Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:18])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-2-fluorophenyl)acetic acid (25.0 g, 133 mmol) was dissolved in MeOH (133 mL). Sulfuryl dichloride (9.67 mL, 133 mmol) was then added, and the reaction was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=203 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)CN1CCC(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCC(C(=O)Nc2ccc(N3CCNCC3)cc2)CC1
Yield: 92.5 %

Procedure:
A solution of Methyl 4-[[[4-(4-t-butyloxycarbonyl-1-piperazinyl)phenyl]amino]carbonyl]-1-piperidine acetate (2.1 g, 4.5 mmol) was treated with CH2Cl2 /TFA (10 mL/15 mL) for 20 min. Solution was concentrated and the residue was treated with MeOH/4M HCl (10 mL/10 mL). Solution was concentrated until precipitation started. Solution was filtered and the solid was washed with Et2O to give the title compound (1.5 g, 87%). MS (ES) m/e 361 [M+H]+. 1HNMR (250 MHz, DMSO[d6]) δ 1.4-4.5 (m, 22H), 6.9-9.5 (m, 5H). Anal. (C18H25N3O3.2.87HCl.0.5H2O) calcd: C, 54.32; H, 7.20; N, 10.29. found: C, 54.52; H, 7.24; N, 10.35.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:2][NH2:3])[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: NN
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: NN=C(C(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Benzoin, 60 g, is suspended in 600 ml acetic anhydride and 60 ml concentrated sulfuric acid is added under ice cooling. Under continued ice cooling, 33 g potassium nitrate is added in small portions. The reaction is stirred at room temperature for two days and poured over ice. The aqeuous portion is decanted off and the remaining oil is taken up in ether, washed with water, sodium bicarbonate solution, dried over potassium carbonate and stripped. The oil residue is added dropwise to concentrated nitric acid at 0°, followed by heating gently on a steam bath for 2 hours. After cooling, the solution is poured over ice. The solid which forms is removed by filtration (~40 g) and recrystallized three times from glacial acetic acid, to yield 5.5 g of a yellow solid, 4-nitrobenzil. To a solution of 0.7 g hydrazine hydrate in 50 ml ethanol is added a suspension of 4-nitrobenzil, 5.1 g, in 150 ml of ethanol. The reaction is heated on a steam bath for 1 hour and cooled. Plate-like crystals separate out and are removed by filtration. Yield 3.5 g. The product is recrystallized from 200 ml ethanol. M.P. 166°-173°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH:37]=[CH2:38])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A solution of {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.183 mmol) in anhydrous toluene (3 mL) was degassed using argon. Tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) and tributyl(vinyl)tin (0.080 mL, 0.274 mmol) were added. The reaction vial was degassed using argon and the reaction mixture was stirred at 90° C. for 2 h. The resultant mixture was allowed to cool to RT and subjected to flash chromatography (SiO2, gradient 0 to 40% EtOAc in cyclohexane) to give the title compound as a gummy solid (81 mg, 90%). LCMS (Method G): RT=4.73 min, [M+H]+=494.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[C:30]([CH2:31][CH2:32][CH3:33])=[C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:28][N:27]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:3][N:4]1[CH2:7][CH:6]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([C:26]3[C:30]([CH2:31][CH2:32][CH3:33])=[C:29]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:28][N:27]=3)[O:23][N:22]=2)=[CH:19][CH:20]=1)[CH2:3][N:4]1[CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Reaction time: 2 h
Yield: 112.4 %

Procedure:
To tert-butyl 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylate (8 mg, 0.015 mmol) was added DCM (2 mL) and TFA (2.000 mL). The reaction mixture was stirred 2 hours. Next, the solvent was removed and the remaining contents were freeze dried from MeCN to yield 8 mg of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (2H, d, J=8.35 Hz), 7.83 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.73 (5H, m), 4.32-4.83 (3H, m), 3.43-4.20 (6H, m), 2.95-3.05 (2H, m), 1.65-1.75 (2H, m), 0.97 (3H, t, J=7.36 Hz). MS (m+1)=475. HPLC Peak RT=3.38 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O-])(O)=[O:17].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([N:13]=[C:16]=[O:17])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)cc1N
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C2CCCCC2)cc1N=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5-cyclohexyl-2-methoxy-phenylamine (106 mg, 0.49 mmol), CH2Cl2 (10 mL) and saturated NaHCO3 (5 mL) was added a 20% solution of COCl2 in toluene (0.39 mL) directly to the organic layer. The mixture was stirred for 15 min at RT, diluted with CH2Cl2 and extracted with water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 4-cyclohexyl-2-isocyanato-1-methoxy-benzene.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:26]([C:37]3[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=3)=[N:25][C:24]=12)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=3[F:35])[C:26]([C:37]3[CH:38]=[CH:39][C:40]([CH2:43][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:41][CH:42]=3)=[N:25][C:24]=12)=[O:19]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc12

