Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:9]1[C:13](=[O:14])[C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:10]1(=[O:33])=[O:32])[CH2:6][CH2:7][CH3:8].CCOC(C)=O>C1COCC1>[C:1]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([NH:15][C:12]3[C:13](=[O:14])[N:9]([CH2:5][CH2:6][CH2:7][CH3:8])[S:10](=[O:32])(=[O:33])[C:11]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)[CH2:22]1)(=[O:3])[CH3:2]
Reactant: CCCCN1C(=O)C(Nc2ccc3c(c2)CCNC3)=C(c2ccccc2)S1(=O)=O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)CCN(C(C)=O)C3)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.4 %

Procedure:
Acetyl chloride (0.020 ml, 0.243 mmol) was added to a solution of 2-butyl-5-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)isothiazol-3(2H)-one 1,1-dioxide (example 60) (0.100 g, 0.243 mmol) and TEA (0.040 mmol, 0.267 mmol) in dry THF (2 ml) and the reaction mixture was stirred at rt for 40 mins. EtOAc was added and the mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 1:5 mixture of EtOAc/petroleum ether 40-60° C. mixture as eluent, to give the title compound (0.071 g, 64%). 1H NMR (500 MHz CDCl3); δ 7.30-7.22 (m, 2H), 7.22-7.14 (m, 4H), 6.88, 6.68 (dd, 1H), 6.68 (td, 1H), 6.36, 6.31 (d, 1H), 4.58, 4.47 (s, 2H), 3.79 (t, 2H), 3.63, 3.48 (t, 2H), 2.43, 2.39 (t, 2H), 2.16, 2.15 (s, 3H), 1.94-1.84 (m, 2H), 1.56-1.44 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz CDCl3): δ 169.8, 159.6, 135.8, 134.4, 131.0, 130.8, 129.6, 129.4, 128.3, 127.0, 126.2, 126.0, 122.6, 122.2, 120.4, 120.0, 111.4, 111.2, 47.8, 43.9, 40.5, 39.4, 30.5, 29.3, 26.8, 22.0, 21.8, 20.3, 13.8; Mass Spectrum M+H+ 454.
Reaction SMILES: COC1C=CC(C[S:10][C:11]2[N:12]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:33])[CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.C(S)C>ClCCl>[CH3:17][C:15]1[NH:16][C:11](=[S:10])[N:12]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[O:33])[CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:14]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)c2ccc([N+](=O)[O-])cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCS
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)NC(=S)N(C(=O)c2ccc([N+](=O)[O-])cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 1.3 g. (0.0022 mole) of 1,6-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1-[(4-nitrophenyl)carbonyl]-5pyrimidinecarboxylic acid, ethyl ester, 0.75 ml. (0.0097 mole) of trifluoroacetic acid and 0.32 g. (0.0050 mole) of ethanethiol in 15 ml. of dichloromethane is stirred at room temperature for 24 hours. The solvent is evaporated and the residue is triturated with isopropyl ether to give 0.95 . g of the title compound as a yellow solid, m.p. 139°-141°. TLC (silica gel; ethyl acetate:hexane, 1:1) Rf =0.35.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].CI.[C:19](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH3:19])[C:6]1=[O:16]
Reactant: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c2ccccc2n(CCCBr)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A mixture of 1-(3-bromopropyl)-2,4(1H,3H)-quinazolinedione (2.83 g), methyl iodide (3 ml), anhydrous potassium carbonate (4.2 g) and N,N-dimethylformamide (25 ml) was stirred for 8 hours at ambient temperature. After the reaction mixture was diluted with cold water, the resultant mixture was extracted twice with chloroform. The chloroform layer was washed with water twice, and with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resultant oily residue was purified by subjecting to a column chromatography on silica gel (100 g) using chloroform for elution, to give 1-(3-bromopropyl)-3-methyl-2,4(1H,3H)-quinazolinedione (1.85 g) as a crystal.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cccnc2n1-c1ccccc1
