Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.C([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1
Reactant: C#CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: O=CO
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 60 °C
Yield: 7.2 %

Procedure:
50% Formic acid (41 ml.) was added to a solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 8.2 g.) and tetrahydrofuran (41 ml.), and stirred at 60° C. for an hour. The resultant solution was concentrated to a half of initial volume under reduced pressure, and the precipitates were collected by filtration and washed with diisopropyl ether. The filtrate and washing solution were combined together and concentrated in vacuo. The residue was added to ethyl acetate (200 ml.) under stirring. The insoluble substance was collected by filtration, and washed with diethyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 0.3 g.). The filtrate and ethyl acetate washing solution were combined together, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride twice in turn, and dried over magnesium sulfate. The solution was treated with activated charcoal and concentrated in vacuo. The residue was dried in vacuo after adding benzene. The residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn. The eluate was concentrated in vacuo, and the residue was triturated with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether to give the same compound as mentioned above (syn isomer, 2.658 g.). The I.R. spectrum and N.M.R. spectrum are the same as those of the compound obtained in Example I-(3).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17](O)=[O:18])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[NH2:29]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:29][C:28]4[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:26]([O:25][CH3:24])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Product: COc1cc(NC(=O)c2ccc(C)c(NC(=O)c3csc4c(N)ncnc34)c2)cc(OC)c1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3,5-dimethoxyaniline to obtain the title compound (see Table 1).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[C:5](=[O:27])[N:6](C2CCCCO2)[N:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:16][C@@H:15]2[CH2:17][C@@H:13]([C:14]2([CH3:19])[CH3:18])[C@H:12]1[CH3:20]>C(O)(=O)C.O1CCCC1.O.Cl>[F:28][CH:2]([F:1])[O:3][C:4]1[C:5](=[O:27])[NH:6][N:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:16][C@@H:15]2[CH2:17][C@@H:13]([C:14]2([CH3:19])[CH3:18])[C@H:12]1[CH3:20]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCCO3)c(=O)c1OC(F)F)C2(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1OC(F)F)C2(C)C
Yield: 76.6 %

Procedure:
4-Difluoromethoxy-2-(tetrahydro-2H-pyran-2-yl)-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (80 mg, 0.20 mmol) in acetic acid-tetrahydrofuran-water (5/1/1) was stirred at 90° C. for 3 hours and then stirred with two drops of concentrated hydrochloric acid for another 3 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) to give the desired product (48 mg, 79% yield).
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:32]2[CH:36]=[N:35][C:34]([C:37]([OH:50])([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:33]2)[CH2:27][CH2:26]1)C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.CCOCC>C(O)C>[NH3:8].[NH2:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:32]2[CH:36]=[N:35][C:34]([C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[OH:50])=[N:33]2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)c3ccccc3)n2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: N
Product: NCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Di-tert-butyl{9-[4-({3-[hydroxy(diphenyl)methyl]-1H-1,2,4-triazol-1-yl}methyl)piperidin-1-yl]nonyl}imidodicarbonate (Preparation 27, 1.7 g, 2.46 mmol) was dissolved ethanol (30 ml) and hydrogen chloride in ether (2M, 30 ml, 60 mmol) added. After stirring at room temperature for 18 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90:10:1 to 80:20:2, by volume) to furnish the title compound as a white solid, in 60% yield, 725 mg.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:51]([O:55][C:56](=[O:59])[CH2:57][NH2:58])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.C(Cl)CCl>[C:51]([O:55][C:56](=[O:59])[CH2:57][NH:58][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:29])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 920 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 46 ml DMF were added 342 mg HOBt, 428 mg EDC, 0.78 ml DIPEA and 374 mg glycine tert-butyl ester hydrochloride. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:18]=[CH:19][C:20]=1[CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:28](=[O:29])[CH:27]([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[C:15]([F:14])[CH:16]=2)[CH3:31])=[CH:6][CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reactant: NCc1ccc(C(F)(F)F)nc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C(=O)NCc1ccc(C(F)(F)F)nc1Cl)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 61.3 %

