Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.P(Cl)(Cl)([Cl:24])=O>>[ClH:24].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(OC)c1
Product: Cl
Yield: 57 %

Procedure:
A mixture of 3,4-diaminopyridine (10.90 g., 100 mmoles) and 2,4-dimethoxybenzoic acid (18.20 g., 100 mmoles) was added to 400 ml. of phosphorous oxychloride and the resulting mixture was heated to reflux for about 4 hours. After cooling, the excess phosphorous oxychloride was removed under reduced pressure and the residue was treated with 200 ml. of 1N hydrochloric acid. The resulting solution was neutralized with 50% aqueous sodium hydroxide and the precipitated product was collected by filtration. Flash chromatography over silica gel (methylene chloride/methanol, 15:1) and recrystallization from ethanol/water saturated with hydrogen chloride gave the title product (16.54 g., 57% yield) as light tan needles, m.p. about 231°-234° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[CH:31]([N:34]([CH:37](C)C)CC)(C)C.C(Cl)(Cl)=[O:41].C1(C)C=CC=CC=1.CN.C1COCC1>ClCCl>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:31]([NH:34][CH3:37])=[O:41])[C:3]4[N:4]([CH:28]=[CH:29][N:30]=4)[CH:5]=3)[C:9]=2[CH3:27])=[O:26])=[CH:17][CH:18]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2c1
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cn2ccnc12
Temperature: 0 °C

Procedure:
To N-[3-(8-Amino-imidazo[1,2-a]pyridin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (120 mg, 0.3 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.13 mL, 2.5 eq). The resulting mixture was cooled to 0° C. and with stirring was added a solution of 20% phosgene in toluene (0.94 mL, 6 eq), and this solution was stirred at 0° C. for 30 minutes. Next, a 2.0M solution of methylamine in THF (3 mL, 20 eq) was added and the resulting mixture was stirred from 0° C. to room temperature overnight. The next day the solvent was removed under reduced pressure at 55° C. and then added ethyl acetate (35 mL) and water (25 mL). The layers were partitioned and then separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by Preparative Thin Layer Chromatography eluting with 50% acetone in hexanes to give the title compound as an off-white powder (47 mg), ((M+H)+=456).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:8]=[C:7]([CH3:21])[N:6]=1.[CH2:22]([O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]N)=[CH:27][C:26]=1[O:34][CH3:35])[CH3:23].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1([O:61][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:22]([O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[C:9]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[N:8]=[C:7]([CH3:21])[N:6]=2)=[O:61])=[CH:27][C:26]=1[O:34][CH3:35])[CH3:23]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOc1ccc(CCN)cc1OC
Reactant: Cc1cc(C)c(Nc2cc(NCCN)nc(C)n2)c(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(CC(=O)NCCNc2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2-aminoethyl){2-methyl-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-4-yl}amine (0.36 g, 1.26 mmol), 4-ethoxy-3-methoxyphenethylamine (0.26 g, 1.26 mmol)) and N,N diisopropylethyl amine (0.24 ml, 1.38 mmol in CH2Cl2 (5 mL), add benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.61 g, 1.38 mmol) and stir at ambient temperature for 14 h. Dilute the resulting mixture with CH2Cl2 (20 mL), and wash with water (20 mL) and saturated aq NaCl (20 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify by preparative TLC (7% methanol-CH2Cl2) to obtain the title compound.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)C1C=CC=CC=1.[CH2:16](O)[CH3:17]>[Pd]>[CH3:10][N:11]1[CH:16]([CH3:17])[CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: c1ccc(CN2CCC3CNCC32)cc1
Reactant: CCO
Agent: [Pd]
Product: CC1C2NCCC2CN1C

