Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CO[CH2:19][CH2:20]OCCOC.[Li+].[Cl-].C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[CH2:20])=[CH:3][CH:4]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(c1ccc(Br)cc1)C(F)(F)F
Reactant: COCCOCCOC
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
Crude 1-bromo-4-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-benzene, (approximately 100 mg of starting material, contaminated with diglyme) was dissolved in toluene (3 ml) in a sealed tub under a nitrogen atmosphere. Tetrakispalladium (15 mg, 0.013 mmol) and LiCl (42 mg, 1 mmol) were added, followed by the addition of tributylvinyltin (155 mg, 0.49 mmol).The reaction mixture was heated to 80° C. for 18 h, and then purified by silica gel column chromatography (100% hexane -2% ethyl acetate/hexane) to yield the title product, whose volatility made yield calculations impossible. 1H NMR (CDCl3) δ=7.49 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.71 (dd, J=10.9, 17.6 Hz, 1H), 5.82 (d, J=17.7, 1H), 5.33 (d, J=10.9 Hz, 1H), 4.06 (septet, JH,F=8.3 Hz,1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH2:36][CH3:37])[CH2:34][OH:35].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[OH:35][CH2:34][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH2:36][CH3:37]
Reactant: CC[C@@H](N)CO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC[C@H](CO)NC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O[C@@H](C)COC)c2)[nH]1
Reaction time: 6 h
Yield: 84.8 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k), (R)-(−)-2-amino-1-butanol (0.38 mL, 4.03 mmol), HOBT•H2O (0.44 g, 3.23 mmol) and N-methylmorpholine (0.59 mL, 5.38 mmol) were dissolved in methylene chloride (30 mL), and WSCI•HCl (0.62 g, 3.23 mmol) was added at room temperature, followed by stirring for 6 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (50 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (1.18 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1>CO.[Ni]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Yield: 98.1 %

Procedure:
A solution of 1-(4,6-dimethyl-2-pyridyl)-4-(4-nitrophenyl)piperazine (49 g, 157 mmol) in methanol was hydrogenated over Raney Nickel (15 g) at 90 psi pressure for 36 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo giving a crude product which was washed with petroleum ether (100 mL) to afford 4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline (43.5 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[C:3]=1[CH3:12]>ClCCl.[O-2].[Mn+2]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1c(CO)cnc(Cl)c1C
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CNc1c(C=O)cnc(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of (6-chloro-5-methyl-4-(methylamino)pyridin-3-yl)methanol (1.4 g, 8.0 mmol) and manganese oxide (2.8 g, 32 mmol) in dichloromethane (100 mL) was stirred at RT for 4 h. LCMS monitored the reaction was completed. The solid was filtered off, and the filtrate was concentrated to get the title compound (1.2 g, crude) as a yellow oil. MS (ES+) C8H9ClN2O requires: 184, 186. found: 185, 187 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N:19]=[N:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.NC1CCN(CCN2C3C(=CC(C#N)=CC=3)N=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N:19]=[N:18][C:17]2=[O:27])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)nnc3ccc(Cl)cc32)CC1
Agent: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)nnc3ccc(Cl)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6-chloro-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 208, 74 mg) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 67 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27](=[O:39])[CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH:18]=[C:19]3[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]3)[CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27](=[O:39])[CH2:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH:18]=[C:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)[CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: O=C1CCC(=Cc2ccn3ncnc(Oc4ccc(NC(=O)CC(=O)Nc5ccc(F)cc5)cc4F)c23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CC(=O)Nc1ccc(Oc2ncnn3ccc(C=C4CCC(O)CC4)c23)c(F)c1)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To N1-(3-fluoro-4-(5-((4-oxocyclohexylidene)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide (80 mg, 0.15 mmol, Example 149) in methanol (2 mL) at 0° C. was added a spatula tip of sodium borohydride. The reaction was stirred at 0° C. for 30 min and was then quenched with saturated aqueous ammonium chloride solution (10 mL) and stirred at 0° C. for 5 min. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% MeOH/EtOAc) to give the title compound (30 mg, 37%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.57 (s, 1H), 10.34 (s, 1H), 8.11 (d, 1H, J=2.8 Hz), 8.10 (s, 1H), 7.86 (dd, 1H, J=12.8, 2.4 Hz), 7.71–7.68 (m, 2H), 7.53 (t, 1H, J=8.4 Hz), 7.46–7.43 (m, 1H), 7.25–7.21 (m, 2H), 6.99 (d, 1H, J=2.8 Hz), 6.64 (s, 1H), 4.65 (br s, 1H), 3.76–3.75 (m, 1H), 3.56 (s, 2H), 2.90–2.85 (m, 1H), 2.51–2.45 (m, 1H), 2.27–2.24 (m, 2H), 1.92–1.85 (m, 2H), 1.46–1.41 (m, 2H); MS(ESI+) m/z 534.3 (M+H)+.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.C(N)C1C=CC=CC=1.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].NC1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:37](=[O:45])[N:36]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)C(=O)C=1.[H][H].C(N1C(=O)C(N)=C(N)N(C2C=CC=CC=2)C1=O)C1C=CC=CC=1>>[CH2:46]([NH:36][C:37]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:45])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Nc1cc(=O)n(Cc2ccccc2)c(=O)n1-c1ccccc1
Reactant: [H][H]
Agent: N#CCC(=O)O
Agent: NC(N)=O
Agent: Nc1c(N)n(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Solvent: O=C=Nc1ccccc1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)Nc1ccccc1