Procedure:
To a stirred solution of (2-chloro-6-(trifluoromethyl)pyridin-3-yl)methanamine (2.9 g, 13.8 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (3.8 g, 13.8 mmol) in tetrahydrofuran (100 mL) were added 1-hydroxybenzotriazol (1.89 mL, 13.8 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.4 g, 13.8 mmol) and N-ethyldiisopropylamine (7 mL, 41.4 mmol) to gave an suspension. After addition of N,N-dimethylformamide (1 mL) the reaction mixture was stirred for 36 h at room temperature. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: cyclohexane/ethyl acetate 1:2) to afford N-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (3.96 g, 61%).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][CH2:6][S:7][CH3:8])=[O:2].ON1C2C=CC=CC=2N=N1.[F:22][C@:23]12[C@@H:43]([OH:44])[CH2:42][C@@:41]3([CH3:45])[C@@H:33]([CH2:34][C@H:35]([CH3:47])[C@:36]3([OH:46])[C:37](=[O:40])[CH2:38][SH:39])[C@@H:32]1[CH2:31][CH2:30][C:29]1[C@:24]2([CH3:49])[CH:25]=[CH:26][C:27](=[O:48])[CH:28]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:22][C@:23]12[C@@H:43]([OH:44])[CH2:42][C@@:41]3([CH3:45])[C@@H:33]([CH2:34][C@H:35]([CH3:47])[C@:36]3([OH:46])[C:37](=[O:40])[CH2:38][S:39][C:9](=[O:11])[CH:4]([NH:3][CH:1]=[O:2])[CH2:5][CH2:6][S:7][CH3:8])[C@@H:32]1[CH2:31][CH2:30][C:29]1[C@:24]2([CH3:49])[CH:25]=[CH:26][C:27](=[O:48])[CH:28]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of N-formyl-L-methionine (11.13 gm) in dry ethyl acetate (200 ml) were added 1-hydroxybenzotriazol (9.71 gm) in dry ethyl acetate (100 ml) and dicyclohexylcarbodiimido (16.43 gm) in dry ethyl acetate (100 ml) each at room temperature. The reaction mixture was stirred for 1.5 hours. To the stirred reaction mixture was added dropwise a solution of 9-fluoro-11β,17-dihydroxy-16β-methylpregna -1,4-diene-3,20-dione-21-thiol (12.95 gm) and triethylamine (35 ml) in dry ethyl acetate (600 ml) at 0° C. for 1 hour. The reaction mixture was stirred at room temperature for 4.5 hours. The title compound (15.68 gm) was prepared by purifying the resulting reaction mixture in the same manner as in Synthetic Example 1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH2:17][CH3:18])[CH:10]=1.O.[N:20]#[C:21]Br>CCO.CCO.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][CH3:18])[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: CCc1cc(Cl)nnc1NN
Reactant: N#CBr
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: CCc1cc(Cl)nn2c(N)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
(6-Chloro-4-ethylpyridazin-3-yl)hydrazine trifluoroacetate (W3.003; 1.35 g) were initially charged in EtOH (25 ml) and water (4 ml) while stirring at RT. Thereafter, cyanogen bromide (997 mg), dissolved in EtOH/water (5/2 ml), was cautiously added dropwise. After stirring at RT for 8 h and standing overnight, the mixture was stirred at 55° C. for another 4 h. Subsequently, the solvent was concentrated and the residue was admixed with water. Once it had been alkalized with saturated potassium carbonate solution, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 918 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[S:35][C:24]2[NH:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[N:28]=[C:29](N)[C:23]=2[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:29]2[C:23]3[CH:22]=[C:21]([CH3:20])[S:35][C:24]=3[NH:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[N:28]=2)[CH2:4][CH:3]1[CH2:8][N:9]1[C:10](=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]1=[O:18]
Reactant: CN1CCNCC1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)C(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A solution of 2-((1-methylpiperazin-2-yl)methyl)isoindoline-1,3-dione, prepared as described in step D, (100 mg, 0.38 mmol), 2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine, prepared as described in step G, (150 mg, 0.52 mmol) and diisopropylethylamine (0.49 g, 3.8 mmol) in dimethylsulfoxide (0.5 mL) was stirred at 170° C. for 2 hrs. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was concentrated and the residue purified by column to give 15 mg of 2-((1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-2-yl)methyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 7.76-7.73 (m, 1H), 7.45-7.35 (m, 3H), 7.18-7.17 (m, 1H), 6.98-6.95 (m, 2H), 6.75-6.73 (m, 1H), 6.46 (s, 1H), 4.28-4.25 (m, 1H), 3.96-6.92 (m, 1H), 3.71-3.64 (m, 3H), 3.47-3.41 (m, 1H), 3.29-3.28 (m, 1H), 3.12-3.09 (m, 1H), 2.87-2.86 (m, 1H), 2.67-2.53 (m, 3H), 2.28 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][S:24]([NH2:27])(=[O:26])=[O:25].CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:27][S:24]([CH2:23][CH2:22][C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: NS(=O)(=O)CCc1cccs1
Agent: [K]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=S(=O)(CCc1cccs1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Yield: 68.7 %

