Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]([O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O-:15])=[O:14])=[O:8])([CH3:5])([CH3:4])[CH3:3].CN(C=O)C.[I-].[K+].[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[C:2]([O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:14])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)[O-])c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCOC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
3-(t-Butyloxycarbonylamino)benzoic acid sodium salt (10 g), DMF (60 ml) and potassium iodide (6.3 g) are mixed, and thereto is added dropwise pivaloyloxymethyl chloride (6 g) under ice cooling. The mixture is stirred at room temperature for 15 hours, and thereto is added ethyl acetate (200 ml). The mixture is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 70% aqueous acetonitrile to give pivaloyloxymethyl 3-(t-butyloxycarbonylamino)benzoate (11.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18](F)[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18]([N:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:34])[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)(C)C
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(F)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(R)-[4-fluoro-6-(2-methyl-5-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.36 g, 0.81 mmol), N-methyl-neopentylamine hydrochloride (411 mg, 3 mmol) and DIEA(0.4 mL) in 1,4-dioxane (0.5 mL) was stirred at 90° C. overnight. After removing the solvent under reduced pressure the desired product (81 mg) was purified by silica gel chromatography. C28H43N7O3 MS m/e=526 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.C1(O)C2C=C[CH:17]=[C:16]([OH:21])[C:15]=2CC1.C(OC1C=CC=C2C=1CCC2O)(=O)C.C(C1OC1)Cl.[OH-].[Na+]>>[O:21]1[CH2:17][CH:16]1[CH2:15][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2
Reactant: Oc1cccc2c1CCC2O
Reactant: O=C1CCc2c(O)cccc21
Agent: CC(=O)Oc1cccc2c1CCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCC1CO1
Product: C1=Cc2c(cccc2OCC2CO2)C1

Procedure:
4-Hydroxy-1-indene is prepared starting from 4-hydroxyindanone via 1,4-indanediol, 4-acetoxy-1-indanol and 4-acetoxy-1-indene in this order. The resulting 4-hydroxy-1-indene is allowed to react with epichlorohydrin in an aqueous solution of sodium hydroxide to give 4-(2,3-epoxypropoxy)indene. [cf. Yakugaku Zasshi 92, 1358 (1972)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[S:32][CH:33]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[S:32][CH:33]=[C:29]([CH3:28])[CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and (4-methyl-2-thienyl)boronic acid (71 mg, 0.50 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and solvent evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E107). MS (ES+) m/e 472 [M+H]+.
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:10])=CC=1)([O-])=O.[OH:28][CH2:29][CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O>[OH:28][CH2:29][CH2:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:9]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2)=[O:10]
Reactant: OCCNC1CCCCC1
Reactant: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Reaction time: 12 h

Procedure:
3.8 Grams of 6-[3-(p-nitrophenoxycarbonyl)propoxy]carbostyril was dissolved in 40 ml of dimethylformamide, then 1.6 ml of N-(2-hydroxyethyl)cyclohexylamine was added thereto and the reaction mixture was stirred at 60°-70° C. for 12 hours. After the reaction was completed, the solvent was removed by distillation and the residue thus obtained was purified by a silica-gel column chromatography [Silica-gel used was "Wako C-200" and the solvent used was a mixture of chloroform:methanol=20:1 (vol/vol)]. The crude crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 1.3 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril as in the form of colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[CH3:8][NH:9][OH:10]>C(Cl)(Cl)Cl>[CH3:8][N:9]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[OH:10]
Reactant: CN(C)CC(=O)O
Reactant: CNO
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=O)N(C)O
Yield: 25.6 %

Procedure:
To the solution of 131 g of sodium hydroxide dissolved in 400 ml of water, 400 ml of an aqueous solution containing 273 g of N-methylhydroxylamine hydrochloride was added, with ice-cooling. Subsequently, 384 g of N,N-dimethylglycine methyl ester was added thereto. The resultant reaction mixture was stirred at room temperature for 3 days. The results of gas chromatography demonstrated a rate of residual raw materials: 2.3%, a rate of formation of N-methyl-α-dimethylaminoacetohydroxamic acid: 51.5%, and a rate of secondary production of N,N-dimethylglycine: 45.1%. After a large portion of the solvent was distilled off under a reduced pressure, chloroform and then anhydrous magnesium sulfate were added to the residue; thereafter, they were fully shaked, followed by filtration, to remove insoluble substances. After the resultant filtrate was concentrated, the residue was recrystallized from aceton/methanol (50/1), to give 186 g of crystals. As a result of analysis of the crystals using gas chromatography and 1H-NMR, it was found that each several percents of each of N,N-dimethylglycine and N-methylhydroxylamine were mixed therein, and therefore the crystals were dissolved again in 3 liters of chloroform, to remove insoluble substances by filtration. After the filtrate was concentrated, the residue was recrystallized from aceton/methanol (12/1), to give 111 g (yield 25.6%) of pure N-methyl-α-dimethylaminoacetohydroxamic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[CH2:17])[C:12]([O:14]CC)=[O:13].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>S1(CCCC1)(=O)=O>[F:23][C:19]1([F:24])[CH2:17][C:11]1([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: C=C(C(=O)OCC)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: O=C(O)C1(c2ccc3ccccc3c2)CC1(F)F
Temperature: 160 °C
Yield: 83.5 %