Procedure:
N-Benzyl-N'-phenylurea was prepared preliminarily from phenyl isocyanate and benzylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-3-benzyl-1-phenyluracil and then reduced with hydrogen gas to prepare 3-benzyl-5,6-diamino-1-phenyluracil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH:21]=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:21]([C@H:18]1[CH2:19][CH2:20][C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)=[CH2:23]
Reactant: O=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Reactant: COC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
A suspension of 0.977 g of methyltriphenylphosphonium bromide in 12 ml of tert.-butyl methyl ether was treated with 0.308 g of potassium tert.-butylate while stirring and gassing with nitrogen and stirred at room temperature for a further 1.5 hours. The yellow suspension was treated dropwise at 2° C. within 15 minutes with a solution of 0.439 g of trans-4-(3',4'-difluoro-4-biphenylyl)cyclohexanecarboxaldehyde in 12 ml of tert.-butyl methyl ether, stirred at room temperature for a further 1.5 hours and concentrated in a vacuum. Purification of the residue by chomatography on silica gel with methylene chloride and subsequent two-fold recrystallization from hexane gave 0.118 g of pure 4-(trans-4-vinylcyclohexyl)-3',4'-difluorobiphenyl; m.p. (C-N) 97.0° C., cl.p. (N-I) 84.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH:13]2[CH2:15][CH2:14]2)O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[CH:13][CH2:14][CH2:15][Br:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(O)C2CC2)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: COc1ccc(CCC=CCCBr)cc1

