Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)([CH3:31])=[CH2:30].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]([CH3:31])=[CH2:30])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Reactant: C=C(C)[Mg]Br
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (300 mg, 0.61 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 18.4 mL, 9.2 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (32 mg, 12%). LC/MS m/e calcd for C25H27NO4 (M+H)+: 406.50, observed: 406.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.20 Hz, 3 H) 1.53 (s, 3 H) 2.57-2.64 (m, 1 H) 2.64-2.71 (m, 1 H) 2.64-2.71 (m, 1 H) 2.71-2.78 (m, 1 H) 2.95-3.04 (m, 1 H) 3.15-3.22 (m, 1 H) 3.72 (s, 3 H) 3.81 (s, 3 H) 4.60 (s, 1 H) 4.72 (s, 1 H) 5.08 (s, 1 H) 6.04 (d, J=4.55 Hz, 2 H) 6.86 (s, 1 H) 6.89 (s, 1 H) 6.96 (s, 2 H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([N:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH2:1][C:3]1[C:4]([N:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:22]
Reactant: CNC
Reactant: CCOC(=O)c1cn(-c2ncccc2C=O)nc1C
Product: CCOC(=O)c1cn(-c2ncccc2CN(C)C)nc1C
Yield: 95 %

Procedure:
This compound is prepared essentially as described in Preparation 7 by using ethyl 1-(3-formyl-2-pyridyl)-3-methyl-pyrazole-4-carboxylate and dimethylamine in a 95% yield and is used with no further purification after workup. MS (m/z): 289 (M+1)
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C([O-])=O.[NH4+].ClCCl.CO>[Pd].CO>[CH3:15][N:4]1[C:3](=[O:16])[CH:2]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:6]=[N:5]1
Reactant: CN1CCN(c2cnn(C)c(=O)c2Cl)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2cnn(C)c(=O)c2)CC1

Procedure:
To a mixture of 4-chloro-2-methyl-5-(4-methylpiperazin-1-yl)pyridazin-3(2H)-one (4.85 g, 20 mmol) and 10% Pd/C catalyst (1.14 g) in methanol (100 ml) was added ammonium formate (2.90 g, 46 mmol), and the mixture was refluxed under argon with TLC monitoring (dichloromethane:methanol (9:1)). Further portions of ammonium formate were added until the starting material was completely consumed. The catalyst was filtered off and washed with methanol, then the solvent was evaporated under reduced pressure. The residue was taken up in water (30 ml) and extracted with dichloromethane (4×40 ml). The combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by recrystallization from ethyl acetate:light petroleum.
Reaction SMILES: [C:1](=[O:16])([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)C>[CH:3]1([NH:2][C:1](=[O:16])[O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C(Nc1ccccc1)OC1CCCCC1
Solvent: CC(C)O
Product: O=C(NC1CCCCC1)OC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 21.9 g. (0.10 mole) of cyclohexyl carbanilate, 77 ml. of 2-propanol, and 3.0 g. of 5% on carbon was added to a 0.5-1., glass, low pressure, Parr (trademark) shaker bottle. The apparatus was assembled, purged first with nitrogen and then with hydrogen, and pressured with hydrogen to 50 psig. The reaction mixture was agitated at room temperature and 50 to 25 psig for 3.0 hr., followed by an additional 0.8 hr. with little or no gas absorption. The reaction product was filtered through Celite filter aid to remove the catalyst. The solvent was removed in a rotary evaporator under vacuum. The solid residue consisted of 22.3 g. (99% yield) of cyclohexyl cyclohexylcarbamate, m.p. 77°-78°. Anal. Calcd. for C13H23NO2 : C, 69.29; H, 10.30; N, 6.21. Found: C, 69.43; H, 10.10; N, 6.20.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:37](=[O:38])[C:31]2[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=2)[C:40]1=[O:39]
Reactant: COc1ccc(-c2nc3cc(-c4ccc5c(c4)OCO5)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4ccc5c(c4)OCO5)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl-5-[3,4-(methylenedioxy)phenyl]benzoxazole (120 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (70 mg, 0.36 mmol) the title compound was obtained (82 mg, 46%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.37–8.32(m, 3H), 8.12(d, 1H), 7.96(d, 1H), 7.79(d, 1H), 7.63(dd, 1H), 7.49(d, 1H), 7.33(d, 1H), 7.20(dd, 1H), 7.02(d, 1H), 6.06(2H, s), 3.88(s, 3H). MS m/z 535.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccccc2)C1
