Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:37][CH2:38][C:39]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])(=[O:25])[CH2:3][CH2:4]2)[CH:22]=1)=[O:40]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CCl)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (500 mg, 1.4 mmol) in chloroform (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL, 2.8 mmol) followed by chloroacetyl chloride (0.17 mL, 2.1 mmol) at room temperature. The resulting solution was heated with stirring at 70° C. for 2 hours under nitrogen. After being cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL), washed with water (50 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% ethyl acetate in petroleum ether) to give 120 mg of the product as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][C:40]=1[F:41])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:37])=[CH:23][C:24]=2[O:26][CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:36])[CH2:34][OH:35])[N:19]=[CH:18][N:17]=1.O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][C:40]=1[F:41])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:37][CH2:2][CH2:3][OH:4])=[CH:23][C:24]=2[O:26][CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:36])[CH2:34][OH:35])[N:19]=[CH:18][N:17]=1
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)N1CCC[C@@H]1COc1cc(OCCO)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 70 °C
Yield: 45 %

Procedure:
2-Bromoethanol (51 μl) and potassium carbonate (86 mg) were added to a mixture of 4-[3-chloro-4-fluoroanilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}-quinazolin-7-ol (70 mg) in DMF and the reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and then water (5 ml) was added to leave a white precipitate. The precipitate was filtered, washed with water and then purified by column chromatography using 2-5% methanol in DCM as eluent. The product was purified further by acidic reverse phase HPLC, and then the combined fractions were reduced to a third of the initial concentration, basified with sodium carbonate and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (35 mg, 45%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1M, 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (m, 2H), 3.60 (m, 1H), 3.50-3.37 (m, 2H), 2.10-1.85 (m, 4H); Mass spectrum MH+ 491.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[N+:17]([O-])([OH:19])=[O:18].C([O-])(O)=O.[Na+]>CC(O)=O.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1nccc(Oc2ccc(O)cc2)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1nccc(Oc2ccc(O)c([N+](=O)[O-])c2)n1
Reaction time: 18 h

Procedure:
4-(2-Methylamino-pyrimidin-4-yloxy)-phenol (Step C, 0.20 g, 0.92 mmol) was dissolved in 5 mL AcOH at RT. Fuming HNO3 (0.064 g, 0.92 mmol) was diluted with about 0.012 mL water, then added dropwise over 1 min to the reaction. The reaction was stirred for 18 h, after which it was added slowly to 40 mL saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using hexanes/EtOAc gradient to yield the title compound. MS (MH+)=263.1; Calc'd 262.23 for C11H10N4O4.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C1([Li])C=CC=CC=1.[CH2:17]([N:20]=[C:21]=[S:22])[CH:18]=[CH2:19].Cl>O.C1C=CC=CC=1>[CH2:17]([NH:20][C:21](=[S:22])[CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH:18]=[CH2:19]
Reactant: C=CCN=C=S
Reactant: COCc1ccccn1
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCNC(=S)C(OC)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.95 g. (0.081 mole) of 2-(methoxymethyl)pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in 80 ml. of dry benzene. The mixture is stirred at 0° C. for 1 hour after the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is then diluted with 500 ml. of water and acidified with 10% hydrochloric acid. The layers are separated and the organic layer is washed several times with water. The aqueous layers are combined, neutralized with 10% aqueous sodium hydroxide solution and then brought to pH 9 with 5% aqueous sodium bicarbonate solution, then extracted with chloroform. The chloroform extracts are washed once with brine and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate. The fractions containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N-allyl-2-methoxy-2-(2-pyridyl)thioacetamide, m.p. 59.5°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH3:12].[CH2:13]([Cl:22])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>C(#N)C>[ClH:22].[CH3:1][O:2][C:3]1[C:11]2[C:6]([N:7]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH:8]=[CH:9][CH:10]=2)=[N:5][C:4]=1[CH3:12]
Reactant: COc1c(C)[nH]c2ncccc12
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Product: COc1c2cccn(CC(=O)c3ccccc3)c-2nc1C
Product: Cl
Yield: 34.3 %

