Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCO[CH2:14][CH3:15].Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]1[C:36]3[C:31](=[CH:32][C:33](Br)=[CH:34][CH:35]=3)[CH:30]=[CH:29][C:28]=1[O:38][CH3:39])=[C:22]([O:40][CH3:41])[CH:21]=[CH:20]2.Cl>ClCCl>[CH2:1]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]1[C:36]3[C:31](=[CH:32][C:33]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:14][CH3:15])=[CH:34][CH:35]=3)[CH:30]=[CH:29][C:28]=1[O:38][CH3:39])=[C:22]([O:40][CH3:41])[CH:21]=[CH:20]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Mg]Br
Reactant: CCOCC
Reactant: COc1ccc2cc(Br)ccc2c1-c1c(OC)ccc2cc(Br)ccc12
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(-c3c(OC)ccc4cc(CCCCCCCC)ccc34)c(OC)ccc2c1
Yield: 72 %

Procedure:
63 mmol (100 ml of ether solution) of C8H17MgBr were added in a nitrogen atmosphere to a ether solution (150 ml) containing 10 g of Compound 1 and 1.25 g of dichloro[1,3-bis(diphenylphosphine)propane]nickel, and refluxed for 20 hours. After cooling down, 800 ml each of dichloromethane and 1M hydrochloric acid were added to obtain an oily reaction product by extraction. By purifying the above reaction product with column chromatography (silica gel, petroleum ether/ethyl ether), 8.1 g of pure 6,6'-dioctyl-2,2'-dimethoxy-1,1'-binaphthyl (Compound 2) were obtained (yield: 72%).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[C:12]1(/[C:18](=[CH:22]\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[C:18](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4]2
Reactant: O=C(O)/C(=C/c1ccccc1)c1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)/C(=C/c1ccccc1)c1ccccc1

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-2,3-diphenylpropenoic acid; MS (ES+) 333 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:12]2[CH2:15][CH2:14][C:13]2=[O:16])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:12]2[CH2:15][CH2:14][C:13]2=[O:16])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N1CCC1=O
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C)c(N2CCC2=O)cc1N
Yield: 90.4 %

Procedure:
21.2 g (0.0965 mol) of the 1-(3'-nitro-4',6'-dimethylphenyl)-azetidin-2-one obtained according to (a) are hydrogenated in 210 ml of methanol with 2 g of Raney nickel at 30°-35° under normal pressure. The reaction solution is filtered and evaporated. Recrystallisation of the crude product from methanol gives 16.6 g (90%) of crystals having a melting point of 123°-124°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=4)[CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3ccc(Br)cc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2ccc3ccc(-c4ccc(C(F)(F)F)cc4)cc32)cc1
Yield: 67.3 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (0.490 g, 1.43 mmol) was coupled to 4-trifluoromethylbenzeneboronic acid (0.300 g, 1.58 mmol), using tetrakis(triphenylphosphine)palladium (0.0560 g, 0.0484 mmol) and sodium carbonate (0.615 g, 5.80 mmol) in water (2.8 mL), ethanol (1.4 mL) and toluene (10 mL). Purification by flash chromatography using hexane as an eluant afforded 1-[4-(tert-butyl)benzyl]-6-[4-(trifluoromethyl)phenyl]-1-H-indole as a white solid (0.392 g, 67%), mp 134-135° C. 1HNMR (200 MHz, DMSO-d6): δ 7.85 (d, 3H, J=7.7 Hz), 7.75 (d, 2H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.55 (d, 1H, J=4.1 Hz), 7.25-7.4 (m, 3H), 7.15 (d, 2H, J=7.7 Hz), 6.5 (d, 1H, J=2.6 Hz), 5.45 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([OH:33])=[O:32])[CH:19]=[C:18]3C(O)=O)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].S(=O)(=O)(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([OH:33])=[O:32])[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 170 °C
Yield: 73.4 %

