Azzindani/Open_Reaction_Data huggingface dataset:
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.[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-:16])=[O:15]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: Nc1cc2ncnc(Nc3cccc([N+](=O)[O-])c3)c2cn1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (127 mg, 0.66 mmol) (described in a previous experimental) and 3-nitroaniline (1.70 g, 12.3 mmol) is stirred under N2 at 200° C. for 1.5 h. The resulting product is chromatographed over alumina (5-20% EtOH/CHCl3) to give 7-amino-4-(3-nitroanilino)pyrido[4,3-d]pyrimidine (81 mg, 39%) as a brown solid. 1H NMR (DMSO) δ 10.17 (1H, brs), 9.37 (1H, s), 8.87 (1H, brs), 8.48 (1H, s), 8.33 (1H, brd, J=7.5 Hz), 7.95 (1H, ddd, J=8.2, 2.1, 1.0 Hz), 7.67 (1H, t, J=8.2 Hz), 6.70 (2H, brs), 6.47 (1H, s).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([CH2:9][NH:10][C:11](=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: CCCCOC(=O)NCCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC(=O)NCC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of pyridine (1.8 mL) in 28 mL of CH2Cl2 was cooled in an ice bath and chromium trioxide (1.12 g) was added in one portion. The mixture was stirred at the same temperature for 20 min and at room temperature for 1 h. A solution of 67 (300 mg) in 2 mL of CH2Cl2 was added in one portion and the mixture was stirred for 1 h at room temperature. It was filtered through a pad of silica gel (5 g) and rinsed through with 50 mL of ethyl acetate. The filtrate was concentrated in vacuo to give the crude aldehyde which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.4 Hz, 3H), 1.38 (sextet, J=7.4 Hz, 2H), 1.61 (pentet, J=7.1 Hz, 2H), 4.09 (t, J=6.7 Hz, 2H), 4.14 (d, J=5.0 Hz, 2H), 5.30 (broad s, 1H), 9.66 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc(C(=O)OC)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(C(C)Br)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 6-ethylpyridine-2-carboxylate (587 mg) in carbon tetrachloride (28.4 mL) were added N-bromosuccinimide (696 mg) and benzoyl peroxide (75%, 11.5 mg). The mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (702 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].ClC([O-])=O>N1C=CC=CC=1>[CH:31]([O:30][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1)([CH3:33])[CH3:32]
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)[nH]c2c1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)[nH]c2c1

Procedure:
The 6-amino imidazopyridine 1-9 (900 mg) was placed in pyridine at 0° C. and isopropyl chloroformate (1M in toluene, 1 eq) was added dropwise. Batches of 100 μl of chloroformate were added until no starting material was detected by LC-MS. The pyridine was evaporated and the residue was purified by ISCO (gradient AcOEt/Hexane) to yield the desired product as an off white powder (360 mg).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][N:12]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][NH:9][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:12][NH:13]1
Reactant: NCc1n[nH]c(=O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Triethylamine (5.9 ml, 42 mmol) was added dropwise to a stirred suspension of 4-aminomethyl-2H-phthalazin-1-one hydrochloride (Geterotsikl. Soedin, 1972, (9), 15) (3.00 g, 14.2 mmol) in DMF (150 ml) at room temperature under nitrogen. The mixture was stirred for 1.5 h before the addition of benzoyl chloride (2.5 ml, 22 mmol) and then stirred at room temperature overnight. The reaction mixture was filtered and water added to the filtrate to form a solid. The mixture was cooled and the solid collected by filtration, washed successively with diethyl ether and isohexane, and dried in vacuo to give the title-compound (3.18 g, 80%), 1H NMR (360 MHZ, d6-DMSO) δ 4.81 (2H, d, J=5.6 Hz, CH2), 7.43-7.53 (3H, m, 3 of Ar—H), 7.83-7.96 (4H, m, 4 of Ar—H), 8.08 (1H, d, J=7.9 Hz, Ar—H), 8.28 (1H, dd, J=7.8 and 1.2 Hz, Ar—H), 8.98 (1H, br s, NH), 12.62 (1H, s NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:16]([N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH3:24])[CH3:2].[C:26]1([N:32]2[CH:36]=[CH:35][C:34]([CH:37]=O)=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:16]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:37][C:34]3[CH:35]=[CH:36][N:32]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:33]=3)[CH2:19][CH2:18]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH3:24])[CH3:2]
Reactant: O=Cc1ccn(-c2ccccc2)n1
