Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.Br[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:21])[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:21])[O:19][CH3:20])[N:2]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)NCCCBr
Reactant: CC(=O)c1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCCn1nc(C(C)=O)c2cccnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone (500 mg) and methyl (3-bromopropyl)carbamate (912 mg) in N,N-dimethylformamide (5 mL) was added potassium carbonate (864 mg), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5→1/1) to give methyl [3-(3-acetyl-1H-pyrazolo-[3,4-b]pyridin-1-yl)propyl]carbamate) [REx(103-2)] (308 mg) as a red oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH2:21])=[S:20])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23]I>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[NH:21])[S:20][CH3:23])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(NC(N)=S)c2)CCC1
Product: CSC(=N)Nc1cccc(C2(NC(=O)OC(C)(C)C)CCC2)c1
Yield: 96 %

Procedure:
Using the compound obtained in Example 158 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 150 mg of the titled compound (yield, 96%).
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].[C:8]1([C:14]([C:28]2[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=2)=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:31]1[CH:30]=[CH:29][C:28]([C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:16]([F:19])([F:18])[F:17])=[CH:33][CH:32]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(C(=C(c2ccccc2)c2ccc(F)cc2)C(F)(F)F)cc1
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(C(=C(c2ccccc2)c2ccc(OCCN(C)C)cc2)C(F)(F)F)cc1
Yield: 90.3 %

Procedure:
0.39 g (0,017 g.-atoms) of sodium are dissolved in 3.12 g (35 mmoles) of 2-dimethylamino-ethanol. 3.15 g (8.5 mmoles) of 1-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propene are added to the solution, and the mixture is heated at 150°-155° C. for one hour. The reaction mixture is cooled, diluted with 200 ml of ether, washed with water until neutral, dried and evaporated. The residue is dissolved in 30 ml of hexane, the solution is filtered, and the filtrate is evaporated. 3.39 g (90%) of 1-[4-(2-dimethylamino-ethoxy)-phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-methoxyphenyl)-propene are obtained as a resinous substance; the product is a 3:4 mixture of the (Z) and (E) isomers.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]([CH:22]=[O:23])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C1N=C(C2[N:41](C(C)C)[C:40]([C:45]([C:47]3SC=[CH:50][CH:51]=3)=O)=NC=2)C=CN=1)C1C=CC=CC=1>>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[C:17]([C:22]([C:47]3[CH:45]=[CH:40][N:41]=[CH:50][CH:51]=3)=[O:23])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C(=O)c1cccs1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C(=O)c1ccncc1

Procedure:
The title compound was prepared by the procedure of Example 6 from 2-anilino-4-(2-formyl-1 -isopropylimidazol-5-yl)pyrimidine (Example 10) and N-methoxy-N-methyl 4-pyridinecarboxamide (Method 7). NMR (CDCl3): 1.55-1.75 (m, 10H), 5.56-5.72 (sept, 1H), 6.98 (d, 1H), 7.10 (t, 1H), 7.20 (br s, 1H), 7.30-7.40 (m, 2H), 7.55 (s, 1H) (7.60 (d, 2H), 7.90-7.94 (m, 2H), 8.51 (d, 1H), 8.78-8.82 (m, 2 H); m/z 385.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)N1CC=C(c2coc3c(O[C@H](C)c4c(Cl)ccc(F)c4Cl)c(N)ncc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask were added 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), isopropyl isocyanate (0.00371 g, 0.0436 mmol), DIPEA (33 μL, 0.19 mmol) and DMF (1 mL) and the reaction mixture was stirred at rt for 15 min. Purification by HPLC followed by prep TLC in 5% NH3 in DCM afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.17 (d, J=6.6 Hz, 6H), 1.88 (d, J=6.8 Hz, 3H), 2.49 (br. s., 2H), 3.63 (t, J=5.7 Hz, 2H), 3.87-3.99 (m, 1H), 4.06 (d, J=2.5 Hz, 2H), 6.13 (d, J=7.6 Hz, 1H), 6.25 (br. s., 1H), 6.49 (d, J=6.8 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H). MS (ES+): m/z 507.04/509.06 (100/71) [MH+]. HPLC: tR=3.14 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH3:17])[C:5]2[N:6]=[C:7](S(C)(=O)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19].C(O)C>CC(O)C>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH3:17])[C:5]2[N:6]=[C:7]([NH:19][CH3:18])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Cn1c(=O)c(Br)cc2cnc(S(C)(=O)=O)nc21
Reactant: CN
Solvent: CCO
Solvent: CC(C)O
Product: CNc1ncc2cc(Br)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Charged a flask with 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.910 g, 2.86 mmol, prepared by reference in Scheme 6E) and 10.0 mL IPA. Chilled suspension to 0° C. and treated with methylamine 33% wt. solution in ethanol (1.78 ml, 14.3 mmol). After addition was complete, the bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The crude reaction mixture was filtered and washed with ethanol (2×30 mL) and air-diced to afford a white microcrystalline solid: 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.637 g, 82.8% yield). MS (M+H)+ 269, 271.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccco1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-furoyl)hydrazine (1.0 g) was dissolved in 10 ml toluene and 2 ml water. 50% aqueous sodium hydroxide (1.0 g) was added followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-furoyl)-N'-benzoylhydrazine, was removed by filtration and washed with water. m.p. 160-162° C.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8].C(COC)OC.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[O:8]=[C:3]1[N:2]([NH:1][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:7][CH2:6][CH2:5][O:4]1
Reactant: O=C=Nc1ccccc1
Reactant: NN1CCCOC1=O
Solvent: CCCCCC
Solvent: COCCOC
Product: O=C(Nc1ccccc1)NN1CCCOC1=O
Yield: 53 %