Procedure:
A solution of 4,6-dichloro-5-(4-chlorophenyl)pyrimidine (848 mg), 2-thiophen-2-yl-ethanesulfonic acid amide potassium salt (1.5 g, Referential Example 14) and Hunig's base (1 ml) in DMSO (20 ml) was stirred at rt for 24 h before it was diluted with water (200 ml) and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate was collected, washed with water and diethyl ether and dried to give 2-thiophen-2-yl-ethanesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide (930 mg) as a beige powder. LC-MS: tR=5.01 min, [M+1]+=413.49, [M−1]−=411.93.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:16][C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[N:14][C:13]=1[C:28]([NH2:30])=[O:29]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[S:16][C:15]([NH:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:14][C:13]=2[C:28]([NH2:30])=[O:29])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Yield: 42.1 %

Procedure:
To solution of 4-fluorobenzoyl chloride (0.16 g, 1.2 mmol) in pyridine (5 mL) was added dropwise a solution of 5-amino-2-(quinolin-6-ylamino)thiazole-4-carboxamide (0.30 g, 1.05 mmol) and a catalytic amount of DMAP in pyridine (5 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed successively with water, MeOH and ether to give 0.18 g (42% yield) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)N1CC(O)C1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1cccc(N)c1
Temperature: 140 °C
Yield: 42.3 %

Procedure:
A mixture of 21.8 parts of m-aminophenol, 22 parts of 1-(tert.-butyl)-3-azetidinol and 0.7 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 39. Recrystallization from benzene gave 17.2 parts of 1-(3'-aminophenoxy)-3-(tert.-butylamino)-2-propanol in the form of colorless needles melting at 105° - 106° C. The yield was 42.3%. The results of infra-red spectrum analysis are as follows:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[CH:5]=[N:4][CH:3]=[N:2]1.CN(C=O)C.[H-].[Na+].[CH2:28](Br)[CH3:29]>O>[CH2:28]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:19][CH:18]=2)[CH2:13][CH2:14][C:15]1=[O:20])[CH3:29]
Reactant: O=C1CCc2cc(OCCCn3cncn3)ccc2N1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CCc2cc(OCCCn3cncn3)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (7.35 mM) of 6-[3-(1,2,4-triazol-1-yl)propoxy]-3,4-dihydrocarbostyril with 20 ml of DMF was added 350 mg (8.8 mM) of sodium hydride (60% in oil) and the mixture was heated at 60° C. for 30 minutes. Then under ice-cooling condition, 0.6 ml (8.1 mM) of ethyl bromide was added dropwise, further the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, then extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by removing the solvent by evaporation. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =30:1), then recrystallized from ethyl acetate-n-hexane to yield 1.8 g of 1-ethyl-6-[3-(1,2,4-triazol-1-yl)propoxy] -3,4-dihydrocarbostyril. Colorless needle-like crystals.
Reaction SMILES: [CH2:1]([C:14]([OH:16])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=O.[N+]([O-])(O)=O>>[CH:14]1([OH:16])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1.[C:14]1(=[O:16])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Solvent: O=[N+]([O-])O
Product: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1

