvents evaporated. The residue is purified by preparative HPLC (method 3) to yield 2-(2,4-dimethoxy-phenyl)-N-{4-[1-hydroxy-2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-ethyl]-phenyl}-acetamide (15 mg, 27%). LC/MS at 254 nm; [M+H] 565; Rt=3.006 min.
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1=CC=CCCCCCCC=C1
Solvent: O
Product: C1=CCCCCCCCCCC1

Procedure:
The hydrogenation of polyenes to monoenes over homogeneous Ru catalysts with addition of water is described, for example, in U.S. Pat. No. 5,180,870. In example 2 of this document, a cyclododecatriene conversion of 98.4% is attained after a reaction time of 4 h with addition of water. What cyclododecene yield is obtained is not stated. In example 1 of this document, only an unsatisfactory conversion of 85.8% is attained with addition of somewhat less water than in example 2 after a reaction time of 8 h.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].Cl.[NH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O.C(=O)(O)[O-].[Na+]>O1CCCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12]1
Reactant: OCC1CCNC1
Reactant: Cc1cccc(C)c1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1CCC(CO)C1
Yield: 27.8 %

Procedure:
To a solution of 2-bromo-1,3-dimethylbenzene (500 mg), pyrrolidine-3-yl methanol hydrochloride (409 mg), bis(dibenzylideneacetone) palladium (155 mg), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos; 222 mg) in tetrahydrofuran (5 mL), molecular sieves 4A (powder; 410 mg) were added. To the mixed solution, a solution (8.9 mL) of 1.0 M lithium hexamethyldisilazide in tetrahydrofuran was added, and the resultant reaction mixture was heated and refluxed for 2.5 hours. To the reaction solution, saturated sodium bicarbonate water and ethyl acetate were added, and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 75:25), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (154 mg) as a yellow oily substance.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([OH:42])[CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)(C)C.CC(O)=O>C1COCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][CH2:32][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=2)[OH:42])=[CH:36][CH:37]=1
Reactant: CC(C)(C)[Si](Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
At 0° C., 1M tetrabutylammonium fluoride (100 mL) was added to a solution of the silyl ether of Step 2 (34 g) and AcOH (15 mL) in THF (200 mL) and the reaction mixture was stirred at 0° C. 2.5 hours. 25% aqueous NH4OAc was then added and the product was extracted with EtOAc, dried over MgSO4 and purified by a swish in EtOAc:hexane 1:2. The title compound so obtained was used as such for the next step.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1.O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C@@H:2]([O:5][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1)[CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC[C@@H](C)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of (2R)-butan-2-ol (0.32 mL) in toluene (8 mL) was added sodium hydride (0.28 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (1.0 g), BINAP (0.066 g), Pd2(dba)3 (0.048 g) and toluene (8 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-{[(1R)-1-methylpropyl]oxy}-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.79 g, 70%) as a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCC)CCC.Br>>[CH3:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC(CCCCC)c1ccc(OC)cc1
Agent: Br
Agent: CCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CCCCCCCCCC(CCCCC)c1ccc(O)cc1
Yield: 11.9 %

Procedure:
The title compound (36.11 g) was prepared from 1-methoxy-4-(pentadec-6-yl)benzene (Example 13, 318 g), tributylpentadecylphosphonium bromide (413 g) and HBr (48% aq., 83.4 g) using the procedure of Example 2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].Cl.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[C:22]([N:34]3[CH2:39][CH2:38][CH:37]([N:40]([CH3:48])[C:41](=[O:47])[C@@H:42]4[CH2:46][CH2:45][CH2:44][NH:43]4)[CH2:36][CH2:35]3)[N:21]=2)=[C:15]([F:49])[CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[C:22]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]([CH3:48])[C:41](=[O:47])[C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[CH2:7][CH3:8])[CH2:38][CH2:39]3)[N:21]=2)=[C:15]([F:49])[CH:14]=1
Reactant: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC[C@H]1C(=O)N(C)C1CCN(c2nc(Nc3ccc(Cl)cc3F)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 50 °C
Reaction time: 19 h