Procedure:
To a mixture of 5.4 g of 3-amino-tetrahydro-1,3-oxazine-2-one and 50 ml glyme was added 5.0 ml of phenyl isocyanate. After an exothermic reaction a white solid formed. The mixture was refluxed for 1 hr; cooled; diluted with hexane and filtered. The solid product was crystallized from 200 ml of ethanol to give 5.8 g (53% yield) of white cotton-like needles of 1-(tetrahydro-2-oxo-1,3-oxazin-3-yl)-3-phenylurea, mp 204°-207°.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Zn+]>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Clc1cccc(C[Zn+])c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: [Cl-]
Product: COC(=O)c1cc(Cl)cnc1Cc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 58 from methyl 2,5-dichloronicotinate and 3-chlorobenzylzinc chloride: 1H-NMR (CDCl3) δ 8.65 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.26–7.12 (4H, m), 4.52 (2H, s), 3.89 (3H, s).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:3].CN(C1C=CC=CN=1)C.[C:41](O)(=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45].O>N1C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:6]3[CH:5]=[C:4]([CH:2]([O:1][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH3:3])[C:9]([CH3:10])=[N:8][C:7]=3[O:11][CH3:12])=[O:15])[CH2:17][CH2:18]2)[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)nc3OC)CC2)c1
Reactant: O=C(O)CCC(=O)O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)OC(=O)CCC(=O)O)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
1-{[5-(1-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(107 mg, 0.25 mmol) and dimethylaminopyridine(3 mg, 0.025 mmol) were dissolved in pyridine and anhydrous succinic acid(50 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 5 hrs. Distilled water was added into the above mixture. The above solution was extracted with CH2Cl2 and the organic phase washed with 1N-HCl and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(dichloromethane:methanol=20:1) to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([CH:32]3[CH2:34][CH2:33]3)([C:29]([NH2:31])=O)[C:27](=[O:35])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:28]([CH:32]3[CH2:34][CH2:33]3)([C:29]#[N:31])[C:27](=[O:35])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: NC(=O)C1(C2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1(C2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-amino-5-cyclopropyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 162, (565 mg, 1.201 mmol) was taken up in pyridine (6 mL) and the solution cooled to 0° C. Phosphorous oxychloride (0.896 ml, 9.61 mmol) was then added dropwise and the reaction mixture was warmed to room temperature. After 15 minutes, the pyridine solvent was concentrated in vacuo and the residue taken up in EtOAc. The mixture was then washed with water, brine and dried over sodium sulfate. The residue was purified by silica gel column chromatography using a hexanes/EtOAc gradient to give the title compound, Chiral separation by SFC provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 9.07 (1H, d, J=8.07 Hz), 8.69 (1H, d, J=4.42 Hz), 7.44 (1H, dd, J=8.08, 4.48 Hz), 7.16 (2H, s), 4.93 (2H, t, J=6.82 Hz), 3.08-2.95 (2H, m), 1.80-1.73 (1H, m), 0.93-0.88 (1H, m), 0.65 (2H, d, J=8.31 Hz), 0.55-0.48 (1H, m). m/z=479.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.Cl.C(OCC)C>CC(O)C>[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1
Reactant: NCC1(O)CCCc2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: NCC1=CCCc2ccccc21
Yield: 59 %

