Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[O:3]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[NH:35][N:36]=[CH:37][C:30]=12.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH:35]1[C:31]2=[N:32][CH:33]=[N:34][C:29]([NH:20][CH:18]([C:4]3[O:3][C:2](=[O:1])[C:11]4[C:6]([C:5]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH3:19])=[C:30]2[CH:37]=[N:36]1
Reactant: CC(NC(=O)OC(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]ncc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 55.6 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Intermediate E1, 141 mg, 0.136 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (42.0 mg, 0.272 mmol) and DIEA (95 μL, 0.543 mmol) were stirred at 80° C. for 3 hrs in tert-butanol (800 μL). The reaction was quenched by the addition of 1 mL of 1M HClaqueous and the resulting crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (29 mg, 56%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([O:25][CH3:37])=[O:24])=[CH:26][CH:27]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(OCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (85.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](O)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:3][N:2]([CH2:4][C:5]1([C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:1]
Reactant: COc1cccc2c1CCNC2CN(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1CCNC2(CN(C)C)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Prepared as Ex. No. 1, from 1.2 g (5.45 mmoles) of 1-dimethylaminomethyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline, 1.3 g (6.37 mmoles) of 3,4-dichlorophenylacetic acid and 2.4 g (11.70 mmoles) of dicyclohexylcarbodiimide in 50 ml of dry methylene chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN1CCCC1=O.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: COc1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccnc(N2CCNCC2)c1
Yield: 16.2 %

Procedure:
46 mg 2-chloro-4-methoxy-pyridine and 277 mg piperazine in 2 mL n-methyl-2-pyrrolidinone were stirred 45 min at 140° C. and 30 min at 200° C. under microwave conditions. The reaction was diluted with water and purified by HPLC to give 10 mg desired product.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].Cl.[Cl:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>CN(C=O)C>[ClH:37].[ClH:1].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]5[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=5)[C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(Cc6ccncc6)C5=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared according to the procedure described for Example 156 using 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 14 mg) and 4-chloromethylpyridine hydrochloride (20 mg). Yield, 19 mg.
Reaction SMILES: [C:1]([NH:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH2:14])=[C:9]([Cl:15])[N:8]=1)=[O:6])(=[NH:3])[NH2:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[NH2:13][C:12]1[C:7]([C:5]([N:4]=[C:1]([NH:2][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:3][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:6])=[N:8][C:9]([Cl:15])=[C:10]([NH2:14])[N:11]=1
Reactant: N=C(N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC(=NC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OCC
Reaction time: 2 h

Procedure:
To a stirred suspension of N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide (27.6 g., 0.12 mole) in pyridine (300 ml.) is added ethyl chloroformate (12.0 ml., 0.15 mole) during a 5 minute period. The reaction is stirred at 25° for 2 hours during which time the starting material dissolves and the hydrochloride of the starting material precipitates. The latter is filtered from the reaction and discarded. The filtrate is treated with water (700 ml.) to give 16 g. (71%) of 3,5-diamino-6-chloro-N-[bis(ethoxycarbonylamino)methylene]-2-pyrazinecarboxamide which melts at 213° C. after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[C:24]1([S:30]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine from General Procedure B-3 (500 mg), benzenesulfonyl chloride (0.30 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:9][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1cc(Br)cc(CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)cc(Br)c1
Temperature: 120 °C
Yield: 85.6 %

Procedure:
Step G3. A mixture of 1-bromo-3-(bromomethyl)-5-chlorobenzene (6 g, ˜21 mmol) and potassium phthalimide (3.15 g, 17 mmol) in DMF (50 ml) was heated at 120° C. for 2 hours. After cooled down, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 85%) was obtained as white solid. 1H NMR (DMSO-d6): δδ3.72 (s, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 7.52 (s, 1H), 7.84, 7.86 (d, 2H), 8.05, 8.07 (d, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)=[O:6]
Reactant: c1ccncc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCl)c1ccncc1