Procedure:
The compound is prepared in analogy to example 27.0. 348.5 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are reacted with 500 mg (1.27 mmol) 6-(2,6-difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester. After the usual work-up and purification 254 mg (32.9%) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:11][C:10]=1[CH:21]=O>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:10]([CH3:21])=[CH:11][C:12]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:13][C:14]=1[CH2:15][NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CN
Reactant: Cc1cc(-n2cncn2)cc(C=O)c1N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNCc1cc(-n2cncn2)cc(C)c1N
Reaction time: 16 h
Yield: 51.7 %

Procedure:
A mixture of ethyl glycinate (0.38 g), 1-(4-amino-3-formyl-5-methylphenyl)-1,2,4-triazole (0.5 g) and 3Å molecular sieves (1.0 g; "Fluka" [Trade Mark] article No. 69828) was stirred and heated under reflux in chloroform (10 cm3) for 4 hours. The cooled mixture was filtered, evaporated in vacuo, and the residue taken into ethanol (30 cm3). The solution was then hydrogenated at 60 p.s.i. (4.13×105Pa) pressure and room temperature (20°) over 10% palladised charcoal (0.2 g) for 16 hours. The catalyst was then removed by filtration through "Solkafloc" (Trade Mark) and the solution was evaporated in vacuo to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of the appropriate fractions afforded the title compound as an oil (0.37 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2c(ccn2Cc2ccc([N+](=O)[O-])cc2)c1

Procedure:
1-(4-Nitro-benzyl)-1H-indole-5-carboxylic acid methyl ester was prepared from 1H-indole-5-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow poder: 1H NMR (DMSO-d6) δ 3.84 (s, 3H), 5.67 (s, 2H), 6.71 (dd, J=3.2, 0.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.73 (dd, J=8.8, 1.7 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.29 (d, J=1.0 Hz, 1H); MS (ESI) m/z 311 (MH+), 309 ([M−H]−); HRMS calcd for C17H15N2O4: 311.1030; found (ESI+): 311.1021.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:6][CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.C[O-].[Na+]>O>[F:19][C:18]([F:21])([F:20])[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][C:2]=2[N:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1Cl)c1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccc(C(F)(F)F)nc2Oc2ccccc21
Temperature: 220 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a stirring solution of title compound 73 (0.76 g, 2.4 mmol) in tetraglyne (10 mL) was added sodium methoxide (0.220 g, 4.08 mmol) and the reaction mixture was stirred at 220° C. for 3 h. The reaction mixture was cooled to room temperature diluted with water (25 mL), stirred for 20 min then filtered to give a light brown solid which was purified by flash chromatography (0% to 60% ethyl acetate in hexanes) to afford title compound 74 (0.37 g, 55%). LRMS (ESI): (calc) 280.05 (found) 281.3 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][N:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:28][CH:29]=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[N:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3=CCN(C(C)(C)C)CC3)cn2)c2ccccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CCN(C(C)(C)C)CC3)cn2)c2ccccc21
Reaction time: 4 h
Yield: 37.6 %

Procedure:
4-(1′-(tert-Butyl)-1′,2′,3′,6′-tetrahydro-3,4′-bipyridinyl-6-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.44 g, 0.98 mmol) is placed in 60 ml of ethyl acetate in a Parr apparatus bottle. Platinum oxide (0.089 g, 0.39 mmol) is added. After stirring for 4 h under 32 psi H2, the catalyst is filtered off and rinsed with ethyl acetate. The filtrate is concentrated to dryness and then the residue is again stirred in 60 ml of ethyl acetate in the presence of 90 mg of platinum oxide under 35 psi for 18 h. The operation is repeated for 5 h and then 7 h. After filtering off the catalyst and rinsing with ethyl acetate, the filtrate is concentrated and then chromatographed on silica gel, elution being carried out with a methanol/aqueous ammonia gradient in dichloromethane varying from 100/0/0 to 9/1/0.1 (dichloro-methane/methanol/aqueous ammonia). 0.166 g of 4-(1′-(tert-butyl)-1′,2′,3′,4′,5′,6′-hexahydro-3,4′-bipyridinyl-6-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[C:12]=2[N:11]2[CH2:31][CH2:32][N:33]([CH3:36])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:34](=[O:35])[N:33]([CH3:36])[CH2:32][CH2:31][N:11]4[C:12]=3[C:13]([N:27]([CH3:37])[C:28](=[O:30])[CH3:29])=[N:14]2)=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N(C)c1nn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazin-4-yl]acetamide (0.13 g, 0.27 mmol) in anhydrous DMF (5 mL), a solution of lithium bis(trimethylsilyl)amide (0.4 mL, 0.4 mmol; 1 M in THF) was added. The mixture was stirred at room temperature for 10 minutes, treated with iodomethane (25 μL, 0.40 mmol), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and the residue partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The title compound was debenzylated in accordance with the procedure set forth in Example 62, step 12.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(-c2ccccn2)c1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Product: O=[N+]([O-])c1cc(I)ccc1Nc1cccc(-c2ccccn2)c1
Yield: 40 %