Procedure:
1-Aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene, the product of Example 7, was refluxed in a 2N solution of hydrogen chloride in 2-propanol (250 mL) for 5 hours. A portion of the 2-propanol was removed under reduced pressure to give a slurry. Diethyl ether was added to precipitate the hydrochloride salt. The resulting suspension was then filtered. The filter cake was then recrystallized from methanol/diethyl ether to give 16.18 g (59% yield based on 1,2,3,4-tetrahydronaphthalene-1-one) of the desired product as a light tan solid; 1H NMR (CD3OD) δ 2.31-2.40 (m, 2H), 2.80 (t, 2H, J=8 Hz), 4.0 (s, 2H), 6.26 (t, 1H, J=4.5 Hz), 7.19-7.29 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:3]=1.[OH:26]O>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:26])[CH:3]=1
Reactant: Cc1ccc(SCCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 8-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH2:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[NH:10]1.[S:23]([NH2:27])([NH2:26])(=[O:25])=[O:24]>C(COC)OC>[NH2:26][S:23]([NH:27][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[N:10]1[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:18]([C:19]([NH:21][O:22][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:22])(=[O:25])=[O:24]
Reactant: NS(N)(=O)=O
Reactant: NC(=O)C1c2ccccc2C(=O)NC1c1ccc(Cl)cc1Cl
Solvent: COCCOC
Product: NS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a mixed liquid of 200 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-Nenzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed by stirring at 80° C. for 2 days. The reaction solution was concentrated, added with chloroform, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), crystallized from ethyl acetate, and collected by filtration to obtain 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[CH:10][C:11]=1[F:12].Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:13]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1nccc(F)c1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12

Procedure:
Under argon, 500 mg (1.97 mmol) of 3-[(2,6-difluorobenzyl)oxy]-4-fluoropyridine-2-amine Example 110A were initially charged in 10 ml of ethanol, and 500 mg of powdered molecular sieve 4 Å and 3.24 g (19.67 mmol) of ethyl 2-chloroacetoacetate were added. The resulting reaction mixture was heated at reflux for 48 h. All volatile components were substantially evaporated on a dry ice rotary evaporator at a water bath temperature of 85° C. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=9/1 isocratic). This gave 368 mg (39% of theory; purity about 76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:23][CH3:24])([CH3:22])[CH3:21])=[CH:16][C:15]=2[C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])[CH2:11][CH3:12])=[CH:4][C:3]=1[NH:31]C(=O)CC(=O)C(C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:23][CH3:24])([CH3:22])[CH3:21])=[CH:16][C:15]=2[C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])[CH2:11][CH3:12])=[CH:4][C:3]=1[NH2:31]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(NC(=O)CC(=O)C(C)(C)C)c1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(N)c1

Procedure:
Io 25 ml of ethyl acetate, was dispersed 5.71 g (0.01 mol) of N-[2-chloro-5-{2-(2,4-di-tert-amylphenoxy)butanoylamino}phenyl]-α-pivaloylacetic acid amide, which is easily obtained by a condensation reaction of 2-chloro-5-{2-(2,4-di-tert-amylphenoxy)butanoylamino}aniline with pivaloylacetic acid ester; and then to this was added, little by little, 1.57 g (0.0055 mol) of 1,3-dibromo-5,5-dimethylhydantoin, on an ice bath. After stirring for 1 hour, water was added to the resultant reaction mixture, followed by separation of solutions, and then a solvent was removed by fraction, to obtain on oily product. This product was subjected to silica gel column chromatography (n-hexane/ethyl acetate=10/1 to 5/1), for purification. As an oily product, 0.05 g of Compound (1)-1 was obtained.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[C:6]([OH:12])=[CH:7][CH:8]=[CH:9][C:10]=1[OH:11])=[O:4].[C:13](OCC)(=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[OH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:3](=[O:4])[CH:2]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11]2
Reactant: CC(=O)c1c(O)cccc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c(O)cccc2o1
Temperature: 25 °C