Procedure:
The title compound was synthesized from chlorobutyryl chloride (141 mg), pyridine (2 ml), and AlCl3 (260 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[NH:4][N:3]=1.C([O:13][C:14](=O)[CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](OCC)=[O:17])C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:13][C:14]1[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([OH:17])[N:3]2[N:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=[C:2]2[N:1]=1
Reactant: COC(=O)c1cc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 3 h

Procedure:
A solution of 5.0 g Methyl 3-amino-1H-pyrazole-5-carboxylate, 8.3 ml diethyl-phenylmalonate and 50 ml diisopropylethylamine in 50 ml DMF is heated to 150° C. for 40 h. The solvent is removed, the solid residue is dissolved in 2-propanol the mixture is stirred for 3 hours. The desired product is filtrated, dried and is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(O)=O.[ClH:39]>C(O)C>[ClH:39].[ClH:39].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][N:33]1[CH2:32][CH2:31][N:30]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Temperature: 25 °C
Yield: 47.7 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (42.1 g; 215 millimoles) and 61.9 g (215 millimoles) of bis(4-fluorophenyl)methylpiperazine were melted in an oil bath at 100° C., and 10 ml (265 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 30 minutes, and allowed to cool to room temperature. A mixture of 40 ml of conc. hydrochloric acid and 400 ml of ethanol was added, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol-ether gave 55.5 g (yield 47.7%) of 1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C1(C)C=CC=CC=1.Cl>[CH2:23]([S:25]([O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:27])=[O:26])[CH3:24]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
8.04 g (0.0389 mol) of 2,4-di-tert-butylphenol and 4.13 g (0.0408 mol) of triethylamine were dissolved in 15 mL of toluene followed by dropping in 5.01 g (0.0389 mol) of ethanesulfonyl chloride over the course of 30 minutes at 10° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 2,4-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in 3% aqueous hydrochloric acid solution and following separation of the organic layer, was washed once with saturated aqueous NaHCO3 solution and twice with saturated brine followed by drying with MgSO4 and concentrating. The resulting crude crystals were purified by crystallization with n-heptane to obtain 8.14 g (yield: 70%) of 2,4-di-tert-butylphenyl ethanesulfonate (white crystals, melting point: 76° C.).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:17](=[O:19])[CH3:18])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCOC(C)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
144.7 g of 4-hydroxybutyl acrylate and 118.7 g of pyridine were charged into a separable flask having a capacity of 1 liter, provided with a stirrer, a Jean-stark water separator, a cooling tube and a nitrogen gas inlet tube, and then 127.8 g of acetic anhydride was dropwise added thereto at 5° C. with stirring over 2 hours, while replacing the flask inside atomosphere with a nitrogen gas. After the dropwise addition, stirring was continued for one hour to conduct reaction. After completion of the reaction, the reaction mixture was recovered by filtration, washed successively with 0.5N hydrochloric acid, an aqueous 2.5% NaHCO3 solution and water, and dehydrated over sodium sulfate. Then pyridine was distilled off under reduced pressure, whereby 142 g of a product of the following chemical formula was obtained:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)=[C:19]([CH3:28])[O:18][N:17]=1>>[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH:26]=[C:25]([NH:27][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[CH:24]=[N:23]2)=[C:19]([CH3:28])[O:18][N:17]=1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: COc1ccc(OC)c(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)c1
Yield: 13 %

Procedure:
Prepared as in Example 4-8 from 2,5-dimethoxybenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 13%. MS M+H calculated 357.5, found 357.3.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CCN(CC)CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 21.6 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), (3-chloro-propyl)-diethyl-amine (319 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant (36% EtOH: 1% NH3 in DCM) gave the title compound as a pale yellow clear oil (160 mg, 22%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.61 (t, 2H), 2.54 (q, 4H), 2.40 (s, 2H), 2.15-1.82 (m, 6H), 1.97 (s, 6H), 1.02 (t, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CN(C)C=O>[N:10]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)cn1
Temperature: 130 °C
Yield: 66.3 %