Procedure:
Ethyl 2-(2-naphthyl)-acrylate (4.28 g) was dissolved in sulfolane 20 ml. Sodium chlorodifluoroacetate (9.1 g) was added in portions to the solution, heated to 160° C., over 35 minutes. The reaction mixture was cooled, quenched into ice water, then extracted with ether. The ether layer was washed several times with water and after separation dried over anhydrous sodium sulphate. After evaporation of the ether, the residual dark oil was chromatographed on silica gel using petroleum ether (b.p. 40°-60°)/methylene chloride mixture as eluent. The major fraction (4.05 g) was distilled under vacuum to yield the product as a yellow oil (3.92 g; 71%). The ester was identified from i.r. and p.m.r. spectra and hydrolysed by refluxing in 1 N sodium hydroxide/ethanol solution. On acidification and extraction the solid acid was recrystallised from petroleum ether/methylene chloride to yield the acid as a white solid, m.p. 190°-2°.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([S:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([C:33]2[NH:34][C:35](=[O:42])[C:36]([CH:39]([CH3:41])[CH3:40])([CH3:38])[N:37]=2)[N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([S:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:25][C:26]=1[C:33]1[NH:34][C:35](=[O:42])[C:36]([CH:39]([CH3:40])[CH3:41])([CH3:38])[N:37]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)C1(C)N=C(c2nc(SCc3ccccc3)ccc2C(=O)O)NC1=O
Solvent: ClCCl
Product: COC(=O)c1ccc(SCc2ccccc2)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.0 g (0.005 mol) dicyclohexylcarbodiimide and 2.0 g (0.005 mol) 6-benzylthio-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-nicotinic acid are dissolved in 30 ml methylene chloride, then stirred for 4 hours at room temperature and allowed to stand overnight. The reaction mixture is filtered and the filtrate is then compressed. The oily residue crystallizes after a while.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:28]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O.ClC1([N+]([O-])=O)C=CC=NC1>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[CH:17][CH:18]=[CH:19][N:28]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=[N+]([O-])C1(Cl)C=CC=NC1
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1[N+](=O)[O-])C(=O)O
Yield: 64 %

Procedure:
was prepared by a similar method as (2S) 2-tert-butoxycarbonylamino-3-(2-nitrophenyl-amino)propionic acid in Step A of the synthesis of 600a/103, except that 3-chloro-3-nitro pyridine was used instead of 2-fluoronitrobenzene, to give 4.05 g (64%) of a yellow solid.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O-])=[O:11])=O)(C)(C)C.[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.[ClH:41].C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[ClH:41].[NH2:8][C:9]([CH3:14])([CH3:13])[C:10]([N:28]1[CH2:29][CH2:30][N:25]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:26][CH2:27]1)=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.06 g) in N,N-dimethylformamide (40 mL) were added 1-(benzyloxycarbonyl)piperazine (6.6 g), 1-hydroxybenzotriazole (3.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.67 g) and triethylamine (11.2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 25 mL), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added diethyl ether (50 mL), and the insoluble material was collected by filtration. The collected solid was washed with diethyl ether and dried under reduced pressure to give the title compound (4.65 g).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH2:18][O:17]1)=[O:15]>C(Cl)Cl>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]([N:16]3[CH2:22][CH2:21][C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[CH2:18][O:17]3)=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCc2ccccc2CO1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: O=C(N1CCN(c2ccccc2)CC1)N1CCc2ccccc2CO1

Procedure:
To a solution of 4.22 g. (26 mmoles) of N-phenylpiperazine in CH2Cl2, 4.24 g. (20 mmoles) of 3-chlorocarbonyl-1,3,4,5-tetrahydro-2,3-benzoxazepine was added and the mixture was refluxed for 2 hours, cooled, washed with NaHCO3 and with H2O, dried over Na2SO4 and the solvent evaporated. Yield 5.5 g. (81.5%), m.p. 123°- 125°C, recrystallized from EtOH.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:34])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:26]=[CH:25]OC=2C(N(CC)CC)=O)=[CH:4][C:3]=1[Cl:35].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:42]1[CH:47]=CC=CC=1>CCOCC>[NH2:1][C:2]1[C:3]([Cl:35])=[CH:4][C:5]([CH:9]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[O:34][C:9]([CH2:10][N:11]([CH2:47][CH3:42])[CH2:12][CH3:13])=[CH:25][CH:26]=2)[OH:34])=[CH:6][C:7]=1[Cl:8]
Reactant: c1ccccc1
Reactant: CCN(CC)C(=O)c1occc1CCCOCCCCCCNCC(O)c1cc(Cl)c(N)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN(CC)Cc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)o1
Reaction time: 24 h