Yield: 52.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-3-nitropyridine (101 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow viscous oil (55 mg, 53%). 1H NMR (DMSO) δ 2.48 (s, 3 H), 7.24 (dd, 1 H), 7.53-7.63 (m, 5 H), 8.02 (d, 1 H), 8.20 (d, 1 H); 13C NMR δ 14.6, 118.3, 125.9, 127.4, 128.7, 129.3, 134.1, 134.3, 143.0, 148.7, 152.9. HRMS (FAB): cal. for C13H12N3 [M-FH+]: 210.1031; found: 210.1027.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](=[O:20])[C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1)[CH3:2].O.[C:22](O)(=[O:24])[CH3:23]>C(OC(=O)C)(=O)C.[Zn]>[C:22]([NH:18][CH:12]([C:11](=[O:20])[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=NO)C(=O)CCc1cccc(CC)c1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(CC)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the product from step (iv) (20.9 g) in acetic acid (100 ml) and acetic anhydride (25 ml) was added zinc dust (30 g) portionwise at a rate to maintain the internal temperature <40° C. The mixture was stirred for 18 hours and water (125 ml) was added at such a rate as to maintain the temperature at around 40° C. The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was extracted with dichloromethane and the extract was washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:15]=[CH:16][C:3]=12.S(=O)(=O)(O)[OH:27].N([O-])=O.[Na+]>O1CCOCC1.O>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][N:14]1[C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([OH:27])=[C:3]2[CH:16]=[CH:15]1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To solution of ethyl 4-amino-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (6 g, 14.8 mmol) in 1,4-dioxane (16 mL) at 0° C. was added dropwise a cold solution of sulfuric acid (16 mL, 300 mmol) in water (24 mL) followed by dropwise addition of a solution of sodium nitrite (4.2 g, 60.5 mmol) in water (12 mL) in 10 min. After stirring for 1 h at 0° C. and 3 h at RT for 3 h the mixture was cooled to 0° C. and more sodium nitrite (1.3 g) in water (3 mL) was added. After 2 h at RT cold water was added and the mixture was filtered washing with water. The solid was dissolved in MeOH and solid NaHCO3 was added. The mixture was stirred for 10 min then filtered and concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3/water and the organic phase was dried (Na2SO4), concentrated and dried in vacuo to provide ethyl 1-(3,4-difluorobenzyl)-4-hydroxy-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.02 g, 13.8 mmol, 93% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (t, J=7 Hz, 3 H), 2.86 (s, 3 H) 4.49 (q, J=7 Hz, 2 H), 5.40 (br s, 2 H), 6.66 (d, J=3.51 Hz, 1 H), 6.91-7.15 (m, 4 H), 12.82 (br s, 1 H); LCMS (m/z) ES+=347 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:22]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:36])[NH:23][S@@](C(C)(C)C)=O)=[C:19]([CH3:21])[N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:23][CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[C:18]1[S:17][C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:12][CH2:11]2)=[O:14])=[N:20][C:19]=1[CH3:21]
Reactant: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N[S@](=O)C(C)(C)C)c1ccccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A), (1.47 g, 2.69 mmol) in MeOH (13 mL) was added 4 M HCl in dioxane (4 mL, 16 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated. The crude product was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (×2) and brine, then dried over MgSO4 and concentrated. The crude product was adsorbed onto silica gel and purified by column chromatography (70-100% EtOAc/hexanes) to provide N-(5-(amino(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (Isomer A), as an orange solid (540 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=7.9 Hz, 1H), 7.40-7.36 (m, 2H), 7.27 (m, 1H), 6.94 (s, 1H), 6.85 (m, 2H), 6.00 (s, 2H), 5.56 (s, 1H), 2.19 (s, 3H), 1.40 (m, 2H), 1.10 (m, 2H); HPLC ret. time 2.65 min, 10-99% CH3CN, 5 min run; ESI-MS 442.5 m/z (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[C:19]([O:22][CH:23]([CH:25]=[CH2:26])[CH3:24])(=[O:21])[CH3:20].C(N)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[C:19]([O:22][CH:23]([CH3:24])[CH:25]=[CH:26][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][Si:2]([CH3:18])([CH3:17])[CH3:1])=[CH:9][N:8]=2)=[CH:11][CH:12]=1)(=[O:21])[CH3:20]