Procedure:
1.1 3.25 g of sodium are dissolved in portions in 300 ml of ethanol with stirring. A solution of 4.3 g of 2,6-dihydroxyacetophenone and 15.5 ml of diethyl oxalate in 25 ml of ethanol is subsequently added dropwise. The reaction mixture is subsequently heated at 80° for 3 hours. The mixture is cooled to room temperature, and 10 ml of 32% HCl are added dropwise. The mixture is heated at 90° for 30 minutes and cooled, and the solvent is removed. Conventional work-up gives 5.9 g of 5-hydroxy-2-ethoxycarbonyl-chromone (“AA”).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1.C(COC)OC.O.[OH-].[Li+].Cl>O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(Br)ccc1C(=O)O
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To methyl 4-bromo-2-cyanobenzoate (4.76 g) described in Preparation Example 191 was added dimethoxyethane (78 mL), a solution obtained by dissolving lithium hydroxide monohydrate (1.25 g) in water (30 mL) under ice-cooling was added dropwise, and the mixture was stirred for 1 hr. Under ice-cooling, the mixture was neutralized with 1N hydrochloric acid and dimethoxyethane was evaporated. Water was added and the mixture was stirred under ice-cooling. The precipitated crystals were collected by filtration to give the title compound (4.19 g).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[N:21]=[C:20]([NH2:32])[N:19]=3)=[CH:13][CH:12]=2)[N:10]=1.CO.[OH-].[Na+].[ClH:38]>O>[NH2:32][C:20]1[N:19]=[C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:10]=[C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])[O:7][CH:8]=3)=[CH:16][CH:15]=2)[CH:23]=[C:22]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[N:21]=1.[ClH:38]
Reactant: COC(=O)CCc1nc(-c2ccc(Nc3cc(-c4cc(Cl)ccc4C)nc(N)n3)cc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(-c3coc(CCC(=O)O)n3)cc2)nc(N)n1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-{4-[2-amino-6-(5-chloro-2-methyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-oxazol-2-yl)-propionic acid methyl ester (106 mg, 0.21 mmol), methanol (15 ml), and a solution of sodium hydroxide (500 mg, 12.5 mmol) in water (10 ml) was heated to 70° C. for 2 hours. After cooled to room temperature, the reaction mixture was neutralized to pH=1 using concentrated hydrochloric acid. Solid was collected via filtration and dried to give title compound in its hydrochloric acid salt form, (106 mg, 64% in two steps). 1H NMR (DMSO-d6) δ 2.40 (s, 3H, CH3), 2.76 (t, 2H, J=7.0 Hz, CH2), 3.04 (t, 2H, J=7.0 Hz, CH2), 6.57 (br s, 2H, NH2), 7.44 (d, 1H, J=8.2 Hz, Ar), 7.53-7.57 (m, 3H, Ar), 7.67 (d, 2H, J=8.7 Hz, Ar), 7.94-8.00 (m, 2H, Ar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([CH3:28])[NH:23][CH2:22][CH2:21]2)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][CH:27]=[C:18]([S:15]([CH3:14])(=[O:16])=[O:17])[CH:19]=4)[CH:24]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(S(C)(=O)=O)ccc21
Product: CC1c2ccc(S(C)(=O)=O)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)=[O:21])[CH:15]=[CH:14][N:13]=[CH:12]1>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:23][CH:24]=2)[N:3]=1
Reactant: Nc1ccc(C(=O)NCCCn2ccnc2)cc1
Reactant: N#Cc1cnc(Cl)nc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc(Nc2ccc(C(=O)NCCCn3ccnc3)cc2)nc1N
Yield: 2.1 %

Procedure:
A solution of 4-amino-2-chloro-5-cyanopyrimidine (200 mg, 1.3 mmol) and 4-[N-(3-imidazol-1-ylpropyl)carbamoyl]aniline (Method 3; 633 mg, 2.6 mmol) in NMP (10 ml) was heated at 120° C. for 48 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried and the solvent removed by evaporation, the residue was triturated with ether/hexane and the product collected by filtration to give the title compound (10 mg, 2%). NMR: 1.92 (q, 2H) 3.20 (q, 2H), 4.00 (t, 2H), 6.87 (s, 1H), 7.19 (s, 1H), 7.55 (s, 2H), 7.62 (s, 1H), 7.86 (d, 2H), 8.32 (t, 1H), 8.38 (s,1H), 9.90 (s, 1H); m/z 363 (MH)+.