Procedure:
6-(4-Methoxyphenyl)-3-hexenyl bromide [V; Ar is 4-CH3OC6H4, R is H] was prepared from 38.2 g. of 2-(4-methoxyphenyl)ethyl cyclopropyl carbinol (Preparation B5), 42.5 g of phosphorus tribromide, 35 g. of lithium bromide and 40 g. of zinc bromide according to the procedure given above in Preparation C1, affording 48 g of product as an oil.
Reaction SMILES: [O:1]=[C:2]([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][CH2:23][CH3:24])[CH2:3][C:4](OC)=[O:5].[BH4-].[Li+]>O1CCCC1>[CH2:4]([OH:5])[CH2:3][CH:2]([OH:1])[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][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-oxoicosanoate (5.2 g, 15.3 mmoles) is dissolved in anhydrous tetrahydrofuran (31 mL) and this solution is added slowly dropwise to an ice-cooled solution of lithium borohydride in anhydrous tetrahydrofuran (2 M, 31 mL, 61.2 mmoles). When the addition is complete, the cooling bath is removed and the reaction is stirred at ambient temperature for 16 hours. The clear, colorless solution is again cooled in an ice bath, and aqueous hydrochloric acid (1 M, 62 mL) is added slowly dropwise to decompose the excess reducing agent (gas is evolved). When a homogeneous solution is obtained, the mixture is concentrated to remove tetrahydrofuran. Methylene chloride (100 mL) is added; the mixture is shaken well and poured into a separatory funnel. The layers are allowed to separate and the bottom aqueous layer is drawn off. The aqueous layer is then washed once more with methylene chloride (100 mL), and the combined methylene chloride solutions are washed with saturated aqueous sodium chloride (50 mL). The methylene chloride solution is then dried over anhydrous sodium sulfate, filtered and co-evaporated five times with methanol (50 mL each) to dryness. The oil is dried well in vacuo. The yield is 3.7 g (77%).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]=3[CH:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Br:29])[CH:23]=3)[C:11]=2[C:10](=[O:30])[CH2:9]1)C1C=CC=CC=1.Cl[C:32]([O:34][CH:35]1[CH:40]([C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])[CH2:39][CH2:38][CH:37]([CH3:50])[CH2:36]1)=[O:33].C1(C(C)(C)C2CCC(C)CC2O)C=CC=CC=1>C1COCC1>[Br:29][C:24]1[CH:23]=[C:22]([CH:12]2[C:11]3[C:10](=[O:30])[CH2:9][N:8]([C:32]([O:34][C@@H:35]4[CH2:36][C@H:37]([CH3:50])[CH2:38][CH2:39][C@H:40]4[C:41]([CH3:42])([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH3:43])=[O:33])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]2=3)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Reactant: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2
Agent: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2CC(=O)C3=C(C2)NC2=C(C(=O)CC2)C3c2ccc(F)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the product from Example 5A (1.9 g, 4.0 mmol) in THF (30 mL) was treated with 8-phenylmenthol chloroformate prepared from (−)-8-phenylmenthol as described in (Yamamoto, Y., J.Amer.Chem.Soc. (1992), 114, 121-125) (1.45 g, 4.92 mmol) in THF (10 mL), stirred for 3 days at ambient temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer was separated, dried with sodium sulfate, filtered and concentrated to provide a mixture of diastereomeric carbamates. The diastereomeric mixture was subjected to column chromatography over silica gel (20% hexanes/ethyl acetate) to provide the title compound (0.32 g) as the less polar diastereomer and mixed fractions containing both diastereomers (0.9 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[CH:29]1([CH:34]=[CH2:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1(/[CH:34]=[CH:35]\[C:2]2[C:10]3[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=3[S:4][C:3]=2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: C=CC1CCCC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(/C=C\C3CCCC3)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
Prepared using 5-bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione and cyclopentyl-ethene. The crude product was purified by flash silica chromatography eluting with a gradient of 5-20% ethanol in dichloromethane to give the title compound as a yellow oil (0.17 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1.Cl>CC(N(C)C)=O.C1(C)C=CC=CC=1.O>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][N:15]2[CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: O=C1CCCO1
Reactant: COc1ccc2c(C)c[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(C)cn(CCCC(=O)O)c2c1
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Anhydrous potassium carbonate (34.5 g, 0.25 mol) was added to a solution of 6-methoxy-3-methylindole (16.1 g, 0.1 mol) and γ-butyrolactone (43 g, 0.5 mol) in dimethylacetamide (750 mL). Under mechanical stirring and protected with a drying tube, the reaction mixture was refluxed for 18 hours, more γ-butyrolactone (21.5 g, 0.25 mol) was added, and the reflux was continued for 12 hours. A final portion of γ-butyrolactone (21.5 g, 0.25 mol) was added and the thick suspension was refluxed for another 12 hours, cooled to ~30° C., and poured into water (600 mL). Toluene (600 mL) was added and the 2 layer system was stirred for 15 minutes. The aqueous layer was separted and acidified with concentrated hydrochloric acid. The product was extracted with toluene (3×250 mL). The combined extracts were washed with water (600 mL), dried over MgSO4, filtered, evaporated, and the dark oily residue was chromatographed on silica gel (480 g). Elution with chloroform/hexane (1:1) afforded 18.2 g (74%) of the title compound as a yellowish oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c1) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=[O:16])C>Cl>[C:12]([C:11]1[C:2](=[O:16])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: CC(=O)O
Reactant: N#Cc1cc2ccccc2nc1Cl
Agent: Cl
Product: N#Cc1cc2ccccc2[nH]c1=O

