Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH2:20][CH3:21]>>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH2:20][CH3:21])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCO
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5.00 g of trans-β-benzoylacrylic acid, 1.67 ml of n-propanol and 1.05 g of sulfuric acid was stirred at 100° C. for 1.5 hours. A pressure was gradually reduced with the aspirator and n-propanol was distilled away for 15 minutes. After a pressure was finally reduced to 20 mmHg, the resultant was stirred at 100° C. for 10 minutes and then cooled, followed by the procedure as in Example 1 to give 5.78 g of n-propyl trans-β-benzoylacrylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>>[CH3:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: COC(=O)CCc1ccccc1-c1ccc(-c2onc(C)c2C(O)CCCc2ccccc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9](/[C:11](/[C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:12]/[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[NH:8][C:5]2=[N:6][CH:7]=1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 45 °C
Yield: 59.6 %

Procedure:
A mixture of 5-fluoro-2-[(E)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 122, 300 mg, 0.75 mmol) and 10% palladium on activated carbon (0.2 g) in methanol (50 mL) was heated at 45° C. under hydrogen (50 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine as a white solid (180 mg, 60%): LC/MS m/e calcd for C21H23FN2O3S [M+H]+ 403.49, observed 403.2; 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (t, J=2.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.60-7.67 (m, 3H), 6.41 (s, 1H), 4.44 (t, J=8.1 Hz, 1H), 3.90 (d, J=11.4 Hz, 2H), 3.25-3.30 (m, 2H), 3.08-3.14 (m, 3H), 2.24 (dt, J=14.1, 7.3 Hz, 1H), 1.99-2.07 (m, 1H), 1.72 (t, J=14.1 Hz, 2H), 1.32-1.52 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[N:13]=O>C(O)C.[Pd]>[NH2:13][C:3]1[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1nc(-c2cccs2)c(N=O)c1N
Agent: [Pd]
Solvent: CCO
Product: Cn1nc(-c2cccs2)c(N)c1N
Yield: 96.7 %

Procedure:
A suspension of 5-amino-4-nitroso-1-methyl-3-(2-thienyl)-pyrazole (1.255 g, 6.03 mmol) in ethanol (90 ml) was hydrogenated at 20 p.s.i. over 10% palladium on carbon (130 mg) at room temperature for 2 hours. The mixture was filtered through Arbocel filter aid and the filtrate was concentrated under reduced pressure to give the title compound as a red-brown solid (1.133 g, 97%), m.p. 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([NH2:13])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([N:13]([C:17](=[O:18])[C:16]1[C:15]([Cl:14])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:24])[C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12][N:11]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2ccc(Cl)cc2)on1
Solvent: Cc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1cc(-c2ccc(Cl)cc2)on1

