Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].C(O)C>C(O)(=O)C>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C
Yield: 89.5 %

Procedure:
A solution of 6.3 g. of acetonine in a mixed solvent comprising 20 g. of acetone and 2 g. of ethanol was added with 0.5 g. of acetic acid. The mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 89.5%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.Cl[C:8]1[S:9][CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])[CH2:2]1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: O[C@@H]1CCOC1
Product: Nc1ccsc1O[C@@H]1CCOC1

Procedure:
Is prepared in a similar manner as intermediate IV.1 from (3R)-tetrahydrofuran-3-ol and 2-chloro-3-nitro-thiophene
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:66]([O:73][C:74](=[O:80])[CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:79][CH2:78][CH2:77][CH2:76][CH2:75][C:74]([O:73][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:80])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: NCCCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (SEQ ID NO. 1) (575 mg), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the solution was stirred for 30 minutes. The resulting solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 560 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1). The Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1) (560 mg) was dissolved in methanol (60 ml) containing 50% of water, and the solution was added with 5% Pd—C (water content; 50%, 1.5 g) and stirred overnight under hydrogen at ordinary pressure. After the catalyst was removed from the reaction mixture by filtration, the mixture was concentrated to dryness to obtain 300 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOH (SEQ ID NO. 1).
Reaction SMILES: C([O:8][C@H:9]([C:11]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]2=[N:13][N:12]=1)[CH3:10])C1C=CC=CC=1.CC#N.[Si](I)(C)(C)C>CCOC(C)=O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]3[N:15]([C:11]([C@H:9]([OH:8])[CH3:10])=[N:12][N:13]=3)[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OCc3ccccc3)n21
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)O)n21
Temperature: 60 °C
Reaction time: 96 h
Yield: 30.9 %

Procedure:
To a round bottom flask was added (S)-4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg, 0.0458 mmol), CH3CN (2 ml) and TMSI (244 mg, 1.22 mmol). The reaction was stirred at 60° C. under argon for 4 days. After this time, the reaction mixture was with EtOAc (50 ml). The resulting organic solution was wash with water (20 ml), 10% NaHSO3(20 ml) and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 0-80% EtOAc/Hex to give product (R)-4-(8-(4-chlorophenyl)-3-(1-hydroxyethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (8 mg, 31% yield).
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]([O:14][CH2:15][CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[C:6]1[S:10][C:9]([C:11](O)=[O:12])=[CH:8][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]([O:14][CH2:15][CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[C:6]1[S:10][C:9]([C:11]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:12])=[CH:8][CH:7]=1
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)NS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
Acid 6 (12 mg, 0.031 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 8.4 mg, 0.044 mmol), 4-dimethylaminopyridine (DMAP, 4.6 mg, 0.038 mmol) and methanesulfonamide (9 mg, 0.095 mmol) were dissolved in DMF (0.2 mL) and the resulting solution was stirred at room temperature under an atmosphere of nitrogen. After 15 h the solution was diluted with EtOAc (20 mL) and washed with 1N aqueous HCl (3×5 mL) and brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 4 g of silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 3.5 mg (25%) of the title compound (7).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:16]I>CS(C)=O.O>[CH3:16][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[O:11][C:10]1=[O:13]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)oc2c([N+](=O)[O-])cccc21
Reaction time: 16 h
Yield: 84.7 %