Reactant: CCOC(=O)COc1c(C)cc2cccnc2c1N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)COc1c(C)cc2cccnc2c1N1CCCN(Cc2ccn(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A mixture of (8-[1,4]diazepan-1-yl-6-methyl-quinolin-7-yloxy)-acetic acid ethyl ester (600 mg, 1.75 mmol), 1-Phenyl-1H-pyrazole-3-carbaldehyde (300.8 mg, 1.75) and NaBH(OAc)3 (408 mg, 1.92 mmol) in DCE (5 ml) was stirred at rt for 3 hrs. The reaction was then diluted with DCE (20 ml), filtered, and purified by flash column chromatography on silica gel to give the desired product (500 mg, 57%). MS (ES) m/z 500.2 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[CH3:15][C:16]1[C:20]([S:21](Cl)(=[O:23])=[O:22])=[C:19]([CH3:25])[O:18][N:17]=1.C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:21]([C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:25])(=[O:23])=[O:22])=[CH:10][CH:9]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a suspension of potassium carbonate (0.18 g (1.28 mmol)) in acetonitrile (5.0 ml), 4-chloroaniline (0.33 g (2.56 mmol)), 3,5-dimethyl-4-isoxazolesulfonyl chloride (0.50 g (2.56 mmol)), 18-crown-6 (0.20 g (0.77 mmol)), were added with stirring at room temperature and the resulting mixture was stirred for 16 hours at the same temperature. Then, water (15.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform as eluent, to give 0.68 g (92%) of N-(4-chlorophenyl)-3,5-dimethyl-4-isoxazolesulfonamide.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[C-:21]#[N:22].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CO>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:13])[C:3]=2[CH2:2][C:21]#[N:22])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:15][CH:16]=1
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: N#CCc1c(-c2ccc(O)cc2)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.3 g, 0.8 mmol) in DMF (15 mL), water (15 mL), and NaCN (0.12 g, 2.4 mmol) was stirred at 45° C. for 24 h. The reaction mixture was extracted with EtOAc (3×100 mL) and concentrated to afford a solid residue. This residue was re-dissolved in MeOH (50 mL) and water (50 mL) and was mixed with potassium carbonate (1 g) and stirred at rt for 0.5 h. MeOH was removed, the aqueous layer was acidified with HCl (1 N) to pH=5. The solid was filtered off and then purified by column chromatography (hexane:EtOAc 1:2). The resulting solid was re-crystallized from dichloromethane and hexanes to give 2-(2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile as a light yellow solid product (0.14 g, 63%). MS (ES) m/z: 278.94 (M+1), 277.93 (M); Mp. 258.2-259.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carbothioamide (2.06 g), ethyl 2-butynoate (0.95 mL), tributylphosphine (1.35 mL), tetrahydrofuran (50 mL) and toluene (100 mL) was stirred at 50° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 85/15, volume ratio) to give the title compound (1.36 g, 51%) as a pale yellow amorphous solid. MS 490 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:22]([C:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[O:17][C:13]=1[CH2:11][CH3:12])(=[O:23])=[O:24]
Reactant: CCc1oc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1oc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3-sulfonamide compound was prepared by the method of Example 41 with 4-chloro-3-methyl-5-amino-isoxazole (1.0 mmols, 0.13 g), NaH (2.5 mmols, 60 mg), 2-ethylbenzo[b]furan-3-sulfonyl chloride (1.2 mmols, 0.28 g) and THF (7 ml). Flash chromatography (20% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexane provided 97 mg (28%) of a white solid, m.p. 132-133.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1cc2ccccc2[nH]1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1cc2ccccc2[nH]1

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 1H-indole-2-carbaldehyde (32 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:11][C:10]1[N:9]=[C:7]([C:6]2[CH:31]=[CH:32][C:3]([C:2]([F:34])([F:33])[F:1])=[CH:4][CH:5]=2)[N:17]2[C:12]=1[CH:13]=[N:14][C:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)=[N:16]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(C(F)(F)F)cc3)nn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc(C(F)(F)F)cc4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 3 %

Procedure:
To a solution of 4-(trifluoromethyl)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 27) (241 mg, 0.51 mmol) in 1,2-dichloroethane (20 mL) was added phosphorus oxychloride (0.37 mL, 4.0 mmol). The mixture was heated to reflux for 24 hours. After cooling to room temperature, the mixture was diluted with DCM and aqueous (saturated) Na2CO3. The aqueous was extracted with DCM and the combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum and purified by silica gel chromatography to give 5-methyl-7-[4-(trifluoromethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.007 g) as yellow solid. 1H NMR (CDCl3): δ8.85 (s, 1H), 8.86 (d J=8.24 Hz, 2H), 7.72 (d, J=8.24 Hz, 2H), 6.88 (m, 3H), 3.87 (s, 3H), 3.83 (s, 6H), 2.63 (s, 3H). MS m/z 459 (M+1).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:44])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41](=[O:43])[CH3:42])=[N:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:10](=[O:44])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:40][C:41](=[O:43])[CH3:42])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (900 mg, 1.550 mmol) and triethylsilane (0.495 mL, 3.10 mmol) in DCM (14 mL) was treated with TFA (7.16 mL, 93 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc and the combined organics were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-10% MeOH/DCM) to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. For C17H18N6O2 [M+1]+ 339. found 339. 