Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:45])[C@@H:10]([NH:37]C(OC(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:45])[C@@H:10]([NH2:37])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][CH3:33])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc([C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc([C@H](N)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
As in Example 17, a solution of (S)-alpha-[[(1,1-dimethyethoxy)carbonyl]amino]-4-[2-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenoxy]ethoxy]benzeneacetic acid benzyl ester (2.59 g) in dichloromethane (8 mL) containing trifluoroacetic acid (8 mL) was stirred at room temperature for 45 minutes. The crude product was isolated in the previously described manner, was purified by HPLC (ethyl acetate-hexane; 1:1) to furnish 1.97 g of (S)-alpha-amino-4-[2-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenoxy]ethoxy]benzeneacetic acid benzyl ester as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:22]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
A mixture of 2.00 g (13.2 mmol) of N-methyl-4-nitroaniline and 1.46 g (14.5 mmol) of Et3N in 20 mL of CH2Cl2 at O° C. under N2 is treated with a solution of 5.33 g (26.4 mmol) of bromoacetyl bromide in 4 mL of CH2Cl2. After 3.5 h, the reaction is poured into ice water and extracted with CH2Cl2. The extract is treated with Darco, dried (MgSO4) and evaporated. The residue is filtered through Magnesol (CHCl3), evaporated and dried in vacuo to give 3.57 g (100%) of yellow solid. 1H NMR (DMSO-d6) δ 8.27 (d, 2H, J=7.47 Hz), 7.66 (d, 2H, J=7.47 Hz), 4.06 (s, 2H), 3.28 (s, 3H); MS (ESI) m/z 273.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:11]=1.[NH2:27][CH2:28][CH2:29][NH2:30]>C(O)C>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:21][C:22]#[N:23])=[N:27][CH2:28][CH2:29][NH2:30])[N:11]=1
Reactant: NCCN
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: N#CNC(=NCCN)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole (0.5 g.) and 1,2-diaminoethane (1.5 ml.) in ethanol (1 ml.) was allowed to stand at room temperature overnight. The mixture was then evaporated to dryness and the residue purified by preparative medium pressure liquid chromatography on silica gel using methanol/chloroform 1:4 v/v as solvent to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-[2-aminoethyl]guanidino)pentyl]thiazole as a straw coloured gum. A sample of the salt prepared with maleic acid included the following n.m.r. resonanes when examined in d6 dimethylsulphoxide containing tetramethylsilane as an internal standard (δ=0) (δ):1.5 (multiplet, 6H); 3.0 (multiplet, 4H); 3.3 (multiplet, 2H); 4.1 (multiplet, 2H); 6.5 (singlet, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[F:9][C:10]1[CH:15]=[C:14]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:30]=[N:29][C:28]([NH2:31])=[N:27][CH:26]=1
Reactant: Nc1ncc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3-c3cnc(N)nc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 838 using 5-bromopyrimidin-2-amine in Step A and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine in Step B. MS (ESI): mass calcd. for C20H15FN6, 358.13; m/z found, 359.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.57 (s, 2H), 8.16 (d, J=2.0, 2H), 7.57-7.45 (m, 5H), 7.14 (t, J=10.3, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[C:10]1([Mg]Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: Cl[Mg]c1ccccc1
Reactant: Cn1ncc(Br)c1C=O
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-methyl-2H-pyrazole-3-carbaldehyde (1.00 g; 5.29 mmol) is dissolved in 5.0 ml of anhydrous THF and cooled down to −78° C. Phenylmagnesium chloride 2 mol/l (6.61 ml; 13.2 mmol) is added and the reaction mixture is stirred for 1 hour. It is warmed up to 0° C. and is quenched carefully with water, then extracted with DCM. The organic layers are pooled, dried over MgSO4 and purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[CH3:12][C:13]1[NH:17][N:16]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:14]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:17]1[C:13]([CH3:12])=[CH:14][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:16]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.7 %