Yield: 10.2 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (100 mg, 0.46 mmol), styrene (1 mL, 8.41 mmol) and NaH (200 mg, 60% dispersion in oil, 8.30 mmol) in DMF (3 ml) at 200° C. for 5 h to obtain 15 mg (4.7% yield) of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)CC(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octyl-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:22]([CH3:21])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CNCc1cccc(SC)c1
Product: CSc1cccc(CN(C)C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and N-methyl-1-(3-methylsulfanylphenyl)methanamine (17.0 mg, 0.12 mmol). The title compound was obtained as a solid (33.5 mg, 67% yield). MS m/z: 500.01, 502.00 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:5]1[CH2:4][CH:3]1[CH2:1][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15]
Reactant: BrCC1CO1
Reactant: NC(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1ccccc1OCC1CO1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A solution of epibromohydrin (0.94 g, 6.84 mmol) in dry DMF (2 mL) was added dropwise to a stirred suspension of N-(2-hydroxyphenyl)urea (0.65 g, 4.27 mmol) and cesium carbonate (2.22 g, 6.84 mmol) in DMF (8 mL). After 2 hours the mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water (3 times), dried and concentrated. The semi-solid residue was disssolved in dichloromethane/ethyl ether, filtered and heptane was added to turbidity. After standing at room temperature overnight, the solid was filtered to afford the subtitle compound (0.28 g, 32%).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: CS(=O)(=O)NCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(CNS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6.04 g (0.03 mol) of N-(4-hydroxybenzyl)methanesulfonamide, 3.04 g (0.03 mol) of triethylamine, and 30 ml of methylene chloride was cooled to approximately 0° C. To this mixture was added a solution of 3.14 g (0.03 mol) of methacryloyl chloride in 15 ml of methylene chloride over approximately 5 minutes. The mixture was stirred for an additional 15 minutes and filtered. The filtrate was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator. The solid residue was recrystallized from 1:1 hexane:1,2-dichloroethane. The yield of N-(4-methacryloyloxybenzyl)methanesulfonamide was 3.0 g (37.13 percent of theory), m.p.=101° to 102.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH:16]C(OC(C)(C)C)=O)[C:10]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:9][N:8]=1)[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH2:16])[C:10]([C:24](=[O:33])[NH:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCN)n1
Reaction time: 2 h
Yield: 112.7 %

Procedure:
[4-(2-tert-Butoxycarbonylaminoethylamino)-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (113 mg, 0.23 mmol) was dissolved in a trifluoroacetic acid/dichloromethane solution (50%, 4 mL) and the resulting solution was stirred under N2 for 2 h. The solvent was removed by rotary evaporation, and trituration with diethyl ether was attempted. The resulting gummy solid was dissolved in water and lyophilized to yield the titled product (102 mg, 88% as trifluoroacetic acid salt) as a hygroscopic and flocculent white solid. 1H NMR: (d6-DMSO) δ 10.28 (s, 1H), 8.64 (m, 1H), 8.60 (s, 1H), 7.65 (in, 2H), 7.18 (t, 2H), 4.09 (q, 2H), 3.98 (s, 2H), 3.62 (m, 2H), 2.98 (m, 2H), 1.17 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](I)[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:28][CH3:29])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCI
