Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/C=C/C1C=CC=CC=1OCCCCCO.COC(=O)[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[CH3:1][O:2][C:3](=[O:19])[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH2:23]
Reactant: COC(=O)C=Cc1ccccc1OCCCCCOS(C)(=O)=O
Reactant: COC(=O)/C=C/c1ccccc1OCCCCCO
Product: C=C(C(=O)OC)c1ccccc1OCCCCCOS(C)(=O)=O

Procedure:
Using the procedure of example 32, 1.09 g (4.13 mmol) of (E)-3-[2-[(5-hydroxypentyl)oxy]phenyl]-2-propenoic acid methyl ester was converted into 1.37 g (97%) of (E)-(3-[2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]phenyl]-2-propenoic acid methyl ester, as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22](O)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][CH2:26][CH2:27][OH:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:25][CH2:26][CH2:27][OH:28])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1csc(C(=O)NCCO)c1)nn2C1CCCC1

Procedure:
A solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (90.0 mg) obtained in Step A of Example 155, 2-aminoethanol (0.024 mL), EDCI hydrochloride (75.0 mg) and HOBt (53.1 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (67.3 mg).
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:18]#[N:19])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N>C(O)C.O.[Ni]>[ClH:26].[ClH:1].[NH2:19][CH2:18][CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: NCC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
14.5 g of 4-(4-benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyronitrile hydrochloride are dissolved in 400 ml of 95° ethanol. A solution of 20 ml of concentrated ammonia in 40 ml of water and Raney nickel (10% by weight of the amount of amine) are added to the mixture, which is then placed under a hydrogen atmosphere, with vigorous stirring, for 4 hours, after which 1.67 l of hydrogen have been consumed. After filtration of the catalyst, the filtrate is concentrated under vacuum and the residue is taken up in ethyl acetate, washed with water, dried and concentrated under vacuum. The residue is taken up in a solution of hydrogen chloride in methanol, filtered off and recrystallized from a 3/7 acetone/ether mixture.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:26][O:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:23][CH3:24])[N:15]=[CH:14][N:13]=[C:12]3[O:11][C:10]2[C:2]([F:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH2:28][CH2:29]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 76 %

Procedure:
A mixture of 4-[(4-fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (250 mg, 0.77 mmol), (prepared as described for the starting material in Example 10), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (199 mg, 0.92 mmol), (prepared as described for the starting material in Example 11), and triphenylphosphine (242 mg, 0.92 mmol) in dichloromethane (15 ml) was stirred and cooled to 0° C. Diisopropyl azodicarboxylate (182 μl, 0.92 mmol) in dichloromethane (2 ml) was added. The mixture was stirred for 3 hours and then a further 0.5 mole equivalent of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, triphenylphosphine and diisopropyl azodicarboxylate added. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1/1) followed by methylene chloride/methanol (99/1) to give 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (306 mg containing 10% w/w triphenylphosphine oxide) which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=1[CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=2[CH2:32][CH2:33][CH3:34])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.776 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and then 1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl] ethanone (1.26 g) was added and rinsed in with a little dimethylformamide. The mixture was heated at 50° C. for 6 hours and worked up as in Example 20. The crude material was purified by HPLC (ethyl acetate-hexane; 1:4) to furnish 0.7 g of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[C:28]([O:27][CH3:26])=[N:36][C:35]([O:37][CH3:38])=[CH:34][CH:33]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ccc(C(=O)O)c(OC)n1
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c(OC)n1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,6-dimethoxynicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=7:3:2) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Yield: 65.2 %

Procedure:
The same procedures as in Example 140 were carried out from the compound obtained in Example 139 (6.2 g), potassium carbonate (3.6 g), iodomethane (1.6 mL), and DMF (100 mL), to give the captioned compound (4.2 g, 65%) as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Br:23])[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1Oc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a solution of (E)-methyl-2-[2-(3-methylphenoxy)phenyl]-2-methoxyiminoacetate (4.60 g) in benzene (120 ml), N-bromosuccinimide (2.88 g) and benzoyl peroxide (0.37 g) were added, and the resultant mixture was refluxed for 1 hour, followed by cooling to room temperature. Insoluble materials were removed by filtration and, after removal of the solvent, the residue was purified by silica gel column chromatography to give (E)-methyl-2-[2-(3-bromomethylphenoxy)phenyl]-2-methoxyiminoacetate (4.60 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC)c2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)c(OC)c2ccccc12