Procedure:
Potassium carbonate (0.19 g, 1.5 mmol) and ethyl isocyanate (0.09 g, 1.3 mmol) were added to a solution of 5-methyl-3-(4-nitrophenyloxy)pyrazole (0.29 g, 1.3 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/20), to give a white solid of N-ethyl-5-methyl-3-(4-nitrophenyloxy)pyrazole-1-carboxamide (0.38 g, yield: 99.2%). mp: 105-107° C., 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.64 (d, J=0.7 Hz, 3H), 3.40 (dq, J=5.9 and 7.2 Hz, 2H), 5.83 (q, J=0.7 Hz, 1H), 6.75 (m, 1H), 7.20-7.30 (m, 2H), 8.26 (dd, J=2.2 and 7.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH3:16])=[N:10]1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:14]([C:12]2[C:11]([CH3:16])=[N:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:13]=2)[OH:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccccc1-n1cc(C=O)c(C)n1
Solvent: C1CCOC1
Product: COc1ccccc1-n1cc(C(O)C2CCCCC2)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution (15 mL) of 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (11.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.1 g, 53%) as a pale-yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([O:32]CC)=O)=O)[CH2:13][CH2:12]1.O.[NH2:36][NH2:37]>C(O)C>[NH2:36][N:37]1[C:30](=[O:32])[C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=2[N:23]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CCCC2
Reaction time: 4 h
Yield: 51 %

Procedure:
In 120 ml of ethanol, 8.0 g of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate as synthesized in above Step 4-1-C was dissolved, and to the solution 60 ml of hydrazine monohydrate was added, followed by 4 hours' heating under reflux. Distilling the solvent off under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 3.8 g (51%) of 3-amino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:28])[C:11]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].I[C:30]1[CH:51]=[CH:50][C:33]([C:34]([NH:36][C@H:37]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:35])=[CH:32][CH:31]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][CH2:20][C:19]([C:30]1[CH:51]=[CH:50][C:33]([C:34]([NH:36][C@H:37]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:35])=[CH:32][CH:31]=1)=[CH:18][C:16]1[CH:15]=[N:14][C:12]2[N:13]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])[N:9]=[C:10]([OH:28])[C:11]=2[CH:17]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(C=CCOC3CCCCO3)cnc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)COC2CCCCO2)cc1)C(=O)OCC
Reaction time: 12 h

Procedure:
A mixture containing 3.48 g (9 mm) of 2-pivaloylamino-4-hydroxy-6-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-pyrido[2,3-d]pyrimidine, 3.12 g, (1.2 equiv.) of diethyl N-(4-iodobenzoyl)glutamate, 546 mg (20%) of tris(2-methylphenyl)phosphine, 201 mg (10%) of palladium acetate and 85.5 mg (5%) of cuprous iodide in 15 ml of triethylamine and 240 ml of acetonitrile was heated at reflux under nitrogen. After 12 hours., 1.17 g of diethyl N-(4-iodobenzoyl)glutamate was added and the reaction mixture was heated at reflux under nitrogen for an additional 12 hours. The reaction mixture then was concentrated under reduced pressure and the residue was chromatographed on silica gel, eluting with 20:1 ethyl acetate:hexane. (Recovered starting material can be recycled through the foregoing procedure.) The concentrated material was dissolved in 1:5 ethyl acetate:ether and this solution was refrigerated for 15 hours. The solid which formed was collected by filtration, washed with cold ethyl acetate and dried to yield diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-2-en-2-yl}benzoyl]glutamate. mp. 273°-275° C. Analysis calculated for C36H45N4O9 ; C, 62.50; H, 6.56; N, 10.12. Found: C, 62.21; H, 6.34; N, 9.83. NMR (CDCL3), delta, 1.24 (t, 3H, J=7 Hz), 1.32 (t 3H, J=7 Hz), 1.32 (s, 9H), 1.53-1.87 (m, 6H), 2.11-2.22 (m, 1H), 2.29-2.41 (m 1H), 2.42-2.58 (m, 2H), 3.53-3.59 (m, 1H), 3.80-3.88 (m, 1H), 4.13 (q, 2H, J=7 Hz), 4.25 (q, 2H, J=7 Hz), 4.33 (d, 1H, J=14 Hz), 4.62 (d, 1H, J=14 Hz), 4.75-4.83 (m, 2H), 6.84 (s, 1H), 7.12 (brs, 1H, NH, J =7 Hz), 7.31 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz), 8.13 (d, 1H, J=1.6 Hz), 8.34 (brs, NH), 8.42 (d, 1H, J=1.6 Hz), 11.99 (brs, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[S:31][C:30]([C:32]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:33])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)c1ccc(-c2ccccn2)s1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[5-(2-pyridyl)thienylcarbonyl]hydrazide (62) was prepared in the manner described in Example 7 on a 10 mmol scale from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, and 5-(2-pyridyl)thiophene-2-carboxylic acid. The yield of product was 1.33 g (28%). Analysis calculated for C24H17N4O3SCl (M.W. 476.95): C, 60.44; H, 3.59; N, 11.75; Cl, 7.43; S, 6.72. Found: C, 60.18; H, 3.66; N, 11.69; Cl, 7.79; S, 6.63.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[C:8]([CH3:21])[CH:7]=1.C([O-])([O-])=[O:23].[K+].[K+].OO>CS(C)=O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:18])=[O:23])=[N:15][CH:16]=2)=[C:8]([CH3:21])[CH:7]=1
Reactant: Cc1cc(C2OCCO2)ccc1Oc1cnc(C#N)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C2OCCO2)ccc1Oc1cnc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 137.6 %