Procedure:
Eighteen mg of the 6-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-2-(2-carboxyphenyl)-4-quinolinecarboxylic acid obtained in Example 17 were dissolved in 5 ml of quinoline. After adding 0.5 ml of conc. sulfuric acid, the mixture was heated at 170° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. Then the precipitate was collected by filtration and purified by flash chromatography on silica gel with the use of chloroform/methanol. Thus 12 mg of 2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}benzoic acid were obtained. NMR (270 MHz, CDCl3): δ 7.5-8.2 (m,8H); 7.4 (s,1H); 7.0 (s,1H); 5.7 (s,2H); 2.8 (q,J=8Hz,2H); 2.7 (s,3H); 2.6 (s,3H); 1.7 (t,J=8Hz,3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:27])[C:8]2[O:14][C:13]3[C:15]([Cl:23])=[CH:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[CH:18][C:12]=3[CH2:11][S:10](=[O:25])(=[O:24])[C:9]=2[CH:26]=1)=[O:4].[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:27])[C:8]2[O:14][C:13]3[C:15]([Cl:23])=[CH:16][C:17]([N:19]([C:30](=[O:31])[CH2:29][Cl:28])[CH2:20][CH2:21][Cl:22])=[CH:18][C:12]=3[CH2:11][S:10](=[O:24])(=[O:25])[C:9]=2[CH:26]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
4-Chloro-2-(2-chloro-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid methyl ester (prepared by following the method described in example 29a or example 29b, 1.9 gm, 4.4 mmol) was added to chloroacetyl chloride (6 mL) at room temperature. Reaction mixture was then stirred at 90° C. for 1 h. Reaction mixture was cooled and diluted using ice water (100 mL). The solid separated was filtered, washed with water and dried to obtain the title compound. Yield: 1.85 g, (83%); 1H NMR (DMSO-d6, 300 MHz): δ 2.60 (s, 3H, CH3), 3.67 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 3.99 (t, 2H, CH2), 4.27 (bs, 2H,CH2), 5.31 (s, 2H, CH2), 7.66 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.17 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 505 (M+1).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]#[CH:24]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:2]1[O:6][C:5]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)o1
Reactant: C#CCOCCCCCCBr
Product: CCN(CC)C(=O)c1ccc(C#CCOCCCCCCBr)o1
Reaction time: 4 h
Yield: 95.4 %

Procedure:
5-Bromo-N,N-diethyl-2-furancarboxamide (2.0 g) was treated with 3-[(6-bromohexyl)oxy]-1-propyne (1.87 g) according to the method of Intermediate 9 except that the reaction mixture was stirred under nitrogen at 60° for 4 h, and hexane-ether (5:1 then 2:1 then 1:1) was used as the eluant for FCC. This afforded the title compound as a dark yellow oil (2.98 g), t.l.c. (diethyl ether) Rf 0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.Cl.Cl.[CH3:25][N:26]([CH3:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([N:26]([CH3:34])[CH3:25])[CH:28]=2)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CCCc1ccc(C(=O)Nc2cc(C(=O)Cl)ccc2Cl)cc1
Agent: Cl
Product: CCCc1ccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2Cl)cc1