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OCC)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Step 3 (0.500 g, 1.55 mmole) in anhydrous DMF (5.0 mL) under a dry N2 atmosphere was added KI (26 mg, 0.155 mmole), K2CO3 (0.643 g, 4.65 mmole) and ethyl iodide (272 uL, 4.65 mmole). After stirring overnight at room temperature, the mixture was poured into H2O (150 mL), saturated with solid NaCI and extracted with EtOAc (200 mL). The extract was then washed with brine (2×200 mL), dried over MgSO4, filtered and concentrated in vacuo to give a quantitative yield of the product as a tan solid: EIHRMS m/z 350.0564 (M+, C15H14ClF3O4, Calc'd 350.0533). 1H NMR (dmso-d6/300 MHz) 7.93 (s, 1H), 7.18 (d, 1H, J=3.0 Hz), 7.13 (d, 1H, J=2.8 Hz), 6.06 (q, 1H, J=7.3 Hz), 4.23-4.31 (m, 2H), 4.01 (q, 2H, 7.0 Hz), 1.29 (q, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[CH3:32][O:33][C:34]([NH:36][C:37](=NC(OC)=O)SC)=[O:35]>C(O)(=O)C>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]6[NH:30][C:37]([NH:36][C:34](=[O:35])[O:33][CH3:32])=[N:29][C:26]6=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1
Temperature: 80 °C
Reaction time: 10 h
Yield: 51 %

Procedure:
A mixture of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (174 mg, 0.42 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (86 mg, 0.42 mmol) in acetic acid (5 mL) was stirred at 80° C. for 10 h. After cooling to room temperature the mixture was concentrated, methanol (10 mL) was added, the precipitate was filtered off, and lyophilized from a mixture of acetonitrile (2 mL), water (6 mL), and 1N hydrochloric acid (0.25 mL) to give the hydrochloride salt of the title Compound (107 mg, 48% yield) as a yellow solid. 1H NMR (400 MHz, methanol-d4): 8.53 (m, 2H), 8.35 (s, 1H), 7.78 (s, 1H), 7.58 (d, 1H), 7.10 (d, 1H), 5.18 (s, 2H), 4.49 (m, 2H), 4.34 (m, 2H), 3.93 (s, 3H), 2.86 (m, 2H), 2.61 (s, 2H), 1.71 (m, 2H), 0.95 (s, 6H); MS (EI) for C27H29N7O3: 500 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH:6]=2)[CH2:3][CH2:2]1.[NH:22]1[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:28]4\[NH:22][C:23](=[O:24])[NH:25][C:26]\4=[O:27])=[C:9]3[N:8]=[C:7]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(NC(=O)C3CC3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(NC(=O)C4CC4)nc23)N1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide (74 mg, 0.26 mmol) in 1.0 mL ethanol was added hydantoin (26 mg, 0.26 mmol) and piperidine (24 ul). The reaction was heated at 80° C. for two hours. The reaction mixture was cooled to room temperature, concentrated and diluted with MeOH. The product was purified by prep HPLC to yield 14 mg (20% yield) (Z)—N-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide. LCMS (M+1=368)
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:22]=1[NH2:23]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:23][C:22]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=3[CH3:20])=[O:12])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C)c(NC(=O)C2c3ccccc3COc3ccc(C)cc32)c(C)c1
Yield: 61.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.47 g of Compound A and 0.71 g of 2,4,6-trimethylaniline in place of aniline to obtain 1.20 g of Compound 9.
Reaction SMILES: C=O.[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7].[CH2:36](Cl)Cl.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][N:21]([CH3:36])[CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]
Reactant: ClCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCNCC4)c3c2)c1F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCN(C)CC4)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
37% Aqueous formaldehyde (100 μL) was added to a solution of 2,6-difluoro-3-(propylsulfonamido)-N-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (22 mg, 0.046 mmol) in 5:1 CH2Cl2/MeOH (6 mL), followed by a drop of AcOH. After 5 minutes, sodium triacetoxyborohydride (49 mg, 5 equiv) was added, and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was quenched with MeOH, concentrated, and purified by silica gel chromatography (10:90:1 MeOH/CHCl3/NH4OH) to afford 2,6-difluoro-N-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a white solid (14 mg, 62%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.88 (m, 1H), 8.62-8.60 (m, 1H), 7.70-7.63 (m, 1H), 7.17-7.11 (m, 1H), 6.57-6.53 (m, 1H), 3.35-3.31 (m, 2H), 3.14-3.09 (m, 2H), 2.90-2.83 (m, 4H), 2.49 (s, 3H), 1.92-1.82 (m, 2H), 1.08-1.04 (m, 3H); m/z (APCI-pos) M+1=491.0.
