Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22]C=[C:20]([CH2:24][OH:25])[CH:19]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]>C(#N)C>[C:1]([C:3]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:24]([OH:25])=[CH:22][CH:23]=2)[C:6]2[N:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(-c2cccc(CO)c2)c2c(c1)ncn2-c1ccccc1
Solvent: CC#N
Product: N#Cc1cc(-c2ccc(O)cc2)c2c(c1)ncn2-c1ccccc1
Yield: 77 %

Procedure:
This was prepared in a similar manner to 5-cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole, with 90 h reflux before removal of solvent using nitrogen to give an oily residue. The residue was taken up in acetonitrile (3 ml) and the resulting solid filtered off and dried under reduced pressure to give the desired product (490 mg, 77%) m/z, 312.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-fluoro-1 -(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and piperidine in tetrahydrofuran are reacted to give 8-fluoro-1-(piperidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[Cl:38]>>[Cl:38][C:31]1[CH:32]=[C:33]([C:34]#[N:35])[CH:36]=[CH:37][C:30]=1[NH:29][C:14](=[O:16])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1
Yield: 62 %

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-chlorobenzonitrile to give the desired compound as a white solid (62%). MS (ES+): M−H: 539.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH:24](=[C:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>>[CH:24](=[C:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC=C1CCNCC1
Reactant: O=C1COc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCC=C1CCN(CCCN2C(=O)COc3ccccc32)CC1
Yield: 76.1 %

Procedure:
4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.068 g, 0.30 mmol), K2CO3 (0.12 g, 0.90 mmol), NaI (0.090 g, 0.60 mmol) and 4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according to GP12. Prep TLC (SiO2; CH2CI2/MeOH 10:1) gave the title compound (81MF25) (0.070 g, 71%). 1H NMR (CDCl3) δ 7.12 (d, J=6.8 Hz, 1H), 7.03-6.95 (m, 3H), 5.12 (J=7.4 Hz, 1H), 4.56 (s, 1H), 3.99 (t, J=7.6 Hz, 2H), 2.41-2.36 (m, 6H), 2.26-2.17 (m, 2H), 1.98-1.81 (m, 4H), 1.38-1.28 (m, 2H), 0.87 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ164.3, 145.5, 136.0, 128.7, 123.8, 122.8, 122.8, 117.1, 115.2, 67.7, 55.7, 55.6, 54.9, 39.7, 36.1, 29.2, 28.4, 24.8, 23.2, 13.8.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([O:30][C:31]([NH:33][CH:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:32])([CH3:29])[CH3:28].CCN(CC)CC>CC(O)C>[C:27]([O:30][C:31](=[O:32])[NH:33][CH:34]1[CH2:35][CH2:36][CH:37]([NH:40][C:13]2[N:12]=[C:11]3[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=4)[C:16]3=[CH:15][N:14]=2)[CH2:38][CH2:39]1)([CH3:29])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Temperature: 25 °C

Procedure:
The mixture of 3-(6-bromo-pyridin-2-yl)-6-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 31 supra) (2.65 g, 6.01 mmol), tert-butyl (1r,4r)-4-aminocyclohexylcarbamate (1.53 g, 7.14 mmol) and Et3N (1.4 mL, 9.7 mmol) in IPA (60 mL) was heated at reflux for 16 hours. After cooling to room temperature, the reaction mixture was filtered and solid dried to give {4-[3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as white powder. (Yield 3.3 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.P(OCC)(OCC)OCC.Cl.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Agent: CCOP(OCC)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)[nH]c1ccccc12
Temperature: 80 °C
Yield: 65.5 %

