Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (600 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.87 mmol) in dichloromethane (13 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.12 mL, 1.55 mmol). After 15 minutes add more methanesulfonyl chloride (0.03 mL, 0.39 mmol). After 30 minutes, extract with 5% sodium bicarbonate solution and water. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound: Rf= 0.15 (silica gel, ethyl acetate).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:35])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:8][C:9]([C:11]1([NH:16][C:17](=[O:26])[C@@H:18]([S:22]C(=O)C)[CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([O:5][C:6](=[O:35])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:8][C:9]([C:11]1([NH:16][C:17](=[O:26])[C@@H:18]([SH:22])[CH:19]([CH3:20])[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C(C)C)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](S)C(C)C)CCCC1
Reaction time: 0.5 h

Procedure:
To a degasseal solution of N-[[1-[(2-(S)-acetylmercapto-3-methyl-1-oxobutyl)-amino]-1-cyclopentyl]-carbonyl]-L-tyrosine n-butyl ester (2.4 g, 4.74 mmole) in methanol at 0° C. is added dropwise 1N sodium hydroxide (4.74 ml, 4.74 mmole). The mixture is stirred for 30 minutes, neutralized to pH 3 with 1N hydrochloric acid and concentrated to dryness. The residue is dissolved in a mixture of water and ethyl acetate. The organic phase is separated, washed with brine, dried over magnesium sulfate and evaporated to dryness to yield N-[[1-[(2-(S)-mercapto-3-methyl- 1-oxobutyl)amino]- 1-cyclopentyl]-carbonyl]-L-tyrosine n-butyl ester, m.p. 182°-183° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[N:4]=1.[Br:30][C:31]1[C:39]2OC(C3C=CC(C([O-])=O)=CC=3)=[N:36][C:35]=2[CH:34]=[C:33]([C:49]#[N:50])[CH:32]=1>>[Br:30][C:31]1[C:39]2[O:25][C:23]([C:22]3[CH:26]=[CH:27][C:19]([C:17]([NH:16][CH2:15][CH:12]4[CH2:13][CH2:14][N:9]([C:5]5[N:4]=[C:3]([C:2]([F:29])([F:1])[F:28])[CH:8]=[CH:7][N:6]=5)[CH2:10][CH2:11]4)=[O:18])=[CH:20][CH:21]=3)=[N:36][C:35]=2[CH:34]=[C:33]([C:49]#[N:50])[CH:32]=1
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Reactant: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Product: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25) and 3-amino-5-bromo-4-hydroxybenzonitrile (INTERMEDIATE 1, Step B) by a procedure analogous to that described in Example 109. Mass spectrum (ESI) 587.0 (M+3).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Br:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NNc1cccc(Br)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc(Br)c1
Yield: 80 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 3-bromophenylhydrazine according to the method described for Example 1 in 80% yield. MS: M=392.8 (M+H)+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:13](O)=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1.CN(C=O)C.Cl>ClCCl>[CH2:16]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[O:14])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccccc1CCc1ccccc1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
Oxalyl chloride (9.1 ml) was added to a suspension of 2-bibenzylcarboxylic acid (2-phenethylbenzoic acid) (20 g) in dichloromethane (200 ml) followed by 0.1 ml of DMF. The mixture was stirred for 15 hours and evaporated to dryness. The residue was dissolved in diglyme (150 ml) and cooled to -70° C. under argon. Lithium tri-t-butoxyaluminohydride (177 ml of a 0.5M solution in diglyme) was added dropwise such that the temperature of the reaction mixture did not exceed -65° C. The reaction mixture was stirred for a further 2 hours at -70° C. and then poured onto ice. The slurry obtained was acidified (HCl) and extracted with diethyl ether (3×75 ml). The combined ether extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue dissolved in petroleum ether (BP 60-80° C.) and washed once with aqueous saturated sodium bicarbonate, five times with water and twice with brine then dried. Removal of the solvent gave an oil which was purified by chromatography on silica, eluting with dichloromethane-hexane (1:1 v/v), to give 2-(phenethyl)benzaldehyde. (4.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=O)=[N:6][CH:7]=1.O.[NH2:35][NH2:36]>C(O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:4]2[C:5]([C:8]3[C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:12](=[O:14])[NH:36][N:35]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:21])=[O:22])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc12
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-benzoic acid (18 mg, 0.0347 mmol) and 2.3 mg of hydrazine hydrate in 1.0 ml of ethanol was refluxed for 4 hours. After cooled to room temperature the mixture was concentrated and the residue was purified via preparative TLC to afford 12 mg of title compound as a white powder. MS: (M+H)/z=515.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2]>C(#N)C>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Solvent: CC#N
Product: C#Cc1ccc(O)cc1
Yield: 30.8 %