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-3-(4-propylbenzamido)benzoyl chloride was reacted with 3-dimethylamino aniline dihydrochloride to give the title compound; NMR Spectrum: (DMSOd6) 0.9 (t, 3H), 1.18 (t, 2H), 1.69 (m, 2H), 2.99 (s, 6H), 7.0 (d, 1H), 7.2-7.5 (m, 4H) 7.64-7.8 (m, 3H), 7.84 (d, 1H), 8.0 (m, 2H), 8.19 (s, 1H); Mass Spectrum: M+H+ 436 and 438.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2Br)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:32][N:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]1=[O:48].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[C:1]([C:4]1[C@@H:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[C:37]2[CH:36]=[CH:35][C:34](=[O:48])[N:33]([CH3:32])[CH:38]=2)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1-c1ccc(=O)n(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-3-bromo-benzonitrile (intermediate 4)(400 mg, 0.81 mmol) and N-methyl-1H-pyridin-2-one-5-boronic acid pinacol ester (248 mg, 1.06 mmol) are suspended in acetonitrile (15 mL) and are degassed with a stream of argon. Potassium carbonate solution (2 mol/L, 1.22 mL, 2.44 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloro-palladium(II), complex with dichloromethane (1:1) (6.34 mg, 0.008 mmol) are added and the reaction is stirred at 100° C. overnight. Additional N-methyl-1H-pyridin-2-one-5-boronic acid pinacol ester (100 mg, 0.4 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) (2 mg, 0.002 mmol) are added and the reaction is continued at 120° C. for 60 min under microwave irradiation. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Yield: 125 mg; ESI mass spectrum [M+H]+=521; Retention time HPLC: 1.01 min (HPLC method Z018_S04).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(O)C.[BH4-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CO)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a 200 ml solution of 50 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde in an ethanol:THF=1:1 mixed solvent there was added 16.4 g of sodium borohydride while cooling on ice. After stirring for 2 hours at room temperature, 1N hydrochloric acid was added to the reaction mixture while cooling on ice. The organic layer was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure to obtain the target compound (50 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:5][O:6][P:7]([C:20]1[CH:39]=[CH:38][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[CH:33]=2)[C:28]([OH:30])=O)=[CH:22][CH:21]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=1)=[O:8].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH2:10][O:9][P:7]([C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[C:27]([C:28](=[O:30])[NH:45][C:46]3[S:47][CH:48]=[CH:49][N:50]=3)[CH:31]=[C:32]([O:34][CH:35]([CH3:36])[CH3:37])[CH:33]=2)=[CH:38][CH:39]=1)(=[O:8])[O:6][CH2:5][C:4]1[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:2]([F:1])[CH:3]=1
Reactant: Nc1nccs1
Reactant: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)O)c3)cc2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)Nc4nccs4)c3)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a solution of 3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoic acid (350 mg, 0.557 mmol) in DMF (6 mL) was added 2-aminothiazole (70 mg, 0.696 mmol), HATU (265 mg, 0.696 mmol), and diisopropylethylamine (368 μL, 2.23 mmol). Stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with H2O (2×) and brine (2×). Dried with MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel using an ethyl acetate-hexanes gradient to provide 164 mg (42%) of the title compound: 1H NMR (300 MHz, DMSO-d6): δ 12.68 (bs, 1H), 7.75 (dd, J=13, 9 Hz, 2H), 7.55 (d, J=4 Hz, 2H), 7.35 (s, 1H), 7.16 (m, 9H), 6.91 (s, 1H), 4.97 (dd, J=8, 2 Hz, 4H), 4.76 (m, 1H), 3.82 (s, 6H), 1.30 (d, J=6 Hz, 6H); LCMS m/z=711.6 [C35H33F2N2O8PS+H]+: Anal. Calcd. for (C35H33F2N2O8PS+1.2H2O): C, 57.41; H, 4.87; N, 3.83. Found: C, 57.06; H, 4.24; N, 3.91.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([O:19][CH3:20])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc2cc3ccccc3cc2c1
Product: COC(=O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 210 °C

Procedure:
Anthracene (89.0 gm) was combined with methyl acrylate (51.5 gm) and xylenes (500 ml) in a Parr bomb and heated to 210° C. for 12 hours. The solvent was removed on a rotary evaporator and the residue was recrystallized from methanol to provide the product as a white solid (m=113-114° C.).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]1[O:24][C:23]2[C:16](=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)[O:15]1>>[O:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:17]([CH2:18][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=4)[CH2:2][CH2:3]3)[C:16]=2[O:15][CH2:14]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc4c3OCO4)CC2)nc[nH]1