Procedure:
A round bottom flask was charged with 4′-bromo-2-nitro-1,1′-biphenyl (14.5 g, 52.1 mmol), triethyl phosphite (50 g, 301 mmol) and heated to reflux under nitrogen overnight. The reaction mixture was allowed to cool to room temperature (20-25° C.) and 60 mL of 6 N HCl was added dropwise. The reaction mixture was then heated to 80° C. for 3 hours. The reaction mixture was then cooled to 5° C. and neutralized with 50% NaOH, diluted with deionized water and extracted with 3×150 mL EtOAc. The combined extracts were washed with 150 mL deionized water and 150 mL brine, dried over MgSO4 and evaporated to dryness. The lower boiling impurities were removed by Kugelrohr distillation and the residue was subjected to a column chromatography (SiO2 gel, 9/1 hexane/EtOAc) to yield 8.4 g (65%) of 2-Bromo-9H-carbazole as an off-white solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[N:13][CH:14]=[C:9]2[CH:8]=[N:7]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][C:26]1=[O:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.[Cu](I)I>[CH3:21][N:19]1[CH:20]=[C:16]([NH:15][C:12]2[N:11]=[C:10]3[N:6]([CH2:5][C:4]4[CH:3]=[C:2]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][C:26]5=[O:31])[CH:24]=[CH:23][CH:22]=4)[N:7]=[CH:8][C:9]3=[CH:14][N:13]=2)[CH:17]=[N:18]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(I)c4)c3n2)cn1
Reactant: O=C1COCCN1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5=O)c4)c3n2)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 1-(3-iodobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (50 mg, 0.12 mmol) in dioxane (1 mL) were added morpholin-3-one (15 mg, 1.25 eq), copper iodide (4.4 mg, 0.2 eq), potassium phosphate (49 mg, 2 eq) and N,N′-dimethylethylene diamine (5 μl, 0.4 eq). After stirring for 16 h at 90° C., the reaction mixture was partitioned between 0.5M EDTA and DCM. The aqueous phase was extracted with DCM, the combined organic phases dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC to yield the title compound (23 mg, 56 μmol, 47%). 1H NMR (d6-DMSO) δ 9.85 (s, 1H), 8.92 (s, 1H), 8.06 (s, 2H), 7.56 (s, 1H), 7.43 (s, 1H), 7.39-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.20-7.13 (m, 1H), 5.57 (s, 2H), 4.17 (s, 2H), 3.96-3.91 (m, 2H), 3.84 (s, 3H), 3.69-3.64 (m, 2H); LC-MS method B, (ES+) 405.1, RT=6.31 min.
Reaction SMILES: [S:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].CC([O-])(C)C.[K+].O>CN(C=O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:4]1[C:5](=[O:7])[CH2:6][S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]1=2
Reactant: O=C1CSc2ccccc2N1
Reactant: Fc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSc2ccccc2N1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 2H-benzo[b][1,4]thiazin-3(4H)-one (1.0 g, 6.1 mmole) and 1-(bromomethyl)-2- fluorobenzene (0.76 mL, 1.05 equiv) in DMF (10 mL) was added t-BuOK (0.75 g) at 0 ° C. The reaction mixture was warmed to room temperature and stirred overnight. Water was added and the resulted solid was filtrated, rinsed with water, and dried under vacuum to provide 4-(2-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1.51 g, 91%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([OH:17])=[O:16])[CH2:3]1>ClCCl>[O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([O:17][C:4]([CH3:15])([CH3:5])[CH3:3])=[O:16])[CH2:3]1
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
To a suspension of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid produced by the method described in Culbertson T. P., Domagala J. M., Nichols J. F., Priebe S., and Skeean R. W., J. Med. Chem., 1987, 30, 1711-1715 (1165 g, 4.994 mol) in dichloromethane (10 L), O-tertiary butyl-N,N′-diisopropylurea (3020 g, 15.00 mol) was added at room temperature with stirring. When increase in the inner temperature and starting of refluxing were noted, the reaction system was cooled in an ice bath, After cooling the reaction mixture to room temperature, the mixture was stirred for 1 hour after removing the ice bath, and for another 3 hours while heating to 40° C. After stirring the reaction mixture for another 1 hour with cooling in an ice bath, the insoluble content was removed, and the filtrate was dried under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 4 kg; elusion by hexane:ethyl acetate, 3:1) to obtain 925.2 g (64%) of the title compound (a mixture of isomers at position 3) as a pale yellow syrup. Although separation of the diastereomers of position 3 of the pyrrolidine was easy, the diastereomers were used without separation since the subsequent step involved epimerization. 1H-NMR spectrum of the isomers aliquoted for evaluation purpose are shown below.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH2:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH3:29]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([NH:33][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2
Product: CCS(=O)(=O)Nc1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3c2CCCC3)n1