Procedure:
N-(3-(2-Pyridyl)phenyl)-4-iodo-2-nitroaniline (6f) was prepared analogously from 1c (Example 1) and 2f (Example 4). Yield: 40%. Mp 195-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]1[CH2:24][C:25](O)=[O:26]>>[Cl:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:7][C:25](=[O:26])[CH2:24][N:15]2[C:16]3[C:21](=[N:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: Nc1scc(Cl)c1-c1nccs1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nccs1
Yield: 1.3 %

Procedure:
The title compound was prepared from 4-chloro-3-(thiazol-2-yl)thiophen-2-amine (0.4 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (165 mg, 0.8 mmol) according to protocol A. The crude product was purified by column chromatography (4% methanol/methylene chloride) and HPLC to afford N-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (2.1 mg) as a white solid. LCMS m/z of 405.1/407.1 and retention of 3.670 min using the [7] LCMS method. 1H-NMR (300 MHz, CDCl3) δ 8.36 (d, J=4.9 Hz, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.1, 5.1 Hz, 1H), 7.36 (d, J=3.4, 1H), 6.82 (s, 1H), 4.92 (s, 2H), 3.44 (t, J=7.1 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:5]=1)(O)=[O:2].[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([O:9][CH3:10])[C:4]([C:1](=[O:2])[NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:5]1
Reactant: NN1CCOCC1
Reactant: COc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (3.5 g, compound obtained in Reference Example 1(6)) in methylene chloride (100 mL) was added N-aminomorpholine (1.47 g), water-soluble carbodiimide HCl (2.76 g) and 1-hydroxybenzotriazole hydrate (2.21 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=40/60 to 20/80) to obtain 1-(2-chloro-phenyl)-5-(4-chlorophenyl)-4-methoxy-3-(N-morpholinocarbamoyl)-1H-pyrazole (3.49 g; yield: 81%) as a powder.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][NH:19][OH:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C.O>C1COCC1>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][N:19]([OH:20])[C:26]([NH2:25])=[O:27])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ONCCn1cc(Cc2ccccc2)c2ccccc21
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N(O)CCn1cc(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of product from Step 4 (150 mg, 0.56 mmol) in THF (4 mL) at room temperature there was added 85% trimethyl silyl isocyanate (TMSNCO, 162 mg, 1.2 mmol) and the mixture was stirred for 30 minutes. H2O (5 mL) was added, and after stirring for a further 10 minutes the THF was evaporated, and the residue extracted with Et2O, the extracts washed with H2O, dried over MgSO4 and evaporated to afford the title compound as a thick oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., a solution of 25.0 g (215 mmol) of tetrahydro-2H-pyran-2-ylmethanol (racemate) in 500 ml of THF was slowly added dropwise to a suspension of 9.47 g (237 mmol, 60% in mineral oil) of sodium hydride in 500 ml of THF, and after the addition had ended, the mixture was stirred at 0° C. for another 30 min 25.7 ml (215 mmol) of benzyl bromide were then added, and the mixture was stirred at 0° C. for another 30 min and at room temperature for another 1 h. The reaction was terminated by addition of 200 ml of saturated aqueous ammonium chloride solution, and the phases were separated. The aqueous phase was extracted twice with 200 ml of methyl tert-butyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 340 g silica cartridge, flow rate 100 ml/min), giving the title compound. Yield: 41.9 g (94% of theory)
Reaction SMILES: [CH:1]([C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:20][NH:21][CH3:22].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:20][N:21]([CH3:22])[CH2:1][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of Example 134A (1.25 g, 4.44 mmol), 2M dimethylamine in THF (2.7 mL, 5.4 mmol), and NaBH(OAc)3 (1.32 g, 6.22 mmol) in dichloromethane at room temperature was stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 311 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:51]2[CH:52]=[N:53][NH:54][CH:55]=2)O1>>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:3][C:2]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(-c3cn[nH]c3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Strem Chemicals), and was isolated as an orange amorphous solid (95%). m/z (ESI, +ve ion) 376.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.98 (1H, br. s.); 11.70 (1H, s); 8.89 (1H, br. s.); 8.59 (2H, br. s.); 8.17 (2H, br. s.); 7.87 (2H, br. s.); 7.74 (1H, br. s.); 6.84 (1H, s); 3.85 (3H, s); 2.46 (3H, br. s.).