Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ccc(F)cn1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncc(F)cc1I
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 116.9 %

Procedure:
A stirred solution of 5-fluoro-pyridin-2-ylamine (50 g, 0.45 mol) in 2M sulfuric acid (250 mL) was treated portionwise with potassium iodate (48 g, 0.22 mol) and the mixture heated to 100° C. A solution of potassium iodide (41 g, 0.24 mol) in water (100 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (×3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2SO4), filtered and evaporated to afford the title compound as a yellow solid (61.2 g, 58%). 1H NMR (400 MHz, CDCl3): 7.94 (d, J=2.7 Hz, 1H), 7.68 (dd, J=7.2, 2.7 Hz, 1H), 4.85 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.[CH3:24]C1C=CC(S(OC[C@H](NC(OC(C)(C)C)=O)C)(=O)=O)=CC=1>>[NH2:1][C@H:2]([CH3:24])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(C[C@@H](C)N)c2)c1

Procedure:
The title compound was synthesized according to procedure described for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide starting with (R)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate was performed according to Bioorg. Med. Chem. 16 (2008) 1966-1982. LC-MS conditions B: tR=0.55 min, [M+H]+=326.11.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[OH:18])(=[O:7])[CH3:6].[Br:19]Br.Cl>ClCCl>[C:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:10]([Br:19])[C:9]=1[OH:18])(=[O:7])[CH3:6]
Reactant: CC(=O)c1cc2c(cc1O)CCCC2
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(Br)c1O)CCCC2
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of aluminium chloride (8.15 g) and 7-acetyl-1,2,3,4-tetrahydro-6-hydroxynaphthalene (4.75 g) in dichloromethane (250 ml) was cooled to -10°. A solution of bromine (6.0 g) in dichloromethane (150 ml) was then added over 1 hour with constant stirring. The reaction mixture was allowed to warm to room temperature overnight, dilute HCl (400 ml) was added and the organic layer was separated, washed with water and dried (MgSO4). The solvent was filtered and the filtrate was evaporated to dryness leaving an oil which solidified on coolig to give 7-acetyl-5-bromo-1,2,3,4-tetrahydro-6-hydroxynaphthalene (5.3 g, 79%) mp 127°-130°.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C[O-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CO.O>[CH2:9]([CH2:2][C:1]([OH:4])=[S:3])[CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(O)=S
Reactant: CCCCCCC/C=C\CCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC/C=C\CCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
Thioacetic acid (35 mg, 0.38 mmol) in methanol (20 ml) was treated successively with sodium methoxide (50 mg, 0.9144 mmol) and bromide 8 (105 mg, 0.381 mmol) and stirred at r.t. for 2 d. The reaction mixture was diluted in water and acidified with cold conc. aq. HCl. The aqueous layer was extracted with hexanes, dried (MgSO4) and concentrated invacuo to afford a crude residue was purified by flash column chromatography (eluent gradient elution 65-75% EtOAc in Hexanes) to afford the pure 4 as a viscous oil (105 mg, 0.367 mmol, 96%); δH(270 MHz, CDCl3); 0.86 (3H, t, J 6.8), 1.35 (14H, m), 1.60 (2H, m), 2.00 (4H, m), 2.65 (21, t, J 7.4), 3.24 (2H, s), 5.34 (2H, m) and 10.0 (1H, br s); δC(67.5 MHz, CDCl3) 14.20, 22.76, 27.09, 27.31, 28.45, 28.89, 29.32, 29.35, 29.35, 29.83, 31.95, 32.82, 33.54, 129.44, 130.36 and 176.77; MS (CI) 304 (M+NH4)+; HRMS: Found [M+NH4]+ 304.230876. Calc. for C16H34NO2S: [M+NH4]+0304.231026.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([NH:28][N:29]=[C:30](OCC)[CH2:31][CH2:32][CH2:33][CH3:34])(OCC)=[O:24]>>[CH2:31]([C:30]1[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:16][CH:17]=2)[C:23](=[O:24])[NH:28][N:29]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(=NNC(=O)OCC)OCC
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CN)cc1
Product: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 72 %