Reactant: C=CC(C)OC(C)=O
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CC(=O)OC(C)C=Cc1ccc(-c2ccc(O[Si](C)(C)C)cn2)cc1
Yield: 74.7 %

Procedure:
17 g of 5-trimethylsilyloxy-2-(4-bromophenyl)pyridine, 12 g of 2-acetoxy-3-butene, 10 g of N-tert.-butylamine, 20 ml of N-methylpyrrolidone, 0.12 g of palladium(II) acetate and 0.3 g of triphenylphosphine are reacted in an analogous manner to Example 1(d) to give 14 g of 2-[4-(3-acetoxy-1-butenyl)-phenyl]-5-trimethylsilyloxy-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([N:11]=[C:12]([C:14](O)=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C[N:20](C)C=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.ClC1C=CC2N=NN(O)C=2C=1.[NH4+].[Cl-].C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([N:11]=[C:12]([C:14]([NH2:20])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccc(Cl)cc21
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Reaction time: 0.17 h
Yield: 5.3 %

Procedure:
To 9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylic acid (0.137 g, 0.515 mmol) in N,N-dimethylformamide (1.20 mL, 15.4 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.587 g, 1.54 mmol) and 6-chloro-1-hydroxybenzotriazole (0.262 g, 1.54 mmol). The mixture was stirred vigorously, and NH4Cl (0.220 g, 4.12 mmol) was added. After 10 minutes, N,N-diisopropylethylamine (0.359 mL, 2.06 mmol) was added. The reaction was stirred at room temperature for 3 hours. Then, the reaction was concentrated, taken to dryness, and washed with water. The crude product was purified by a silica gel plug, eluting with DCM/MeOH, and then by reverse phase HPLC to give 9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxamide (5.3% yield)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>C(OCC)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:9][CH:10]([CH2:12][CH2:13][O:14][CH3:17])[CH2:11]2)[CH:3]=1
Reactant: OCCC1CC(c2cccc(Br)c2)C1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Product: COCCC1CC(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
2-[3-(3-Bromo-phenyl)-cyclobutyl]-ethanol (0.500 gm, 1.96 mmol) was dissolved in diethylether (7 mL) and combined with tetrabutylammonium iodide (75 mg, 0.203 mmol), an aqueous solution of sodium hydroxide (5 gm, 50% wt/wt, 62.5 mmol) and dimethylsulfate (0.50 ml, 5.27 mmol). The mixture was stirred overnight at ambient temperature then diluted with diethyl ether and decanted. The supernatant was concentrated onto silica and purified by column chromatography (25% diethylether in hexanes) to afford 389 mg of an oil (74%). This material was used in next step without further characterization.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]([CH3:14])=[CH2:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([N:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][NH:10][C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)CNC(=O)NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNC(=O)N1C1CCCCC1
Yield: 100 %

Procedure:
A solution of 1-cyclohexyl-3-(2-methylallyl)urea (0.34 g, 1.732 mmol) in TFA (3 mL) was stirred at RT overnight, then concentrated to dryness. The residue treated was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford crude 1-cyclohexyl-5,5-dimethylimidazolidin-2-one (100% yield assumed) which was used without further purification. MS (ESI) m/z: 197.2 (M+H+).