Procedure:
5-(4-Chlorophenyl)-3-aminoisoxazole (400 milligrams prepared according to the teaching of Examples 11-14) was added to 2,6-dichlorobenzoylchloride (430 milligrams) in 50 ml. toluene and refluxed for 48 hours. The solvent was then evaporated and ethyl alcohol added; upon subsequent heating and filtering the bis acylated product was recovered; m.p. 219°-223° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].C[Li].C([Li])(C)(C)C.ClC1CC2C(=CC=CC=2)C1=O.[OH-].[K+].Cl>O1CCCC1.C(OCC)C.CCCCC.CO>[F:7][C:6]([F:8])([F:9])[C:5]([NH:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:2]=1)=[O:10]
Reactant: O=C(Nc1ccccc1Br)C(F)(F)F
Agent: Cl
Agent: O=C1c2ccccc2CC1Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A solution of o-bromotrifluoroacetanilide (325 mg, 1.2 mM) in tetrahydrofuran (THF)(20 cm3) was cooled to -78° C. and to this was added methyl lithium (1 molar equivalent of a 1.4 M solution in diethyl ether). This addition was followed 10 minutes later by the introduction of tert-butyllithium (2 molar equivalent of a 1.7 M solution in pentane). The reaction mixture was stirred for 1 hour at -78° C., and then a solution of the chloroindanone (272 mg. 1.2 mM) in THF (3 cm3) added dropwise via a cannula. The solution was allowed to warm slowly to room temperature, and stirred for one hour, then a 10% solution potassium hydroxide in methanol (3 cm3) was introduced. After stirring for 30 minutes, the reaction mixture was poured into 2 M HCl, and extracted with dichloromethane (3 ×10 cm3). The combined organic extracts were dried (Na2SO4 ) and evaporated in vacuo to afford a solid residue which was chromatographed on silica, eluting with 10% ethyl acetate/petroleum ether (60°-80° C.) to yield trifluoroacetanilide (RF 0.4)(50 mg), and the 2-chloro-1-hydroxy-5-methoxy-4,6-dimethyl-1-(2'-trifluoroacetamidophenyl)indane (RF 0.3) (220 mg, 44%). The latter compound is a colourless solid. M.p. 182° C. 1H NMR (CDCl3)δ: 10.7 (1H, br), 8.25 (1H, dd), 7.36 (1H, ddd), 7.06 (1H, s), 6.98 (1H, ddd), 6.39 (1H, dd), 4.76 (1H, dd, J=4.8, 2.7Hz), 3.78 (3H, s), 3.63 (1H, s, exchanges with D2O), 3.11 (2H, 2 ×2nd order multiplets), 2.33 (3H, s), 2.23 (3H, s).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:8])(=[O:3])[CH3:2].C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCC(O)CCCNC(=O)CCNC(C)=O
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)CCCNC(=O)CCNC(C)=O

Procedure:
A 160 mg portion of 3-(acetylamino)-N-(4-hydroxy-12(Z)-heneicosenyl)propanamide was dissolved in 5 ml of dichloromethane and treated with 157 mg of pyridium chlorochromate for 2 hours. The solution was passed through a short pad of hydrous magnesium silicate and washed repeatedly with fresh dichloromethane. The filtrate and washes were combined and evaporated, giving 92 mg of the desired product as an off-white solid, mp 123°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=O)[CH2:13]C[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:25]C(C)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][OH:25])[CH2:10][CH2:11][O:16][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCOC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (6.57 g, 28.4 mmol) in THF (60 mL) was added LiAlH4 (2.89 g, 61.0 mol) at room temperature. After stirred for 5 h, the reaction mixture was poured into ice-water and stirred for 30 min. To the mixture was added AcOEt and stirred for 30 min. The mixture was filtered and the filtrate was extracted with AcOEt. The extraction mixture was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (Hexane:AcOEt 1:1) to give [3-(tert-butoxycarbonylamino)oxolan-3-yl]methanol (2.82 g, 46%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ1.36 (9H, s), 1.84-1.91 (1H, m), 1.93-2.02 (1H, m), 3.46 (2H, d, J=5.5 Hz), 3.59-3.62 (1H, d, J=8.6 Hz), 3.66-3.70 (3H, m), 4.83 (1H, t, J=5.5 Hz), 6.78 (1H, brs).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=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.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(I)ccc2n(C)c1=O
Reactant: OB(O)c1ccccc1
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: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(-c3ccccc3)ccc2n(C)c1=O
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (200 mg, 465 μmol), phenylboronic acid (85 mg, 697 μmol), 2M Sodium carbonate (0.7 ml, 1395 μmol), Tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 μmol) and N,N-Dimethylformamide (10 ml) was stirred at 100° C. After 8 hrs, an additional equivalent of the phenyl boronic acid was added, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated on a roto-evaporator and extracted with EtOAc. This product was then washed with water and brine, then dried with MgSO4 and concentrated on a roto-evaporator to give the crude product as a red-orange oil. The crude product was purified by silica flash chromatography (10-75% EtOAc:Hex step gradient) to give the desired product as a white solid. Yield=120 mg. In some cases, ester hydrolysis was observed and the carboxylic acid was isolated.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(Nc2nc3ccccc3[nH]2)ccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-chloro-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and recrystallisation to give the title compound as a hydrochloride salt (white solid, mp 255-260° C.). MS(ES+) m/z 312 ([M+1]+, 100).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:33](=[O:34])[N:5]2[C:6]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:18])=[C:7]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:8][S:9][C@H:4]12.[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][C:66]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)/[C:61](O)=[O:62])[N:59]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][C:66]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)/[C:61]([NH:2][CH:3]2[C:33](=[O:34])[N:5]3[C:6]([C:17]([O:19][CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[S:18])=[C:7]([CH2:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[CH2:8][S:9][C@H:4]23)=[O:62])[N:59]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 57.7 %