1H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.71 (s, 1H), 8.99 (s, 1H), 8.94 (s, 1H), 7.80-7.72 (br s, 1H), 7.50 (s, 1H), 7.36-7.29 (m, 4H), 7.26-7.19 (m, 1H), 4.91-4.81 (m, 1H), 2.09 (s, 3H), 1.39 (d, J=6.9, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([F:28])[N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1.[CH3:29][N:30]=[C:31]=[O:32]>CCOCC>[F:28][C:6]1[N:7]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31]([NH:30][CH3:29])=[O:32])[N:5]=1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Aminoethyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in ether, treated with methylisocyanate, and stirred overnight at ambient temperature. Work-up gave 1-[2-(2-fluoro-1-triphenylmethylimidazol-4-yl)ethyl]-3-methylurea, having the following n.m.r. spectrum in CDCl3 : 2.54 (t, 2H); 2.7 (d, 3H); 3.35 (q, 2H); 5.1 (m, 1H); 6.4 (m, 1H); 6.3 (s, 1H); 7.2 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH2:20][S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:23])=[O:22])[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])=[O:9])=[O:4].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(P(=O)(OCC)OCC)#N.Cl>CN(C)C=O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[S:21]([CH2:20][CH:7]([C:8](=[O:9])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:13])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])(=[O:22])=[O:23]
Reactant: C1CCNCC1
Reactant: CCCCCN(CC(=O)O)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCN(CC(=O)N1CCCCC1)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
To a solution of N-[2-(2-methoxycarbonylethyl)-3-(2-naphthylsulfonyl)propionyl]-N-pentylglycine (0.30 g), piperidine (0.12 ml) in N,N-dimethylformamide (5 ml) was added diethyl cyanophosphonate (0.1 ml) with stirring at 0° C. After stirring at room temperature for 16 hours, a dilute hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (20:1) to give 0.18 g of methyl 5-(2-naphthylsulfonyl)-4-(N-pentyl-N-piperidinocarbonylmethylcarbamoyl)pentanoate as oil. ##STR26##
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH:7]=1.C(N(CC)C(C)C)(C)C.[Br:26][CH2:27][C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[Br:26][CH2:27][C:28]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:8][CH:7]=1)=[O:29]
Reactant: O=C(Cl)CBr
Reactant: Nc1coc2ccccc2c1=O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1coc2ccccc2c1=O
Temperature: 40 °C

Procedure:
10 ml of chloroform are added to 8 g of 3-aminochromone in 200 ml of toluene and the mixture is warmed to 40° C. After cooling to 20° C., 10 ml of N,N-diisopropylethylamine are added with stirring, followed by the addition of 4.8 ml of bromoacetyl chloride in 20 ml of toluene at 10° C. in the course of 5 minutes. When the addition is complete, the reaction mixture is stirred for 1 hour at room temperature. The crystalline precipitate which has formed is collected by suction, washed with water and recrystallised from ethanol/petroleum ether, yielding 11.8 g of 2-bromo-N-(4-oxo-1-benzopyran-3-yl)-acetamide with a melting point of 198° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:27]([C:23]3[CH:22]=[C:21]([CH3:30])[CH:26]=[CH:25][CH:24]=3)=[O:28])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Cc1cccc(C(=O)N2CCC(COc3cccc4nc(N)nc(N)c34)CC2)c1
Yield: 66 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using m-toluoyl chloride (56 mg; 0.36 mmol) via Method AA to yield 47 mg. (66% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.34 (m, 2H), 7.26 (m, 2H), 7.12 (m, 3H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.53 (br s, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.63 (br s, 1H), 3.08 (br s, 1H), 2.82 (br s, 1H), 2.34 (s, 3H), 2.21 (m, 1H), 1.86 (br s, 1H), 1.75 (br s, 1H), 1.31 (m, 2H). MS m/z (ESI) 392 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH3:28]
Reactant: CCN
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CCNS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and ethylamine. MS (ESI): 422.3 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:30])=[C:26]([N+:27]([O-:29])=[O:28])[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:30][CH2:35][C:36]([NH2:38])=[O:37])=[C:26]([N+:27]([O-:29])=[O:28])[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:2][CH2:3]1
Reactant: NC(=O)CBr
Reactant: O=c1c(C2=NS(=O)(=O)c3c(ccc(O)c3[N+](=O)[O-])N2)c(O)c2ccccc2n1NCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc2c(c1[N+](=O)[O-])S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
The product of Example 381 (20 mg, 0.042 mmol) in N,N-dimethylformamide (2 mL) was treated with 2-bromoacetamide (11.6 mg, 0.084 mmol), potassium carbonate (54.7 mg, 0.168 mmol) and tetrabutylammonium iodide (catalytic) at 25° C., stirred at 25° C. for 18 hours. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and washed with water to give the title compound (12 mg, 54%).