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1)=[O:22])C(=O)[O-])(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)Cc2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)Cc2cccnc2)cc1
Reaction time: 0.33 h

Procedure:
1,1-dimethylethyl[2-{[(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate was stirred in 10 mL of TFA/DCM (1:1 v/v) for 2 hours. Then 20 mL of saturated NaHCO3 was added to the reaction mixture and the resulted solution was stirred for 20 minutes, 50 mL of DCM was added to the reaction mixture and the organic layer was separated and the aqueous phase was extracted with DCM (50 mL×2), the combined organic layers were washed with brine, dried over Na2SO4, the solvent was removed and the residue was washed with 10 mL of anhydrous ethyl ether, filtered to give N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamide as a beige solid. 1H NMR (MeOD, 600 MHz) δ 8.49 (s, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.40 (m, 5H), 7.21 (m, 2H), 7.02 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.48 (s, 2H), 3.64 (s, 2H). MS: cal'd 443 (MH+), exp 443 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26][CH:27]5[CH2:28][CH2:29][N:30]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:31][CH2:32]5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCN(S(C)(=O)=O)CC3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 50 mg, 0.085 mmol) and methanesulfonyl chloride (7.9 μL, 0.102 mmol) using a similar method to that employed for Example 27 (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=4[F:27])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CO.[NH4+].[Cl-].Cl>[Zn].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:27])=[C:11]3[CH:10]=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (0.560 g, 1.42 mmol) in a MeOH (20 mL) and THF (5 mL) co-solvent was added zinc (0.464 g, 7.10 mmol), followed by saturated aqueous NH4Cl (5 mL). Next 6N aqueous HCl (3-4 mL) was added until all solids dissolved and the pH was 1-2. The reaction was stirred at room temperature for 18 hours. The resulting mixture was partitioned between DCM (30 mL) and saturated aqueous NH4Cl (30 mL). The phases were separated, and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting waxy solid (504 mg, 72%) was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=5.5 Hz, 1H), 7.72 (s, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.02 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.40-6.55 (m, 3H), 5.61 (s, 2H), 3.82 (br s, 2H), 3.75 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −129.0 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=O)[CH:5]=[C:6]([CH:14]=1)[C:7]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=O.B.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:7][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:14]=1)[CH2:15][NH:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CNC(=O)c1cc(Cl)cc(C(=O)NCC(C)C)c1
Agent: B
Agent: Cl
Solvent: CO
Product: CC(C)CNCc1cc(Cl)cc(CNCC(C)C)c1
Temperature: 25 °C
Reaction time: 32 h
Yield: 81.3 %

Procedure:
To 5-chloro-N1,N3-diisobutylisophthalamide (8.1 g, 26.1 mmol) was added borane (1 M solution in THF, 130.0 mL, 130.0 mmol). The reaction mixture was stirred at rt under nitrogen for 32 h. The starting material was still remaining. Additional borane (50 mL of 1 M solution in THF) was added and the reaction mixture was heated at 60° C. for another 6 h, then cooled to rt. To the mixture were added 100 mL of MeOH and HCl solution (100 mL of 4 N HCL) were added and the mixture was stirred for 2 h. The resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The pH of the aqueous layer was adjusted ro pH 9 using act NaOH. It was mixed with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the product as a colorless oil (6.0 g, 72%). 1H NMR (CD3OD): δ 7.31 (s, 2H), 7.26 (s, 1H), 3.76 (s, 4H), 2.39 (d, J=6.8 Hz, 4H), 1.80 (m, 2H), 0.94 (d, J=6.8 Hz, 12H); MS (ESI): (M+H)+=283.4.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].S(=O)(=O)(O)O>O1CCCC1.CCCCCC.C(OCC)C>[C:4]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([CH:22]=[O:23])=[CH:3]2
Reactant: CN(C)C=O
Reactant: BrC1=CC2(CCCC2)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=CC1=CC2(CCCC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To 3'-bromospiro(cyclopentane-1,1'-indene) (7.5 g) in tetrahydrofuran, (500 ml) is added at -70° C. a solution of n-butyllithium in hexane (200 ml of a 1.8 M solution) in two portions. The temperature is kept at -70° C. for a further 30 minutes. Dimethylformamide (73 g) is then added and the mixture is allowed to come to about 20° C. After 3 hours sulphuric acid (400 ml; 1 M) and diethyl ether (200 ml) are added. The ether phase is separated, washed with saturated sodium chloride solution and dried over sodium sulphate. Evaporation of the ether and distillation gives the title aldehyde; b.p. 130°-135° C./0.1 torr.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Br:15]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2cc(C)ccc2o1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(CBr)ccc2o1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide (561 mg, 3.15 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (Vazo) (63 mg, 0.26 mmol) in 15 ml of CCl4 was heated overnight under reflux. The mixture was cooled to room temperature, quenched by adding water and extracted with DCM. The organic layer was washed with brine and dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound 585 (680 mg, 96% yield). 1H NMR: (CDCl3) δ (ppm): 7.79 (s, 1H), 7.70-7.52 (m, 3H), 4.69 (s, 2H), 4.06 (s, 3H), 3.72 (s, 2H). LRMS: 268.2 (Calc.); 269.1 (found).