Procedure:
Diphenylmethyl 7-amino-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate hydrochloride (300 mg) was reacted with (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (403 mg) in accordance with the procedure of Example 1(d). The crude reaction product was purified by a column chromatography on a silica gel column (30 g) with elution using benzene-ethyl acetate (7:1 by volume) as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected gave the titled compound (380 mg; 60%).
Reaction SMILES: CS(O)(=O)=O.[CH:6]1([NH:12][C:13]([CH:15]2[CH:23]3[C:18]4([CH:27]=[CH:26][CH:25]=[CH:24][C:19]4=[N:20][CH2:21][CH2:22]3)[S:17][CH2:16]2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(Cl)Cl.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(N(CC)CC)C>[CH:6]1([NH:12][C:13]([CH:15]2[CH:23]3[C:18]4([CH:27]=[CH:26][CH:25]=[CH:24][C:19]4=[N:20][CH2:21][CH2:22]3)[S:17][CH:16]2[C:40]([O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:41])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(NC1CCCCC1)C1CSC23C=CC=CC2=NCCC13
Reactant: O=C(Cl)OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)C1SC23C=CC=CC2=NCCC3C1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
30 g of N-cyclohexyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxamide methanesulfonate was added to a solution of 300 ml of chloroform and 16.23 g of triethylamine and the resulting mixture was stirred at room temperature for 1 hour. Then 41.5 ml of benzyloxycarbonyl chloride was added thereto under ice-cooling and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 20 ml of water thrice and dried over magnesium sulfate. The reaction mixture was distilled under reduced pressure and the residue was separated by silica gel column chromatography (solvent: chloroform). Thus 23.6 g of N-cyclohexyl-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxamide (yield: 87%) was obtained. The NMR data of this product were as follows. It was confirmed that this product is N-cyclohexyl-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxamide.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:24]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[N:30][CH:31]=[N:32][CH:33]=2)=[N:3]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CNc2nc(Cl)nc3cccc(-c4ccccc4)c23)cc1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2nc(-c3cncnc3)nc3cccc(-c4ccccc4)c23)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a solution of methyl 4-((2-chloro-5-phenylquinazolin-4-ylamino)methyl)benzoate (550 mg, 1.36 mmol) in DMF (16 mL) and H2O (0.5 mL) under nitrogen were added pyrimidine-5-ylboronic acid pinacol ester (422 mg, 2.04 mmol) and potassium carbonate (377 mg, 2.72 mmol). The resulting mixture was degassed with nitrogen for 15 min and then (1,1′-bis(diphenylphosphino)ferrocene)-palladium (II) chloride dichloromethane complex (50 mg, 0.068 mmol) was added. Upon completion of addition, the reaction mixture was again degassed for 10 min. with nitrogen. The reaction mixture was then heated to 110° C. where it stirred for 12 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then extracted with ethyl acetate. The organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 0.5% MeOH in CH2Cl2 to afford methyl 4-((5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-ylamino)methyl)benzoate (400 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.62 (s, 2H), 9.31 (s, 1H), 7.93-7.86 (m, 4H), 7.54-7.49 (m, 5H), 7.37 (d, J=6.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 5.94 (t, J=4.8 Hz, 1H), 4.71 (d, J=5.2 Hz, 1H), 3.85 (s, 3H). LCMS Method C: retention time 2.15 min, [M+1]=448.2. HPLC Method B: purity 98.5%, retention time 9.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1C(=O)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nc2ccccc2cc1C(=O)NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-methoxyquinoline-3-carbonyl)hydrazinecarboxylate (1.23 g, 3.87 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Trifluoroacetic acetic acid (10 mL) was added and the mixture was stirred at room temperature for 1 h. Solvents were evaporated and the residue was washed with water. The product was used without purification in the next step. MS (ES) C11H11N3O2 requires: 217.22, found: 218.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH2:7][CH2:6]1.ClC1N=C(Cl)C=CN=1.C(N(C(C)C)C(C)C)C>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(NC=O)C1CCNCC1
Agent: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC=O)c1ccncc1