Procedure:
A process for the production of 1,10-decanedicarboxylic acid with low melt color values from crude crystalline acid having an organically bound nitrogen content of 0.05% by weight or less and having a nitric acid content above 0.1% by weight and produced by oxidizing cyclododecanol, cyclododecanone or both with nitric acid at low temperature and under mild conditions and subjecting the thus-produced crude acid to a thermal treatment under oxidative conditions, at a temperature above the oxidation temperature, which reduces the organically bound nitrogen content of the crude acid to 0.05% by weight or less, which consists essentially of (a) reducing the nitric acid content of the starting crystalline crude acid to 0.02% by weight or less by a thermal treatment of the crude acid under vacuum at a temperature at which nitrous gases evolve from the crude acid and above the oxidation and thermal treatment temperatures employed to produce the starting crude crystalline acid; (b) distilling the thus pre-purified 1,10-decanedicarboxylic acid at a sump temperature of 215°-225° C. and at a pressure of 0.5 - 2 torr.; and (c) recovering the 1,10-decanedicarboxylic acid as the distillate.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH3:8])[CH:7]=1>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)c(N)cc1N
Yield: 50 %

Procedure:
2 g (0.01 ml) 5-fluoro-2,4-dinitrotoluene from Step 1 are hydrated with catalytic amounts of palladium/carbon (10% Pd) in 50 ml absolute ethanol. After removing the catalyst by filtration, the solvent is completely removed by distillation and the obtained product is recrystallized from toluene. 0.7 g (50% of theory) 5-fluoro-2,4-diaminotoluene are obtained which melts at 112° C. accompanied by decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[I:12][CH3:13]>C(O)C>[I-:12].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N+:7]([CH3:13])[C:6]=2[CH:11]=1
Reactant: CI
Reactant: Cc1nc2cc(F)ccc2s1
Solvent: CCO
Product: Cc1sc2ccc(F)cc2[n+]1C
Product: [I-]

Procedure:
13.0 g (10.4 ml, 77.7 mmol) 5-Fluoro-2-methyl-benzothiazole and 22.1 g (9.47 ml, 156 mmol) iodomethane were boiled in ethanol for 7 h. The residue was filtrated. 4.00 g=17% white powder
Reaction SMILES: [CH2:1]([C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])[CH:17]=[CH:18][CH:19]=2)[N:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([N:8]4[CH2:7][CH2:6][C:5]([OH:11])([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]4)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Nc1ccc2cccc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Reactant: CC(C)CC1(O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4ccc(N)nc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-isobutylpiperidin-4-ol (70 mg, 0.44 mmol), 4-(2-aminoquinoline-8-sulfonamido)benzoic acid (100 mg, 0.44 mmol), and HBTU (134 mg, 0.53 mmol) in DCM (5 mL) was added DIPEA (1 mL) dropwise at room temperature, and then the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated, purified by a standard method to yield the title compound. 1H NMR (CHLOROFORM-d) δ: 8.10-8.20 (m, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.69-7.82 (m, 1H), 7.06-7.26 (m, 5H), 6.80 (d, J=9.1 Hz, 1H), 5.41 (s, 2H), 4.33 (br. s., 1H), 3.41-3.19 (m., 3H), 1.82 (dt, J=12.9, 6.4 Hz, 1H), 1.63-1.46 (m, 4H), 1.40 (d, J=5.9 Hz, 2H), 0.97 (d, J=6.7 Hz, 6H). LCMS (m/z): 483.7 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(O)c1
Product: Nc1cc2ncnc(Nc3cccc(O)c3)c2cn1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (299 mg, 1.56 mmole) and 3-aminophenol (1.60 g, 14.7 mmole) is stirred at 160° C. for 15 min. The resulting product is chromatographed over silica gel (9% MeOH/CH2Cl2) to give 7-amino-4-(3-hydroxyanilino)pyrido[4,3-d]pyrimidine (108 mg, 18%) as a pale orange solid. 1H NMR (DMSO) δ 9.69 (1H, brs), 9.44 (1H, brs), 9.33 (1H, s), 8.38 (1H, s), 7.37 (1H, t, J=2.1 Hz), 7.21 (1H, brd, J=8.4 Hz), 7.14 (1H, t, J=8.0 Hz), 6.59 (2H, brs), 6.53 (1H, ddd, J=7.9, 2.2, 0.8 Hz), 6.43 (1H, s).