Procedure:
6-(4-Benzo[1,3]dioxol-4-ylmethyl-piperazin-1-yl)-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,3-(methylenedioxy)benzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.51-2.54 (m, 4H), 3.48-3.58 (m, 6H), 5.35 (s, 1H), 5.95 (s, 2H), 6.74-6.82 (m, 2H), 7.81 (s, 1H). Mass spectrum (ES) MH+=315.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:32][CH2:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:7]=2[CH:6]=1)=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(ncn2CCC(=O)OC(C)(C)C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.50 g, 1.25 mmol) is dissolved in DMF (8 mL) under N2 and K2CO3 (0.26 g, 1.88 mmol) is added followed by t-butyl acrylate (1.84 mL, 12.54 mmol). The reaction mixture is heated to 90° C. with stirring. After 4 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with water (3×) and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 19:1 methylene chloride:ethyl acetate provides 0.41 g (62%) desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.C(Cl)Cl>CO>[ClH:1].[Cl:1][C:2]1[C:3]([SH:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2
Reactant: Sc1ccc2ccncc2c1Cl
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: Sc1ccc2c(c1Cl)CNCC2
Temperature: 5 °C

Procedure:
To a solution of (11.7 g., 0.06 m.) 8-chloro-7-mercaptoisoquinoline in 150 ml. of methylene chloride was added a solution of 1 M borane-methylsulfide complex (120 ml., 0.12 m.). The addition was carried out dropwise with stirring under a nitrogen atmosphere. After stirring for half an hour the reaction mixture was refluxed for 2.5 hours, cooled to 5° C., and treated with 135 ml. of methanol dropwise. The reaction mixture was evaporated to a residue under reduced pressure and was then repeatedly evaporated from methanol. The residue was dissolved in methanol and treated with ethereal hydrogen chloride. The resulting precipitate was collected by filtration and dried to give 8-chloro-7-mercapto-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 230°-234° C. dec.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19](N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C>O1CCCC1>[CH2:19]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33]
Reactant: CCOC(=O)c1[nH]c2cc([N+](=O)[O-])ccc2c1N
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cc([N+](=O)[O-])ccc2c1NCC(=O)c1ccccc1

Procedure:
Suspend the 3-amino-2-carbethoxy-6-nitroindole (0.6 mmol) in tetrahydrofuran (mL) and add triethylamine (0.62 mmol). Add benzoyl chloride (0.62 mmol) and stir for 30 minutes at room temperature. Dilute the reaction with ethyl acetate, rinse with 1M HCl, water, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize from hot ethyl acetate/hexane to yield 3-[(phenacyl)amino]-2-carbethoxy-6-nitroindole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:36][CH2:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[C:27]([F:35])[CH:26]=2.[Li+].[OH-]>C1COCC1.CO>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[F:35])[N:24]=[C:23]([NH:36][CH2:37][CH3:38])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2cc(F)c(OCC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)c(F)cc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (55 mg, 222 μmol) in THF (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a solution of 3-(chloromethyl)-6-ethoxy-N-ethyl-7-fluoroquinolin-2-amine hydrochloride SMA 44106 (76 mg, 238 μmol) in MeOH (0.5 mL) at RT followed by a 2 N aq. LiOH solution (240 μL, 480 μmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. After cooling to RT, THF and MeOH were removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol 86 as a brown solid (15 mg, 12% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)(O)[O-].[Na+].Br[CH2:17][C:18](Br)=[O:19]>C(Cl)(Cl)Cl>[O:19]=[C:18]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH2:17]1
Reactant: O=C(Br)CBr
Reactant: N#Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared similarly to literature procedure (Caliendo, G; et. al.; Bioorg. Med. Chem. Lett., 2002, 10, 2663), but in one step. Commercially available 3-amino-4-hydroxybenzonitrile (2.5 g, 18.6 mmol) was dissolved in chloroform (300 mL) and saturated sodium bicarbonate (90 mL). The biphasic reaction mixture was cooled to 0° C. and bromoacetyl bromide (2.4 mL, 28 mmol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a tan solid, 2.3 g (69%).