Procedure:
N-(1-Piperidin-4-yl-ethyl)-formamide; compound with acetic acid (350 mg, 1.61 mmol), 2,4-dichloro-pyrimidine (265 mg, 1.78 mmol) and ethyl-diisopropyl-amine (848 mg, 6.56 mmol) in 20 ml of ethanol were heated under reflux for 5 hours. The mixture was evaporated and the residue dissolved in water and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: OCc1cnc(C(F)(F)F)c(Br)c1
Solvent: ClCCl
Product: O=Cc1cnc(C(F)(F)F)c(Br)c1
Temperature: 40 °C
Yield: 78.1 %

Procedure:
To a solution of [5-bromo-6-(trifluoromethyl)-3-pyridinyl]methanol (155 mg, 0.605 mmol) in DCM (10 mL) was added CrO2 (Magtrieve) (1017 mg, 12.11 mmol). The suspension was heated at 40° C. in a pressure tube overnight. TLC showed starting material remaining, an excess of CrO2 (254 mg, 3.03 mmol) was added. The reaction mixture was heated at 40° C. for 4 h. The suspension was filtered over nylon membrane 0.45 μm and it was rinsed with DCM. The filtrate was evaporated under vacuum to afford 120 mg (78%) of title compound pure enough to be used in the next step.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])(OC)(OC)=[O:10].P([O-])([O-])(OC)=O.CCC(OO)=O.C(CC(O)=O)C.COC1C(=CC=CC=1)O>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([OH:10])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: COP(=O)([O-])OC
Agent: CCC(=O)OO
Agent: COP(=O)([O-])[O-]
Agent: COc1ccccc1O
Solvent: CCCC(=O)O
Product: COc1ccc(O)cc1
Temperature: 80 °C

Procedure:
The procedure of Example 23 was repeated, except 1 mol of anisole was used in place of phenol. To the solution in the flask, 0.2g of a mixture of dimethyl phosphate and monomethyl phosphate (available on the market under the designation of "dimethyl phosphate" and containing about 50 percent of dimethyl phosphate, the remainder being monomethyl phosphate) was added and heated to 80°C. Then 0.1 of perpropionic acid (prepared in the form of 30 percent ethyl acetic acid solution) was introduced dropwise over a period of about 20 minutes. At the end of three hours following the start of said dropwise introduction of acid solution, the reaction solution was analyzed by repeating the procedure of Example 23. The analysis showed that 2.85g of pyrocatechol monomethyl ether and 1.44g of hydroquinone monomethyl ether were produced, with the conversion of perpropionic acid at 99.1 percent and that of anisole at 6.0 percent. When this reaction was performed in the absence of the catalyst, the yield of pyrocatechol monomethyl ether was 2.01g and that of hydroquinone monomethyl ether was 1.00g, although the conversion of each of the reactants was substantially the same.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:30]2[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[CH:23][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:21][CH2:22]3)=[O:19])[N:16]=2)[N:13]=1
Reactant: Nc1ccc(Cl)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Yield: 91.6 %

Procedure:
Using N-[6-(5-amino-2-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (131 mg, 0.382 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (91 mg, 0.573 mmol), triethylamine (116 mg, 1.15 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (163 mg, 92%) was obtained as a white powder.