Procedure:
29.1 g of the thus-obtained p-vinylphenol fraction as a polymerization raw material was placed in a 300-ml flask together with 24.5 g of acetonitrile. Thereto was dropwise added 0.8 ml of an acetonitrile solution of 2% of a boron trifluoride-diethyl ether complex with stirring and with the flask being cooled. A polymerization reaction as conducted in the same manner as in Example 1, and the reaction mixture was treated in the same manner as in Example 1 to obtain 8.8 g of a white poly(p-vinylphenol).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[N:13]=[CH:14][C:9]([N:4]4[CH2:5][CH2:6][N:2]([CH3:1])[C:3]4=[O:7])=[CH:10][CH:11]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 62.3 %

Procedure:
Using 1-methyl-2-imidazolidinone (53 mg) and (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[CH:9]=[CH:8]2.Cl>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 60 °C

Procedure:
To a mixture of 20 g. of sodium hydroxide and 400 ml. of methanol are added 24.5 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate. The resulting reaction mixture is heated to 60° C for five hours. The cooled mixture is neutralized by the addition of aqueous 1N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-methoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][Mg]Br.[NH4+].[Cl-]>C(OCC)C>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:2]1([OH:1])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: Fc1ccccc1C[Mg]Br
Reactant: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCCC(O)(Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-oxocyclohexylcarbamate (2 mmol, 426 mg) in ethyl ether (10 mL) was added a solution of (2-fluorobenzyl)magnesium bromide in ether (5 mmol, 0.25 M, 20 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for overnight. The reaction mixture was added to the NH4Cl aqueous solution. The organics were extracted with EtOAc. The EtOAc solution was concentrated. The product, tert-butyl 3-(2-fluorobenzyl)-3-hydroxycyclohexylcarbamate was purified by column chromatography on silica gel.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H][H].[ClH:20]>C(O)C.[Pd]>[ClH:20].[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: OCc1ccc(-c2cccc3cncn23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 0.36 g of 5-(p-hydroxymethylphenyl)imidazo[1,5-a]pyridine in 25 ml of ethanol and 6.4 ml of concentrated hydrochloric acid is hydrogenated with 0.15 g 10% palladium on charcoal at 40 psi of hydrogen and 60° for 4 h. The reaction mixture is filtered and evaporated and the residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated to an oil which is purified by preparative layer chromatography on silica with ethyl acetate. The hydrochloride salt is prepared in acetone with 1.1 molar equivalents of ethereal hydrogen chloride to yield the title compound, m.p. 173°-175°.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:39]=[O:40])[CH2:26][CH2:27][C:28](=NNC(N)=O)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:41])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[O:43].Cl>CO>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:39]=[O:40])[CH2:26][CH2:27][C:28]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:43])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:41])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(CCC(C=O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)=NNC(N)=O
Reactant: C=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CCC(C=O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of semicarbazone 233e (390 mg, 0.68 mmol) in methanol (10 ml) was cooled at 0° C. and then treated with a 38% aq. solution of formaldehyde (2 ml) and 1M HCl (2 ml). The reaction mixture was then stirred overnight at room temperature. The solution was concentrated to remove the methanol. The aq. solution was extracted with EtOAc (30 ml). The organic solution was successively washed with 10% NaHCO3 (30 ml) and sat. aq. NaCl (30 ml), dried (MgSO4) and concentrated. Purification by flash chromatography on silica gel (2-5% methanol in CH2Cl2) afforded 234e (179 mg, 51%) as a white foam: [α]D20 -101° (c 0.064, MeOH); IR (KBr)3346, 2976, 2934, 1730, 1657, 1535, 1456, 1425, 1278, 1255, 1156, 708; 1H NMR (CDCl3) δ 9.56 (1H, s), 7.88-7.38 (5H, m), 7.01 and 6.92 (2H, 2d), 5.27-5.08 (2H, m), 4.69-4.46 (1H, m), 3.50-3.27 (2H, m), 3.15-2.73 (2H, m), 2.46-1.83 (10H, m), 1.45 (9H, s).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=2)=[C:8]([C:27]#[N:28])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([C:27]#[N:28])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])[CH:16]=3)[CH:25]=[CH:26][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: N#Cc1cc(N)ccc1Oc1ccc(F)c(NC(=O)C(F)(F)F)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
Potassium thiocyanate (7.72 g, 79.4 mmol) was suspended in acetic acid (30 mL), and the suspension was stirred at room temperature for 10 min. A solution of N-[5-(4-amino-2-cyanophenoxy)-2-fluorophenyl]-2,2,2-trifluoroacetamide (5.4 g, 15.9 mmol) in acetic acid (200 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (5.05 g, 31.5 mmol) in acetic acid (30 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (500 ml), washed successively with saturated aqueous sodium hydrogen carbonate solution (250 mL×2) and saturated brine (250 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (5.36 g, 85%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][NH:23][CH2:22][CH2:21]2>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][N:23]([C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14])[CH2:22][CH2:21]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(C(=O)c1cnoc1-c1ccc(C)cc1)CC2
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (11 mg, 0.052 mmol, 1.2 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O4: 378.1580, found 378.1585.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:15]([O:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](Br)[CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:26]=[N:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(OCc2ccccc2)c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611) and 3-(benzyloxy)-5-bromopyridine, prepared as described in (U.S. Pat. No. 5,733,912) were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(OC(=O)C)(=O)C.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>[Cl-].[Zn+2].[Cl-]>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:3]1[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]1[CH:1]=[CH:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[F:26]
Reactant: O=Cc1ccccc1F
Reactant: Cc1ccccc1-n1c(C)nc2ccsc2c1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C=Cc2ccccc2F)nc2ccsc2c1=O
Temperature: 25 °C
Yield: 136.9 %