Procedure:
Take up 5-(4-[1,3]dioxolan-2-yl-2-methylphenoxy)pyrazine-2-carbonitrile (0.082 g, 0.305 mmol) and K2CO3 (0.020 g, 0.152 mmol) in DMSO (3.0 mL). Add 30% H2O2 (0.090 mL, 0.792 mmol) and stir at room temperature for 1.5 hours before quenching with water (10 mL). Extract with ethyl acetate (50 mL). Wash the organic layer with water (1× 10 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 40% ethyl acetate in dichloromethane to give the title compound (0.063 g, 68.6%): MS ES+ 302.0 (M+H)+; TLC [silica gel 60 F254, 40% ethyl acetate in dichloromethane] Rf=0.17.
Reaction SMILES: N1CCCCC1.[N+:7]([C:10]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:11]=1[C:12](=[O:25])[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=1[C:19]2=[O:24])([O-])=O.[H][H]>[Pd].COCCO>[NH2:7][C:10]1[C:11]2[C:12](=[O:25])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:24])[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCNCC1
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 1 h
Yield: 85.3 %

Procedure:
1.4 Grams of 5% palladium on carbon catalyst and 52 grams of piperidine were added to a mixture of 154 grams of 5-nitrotetrahydroanthraquinone and 3,000 grams of methyl cellosolve, into which was fed hydrogen at room temperature and under normal pressure for having hydrogen absorbed in the starting 5-nitro compound in an amount of 2 mols per mol of the 5-nitro compound. After completion of the hydrogenation, the catalyst was separated by filtration and air was fed into the resultant filtrate at normal temperature for 1 hour. Then, the resultant solution was concentrated by distilling off the methyl cellosolve until crystals began to precipitate. The thus concentrated solution was allowed to cool and the resultant crystals were separated by filtration, washed with water and dried to obtain 114 grams of 1-aminoanthraquinone having a purity of 98.0%.
Reaction SMILES: C(O)C.[O:4]([C:11]1[CH:31]=[CH:30][C:14]2[CH:15]=[C:16]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[O:17][C:13]=2[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.NN>O>[O:4]([C:11]1[CH:31]=[CH:30][C:14]2[CH:15]=[C:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(Oc3ccccc3)cc2o1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc2ccc(Oc3ccccc3)cc2o1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To an ethanol (5 mL) solution of 2-(6-phenoxy-benzofuran-2-ylmethyl)-isoindole-1,3-dione (209 mg, 566 μmol) described in Production Example 49-1-3 was added hydrazine hydrate (549 μL, 11.3 mmol) at room temperature, which was stirred for 1 hour while heating under reflux. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (92 mg, 68%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:35][CH3:34])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CO
Product: CNc1ncnc2c1nc(OC)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)purin-9-yl)phenyl]urea and methanol by using the same technique as in Example 136.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([NH:39][C@H:40]([C:42]([OH:44])=O)[CH3:41])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[CH:45]1[C:53]2[C:52]3[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:51]=3[O:50][C:49]=2[CH:48]=[CH:47][C:46]=1[NH2:59]>>[CH3:41][C@H:40]([NH:39][C:29](=[O:30])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:42](=[O:44])[NH:59][C:46]1[CH:47]=[CH:48][C:49]2[O:50][C:51]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][C:52]=3[C:53]=2[CH:45]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 13.1 %