Procedure:
The title compound of Example 163, step 4 was treated with treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1H), 7.64 (s, 1H), 3.83 (d, J=6.8 Hz, 2H), 3.44 (s, 3H), 3.30-3.20 (m, 2H), 2.47-2.41 (m, 4H), 1.67-1.57 (m, 4H), 1.19-1.13 (m, 4H), 0.51-0.49 (m, 2H), 0.24-0.22 (m, 2H). LCMS: 419.1 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:17][CH:18]([OH:25])[CH2:19][NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)C>[C:21]([NH:20][CH2:19][CH:18]([OH:25])[CH2:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
A stirred mixture of 6-chloro-3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]pyridazine and hydrazine hydrate in ethanol was heated under reflux for 3 hours. Evaporation of the reaction mixture under reduced pressure gave the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[N:23]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: Nc1nccc(Cl)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nccc(Cl)n2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Chloro-pyrimidin-2-ylamine instead of 3-chloroaniline to yield the final compound as a light brown solid, MS (ISP): m/e=361.1, 363.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:21]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C(Nc1cnc2[nH]ccc2c1)OCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cnc2[nH]cc(Br)c2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Benzyl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (9.48 g, 35.5 mmol) in chloroform (100 mL) was cooled to 5° C. and treated dropwise with bromine (1.86 mL, 36.21 mmol, 1.02 Eq). The reaction was allowed to to stir at 0° C. for 1 hour and then at room temperature for 1 hour. The mixture was diluted with DCM and washed with a 1:1 sat. aq. sodium thiosulfate/sodium bicarbonate solution (200 mL). The organic layer was separated and the aqueous layer taken to pH 12 and re-extracted with EtOAc. The combined organics were dried over magnesium sulphate, filtered and dried under vacuum and the resultant brown solid triturated with diethyl ether/EtOAc to give 10.24 g (83%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>O1CCCC1>[CH3:21][O:20][C:18]1[N:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([NH:13][C:11]([NH:10][S:7]([C:3]2[C:2]([CH3:1])=[CH:6][S:5][CH:4]=2)(=[O:8])=[O:9])=[O:12])[N:19]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: Cc1cscc1S(=O)(=O)N=C=O
Solvent: C1CCOC1
Product: COc1nc(NC(=O)NS(=O)(=O)c2cscc2C)nc(OC)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
A solution of 2 g of 4-methyl-3-thiophenesulfonyl isocyanate was added to a suspension of 1.5 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 20 ml of tetrahydrofuran and the resulting mixture stirred for 16 hours at ambient temperature. The precipitate thus obtained was filtered off and recrystallized to yield 1.5 g of the desired product, m.p. 154°-156°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>FC(F)(F)C(O)=O>[CH3:9][C:4]1[N:5]=[C:6]([OH:8])[C:7]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(O)cc(O)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Powdered 4,6-dihydroxy-2-methylpyrimidine (9 g, 71 mmol) was dissolved in trifluoroacetic acid (54 mL). The reaction mixture was cooled in ice-water as nitric acid (4.3 mL) was added dropwise over a period of 30 minutes. During addition the internal temperature was maintained below 15° C. After the addition, the cooling was removed and the reaction stirred overnight. Water (50 mL) was added to the reaction mixture and the resulting solid was filtered and dried under vacuum to obtain 2-methyl-5-nitropyrimidine-4,6-diol (5.8 g). 1H NMR (400 MHz, DMSO-d6): δ 12.97 (br, 2H), 2.32 (s, 3H). MS (m/z) 172 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:33]I>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=3)(=[O:18])=[O:17])[CH3:33])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(C)C)cc(C(F)(F)F)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(C)C)cc(C(F)(F)F)c1
Yield: 82.9 %