Procedure:
A solution of 0,75 g (4,6 mmol) 3-methoxy-2-methylpyrrolo[2,3-b]pyridine and 0,75 g (4,8 mmol) phenacyl chloride in 50 ml acetonitrile was refluxed for 14 h. Working up in the same manner as ex. 17 gave 0,5 g (34%) of the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Br:21].[Cl:22]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>O1CCCC1>[Cl:22][C:19]1[C:14]([F:13])=[C:15]([Br:21])[CH:16]=[CH:17][C:18]=1[F:20]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 19 ml (0.135 mole) of diisopropylamine in 125 ml of tetrahydrofuran (THF) cooled at −20° C. is added 80 ml of n-butyllithium (1.6 M in hexane). The temperature is raised to 0° C. for 5 minutes and lowered to −78° C. Then 25 g (0.129 mole) of 2,4-difluoro-bromobenzene is then added and the reaction is stirred at −65° C. for 2 hours. Then, 25 ml (0.164 mole) of hexachloroacetone is added and the solution is warmed at room temperature. After evaporation of the solvent, the residue is distilled under vacuum to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[NH2:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:15]=[CH:14][C:13]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([OH:30])=[O:12])=[CH:23][CH:22]=1
Reactant: NC(=O)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: NC(=O)COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 21.3 %

Procedure:
To a mixture of 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]acetamide (100 mg, 0.30 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (540 mg, 6.00 mmol) and sodium phosphate monobasic hydrate (850 mg, 6.00 mmol) in water (5 mL) dropwise via additional funnel. The ice bath was removed and the reaction was stirred at room temperature for 48 h. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Prep-HPLC: Column: Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 24% MeCN in water (0.225% FA) to 34% MeCN in water (0.225% FA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 5-[4-(2-amino-2-oxoethoxy)phenyl]-6-chloro-1H-indole-3-carboxylic acid (22 mg, 20% yield) as a white solid. MS (ES+) 344.8 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.01-7.99 (m, 2H), 7.57 (s, 1H), 7.43-7.39 (m, 2H), 7.07-7.05 (m, 2H), 4.56 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[ClH:22].[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC(C)C)CC)C(C)C>CN(C=O)C>[ClH:22].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:28]([NH2:29])=[NH:23])[CH2:15][CH2:16]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N=C(N)n1cccn1
Reactant: NCCCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Agent: CCN(CC(C)C)CC(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCCCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 6-fluoro-3-(1-(3-cyanopropyl)-4-piperidyl)indole (453 mg, 1.6 mmol) in ethanol (30 mL) was added platinum oxide (110 mg) and a concentrated hydrochloric acid (0.8 mL), and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated, and a saturated aqueous sodium hydrogencarbonate was added to pH of 10, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford 6-fluoro-3-(1-(4-aminobutyl)-4-piperidyl)indole (470 mg, yield: 100%) as a pale yellow solid. To a solution of this amine (68 mg, 0.23 mmol) in DMF (0.22 mL) was added lH-pyrazole-1-carboxamidine hydrochloride (35 mg, 0.23 mmol) and diisobutylethylamine (31 mg, 0.23 mmol), and the mixture was stirred at room temperature overnight. After washing with diethyl ether, the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1) to afford a free form (61 mg, yield: 77%) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form (61 mg) in methanol was concentrated and was then freeze-dried to afford the title compound (53 mg) as a white amorphous solid.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([CH3:34])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.[Cl:43]CCl>>[ClH:43].[CH3:34][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:35])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3cccc(C(F)(F)F)c3)cn2)cs1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ncc(-c3cccc(C(F)(F)F)c3)cn2)cs1)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Methyl-2-({4-[2-({5-[3-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (190 mg) obtained in Example 164-1 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1). The obtained compound was dissolved in diethyl ether (4 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give the title compound (151 mg) as a white solid.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.N1CCCC[CH2:21]1>C(O)(=O)C>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[C:11]2[CH2:1][CH:2]([CH3:21])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=C1CCCc2ccccc21
Reactant: C1CCNCC1
Reactant: O=Cc1ccncc1
Solvent: CC(=O)O
Product: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21