Procedure:
Anhydrous zinc chloride (7.0 g, 51.4 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (100 mL) was added. To this mixture was added 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one (7.0 g, 27.34 mmol, preparation 2), acetic anhydride (7.7 mL, 82.0 mmol), and 2-fluorobenzaldehyde (8.6 mL, 10.2 mmol). The reaction was refluxed 14 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was filtered to obtain a small amount of product which had precipitated. The filtrate was washed with water and brine, dried over magnesium sulfate and concentrated to leave a mustard colored solid. This material was added to the product which had previously been collected and the combined material was flash chromatographed on silica gel (60×185 mm) eluting with 25-40% ethyl acetate/hexane to afford 5.06 g (51%) of 3-(2-methyl-phenyl)-2-[2-(2-fluoro-phenyl)-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one as a light yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](C#N)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:15][C:16]1C=C2C(=CC=1)N(C(=O)C)CC2>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]#[N:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C#N)ccc21
Reactant: CC(=O)N1CCc2cc(N)ccc21
Product: CC(=O)N1CCc2ccc(C#N)cc21

Procedure:
The title compound was prepared following the procedure described for 1-acetoylindoline-5-carbonitrile but starting from 1-(5-aminoindolin-1-yl)ethanone (Aldrich, 844 mg; 4.79 mmol), to give 1-acetoylindoline-6-carbonitrile as an orange solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.31 (1H, s), 7.52-7.45 (2H, m), 4.18 (2H, t, J=8.6 Hz), 3.32-3.23 (2H, m), 2.23 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[Cl:13][CH2:14][C:15](OCC)(OCC)OCC>>[Cl:13][CH2:14][C:15]1[O:5][C:4]([C:3]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:2]=2[F:1])=[N:6][N:7]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Cc1ccc(F)c(C(=O)NN)c1
Product: Cc1ccc(F)c(-c2nnc(CCl)o2)c1
Yield: 66 %

Procedure:
2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 92.2 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), piperidine (0.099 mL, 0.998 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (189 mg, 0.460 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H); 8.17 (s, 1H); 7.79 (dd, J=8.84, 2.56 Hz, 1H); 6.75 (d, J=8.77 Hz, 1H); 6.63 (s, 1H); 3.94 (s, 3H); 3.57-3.73 (m, 4H); 1.47-1.69 (m, J=4.68 Hz, 6H). m/z (ESI, +ve ion) 412.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[C:33](=[O:34])[C:32]4=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]4[C:30]3=[O:39])[CH:23]=2)[C:9]1=[O:40].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>C(OCC)(=O)C>[NH:41]([C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]4[C:33](=[O:34])[C:32]5=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]5[C:30]4=[O:39])[CH:23]=3)[C:9](=[O:40])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccccc1Br)C2
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 180 °C
Yield: 83 %

Procedure:
270 mg (0.44 mmol) of 3-(2-bromophenyl)-3,4-dihydro-7-(methanesulfonyl)-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one was treated with 3 ml of aniline and the mixture heated to 180° C. for 20 minutes and cooled. 20 ml of ethyl acetate and 20 ml of 2M aqueous hydrochloric acid were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 230 mg (83%) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a tan solid. [Mass spectrum (ESI)=632].