Procedure:
10.8 g (46.9 mmol) of 2-benzyl-2,7-diazabicyclo[3.3.0]octane in 200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2.5 g of palladium-active carbon. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:19](=[O:22])([O-])[O-:20].[K+].[K+].[CH3:25]C(C)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[O:8][C:25]([C:19]([OH:20])=[O:22])=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(C)=O
Agent: [K+]
Product: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-bromo-2-benzoylbenzoic acid (57.6 g) in acetone (500 ml) was added potassium carbonate (26.1 g), and the mixture was stirred at room temperature for 10 min. to allow precipitation of potassium salt. Then diethyl bromomalonate (54.2 g) and DMF (25 ml) were added, and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated, and ethyl acetate (200 ml) and water (200 ml) were added to the residue. The mixture was stirred at room temperature for 30 min. After separating the organic layer, the layer was washed with water and brine, dried over sodium sulfate and concentrated. A mixed solution of acetic acid (200 ml) and conc. hydrochloric acid (200 ml) was added to the obtained residue, and the mixture was stirred at 120° C. for 15 hrs. After cooling, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The obtained residue was crystallized from isopropyl ether and collected by filtration to give the title compound (53 g) as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:43])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1>C(O)(C(F)(F)F)=O.CS(C)=O>[F:43][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cccc(OC(F)F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc(OC(F)F)c2)n1
Yield: 3.4 %

Procedure:
A solution of 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.121 g, 0.207 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight using a hotplate and a metal heating block. The crude product was dissolved in 2.5 mL of DMSO, and was purified by reversed phase chromatography (Gilson; 10-90% CH3CN in water with TFA additive: 0.1% v/v in each solvent). The fractions were combined and the CH3CN was removed. DCM was added and the whole was washed with a saturated solution of NaHCO3 (1×), brine (1×), dried over MgSO4, filtered and concentrated to give 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (24 mg, 6.97 μmol, 3.37% yield) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 12.17 (br. s., 1H); 8.80 (d, J=8.2 Hz, 1H); 8.41 (br. s., 1H); 7.97 (br. s., 1H); 7.83-7.90 (m, 1H); 7.78 (br. s., 1H); 7.62 (d, J=8.6 Hz, 1H); 7.31-7.40 (m, 1H); 6.93-7.01 (m, 1H); 6.78 (d, J=8.2 Hz, 1H); 2.45 (br. s., 3H). m/z (ESI, +ve ion) 345.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[CH:17]1([C:23]([Cl:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[ClH:25].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)C3CCCCC3)n2)CC1
Product: Cl
Yield: 88.2 %

Procedure:
Prepare according to procedure in Example 69 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, 175 mg, 0.794 mmol), cyclohexanecarbonyl chloride (159 μL, 1.19 mmol), and pyridine (15 mL) to yield 257 mg (88%) of the title compound. Mass spectrum (ion spray): m/z 331.2 (M+1); Analysis Calcd for C19H31N4OCl: C, 62.19; H, 8.51; N, 15.27. Found: C, 61.22; H, 8.44; N, 15.39. mp 250–2° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.CI.O>CN(C=O)C>[CH3:11][N:8]1[C:7](=[O:9])[CH:6]=[CH:5][N:4]=[C:3]1[S:2][CH3:1]
Reactant: CSc1nccc(=O)[nH]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSc1nccc(=O)n1C
Temperature: 0 °C

Procedure:
2-Methylthio-3H-pyrimidin-4-one (Step 1, 6.29 g, 44.2 mmol) was suspended in DMF (100 mL), cooled to 0° C., and additional DMF (50 mL) was added. Solid LiHMDS (9.58 g, 57.3 mmol) was added in one portion, and the reaction was stirred at 0° C. MeI (3.6 mL, 57.8 mmol) was added via syringe, and the reaction was warmed to RT and stirred for 20.75 h. At this time, the mixture was poured into 300 mL H2O and extracted exhaustively with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, concentrated, and purified on silica gel (3:1→3:2→1:1 hexanes/EtOAc) to give the title compound. MS (ESI pos. ion) m/z: 157. Calc'd for C6H8N2OS: 156.04.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:16]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][C:13]2([C:9]3=[N:10][CH:11]=[CH:12][N:8]3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:26]2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccn2-c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1ccnc12
Yield: 50.3 %