Procedure:
Following the procedure of Example 30, triethylamine (0.52 mL, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.37 g, 1.9 mmol), N-hydroxybenzotriazole (0.26 g, 1.9 mmol), N-carbobenzyloxy-L-alanine (0.37 g, 1.6 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) provided benzyl [(1S)-1-methyl-2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.08 g) after purification by flash column chromatography (elution with 40% ethyl acetate-hexanes). MS (ES) m/z 407.2 ([M+H]+).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:24]>>[NH2:24]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:19])[C:11]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=2[S:13]\1
Reactant: [NH4+]
Reactant: Cc1ccc2c(O)c(C(=O)c3ccccc3)sc2c1
Agent: CC(=O)[O-]
Product: Cc1ccc2c(c1)S/C(=C(/N)c1ccccc1)C2=O
Yield: 57 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-6-methyl-benzo[b]thiophen-3-ol and ammonium acetate with a yield of 57% of theory. M.p. 166°-167° C. (ethyl acetate/petroleum ether 1:1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([O:23][CH:24](OCC)[CH:25]=[CH2:26])[CH3:22].[OH-].[Na+]>O.C(#N)C>[CH2:21]([O:23][CH:24]1[CH2:25][CH2:26][C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2]1)[CH3:22]
Reactant: C=CC(OCC)OCC
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC1CCc2ccc(O)cc2O1
Reaction time: 1 h
Yield: 62 %

Procedure:
A 500-milliliter (ml) flask fitted with a dropping funnel was charged with 10.0 g of resorcinol, 0.2 g of p-toluenesulfonic acid monohydrate, and 100 ml of acetonitrile for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 11.1 ml of acrolein diethyl acetal under room temperature. After the dropwise addition, the mixture was stirred for 1 hour while being cooled with ice. After 5 ml of a 5% sodium hydroxide aqueous solution and 30 ml of water were added thereto, the acetonitrile was removed by distillation in vacuo (under vacuum pressure), and the residue was extracted three times with 50 ml of chloroform. Subsequently, the chloroform layer obtained was washed with 30 ml of water, the chloroform was then removed by distillation in vacuo, and the resulting residue was purified by distillation to obtain 10.9 g of a colorless liquid (yield 62%).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18].[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[N:8]([CH3:22])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18]
Reactant: CI
Reactant: CC(C)CC1NC(=O)N(c2cc(F)ccc2F)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC1C(=O)N(c2cc(F)ccc2F)C(=O)N1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
5-(2'-Methylpropyl)-3-(2,5-difluorophenyl)imidazoline-2,4-dione (3.0 g, 11.1 mmol) in DMF (15 mL) was added dropwise to an ice-cold suspension of sodium hydride (0.30 g, 12.5 mmol) in DMF (4 mL). The solution was allowed to stir for 2 hours, after which methyl iodide (1.04 mL, 2.38 g, 16.8 mmol) in DMF (5 mL) was added dropwise. The solution was stirred overnight and then diluted with water. The product was extracted with ethyl acetate (3×), and the combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated. Purification by column chromatography gave 2.7 grams of 5-(2'-methylpropyl)-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, as an oil (compound 3 under Table A).