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[C:32]2[C:23](=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[CH:31]=2)[CH:22]=[C:21]2[C:16]=1[C:17]1[CH:48]=[CH:47][C:46]3[C:33](=[CH:34][C:35]4[C:44]([CH:45]=3)=[CH:43][C:42]3[C:37](=[CH:38][C:39](Br)=[CH:40][CH:41]=3)[CH:36]=4)[C:18]=1[CH:19]=[CH:20]2>O.[Cu]>[C:1]1([NH:7][C:15]2[C:32]3[C:23](=[CH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[CH:31]=3)[CH:22]=[C:21]3[C:16]=2[C:17]2[CH:48]=[CH:47][C:46]4[C:33](=[CH:34][C:35]5[C:44]([CH:45]=4)=[CH:43][C:42]4[C:37](=[CH:38][C:39]([NH:7][C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:40][CH:41]=4)[CH:36]=5)[C:18]=2[CH:19]=[CH:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc2cc3cc4ccc5c(ccc6cc7cc8ccccc8cc7c(Br)c65)c4cc3cc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(Nc2ccc3cc4cc5ccc6c(ccc7cc8cc9ccccc9cc8c(Nc8ccccc8)c76)c5cc4cc3c2)cc1

Procedure:
Naphthacenonaphthacene is dissolved in carbon tetrachloride. While the resultant mixture is cooled, 1 mol equivalent of bromine is added thereto. The mixture is reacted for 4 hours and brominated. Thereafter, the mixture is purified in accordance with a usual method, and 6,13-dibromonaphthacenonaphthacene is obtained. Phenylamine, potassium carbonate, and copper powder are added to the 6,13-dibromonaphthacenonaphthacene obtained in this way, and the mixture is reacted for 30 hours at 200° C. After the reaction solution is diluted with water, the reactant is eluted with chloroform. Thereafter, the resultant substance is purified in accordance with a usual method, and the 6,13-bis(phenylamino)naphthacenonaphthacene represented by the following formula is synthesized. (Note that, in the formula, “Ph” represents a phenyl group.)
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(Cl)Cl>[O:8]=[C:7]1[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3][CH:2]1[C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccccc2SC1Cl
Reactant: c1ccsc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2SC1c1cccs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (9.38 g) and thiophene (7.91 g) in methylene chloride (250 ml) is added in portions stannic chloride (12.2 g) at 0° to 5° C. After stirring at the same temperature for 45 minutes, the mixture is poured into ice water, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate, and the ethyl acetate layer is combined with the above organic layer and distilled to remove the solvent. The resulting solid material is recrystallized from ethanol to give 3-oxo-2-(2-thienyl)-3,4-dihydro-2H-1,4-benzothiazine (8.17 g) as crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:6]=[CH:7][S:8][CH3:9])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(OCC)(=O)C>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3](=[O:4])[C:2]([CH3:10])([CH3:1])[CH:6]=[CH:7][S:8][CH3:9])=[CH:26][CH:25]=1
Reactant: CSC=CC(C)(C)C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Product: CSC=CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 32.1 %

Procedure:
A solution of 0.5 g of 2,2-dimethyl-4-methylthio-3-butenoic acid in 20 mL of ethyl acetate was treated with 0.6 g of carbonyldiimidazole, and the solution was heated for 10 minutes at reflux. After the solution had cooled, 0.65 g of p-chloroaniline was added and heating continued for 16 hours. The solution was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with 50 mL of 1N HCl, dried over MgSO4, and concentrated. The residual solid was recrystallized from CHCl3 /hexane to give 0.27 g of N-(4-chlorophenyl)-2,2-dimethyl-4-(methylthio)-3-butenamide, m.p. 105°-106° C.