Procedure:
tert-Butyl 4-[1-(2-fluorophenyl)imidazol-2-yl]-4-hydroxy-piperidine-1-carboxylate (294 mg, 0.81 mmol) and K2CO3 (337 mg, 2.44 mmol) were heated at 110° C. for 16 h in DMF (5 mL). The solvent was evaporated and the resulting material was partitioned between dichloromethane and water. The organics were separated and washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography (0-50% ethyl acetate in hexanes) to give tert-butyl spiro[imidazo[2,1-c][1,4]benzoxazine-4,4′-piperidine]-1′-carboxylate (139 mg, 50%). ESI-MS m/z calc. 341.2. found 342.3 (M+1)+. Retention time 1.31 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C[Mg]I.[C:18](#N)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C1C[O:30]CC1>>[C:18]([C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1)(=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Reactant: C1CCOC1
Reactant: N#Cc1ccccc1
Agent: C[Mg]I
Agent: Cl
Product: CC(C)(Oc1ccc(C(=O)c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
26 g (0.1 mole) of 2-[(para-bromo)-phenoxy]-2-methyl-propionic acid is dissolved in 200 cc of anhydrous THF and placed in a 500 cc flask. The mixture is cooled in an ice bath and 0.2 mole of methylmagnesium iodide (prepared in solution of THF) is added slowly. After this addition, the temperature is allowed to rise and the mixture stirred at ambient temperature for 11/2 hours. Then slowly and drop by drop a solution of 4.1 g (0.1 mole) of benzonitrile in 20 cc of THF is added and the mixture is stirred for 2 hours 30 minutes at ambient temperature. The reaction mixture is poured on to 500 cc of 10% hydrochloric acid, cooled by 500 g of ice, and vigorously stirred. The reaction mixture is extracted with ether and the ethereal phases are washed, dried and decolorised. The ether solvent is evaporated under vacuum and the oily residue placed in a desiccator under vacuum. 2-[(para-benzoyl)-phenoxy]-2-methylpropionic acid slowly crystallises (22 g). The yield is 77% and the melting point 130° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:10]([C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=1[NH2:20])([O-:12])=[O:11].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)CC)C>C(#N)C>[NH2:20][C:14]1[CH:15]=[CH:16][C:17]([NH:19][C:7](=[O:9])[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C(O)Cn1ccnc1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(NC(=O)Cn2ccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 77.6 %