Procedure:
Potassium carbonate (62 mg) and ethyl iodide (36 μl) were added in that order to an acetonitrile (5 mL) solution of N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide dihydrochloride (250 mg), followed by stirring at room temperature for 2 hours and at 50° C. for 19 hours. The solvent was evaporated, and a saturated sodium bicarbonate aqueous solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated. By purifying the resulting residue by a silica gel column chromatography (chloroform-MeOH), N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-1-ethyl-N-methyl-L-prolinamide was obtained. This compound was dissolved in MeOH (3 mL), 4 M HCl/ethyl acetate solution (198 μl) was added thereto, and the solvent was evaporated. By recrystallizing the resulting crude crystals from isopropanol-diisopropyl ether, N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-1-ethyl-N-methyl-L-prolinamide dihydrochloride (101 mg) was obtained as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:18]([F:33])[CH:17]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.[CH3:36]B1OB(C)OB(C)O1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:33][C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([CH3:36])=[CH:3][C:4]=2[O:34][CH3:35])[CH:21]=[CH:20][C:19]=1[CH:22]([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28]
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 52.4 %

Procedure:
Following General Procedure I, tert-butyl 2-(4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-fluorophenyl)propylcarbamate (282 mg, 0.50 mmol) was reacted with trimethylboroxine (170 mg, 1.35 mmol) and Pd(pph3)4 (50 mg, 0.04 mmol) to afford the desired product (130 mg, 52%) as a yellow solid. ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[CH:15]=3)[NH:10][C:9]=2[N:30]=1)([CH3:3])[CH3:2].[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)[CH:15]=3)[NH:10][C:9]=2[N:30]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ncc2c(n1)[nH]c1ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1ncc2c(n1)[nH]c1ccc([C@H]3CNCCO3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
(S)-tert-Butyl 2-(2-isopropoxy-9H-pyrimido[4,5-b]indol-6-yl)morpholine-4-carboxylate (11 mg, 0.027 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 0.08 ml, 0.32 mmol) was added. The reaction mixture was stirred for 1 h at 60° C. After cooling ether (1 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(2-isopropoxy-9H-pyrimido[4,5-b]indol-6-yl)morpholine hydrochloride (6 mg, 64%) as an off-white solid. MS (ISP): 313.3 ([M+H]+).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH2:13][O:14][C:15]([NH:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)C>[Pd].C(O)C>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]([NH:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]2)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(/C=C/c1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 80.4 %

Procedure:
A dry 100 mL round-bottomed flask equipped with a magnetic stir bar and a rubber septum was charged with 1-{[((2E)-3-phenylprop-2-enoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid (16) (0.8 g, 2.5 mmols) and 10% palladium on carbon in 1:1 mixture of ethylacetate and ethanol. The reaction was done at 1 atm pressure under a hydrogen balloon at room temperature. After the reaction was complete, the solution was filtered through Celite and the solvents removed in vacuo using a rotary evaporator. The dry, crude residue was dissolved in a small amount of a mixture of 60% (v/v) acetonitrile/water (ca. 10 mL), and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative HPLC. After lyophilization of the solvents, 0.646 g (80% yield) of the title compound (17) was obtained as a white solid. M.p: 132.9-134.4° C. 1H NMR (CDCl3, 400 MHz): δ=7.31 (t, 2H), 7.19 (t, 3H), 6.82 (q, 1H), 6.38 (s, 0.3H), 5.50 (s, 0.7H), 2.99 (t, 2H), 2.72 (m, 2H), 1.71 (m, 2H), 1.42 (d, 3H), 1.30 (m, 2H). MS (ESI) m/z 343.93 (M+Na)+, 319.96 (M−H)−.
Reaction SMILES: [CH2:1]([NH:6][OH:7])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([N:16]=[C:17]=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(OC(C)C)(C)C>[CH2:1]([N:6]([OH:7])[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCCCCNO
Solvent: CC(C)OC(C)C
Product: CCCCCN(O)C(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of 16 g of N-pentyl-hydroxylamine in 80 ml of isopropyl ether was added to 29.2 g of 3,4-dichlorophenyl isocyanate in 500 ml of isopropyl ether and the mixture was stirred for 16 hours and was evaporated to dryness. The residue was taken up in petroleum ether to obtain 45 g of N-pentyl-N-hydroxy-N'-(3,4-dichlorophenyl)-urea melting at 88° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C[C@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 220 was synthesized using 9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=77-79° C.; 400 MHz 1H NMR (CDCl3) δ: 8.08 (dd, J=8.6, 5.9 Hz, 1H), 7.37 (dd, J=9.4, 2.7 Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 3H), 7.14 (td, J=8.2, 2.7 Hz, 1H), 4.04-3.95 (m, 1H), 2.98-2.82 (m, 2H), 2.93 (s, 2H), 2.79-2.66 (m, 3H), 2.54-2.37 (m, 3H), 2.16-2.08 (m, 2H), 1.97-1.80 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1>>[CH3:13][C:12]1[C:7]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:32])([F:33])[F:23])[CH:26]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(C(F)(F)F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [3-(trifluoromethyl)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.34 (s, 3H), 4.73 (d, J=5.6 Hz, 2H), 5.91 (bs, 1H), 6.47 (bs, 1H), 7.15 (t, J=8.2 Hz, 1H), 7.24-7.40 (m, 3H), 7.57-7.67 (m, 2H), 8.09 (s, 1H), 8.57 (d, J=2.4 Hz, 1H); MS (ESI) m/z 374.7 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([NH2:14])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:17]([CH:25]([CH3:29])[C:26](O)=[O:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:26](=[O:27])[CH:25]([N:17]3[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[N:20]=[C:16]3[CH3:15])[CH3:29])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-methylpyrazol-4-amine (0.03 g, 0.16 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.035 g, 0.16 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.067 g, 0.18 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.038 mmol, 24%). 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.93 (s, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.42-7.32 (m, 2H), 7.24-7.14 (m, 2H), 5.35 (q, J=6.8 Hz, 1H), 2.48 (s, 3H), 2.19 (s, 3H), 1.86 (d, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C18H17F4N5O [M+H]+ 396.1, found 396.1.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[F:25])[NH:8][CH:7]=1)=[O:5].C1COCC1.CO.[Cl-].[NH4+]>CCOC(C)=O.[Zn]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:8][CH:7]=[C:6]([C:4](=[O:5])[CH2:3][N:2]([CH3:26])[CH3:1])[C:14]=23)=[C:17]([F:25])[CH:18]=1
Reactant: CN(C)CC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC(=O)c1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethylamino)-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (80 mg, 0.22 mmol) in a mixed solvent (5 mL of THF and 5 mL of MeOH) were added ammonium chloride (64.2 mg, 1.2 mmol, EMD) and Zn dust (78.4 mg, 1.2 mmol, Aldrich). The reaction mixture was stirred at room temperature overnight, diluted with 30 mL of EtOAc and filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the resulting residue was purified by preparative HPLC. The desired fractions were combined, neutralized with saturated aq. NaHCO3 solution, and concentrated in vacuo. The solid that formed was collected by filtration (51 mg, 71%). MS(ESI+) m/z 328.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=1)=[CH2:11].[H][H]>CO.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=1)[CH3:11]
Reactant: [H][H]
Reactant: C=C(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1