Procedure:
Alternatively, the acetanilide can be heated with dimethylformamide, phosphoryl chloride and hydroxylamine hydrochloride to give a 2-chloro-3-cyanoquinoline. This process is a particularly convenient method for obtaining the chlorocyanoquinoline directly from an acetanilide. The indicated chloro-cyano-compound can then be hydrolyzed either under acidic or basic conditions to give the corresponding desired 3-cyano-2(1H)-quinolinone. Specifically, if the 2-chloro-3-cyanoquinoline is boiled in acetic acid for 1 hour or refluxed in 4N hydrochloric acid for 10-15 minutes, the corresponding 3-cyano-2(1H)-quinolinone is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:3]=12.Cl.[NH2:26]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:23]([N:20]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:26][O:19][C:8]=3[C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=3)[C:3]=2[CH:22]=[N:21]1)[CH3:24]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(C(F)(F)F)cc3)cnc21
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c3noc(-c4ccc(C(F)(F)F)cc4)c3cnc21

Procedure:
4-Chloro-1-ethyl-5-(4-trifluoromethylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (3.10 g) was refluxed for 2 hours in 300 ml of acetic acid containing 9 g of hydroxylamine hydrochloride and 0.6 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed well with water, dried, evaporated, and purified by chromatography over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). In this way, 2.15 g of product was obtained, mp 243°-245°. Recrystallization from ethyl acetate gave analytically pure product, mp 244°-245° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][CH:2]=1.[BH4-].[Na+].Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][OH:12])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of quinoline-4-carbaldehyde (0.50 g, 3.24 mmol) dissolved in methanol (5 mL) was cooled to 0° C. Sodium borohydride (0.11 g, 2.91 mmol) was then added portion-wise. After 1 h of stirring at 0° C., 2M HCl (aq) was added drop-wise until pH˜5. The methanol was then evaporated in vacuo and the aqueous phase was neutralized by addition of saturated aqueous NaHCO3. The aqueous solution was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with saturated NaHCO3 (aq) and brine. The organic solution was dried over Na2SO4, filtered, and concentrated in vacuo to yield quinolin-4-ylmethanol as a yellow solid. MS (ES+): 160 [MH+]. 1H NMR (CDCl3, 400 MHz): δ 2.41 (bs, 1H), 5.25 (bs, 2H), 7.55 (ddd, J=4.4, 1.2, 1.2 Hz, 1H), 7.58 (ddd, J=8.4, 7.2, 1.2 Hz, 1H), 7.73 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.97 (ddd, J=8.4, 1.2, 0.4 Hz, 1H), 8.14 (ddd, J=8.0, 1.2, 0.4 Hz, 1H), 8.90 (d, J=4.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([OH:20])[CH:11]=2)[CH:5]=[C:4]([C:21]2[C:26]([O:27]CC3C=CC(OC)=CC=3)=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1.Cl>O1CCOCC1.C(OCC)C>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([OH:20])[CH:11]=2)[CH:5]=[C:4]([C:21]2[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(CO)c(N)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(-c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CO)cc1O
Reaction time: 8 h

Procedure:
To a solution of N-{4-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-hydroxyphenyl}acetamide (0.013 g, 0.023 mmol) in 1,4-dioxane (0.5 mL) was added a solution of HCl in 1,4-dioxane (4N, 1.0 mL). After being stirred overnight, the mixture was diluted with diethyl ether. The resulting precipitate was collected by filtration under argon atmosphere, washed with Et2O, and dried under reduced pressure to give of N-{4-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(hydroxymethyl)-4-pyridinyl]-2-hydroxyphenyl}acetamide. (0.025 g, 80%); LC-MS (m/z=436, M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[OH-].[Na+].[C:25](OC(=O)C)(=O)[CH3:26]>C(Cl)(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:25]([CH3:26])=[N:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=C(C)N3c1ccccc1

Procedure:
A solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (60 mg, 0.20 mmol) (from Example 1, Step C, supra) in acetic anhydride (2 mL) was heated at 150° C. for 2 hours. Aqueous NaOH solution was then added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 8,9-dimethoxy-2-methyl-3-phenyl-3H-1,3,4,6-tetraaza-phenalene as a yellow solid. (Yield 20 mg, 62%).