Procedure:
To a solution of 1H-imidazole-1-ylacetic acid (284 mg, 2.25 mmol) and 2-nitrobenzene-1,4-diamine (324 mg, 2.12 mmol) in acetonitrile (20 mL) was added 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT, 632 mg, 2.11 mmol) and triethylamine (600 μL, 4.4 mmol). The mixture was stirred for 4 d at room temperature. The red precipitate was collected by filtration and washed with acetonitrile to give N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (430 mg, 88% yield), 98% pure. A solution of N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (430 mg, 1.65 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (100 mg, 0.09 mmol) at room temperature overnight. The mixture was filtered, giving a blue solution. Removal of the solvent under reduced pressure gave N-(3,4-diaminophenyl)-2-(1H-imidazol-1-yl)acetamide (413 mg) as a blue semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH3:15])[C:11]3[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:10]=3[C:9]=2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][CH:3]=1.[Li]CCCC.CN(CCN(C)C)C.[C:41]([O-:44])([O-])=O.[K+].[K+].[CH3:47]I>C1COCC1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH3:15])[C:11]3[C:16]([CH:41]=[O:44])=[C:17]([C:19]([O:21][CH3:47])=[O:20])[S:18][C:10]=3[C:9]=2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: COCn1c(-c2ccc(Cl)cc2)c(C2CCCCC2)c2sc(C(=O)O)cc21
Agent: CN(C)CCN(C)C
Agent: [K+]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCn1c(-c2ccc(Cl)cc2)c(C2CCCCC2)c2sc(C(=O)OC)c(C=O)c21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution (0.27 M) of 5-(4-chlorophenyl)-6-cyclohexyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in THF was added dropwise to a solution of n-BuLi (3 eq.) and TMEDA (3 eq.) in THF (50 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 h then the resulting solution was treated with DMF (10 eq.). The mixture was stirred at −78° C. for 2 h, then quenched with aqueous NH4Cl (saturated solution), quickly diluted with AcOEt and poured into aqueous HCl (1 N). The aqueous layer was separated and extracted with AcOEt. The combined organic phase was dried and concentrated under vacuum. The resulting residue was azeotropically dried by co-evaporation with toluene, giving a crude that was dissolved in DMF. The resulting solution (0.22 M) was treated with K2CO3 (1.5 eq.) and MeI (5 eq.). The mixture was stirred at RT overnight then diluted with AcOEt and washed with water and brine. Evaporation of the solvent under reduced pressure afforded a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether and AcOEt) to afford the title compound (72%) as a solid.
Reaction SMILES: OC1C=CC([C:8]2[NH:9][C:10](=[O:22])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14](OC)=[CH:13][C:12]=3OC)=CC=1.C([Li])CCC>C1COCC1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:8][N:9]=1.[NH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:22]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1ccc2ccccc2[nH]1
Product: c1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.27 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.54 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent and excess of oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 hours. The solvent was removed and the crude product was purified by chromatography by using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate in 43% yield. To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath) maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and allowed to warm to room temperature and stirred for 16 h at room temperature. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinolone product in 27% yield. To a suspension of the above quinolone product (2) (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography using 5% methanol in CH2Cl2 to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). MS (ES) m/z: 297.93 (M); MP 245-247° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>C1(C)C=CC=CC=1>[CH2:3]1[CH2:2][O:1][C:6]2[CH:7]=[CH:8][C:9]([N:11]=[C:19]=[S:20])=[CH:10][C:5]=2[O:4]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a mixture of 1,4-benzodioxan-6-amine (15.1 g; 100 mmol) and triethylamine (20.2 g, 200 ml) in toluene (350 ml) was added dropwise over 10 min. thiophosgene (11.5 g, 100 mmol) in toluene (50 ml). The mixture was stirred at 80° C. for 30 min., cooled to room temperature and filtered. The filtrate was evaporated. The product was redissolved in toluene and concentrated in vacuo. The resulting oil was taken up in warm petroleum ether, which was filtered. The filtrate was concentrated to a small volume, which afforded 7.2 g of 3,4-ethylenedioxyphenylisothiocyanate. 3,4-Ethylenedioxyphenylisothiocyanate (1.1 g; 5.7 mmol) in toluene (15 ml) was added to 3-[4-(2-chlorophenyl)piperazin -1-yl]propylamine (1.45 g, 5.7 mmol) in toluene (45 ml). The mixture was refluxed for 6 h, cooled to room temperature and purified by column chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:1). The product was triturated with petroleum ether and redissolved in ethanol. Addition of hydrogen chloride in ether precipitated the title compound, which was recrystallized from ethanol to give 180 mg. M.p. 210°-212° C. MS (70 eV): m/z 447 (M+, 1%), 445 (1), 295 (4), 193 (100), 166 (10), 151 (20).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[Cl:14].C[N+]1([O-])CC[O:19]CC1>O1CCOCC1>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:8][C:3]=1[CH:2]=[O:19]
Reactant: COCCOc1ccc(Cl)c(CBr)c1
Reactant: C[N+]1([O-])CCOCC1
Solvent: C1COCCO1
Product: COCCOc1ccc(Cl)c(C=O)c1

Procedure:
2-(Bromomethyl)-1-chloro-4-(2-methoxyethoxy)benzene (1 eq.) from the previous step and NMO (3 eq.) were stirred in dioxane (0.3 M) at 90° C. for 6 h. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:42])[CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:42][CH:39]([CH2:40][CH3:41])[CH2:38][CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 91.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-pentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 87%).