Procedure:
3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolinone (for preparation of the latter compound, and European patent EPO189612 and references cited therein) were dissolved in 40 ml of DMSO after which 1.72 g of 85% powdered KOH (26.2 mmol) were added. While stirring and cooling (water) 3.72 g (26.2 mmol) of MeI dissolved in 6 ml of DMSO, were added dropwise over a period of 10 minutes. Stirring was continued at room temperature for 16 hrs, during the latter period an extra amount of MeI (0.5 g) was added. After the reaction was completed, the reaction mixture was diluted with water after which extraction took place with CH2Cl2. The combined organic fractions were washed with respectively water and brine after which the organic fraction was dried on MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo, 4.1 g of a solid residue was left. Flash column chromatography (SiO2, eluent: CH2Cl2) of the latter yielded 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([C:23]([OH:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:27]>C(Cl)Cl.CO>[C:17]1([C@H:15]([NH:14][C@@H:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@H:10]2[C:23]([O:25][CH3:27])=[O:24])[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 261A (280 mg, 0.80 mmol) in 6 mL of 1:1 CH2Cl2/MeOH was added a solution of TMSCHN2 (0.82 ml, 1.64 mmol, 2N in hexane). The mixture was stirred at room temperature for 30 min, then concentrated in vacuo and purified by flash chromatography (hexane/EtOAc: 80:20) on silica gel to give Compound 261B as an oil. It had an analytical HPLC retention time=2.187 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=363.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]O)=[CH:8][CH:7]=1)=[O:4].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P>O1CCCC1.C(OCC)C>[F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][Br:24])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(CCO)cc1)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: P
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CCBr)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-hydroxyethyl)phenyl]butanamide (25 g), carbon tetrabromide (51 g), diethyl ether (140 mL) and tetrahydrofuran (140 mL) was cooled in ice and treated with triphenylphosphine (39.3 g), portionwise. When addition of the phosphine was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The precipitate was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel, eluted with dichloromethane to give 16.2 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-bromoethyl)phenyl]butanamide as a white solid.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
To a N,N-dimethylformamide (10 mL) solution of N-benzyl-4-hydroxypiperidine (1.90 g, 9.93 mmol) was added imidazole (1.35 g, 19.9 mmol) and tert-butyldimethylsilyl chloride (1.57 g, 10.4 mmol). After 1.5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 7.36-7.21 (m, 5H), 3.75-3.65 (m, 1H), 3.49 (s, 2H), 2.72-2.63 (m, 2H), 2.26-2.12 (m, 2H), 1.78-1.71 (m, 2H), 1.62-1.53 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H); LC-MS: m/z 306.1 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[N:42]1([CH2:47][CH2:48][CH2:49][NH2:50])[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH2:49][CH2:48][CH2:47][N:42]5[CH:46]=[CH:45][N:44]=[CH:43]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCn2ccnc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.029 mL (0.25 mmole) of 3-imidazol-1-yl-propylamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.086 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-imidazol-1-yl-propyl)-3-methoxy-benzamide (I-61) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:5]=1[C:6]#[N:7].C([O-])=O.[NH4+]>CO.O.[Zn]>[NH2:12][C:9]1[CH:10]=[CH:11][C:4]([CH2:3][CH:2]([CH3:15])[CH3:1])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(N)cc1C#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 273.5 %

Procedure:
To a solution of 2-isobutyl-5-nitrobenzonitrile (D56) (7.5 g) in methanol (80 mL) and water (80 mL) was added ammonium formate (51.9 g) and zinc (26.9 g). The reaction mixture was stirred at 80° C. for 4 h. After cooling the reaction, the solid was filtered, the filtrate was concentrated under reduced pressure, the residue was extracted with EtOAc (300 mL*2), the combined organic layers were washed with water (30 mL*2), dried and concentrated to give 5-amino-2-(2-methylpropyl)benzonitrile (D57) (17.5 g) as a colorless solid. MS (ES): C11H14N2 requires 174. found 175.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:37]1[S:38][C:39]2[C:44](=[O:45])[NH:43][N:42]=[CH:41][C:40]=2[N:46]=1.C(O)(C)C>C(N(CC)CC)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:38][C:39]4[C:44](=[O:45])[NH:43][N:42]=[CH:41][C:40]=4[N:46]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: O=c1[nH]ncc2nc(Cl)sc12
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3cn[nH]c(=O)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 92.7 %