Procedure:
By the procedure of Example 9, Step C, [[2'-(N-t-butylsulfamoyl)biphenyl-4-yl)methyl]amine (from Step F) was reacted with ethyl valerimidate carbethoxyhydrazone (from Example 2, Step A) to give a 72% yield of the title compound as a white foam; satisfactory purity by TLC in 94:6 CH2Cl2 --MeOH.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]([CH:12]([C:18]([O:20]CC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:11])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([N:10]([CH3:11])[C@H:12]([C:18]([OH:20])=[O:19])[C:13](=[O:14])[O:15][CH2:16][CH3:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
An ethanol solution (4.0 mL) of potassium hydroxide (0.19 g) prepared under ice cooling was added to an ethanol (2.0 mL) solution of diethyl [(t-butoxycarbonyl)(methyl)amino]propanedioate (Intermediate 3-1, 1.0 g), and the mixture was stirred for 23 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and a 1.0 mol/L-sodium hydrogen carbonate aqueous solution was added, followed by extracting the mixture with ethyl acetate. The aqueous layer was cooled with iced water, and potassium hydrogen sulfate was added to adjust it to pH 2, followed by extracting the mixture with chloroform. The extract was dried over anhydrous sodium sulfate, and the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure to obtain N-(t-butoxycarbonyl)-O-ethyl-N-methyl-3-oxoserine (Intermediate 7-1, light yellow oil) (0.26 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2I)[CH2:17][CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:18]=3[CH:15]3[CH2:17][CH2:16]3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1Cl)C(=O)NCC2
Reactant: Ic1cnccc1C1CC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C1CC1)CC2
Yield: 22.5 %

Procedure:
7-Chloro-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 100 mg, 0.473 mmol) was reacted with 4-cyclopropyl-3-iodopyridine (I-73c: 127.6 mg, 0.521 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.047 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.7 mg, 0.047 mmol) and potassium phosphate (301.6 mg, 1.421 mmol) for 12 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afford 35 mg of the product
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:74][CH3:75])[C:66]([CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1)=[O:67])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]1[C:66]([N:65]([CH2:74][CH3:75])[CH2:63][CH3:64])=[O:67])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)C(=O)C1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)C(=O)C1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-diethylaminocarbonyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: C=O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].[C:31](#N)C>CO.C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Reactant: CC#N
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Reaction time: 0.5 h

Procedure:
37% Aqueous formaldehyde (0.060 ml) was added to a stirred solution of 3-(1,3-benzothiazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.250 g) dissolved in methanol (2.5 ml) and DCM (2.5 ml). Sodium triacetoxyhydroborate (0.141 g) was added and the resulting solution was for 30 minutes. The mixture was concentrated. DCM and 7N methanol/ammonia were added. The mixture was concentrated on silica gel and the residue was purified by flash chromatography on silica gel eluting with 2 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford a solid. Acetonitrile (4 ml) was added and the solution was stirred overnight. The solid was filtered, and dried under vacuum. There was thus obtained 3-(1,3-benzothiazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.198 g); Mass Spectrum: M+H+ 391; NMR Spectrum (DMSOd6): 8.48 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.93 (s, 1H), 7.88 (bs, 2H), 7.57 (dd, 1H), 7.49 (dd, 1H), 4.08-4.18 (m, 1H), 2.84-2.92 (m, 2H), 2.22 (s, 3H), 1.94-2.12 (m, 6H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=2)[O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:26]([O-])=O)=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO>[Pd].C1(C)C=CC=CC=1>[NH2:26][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:29]=[CH:30][CH:31]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=2)=[CH:16][C:15]=1[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1N
Yield: 96.8 %