Procedure:
A solution of 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl -N,N-diethyl-2-furancarboxamide (0.83 g) in benzene (6 ml) was added dropwise over 10 min to a stirred suspension of lithium aluminium hydride (175 mg) in dry ether (15 ml) under nitrogen. The mixture was stirred under nitrogen at 22° for 24 h, then quenched sequentially with water (1 ml), 2N sodium hydroxide solution (1 ml) and water (2 ml). The mixture was filtered through hyflo and the solids washed with toluene-ether (1:1, 10 ml). The combined filtrate and washings were dried and evaporated in vacuo to an oil. Purification by FCC eluting with System C (93:5:2) afforded the title compound as a pale yellow oil (0.59 g), t.l.c. (System A 39:10:1) Rf 0.5.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:16])=[O:15].Cl>CCOCC>[C:1]1([CH2:7][C:8](=[O:10])[CH2:13][C:14](=[O:15])[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)CC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of NaNH2 (19.02 g, 480 mmol) in anhydrous ether (400 mL) under N2 at −5° C. was added dropwise ethyl phenylacetate (19.2 g, 150 mmol) and then acetone (21.23 g, 370 mmol) with vigorous stirring. After addition, the reaction mixture was stirred at room temperature overnight. The mixture was then acidified to pH 4.0-5.0 with 1N HCl. The organic layer was separated and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1-phenyl-2,4-pentanedione (18.32 g, 44%). 1H NMR (400 MHz, CDCl3-d3) δ 15.49 (br s, 1H), 7.33-7.45 (m, 5H), 5.53 (s, 1H), 3.66 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(N(CC)CC)C.[Cu](I)I>[C:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Nc1ccccc1I
Reactant: C#CCCCC
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
32 mg of copper iodide and 140 mg of bistriphenyl phosphine palladium chloride and 2.3 ml of 1-hexyne were added to a solution of 4.4 g of 2-iodo aniline in 100 ml of triethylamine and the mixture was stirred for 15 hours at ambient temperature, then evaporated to dryness. The residue was taken up in ether and the insoluble part was filtered out, washed with ether and the ethereal fractions were evaporated to dryness. The residue was chromatographed on silica (eluant:hexane-ethyl acetate (9-1)) to obtain 3.27 of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([NH:21][CH2:22]CC)=[N:11][N:10]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]([CH3:26])[CH3:22])=[N:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCCNc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N(C)C)c2c1
Temperature: 50 °C
Yield: 48.8 %

Procedure:
At room temperature a solution of [4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-yl]-propyl-amine (3.5 g, 5.64 mmoles), prepared as described in example 78, in DMF (35 ml) was stirred under N2, then added with K2CO3 (0.78 g, 5.64 mmoles) and methyl iodide (0.35 ml, 5.64 mmoles). The mixture was heated at 50° C. and after 20 hours was dried and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give an oil which was flash chromatographed (eluent: hexane/ethyl acetate 4:6) to give 1 g of the title compound (yield: 50%). m.p.: 170-173° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccccc1F
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2F)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-fluorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-fluorophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](Cl)=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][CH:34]=[C:33]5[CH3:39])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A mixture of 7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-chloro-6-methoxyquinazoline (4.6 g), 5-hydroxy-3-methylindole (2 g), (Journal of Organic Chemistry 1993, 58, 3757), potassium carbonate (3.1 g) and DMF (20 ml) was stirred and heated to 90° C. for 2 hours. The solid was removed by filtration washed with acetonitrile and the combined filtrates concentrated to dryness under vacuum. The product so obtained was triturated under ether/petroleum ether (8/2), collected by filtration and dried to give 7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (5.8 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (trans-4-hydroxycyclohexyl)carbamate (from AstaTech, 0.133 g, 0.618 mmol) and triethylamine (0.12 mL, 0.86 mmol) in methylene chloride (1 mL) was added methanesulfonyl chloride (0.057 mL, 0.74 mmol). The reaction mixture was stirred at room temperature for 2 h. After dilution with sat. aq. NaHCO3 solution, the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (0.18 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N:10]2CCCC2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Cl.N[NH:20][C:21]([NH2:23])=[O:22]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[N:10]/[NH:20][C:21]([NH2:23])=[O:22])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1/C=C/N1CCCC1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)N/N=C/Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]pyrrolidine (77.25 g, 0.327 mol) in warm MeOH (500 mL) was added a solution of semicarbazide HCl (38.3 g, 0.343 mol) in warm water (200 mL). The reaction mixture was stirred at room temperature for 1 h and was then cooled in ice and filtered. The solid was washed with cold 1:1 MeOH/water (2×30 mL) and dried to give 71 g (90% over two steps) of the title compound.