Procedure:
The process of preparing the novel compounds of this invention comprises the steps of (1) brominating 1,4-dimethoxynaphthalene with liquid bromine in an organic solvent such as acetic acid at room temperature to form the 2-bromo-1,4-dimethoxynaphthalene, (2) converting the bromine derivative to the carboxylic acid derivative by lithiation and carboxylation. The lithiation is conducted in a known procedure, as for example, by treating the bromo derivative with n-Butyllithium in an organic solvent under anhydrous conditions at a low temperature, such as -78° C. The resulting lithium compound is not isolated, but converted into the carboxylic acid by adding dry ice to the cooled lithium compound and allowing the reaction mixture to come to room temperature. (3) The carboxylic acid derivative is then converted to the acid chloride by treating with thionyl chloride at room temperature. (4) The resulting acid chloride is condensed with the appropriate amine to form the carboxamide. The condensation reaction is carried out by treating the acid chloride in an organic solvent with the appropriate amine at room temperature in the presence of a proton acceptor.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][CH:20]=[C:21]([CH:23]([OH:30])[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][CH:20]=[C:21]([C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:30])[N:22]=3)=[O:17])=[CH:8]2)=[CH:31][CH:32]=1
Reactant: O=C(c1nc(C(O)c2cccnc2)c[nH]1)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1cccnc1)c1c[nH]c(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of [1-(4-chlorobenzyl)-1H-indol-3-yl-[4-(hydroxypyridin-3-yl-methyl)-1H-imidazol-2-yl]methanone (20 mg, 4.5×10−5 mol) in CH2Cl2 (5 mL) was added MnO2 (50 mg). The reaction was stirred for 1 hour at room temperature and filtered through celite to produce the desired product as a white solid (yield 15 mg, 75%). Rf0.5 (ethyl acetate:methanol, 9:1);1H NMR δ 5.61 (s, 2H), 7.36 (m, 6H), 7.61 (m, 1H), 7.68 (m, 1H), 8.28 (s, 1H), 8.39 (m, 1H), 8.60 (d, 1H), 8.86 (d, 1H), 9.16 (s, 1H), 9.40 (s, 1H); ESMS Calcd (C25H17ClN4O2): 440.10, found 441.2 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=O)C.Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:21]=[C:19]([CH3:20])[NH:22][C:4](=[O:17])[CH:5]=2)[CH:13]=1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(C)n1
Temperature: 100 °C
Reaction time: 60 h
Yield: 66.1 %

Procedure:
A mixture of 3-(5-chloro-2-methoxy-phenyl)-3-oxopropionic acid ethyl ester (0.9 g, 3.2 mmol), acetamidine hydrochloride (448 mg, 4.7 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in ethanol (15 ml) was stirred at 100° C. in thick wall tube for 60 hours. After cooling to room temperature, the mixture was poured into ice cold water. The solid was collected by filtration, washed with water and ether and dried under vacuum to provide 6-(5-chloro-2-methoxy-phenyl)-2-methyl-3H-pyrimidin-4-one (530 mg, 68% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 3.85 (s, 3H, CH3), 6.77 (s, 1H, CH, Ar), 7.15 (d, 1H, J=8.8 Hz, Ar), 7.45 (dd, 1H, J=8.8 Hz, J=2.9 Hz, Ar), 7.90 (d, 1H, J=2.9 Hz, Ar), 12.42 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1>[Fe].C(O)(=O)C.O>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH2:18])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1(Oc2cc([N+](=O)[O-])c(F)cc2Cl)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1(Oc2cc(N)c(F)cc2Cl)CC1
Temperature: 25 °C

Procedure:
The obtained ethyl 1-(2-chloro-4-fluoro-5-nitro-phenoxy)cyclopropanecarboxylate (1 equivalent) is added dropwise to a mixture of acetic acid/ water (1/1) containing iron powders (3 equivalents) at 6° C. After completion of addition, the mixture is allowed to cool to room temperature and extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 1-(2-chloro-4-fluoro-5-aminophenoxy)cyclopropanecarboxylate.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cc(C=C(c2ccccc2)c2ccccc2)cc(-c2ccccc2)c1
Yield: 55.8 %