Procedure:
To a mixed solution of the compound (26 mg) obtained in Example 783, the compound (10 mg) obtained in Step 6 and isopropanol (1.0 ml) was added triethylamine (14 μl) at room temperature, and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:20, developed twice) to give the title compound (31 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:36][CH2:37][CH2:38][OH:39])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of Compound (1) (50 mg, 0.11 mmol) in ACN (4 mL) was added potassium carbonate (30 mg, 0.22 mmol) followed by 3-bromo-1-propanol (38 μL, 0.32 mmol). The mixture was heated to 80° C. and stirred for 16 h at which time no starting material was observed. The mixture was cooled to RT, diluted with EtOAc (10 mL), washed with water (3 mL), brine (3 mL) and dried (MgSO4). The solvent was removed in vacuo to give the crude mixture which was purified by flash column chromatography eluting with EtOAc/hexane (5-100%) to give 2-(4-bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (4) (28 mg, 50%). ESI-MS m/z calculated for [M+H]+: 521.09/523.08; found: 521.03/523.03.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>CC(C)=O.CCCCCC>[N+:13]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2cccnc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
3-Phenylpyridine (25.0 g, 0.161 mole) is added carefully and with cooling (ice-bath) to 70% nitric acid (140 ml). The resulting solution is stirred and, when TLC (1:1 acetone-hexane) shows no reaction after 24 hr, it is heated in a 70° C. oil bath. Some reaction is observed by TLC but it is very slow and so, after 4 days, concentrated sulfuric acid (50 ml) is added. The mixture is stirred over several days at room temperature after which the starting material is entirely consumed. The solution is poured onto ice and the mixture is made alkaline by the cautious addition of 50% aqueous NaOH. The mixture is extracted 3 times with ethyl acetate. (650 ml), the combined organic layers are washed with brine, dried over MgSO4, filtered, and reduced in volume to 400 ml. Crystallization occurred, giving a first crop of 13.139 g of tilted product, melting point of 145°-148° C. and, from the concentrated filtrate, a second crop of 4.16 g (total 17.299 g, 0.0865 mole, 53%) of product, melting point 143°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31].CCOCC.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)([OH:14])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 120 mg (0.278 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (Example 19, Step 4) in 3 mL of THF, 0.35 mL (0.69 mmol) of tert-butyl magnesium chloride (2M in THF) was added and stirred for 1 h at −78° C. Then to the reaction mixture was added 30 μL of ether and 5 mL of 7 mL of qNaHCO3. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford of the title compound as a white solid; 1H-NMR (CDCl3) δ 0.88 (s, 9H), 2.46 (t, J=7.2 Hz, 1H), 2.97 (s, 1H), 3.05 (t, J=7.6 Hz, 1H), 3.31-3.39 (m, 2H), 3.42 (m, 1H), 4.25 (s, 1H), 6.56 (m, 2H), 6.68 (m, 1H), 7.24-7.36 (m, 8H); Mass Spectrum m/e=490 (M+1 35Cl, 35Cl) and 492 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1ccc(C=O)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: Cc1ccc(C=NNc2ccc(S(N)(=O)=O)cc2)cc1
Yield: 45 %

Procedure:
A solution of 4-methylbenzaldehyde (5 mmol) and 4-sulfamyl-phenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 216–218° C., was obtained in 45% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:23]=3)[CH:20]=2)=[C:11]([C:31](O)=[O:32])[CH:10]=[N:9]1>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:12]4[N:8]([CH3:7])[N:9]=[CH:10][C:11]=4[C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])=[O:30])=[CH:20][N:19]3[N:21]=2)[CH:25]=1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1

Procedure:
Using morpholine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (53 mg, 32%). Mp.: 229° C. MS: m/z=433.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16]C)[CH:10]=[CH:9][CH:8]=3.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([OH:16])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1c2ccc(Cl)cc2oc2c(O)cccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-chloro-5-methoxyxanthone (12.5 g.) [see Examples 32 and 33] in dry dichloromethane at 0° C. is slowly added boron tribromide (24 ml.). The mixture is stirred at room temperature for 24 hours, then poured into water. The resulting precipitate is filtered off and dried to give 3-chloro-5-hydroxyxanthone which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][N:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:8]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Cc1ccc(C(N)=S)cn1
Product: COC(=O)Cc1csc(-c2ccc(C)nc2)n1

Procedure:
This material was prepared by the procedure described for Example 24(a) using 6-methyl-thionicotinamide (Maybridge) (1.52 g, 10.0 mmol) and methyl 4-chloroacetoacetate (Fluka) (1.42 g, 10.0 mmol). Chromatography (gradient elution: 10-50% EtOAc in hexanes) of the crude material afforded the title compound as an off-white solid. MS m/z: 249 (M+1). Calc'd for C12H12N2O2S: 248.06.