Procedure:
A mixture of 80.0 grams (0.50 moles) of α-tetralone, 64.2 grams (0.60 moles) of 4 -pyridinecarboxaldehyde, 10 grams of piperidine and 10 grams of acetic acid are heated at 80° for 19 hours. The resultant solid is crystallized from about 400 ml. of ethanol to give 2-(4-pyridylmethylene)-3,4-dihydro-4-methyl-1(2H)-napthalenone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 4-methyl-2-nitro-phenylamine (202 mg, 1.33 mmol) and benzaldehyde (0.68 mL, 6.65 mmol) in 5 mL dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (282 mg, 1.33 mmol). Then acetic acid (76 μl, 1.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 300 mg (1.24 mmol, 94%) of benzyl-(4-methyl-2-nitro-phenyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([OH:13])(=[O:12])[CH:10]=O.[CH2:14]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1)[CH2:15][CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][CH:10]([C:9]([OH:13])=[O:12])[CH2:23][CH:22]2[C:21]1[CH:24]=[CH:25][C:18]([O:17][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: C=Cc1ccc(OCCC)cc1
Reactant: Nc1ccccc1Cl
Reactant: O=CC(=O)O
Product: CCCOc1ccc(C2CC(C(=O)O)Nc3c(Cl)cccc32)cc1

Procedure:
Compound 74 was prepared from 2-chloroaniline, glyoxylic acid and 4-propoxystyrene by the automated process.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].Cl.[O:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N:9]1[C:8](=[O:25])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][CH2:33][O:27][CH2:28][CH2:29]3)[CH:6]=2)[N:11]=[CH:10]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: C1CNCCOC1
Agent: Cl
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN3CCCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), 1,4-oxazepane hydrochloride (0.77 g), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[6-[2-(1,4-oxazepan-4-yl)ethoxy]-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.31 g); NMR Spectrum: (DMSOd6) 1.87 (m, 2H), 2.10 (s, 3H), 2.91 (m, 2H), 3.02 (m, 4H), 3.66 (m, 4H), 4.20 (m, 2H), 7.46 (m, 2H), 7.58 (s, 1H), 7.69 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.16 (s, 1H); Mass Spectrum: M+H+ 424.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:20])[CH3:19].C(O)(=O)C.[C-:25]#[N:26].[K+]>O>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH:4]([C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[C:25]#[N:26])(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccccc1N
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1NC(C#N)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A mixture of 8.75 parts of 2,6-dichlorobenzaldehyde, 5.4 parts of 1-(2-aminophenyl)-1-ethanone and 105 parts of acetic acid was stirred for 1/2 hour at room temperature. There were added 3.26 parts of potassium cyanide and stirring was continued for 20 hours. The reaction mixture was diluted with water. The precipitate was filtered off, washed with water and recrystallized from acetonitrile. The product was filtered off and dried, yielding 9.1 parts (71.3%) of (±)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetonitrile; mp. 178.7° C. (interm. 3).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39]COC)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCCC1.C(O)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCOC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
A mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl)oxy]-1H-pyrazole-4-carboxylate (8.65 g), 1N hydrochloric acid (50 mL), tetrahydrofuran (100 mL) and ethanol (100 mL) was stirred at 50° C. for 5 hrs. The reaction mixture was diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (5.37 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=1[Cl:54].BrCCCCC>>[Cl:54][C:48]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:47]=1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2ccc(F)cc2Cl)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-chloro-4-fluorobenzene to replace 1-bromopentane, 1′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.60 (m, 1H), 7.35-7.17 (m, 4H), 7.10-7.02 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 4.97 (ABq 2H), 4.75 (ABq, 2H), 4.22-4.08 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.8, 144.2, 142.1, 137.8, 132.9, 131.7, 130.1, 129.5, 129.4, 128.9, 123.8, 123.2, 121.0, 117.2, 116.9, 114.9, 111.3, 109.3, 98.8, 79.6, 64.2, 63.6, 57.2, 41.1; MS (ES+) m/z 437.6 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.CCN(CC)CC>COCCOC>[C:1]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCc2ccccc21
Reactant: CCCC(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCC(=O)NC1CCc2ccccc21
Yield: 58 %

Procedure:
A solution of butyryl chloride (5.33 g, 50 mmole) in anh. DME (60 ml) was added slowly to a stirred and ice-cooled solution of 1-aminoindan (6.66 g, 50 mmole) and Et3N (10.0 g, 100 mmole) in anh. DME (75 ml), and the mixture stirred at ambient temperature for 24 hr. After removal of volatiles under reduced pressure, the residue was taken up in 1:1 water/EtOAc mixture (300 ml). The organic layer was separated, dried on Na2SO4 and evaporated to dryness. The crude product was crystallized from EtOAc, to give 5.9 g (58%) of the title compound as a white solid, m.p.: 84°-5° C.