Procedure:
Under an atmosphere of argon, 1-(2,2-diphenylvinyl)-3,5-dibromo-benzene (7.0 g, 17 mmole), phenylboronic acid (2.1 g, 17 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.35 mmole, 2% Pd) were dissolved into toluene (40 ml). To the obtained solution, a 2 M aqueous solution of sodium carbonate (25 ml, 51 mmole, 3 eq) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (30 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (3.9 g, 56%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.Cl.[NH2:14][N:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17].N1C=CC=CC=1>O=S(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:14][N:15]2[CH2:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])=[O:10])=[CH:11][CH:12]=1
Reactant: NN1CC(=O)NC1=O
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=Cc1ccc(F)cc1)NN1CC(=O)NC1=O
Reaction time: 1 h

Procedure:
A mixture of p-fluorocinnamic acid (36 g, 0.22 mole) in SOCl2 (75 ml) was heated under reflux with stirring for 1 hour. The excess SOCl2 was removed in vacuo and the residue fluxhed with benzene. To the resulting acid chloride was added 1-aminohydantoin hydrochloride (39 g, 0.26 mole) and 250 ml of pyridine and the resulting reaction mixture was heated on the steam bath for 3 hours. The mixture was poured onto HCl/ice and the product allowed to crystallize.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]1([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)[CH2:36][CH2:35]1.N1C=CC=CC=1>O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:39]3[CH:38]=[C:37]([CH:34]4[CH2:36][CH2:35]4)[CH:41]=[N:40]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Reactant: c1n[nH]cc1C1CC1
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(C3CC3)cn2)cc1
Temperature: 40 °C
Yield: 79.3 %

Procedure:
A mixture of (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy) quinolin-3-yl]methyl}phenyl)boronic acid (0.1 g), 4-cyclopropyl-1H-pyrazole (0.047 g), cuprous acetate (0.078 g) and pyridine (3 mL) was heated at 40° C. for 24 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as pale green oil (0.09 g).
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:5]([O:4][C:2](=[N:7][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3])[CH3:6]
Reactant: CCOC(C)=N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(C)=NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
First, 15.5 g of ethyl acetimidate hydrochloride, 150 mL of toluene, and 31.9 g of triethylamine (Et3N) were put into a 500-mL three-neck flask and stirred at room temperature for 10 minutes. With a 50-mL dropping funnel, a mixed solution of 17.7 g of benzoyl chloride and 30 mL of toluene were added dropwise to this mixture, and the mixture was stirred at room temperature for 24 hours. After a predetermined time elapsed, the reaction mixture was suction-filtered, and the solid was washed with toluene. The obtained filtrate was concentrated to give N-(1-ethoxyethylidene)benzamide (a red oily substance, 82% yield). A scheme of the synthesis of Step 1 is shown below.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[N:18]1([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[NH4+].[OH-].CO>C(Cl)Cl>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: OB(O)c1cccc(CN2CCCCC2)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CN4CCCCC4)c3)nc12

Procedure:
2,2-Dimethyl-1-[2-(3-piperidin-1-ylmethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(piperidin-1-ylmethyl)phenylboronic acid hydrochloride following general procedures as described in these Examples. Silica gel chromatography using 0-20% [5% NH4OH:MeOH]/DCM as eluant gave a brown solid which was washed with 1:2 Et2O/Hexanes to provide 70 mg (36%) of a pale brown solid. MP 176-177° C., M+H=377.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10](O)[C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([F:22])[C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(O)C(F)(F)F)ccc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C(F)C(F)(F)F)ccc1F
Yield: 100.2 %

Procedure:
2-Fluoro-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzonitrile (1 g, 4.56 mmol) in DCM (5 mL) was treated with DAST (Aldrich, 1.12 mL, 9.13 mmol) at −78° C. for 2 hours. The reaction was quenched with saturated NaHCO3 and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 4:1) to afford the title compound as colorless solid (1.01 g, 100%).
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:16].[Al+3].[Cl-].[Cl-]>>[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[O:8]
Reactant: [Cl-]
Reactant: CC(C)(CC(=O)c1ccccc1)C(=O)O
Agent: [Al+3]
Product: CC(C)(CC(=O)c1cccc(Cl)c1)C(=O)O

Procedure:
Using the procedure of T. Joyima et al., Bull. Chem. Soc. Jap., 52(8) 2441-2442 (1979), 3-benzoyl-2,2-dimethylpropionic acid was converted into the title compound by chlorination in the presence of excess aluminum chloride.