Procedure:
5-bromopicolinonitrile (2.0 g, 10.9 mmol), imidazole (818 mg, 12 mmol) potassium carbonate (1.66 g, 12 mmol) and dimethylformamide (40 mL) were combined and heated to 130° C. for 20 hours. The reaction solution was evaporated and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The phases were separated and the organic phase was washed with water (50 mL), dried over magnesium sulfate and evaporated to give a residue which was purified by flash chromatography eluting with 2-3% methanol in dichloromethane gradient to give 5-(1H-imidazol-1-yl)picolinonitrile (1.23 g, 66%).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH:10]([OH:24])[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[C:14]1([O:13][C@@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[OH:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OC1CN(Cc2ccccc2)CC1Oc1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CNC[C@H]1Oc1cccc2ccccc12

Procedure:
Eighteen grams of 1-benzyl-4-(1-naphthoxy)-3-pyrrolidinol in 200 ml. of ethanol was treated with ca. 2 g. of 10% palladium-on-charcoal under hydrogen at 60° C. for 20 hr. The mixture was cooled filtered and ethanol removed. The residue was crystallized from benzene and had a melting point of 112°-115° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:24])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-chloro-1-butanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-hydroxybenzenesulfonyl azide synthesized in Synthetic example 2 (1.72 g, 8.63 mmol, and 1.00 Eq) was dissolved in DMF (17 mL), and then sodium hydroxide (354 mg, 8.85 mmol, and 1.03 Eq) and allylbromide (14.0 g, 116 mmol, and 13.4 Eq) were added thereto. The solution was stirred at room temperature for 16 hours and water (50 mL) was added thereto, followed by extraction with diethylether (3×20 mL). The obtained organic layer was dried with sodium sulfate and the organic solvent was removed by the evaporator (30° C.). The product was purified by column chromatography (hexane/ethyl acetate 10:1) to obtain 4-allyloxybenzenesulphonyl azide as pale yellow oil (0.89 g, and 32%).
Reaction SMILES: [Na].[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1>C1COCC1.O>[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][O:2][CH2:3][CH2:4]4)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Reactant: OCCCN1CCOCC1
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Sodium metal (27.6 mmol, 0.63 g) was added to a solution of 3-morpholinopropan-1-ol (22.0 mmol, 3.20 g) in THF (60 mL) under N2. The resulting suspension was stirred at 20° C. for 2 hours and then cannulated into a solution of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitro-quinazoline, J. Med Chem., 1996(39):918) (2.0 g, 5.51 mmol) in THF (50 mL) under N2. The solution was then heated at reflux for 24 hours before being diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on alumina eluting with EtOAc/hexane (1:1) to MeOH/CH2Cl2/EtOAc (2:3:5) to give 4-[(3-bromophenyl)amino]-7-[(3-morpholino)propyloxy]-6-nitroquinazoline (1.75 g, 65%) as a yellow powder, mp (MeOH) 216-220° C.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:39]=[C:40]([C:45]2[CH:49]=[C:48](C(=O)C)[O:47][N:46]=2)[CH:41]=[CH:42][C:43]=1[Cl:44].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:48]2[O:47][N:46]=[C:45]([C:40]4[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=4)[CH:49]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)no1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(-c5ccc(Cl)c(Cl)c5)no4)ccc3c1)n2C1CCCCC1
Yield: 15 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[3-(3,4-dichloro-phenyl)-isoxazol-5-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (21 mg, 15% yield). MS: 583.16 (M+H+); HPLC Procedure B, retention time=8.77 min.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=[O:20])[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14]([OH:18])[CH:13]=[CH:12][C:11]=3[Cl:19])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:18][C:14]1[CH:13]=[CH:12][C:11]([Cl:19])=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][CH:21]=1)[C:8](=[O:20])[NH:9]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-(4-bromobenzyl)-8-chloro-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:6]=2.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.22 g, 2.88 mmol), NBS (0.667 g, 3.75 mmol) and diphenylperoxyanhydride (0.070 g, 0.288 mmol) in carbon tetrachloride (50 mL) were heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed in vacuo to afford methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 502.0 (M+H+).