Procedure:
Starting with [(R)-4-(3-isopropyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (Example 12-1) and methyl iodide, using the method analogous to the one described for example 2-1, {(R)-4-[(3-isopropyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 82.9%) was obtained as an off-white semisolid. MS cald. for C22H28F3N3O4S 487, obsd. (ESI+) [(M+H)+] 488
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([N:25]([CH2:34][CH2:33][C:32]([CH3:37])([CH3:36])[CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CCN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)CCN(CCC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(3-methyl-butylamino)-propionamide mono-hydrochloride (0.78 g, 1.8 mmol, Example 2) and 3,3-dimethylbutyraldehyde (0.18 g, 1.8 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (19 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.60 g, 2.7 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (20 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (20% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.62 g (67%) of the pure titled compound as a white foam; mp 65-72° C.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]([N:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]=[N:30][CH:31]([C:35]([NH:37][C:38]4[CH:43]=[CH:42][C:41](C)=[CH:40][C:39]=4C)=[O:36])[C:32]([CH3:34])=[O:33])=[C:25]([Cl:46])[CH:24]=3)=[CH:19][C:18]=2[Cl:47])[C:12]([CH3:14])=[O:13])=[O:10])=[C:4](C)[CH:3]=1.ClC1C=C(C2C=CC(N)=C(Cl)C=2)C=CC=1N.C(NC1C=CC=CC=1)(=O)CC(C)=O>>[CH3:34][C:32]([CH:31]([N:30]=[N:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]=[N:15][CH:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[O:10])[C:12]([CH3:14])=[O:13])=[C:18]([Cl:47])[CH:19]=2)=[CH:24][C:25]=1[Cl:46])[C:35]([NH:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:36])=[O:33]
Reactant: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccc(C)cc3C)c(Cl)c2)cc1Cl)C(=O)Nc1ccc(C)cc1C
Agent: CC(=O)CC(=O)Nc1ccccc1
Agent: Nc1ccc(-c2ccc(N)c(Cl)c2)cc1Cl
Product: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccccc3)c(Cl)c2)cc1Cl)C(=O)Nc1ccccc1

Procedure:
The pigment suspension was prepared similarly to C.I. Pigment Yellow 13 by coupling 80.4 g of tetrazotized 3,3'-dichlorobenzidine (44.7 g of sodium nitrite) with 118 g of acetoacetanilide.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:16]=[O:17])=[C:11]([Cl:18])[CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([Cl:18])[C:12]=1[CH:16]=[O:17])[NH:8][CH3:1]
Reactant: CN(Cc1ccccc1)c1cc(Cl)c(C=O)c(Cl)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CNc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of N-benzyl-3,5-dichloro-4-formyl-N-methylaniline (820 mg) in ethyl acetate (10 ml) was added palladium hydroxide (80 mg) under nitrogen atmosphere. This mixture was stirred under hydrogen atmosphere under atmospheric pressure at ambient temperature for one and half an hour. The precipitate was dissolved into chloroform and filtered through celite and the filtrate was concentrated in vacuo. The residual solid was suspended in diisopropyl ether and warmed at 90° C. After being stirred and cooled, the solid was collected by filtration to afford 3,5-dichloro-4-formyl-N-methylaniline (470 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: COC(=O)C=Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cc(F)ccc1C=CC(=O)OC

Procedure:
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (106 mg) was reacted with K2CO3 (125 mg) and butyl iodide (0.1 ml) at 80° C. for 3 hrs as described above to yield title compound (121 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].[Cl:13][CH2:14][C:15](OCC)(OCC)OCC>C(O)C>[Cl:13][CH2:14][C:15]1[O:12][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1ccc2ccccc2c1O
Solvent: CCO
Product: ClCc1nc2ccc3ccccc3c2o1

Procedure:
Prepared by reacting 2.93 g of 2-amino-1-naphthol with 3.54 g of 2-chloro-1,1,1-triethoxy-ethane in 25 ml of ethanol at 60° C.