Procedure:
The title compound was obtained by catalytic hydrogenation of 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene obtained as in Example 3 or Example 4. To a solution of 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene in methanol was added palladium on carbon, and hydrogen gas was bubbled vigorously through the solution for ten minutes. Removal of the catalyst and evaporation of the solvent afforded the title compound.
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:26]=[CH:25][C:14]([NH:15][C:16]([NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[CH:25][CH:26]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NC(=O)NCC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl {[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)carbonyl]-amino}acetate (which was obtained in Example 377) by NaOH hydrolysis as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.55 (m, 2H), 1.80-2.00 (m, 2H), 2.50-2.90 (m, 5H), 2.92 (s, 3H), 3.30-3.50 (m, 2H), 3.59 (d, J=5.9 Hz, 2H), 4.60 (dd, J=8.8, 3.5 Hz, 1H), 6.14 (t, J=5.0 Hz, 1H), 6.80 (d, J=9.1 Hz, 2H), 6.84 (d, J=8.3 Hz, 1H), 7.03 (dd, J=8.3, 2.0 Hz, 1H), 7.15-7.25 (m, 3H), 8.54 (s, 1H); MS (ES) m/z: 520.3 (M−H)−; HRMS Calcd. for C23H32N5O7S(MH+): 522.2017. Found: 522.2000.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19][CH2:20][SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:26]([Sn:21]([CH2:20][CH2:19][CH2:18][CH3:17])([CH2:22][CH2:23][CH2:24][CH3:25])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[CH2:16])[CH2:27][CH2:28][CH3:29]
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(OCc2ccccc2)cc1)[Sn](CCCC)(CCCC)CCCC

Procedure:
1-benzyloxy-4-ethynyl-benzene (70 g, 0.3365 mol), Bu3SnH (59 mL, 0.3365 mol) and Ph(PP3)2Cl2 (120 mg, 0.1718 mmol) were stirred in THF (500 mL) at 25° C. for 16 h and then refluxed for 1 h. The resulting solution was concentrated and then purified on SiO2 (2% ˜5% ethyl acetate/hexane) to yield tributyl-[1-(4-benzyloxy-phenyl)-vinyl]-stannane.