Procedure:
By using 5.0 g of t-butyl N-{5-[3-(morpholin-4-yl)phenoxy]-2-nitrophenyl}-N-methylcarbamate, 0.5 g of 10% palladium on carbon and a mixed solvent of 30 ml of methanol and 70 ml of toluene, reaction and purification were carried out in a similar manner to that described in Reference Example 7, whereby 4.5 g of the title compound were obtained.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[S:16][C:15]2[C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25]4)=[CH:20][CH:19]=3)[CH:12]=[N:11][C:10]=2[CH:9]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:30][N:29]([CH3:31])[CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[CH:20]=[CH:19][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([CH2:7][OH:6])=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:23][CH:22]=2)[CH2:25]1
Reactant: CN(C)C1CCN(c2ccc(-n3cnc4cc(C(O[SiH2]C(C)(C)C)(c5ccccc5)c5ccccc5)sc4c3=O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(-n3cnc4cc(CO)sc4c3=O)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (1.4 g) and 1 M solution of Tetra-N-butylammoniumfluoride in THF (2.7 mL) in THF (20.0 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo and the crude product was purified by preparative HPLC. The product with the molecular weight of 370.47 (C19H22N4O2S) was obtained in this way; MS (ESI): 371 (M+H+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[O:32])[CH:26]=2)=[CH:21][CH:20]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH2:43][N+:44]#[C-:45])(=[O:42])=[O:41])=[CH:36][CH:35]=1.[C-]#N.[Na+]>CCO.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]3[O:32][CH:45]=[N:44][CH:43]3[S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH:26]=2)=[CH:23][CH:24]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2cccc(C=O)c2)cc1)C1Cc2ccccc2C1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)C2N=COC2c2cccc(-c3ccc(CN(C(=O)OC(C)(C)C)C4Cc5ccccc5C4)cc3)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl 2,3-dihydro-1H-inden-2-yl[(3′-formyl-4-biphenylyl)-methyl]carbamate (0.188 g; 0.44 mmol) and TosMIC (0.086 g; 0.44 mmol) in EtOH at room temperature was added NaCN (0.002 g; 0.04 mmol). The mixture was stirred 30 min, diluted with water and extracted with EtOAc (×3). combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a colorless gum, used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 2.41 (s, 3H), 2.99 (d, J=8.38 Hz, 4H), 4.50 (br. s., 2H), 5.65 (dd, J=5.98, 1.69 Hz, 1H), 5.96 (d, J=5.89 Hz, 1H), 7.07-7.18 (m, 5H), 7.25 (partially resolved dd, J=7.85 Hz, 1H), 7.28-7.34 (m, 2H), 7.40 (unresolved dd, 1H), 7.46-7.52 (m, 3H), 7.57-7.64 (m, 2H), 7.68 (dd, J=8.03, 1.25 Hz, 1H), 7.74 (d, J=1.25 Hz, 1H), 7.83-7.90 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17]C)=O)=[C:4]2[N:3]=1.[NH3:19]>>[SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([NH2:19])=[O:17])=[C:4]2[N:3]=1
Reactant: N
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reaction time: 24 h

Procedure:
A solution of 1.80 g of methyl 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate in 800 ml of 25 percent aqueous ammonia was allowed to stand at 20° for 24 hours. The solution was concentrated to a small volume in a vacuum, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. The residual crystal slurry was treated with petroleum ether and filtered. There was obtained 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1>CN(C=O)C>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[S:16])[N:14]([CH3:18])[CH3:13])=[CH:10][CH:11]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(OC(=S)N(C)C)cc1
Yield: 76.2 %

Procedure:
Stir a mixture of 4-(1,1-dimethyl-propyl)-phenol (1.96 g, 11.9 mmol), N,N-dimethylthiocarbamoyl chloride (2.94 g, 23.8 mmol) and DABCO (2.82 g, 25.1 mmol) in anhydrous DMF (30 mL) at room temperature for 16 h under a nitrogen atmosphere. Pour reaction onto ice and extract the mixture with EtOAc (3×75 mL). Combine the organic extracts and wash with 0.5 M aqueous HCl. Dry the organic phase over MgSO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as a yellow solid (2.28 g, 76%). MS (ES+) m/z: 252.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>C(O)(C)C>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4c(C)cccc4C(=O)NC)n3)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A microwave vessel was charged with 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (56.8 mg, 0.182 mmol) 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (49.5 mg, 57%) as a white powder that had the following properties: m.p: 210-212° C.; LC/MS (ESI+): 479 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.29-9.20 (m, 2H), 8.30 (m, 1H), 8.14 (s, 1H), 7.48-7.40 (m, 2H), 7.36 (d, J=8.3, 1H), 7.29-7.20 (m, 2H), 6.93 (d, J=8.3, 1H), 3.55 (br s, 2H), 2.70 (d, J=4.1, 3H), 2.50 (m, 2H), 2.15 (s, 3H), 2.10-1.85 (m, 4H), 0.92 (t, J=7.0, 3H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17](O)[CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.COC1C=CC(C2C=CC(C(Cl)C)=CC=2)=CC=1.Cl.[CH3:38][O:39][C:40](=[O:43])[CH2:41][SH:42].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1CCCCC1.CO>[CH3:38][O:39][C:40](=[O:43])[CH2:41][S:42][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)[CH3:18]
Reactant: COC(=O)CS
Reactant: COc1ccc(-c2ccc(C(C)O)cc2)cc1
Agent: COc1ccc(-c2ccc(C(C)Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCCCC1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)CSC(C)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(4'-Methoxy-4-biphenyl)-methyl-ketone [see W. S. Johnson et al, J. Amer. Chem. Soc. 68, 1648 (1946)] was reduced with sodium borohydride to 1-(4'-methoxy-4-biphenylyl)-ethanol (m.p. 120°-122° C, from cyclohexane), and the carbinol was converted into 1-(4'-methoxy-4-biphenylyl)-1-chloroethane, m.p. 122°-124° C (from cyclohexane), with hydrogen chloride. 5.2 gm of 1-(4'-methoxy-4-biphenylyl)-1-chloroethane (0.021 mol) were admixed in 21 ml of dry dimethyl sulfoxide with 2.7 gm (0.026 mol) of thioglycolic acid methyl ester and then with 3.5 gm (0.026 mol) of dry potassium carbonate. The mixture was stirred at room temperature for 45 minutes. The reaction product was precipitated with water, suction-filtered off, washed and dried. Yield: 6.8 gm (100% of theory); m.p. 59°-61° C. A sample recrystallized from cyclohexane, analized as follows:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[CH:22]([N:25](C(C)C)CC)(C)[CH3:23].C(N)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:22]([NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[N:11][C:12]=2[CH:18]=1)=[O:20])[CH3:23]
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 80 °C

Procedure:
A stirred solution of [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid [130 mg, Example 247(a)], hydroxybenzatriazole (189 mg) and diisopropyl ethylamine (732 μL) in dimethylformamide (3 mL) was treated with ethylamine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (267 mg). The reaction mixture was heated at 80° C. overnight and then partitioned between ethyl acetate and 5% citric acid. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, then with brine, then dried over magnesium sulfate and then evaporated. The residual oil was subjected to preparative HPLC to give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, ethylamide as a white solid. LC-MS (METHOD B): RT=2.37 minutes; 306.27 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][S:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([CH3:36])[C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][S:47][CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Reactant: C1CSCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCSCC3)sc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (141 mg, 271 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (113 μL, 813 μmol) and thiomorpholine (77 μL, 813 μmol), and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (15 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the fractions containing the object product were concentrated under reduced pressure. To the obtained residue were added diisopropyl ether and ethyl acetate, and the obtained precipitate was collected by filtration to give the title compound (117 mg, 73%) as a colorless amorphous solid.