Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-valinol (8.80 g, 0.037 mol) and triethylamine (30.00 g, 41.3 mL, 0.30 mol) in 100 mL dimethylsulfoxide under a nitrogen atmosphere was added a solution of sulfur trioxide pyridine complex (20.62 g, 0.130 mol) in dimethylsulfoxide (100 mL) dropwise via an addition funnel. An ice water bath was used to maintain the temperature of the reaction mixture below room temperature during the addition. After 30 min the cooling bath was removed and the reaction was allowed to warm to room temperature over 2 h. The brown solution was acidified with cold 2N HCl to approximately pH 2 and extracted with ether (3×150 mL). The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and evaporated to give 7.40 g of N-benzyloxycarbonyl-L-valinal (84.8%) as a yellow oil. The resulting material can be used without purification or further purified using column chromatography (silica gel, 9:1 hexanes:ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:10]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:11](=O)[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:10]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([CH3:12])[N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cn1
Reactant: COCCCC(Cl)C(C)=O
Product: COCCCc1c(C)nc2ncc(Br)cn12

Procedure:
0.85 mmol of 5-bromopyrimidin-2-ylamine [7752-82-1] and 1.7 mmol of 3-chloro-6-methoxyhexan-2-one are reacted in analogy to building block 35. The title compound is identified by means of the Rf.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[NH:10][C:9]2=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)nc2c([N+](=O)[O-])cccc12
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2c(Cl)nc(C(F)(F)F)nc12
Yield: 186.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-7, step-2 using 8-nitro-2-(trifluoromethyl)quinazolin-4(3H)-one (500 mg, 1.93 mmol) and PCl5 (477 mg, 2.32 mmol) in POCl3 (2.5 mL) to afford 1.0 g of the title product.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:23])[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[CH2:7]1)(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:14]=2)[CH2:9]1)(=[O:27])[CH3:25]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.28 g, 3.85 mmol) (obtained as described in Reference Example 32(3)) in dimethylformamide (40 ml) was added potassium thioacetate (2.60 g, 23.1 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (893 mg, yield 70%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].O.[OH-].[K+].S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[CH3:22][O:14][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of 2,3,5,6-tetrafluoro-1,4-benzenedimethanol, 15.00 g of water and 1.30 g (23.1 mmol) of potassium hydroxide were charged subsequently, and heated to 60° C. with stirring. At this time, solid 2,3,5,6-tetrafluoro-1,4-benzenedimethanol was completely dissolved to be a clear solution. Then, a mixture of 15.0 g of toluene and 3.07 g (23.1 mmol) of dimethyl sulfate was added at 55±5° C. After stirring at 50±5° C. for 1.5 hours, 0.64 g (11.4 mmol) of potassium hydroxide and 1.51 g (12.6 mmol) of dimethyl sulfate were added. After 1.5 hours, 0.66 g (11.7 mmol) of potassium hydroxide and 1.51 g (12.6 mmol) of dimethyl sulfate were further added and stirred at the same temperature for 1.5 hours. Allowing the reaction mixture to cool to room temperature, the layers of the reaction mixture were separated and the water layer was extracted with 30 ml of ethyl acetate. The organic layers were combined, washed with 30 ml of water, concentrated, and dried under reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol. The crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol was subjected to content analysis by GC internal standard method (Analytical method 1 given later). GC area percentage of the crude product: 87% of the objective compound, 4% of the starting compound and 8% of the by-product compound Content analysis by GC internal standard method: 85% of the objective compound and 86% of the yield of pure compound
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cccnc2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1-c1nc2cccnc2o1

Procedure:
A mixture of 700 mg. of 2-(2-nitrophenyl)oxazolo[5,4-b]pyridine in 50 ml. of ethanol was hydrogenated over 150 mg. of 5% palladium on carbon catalyst. The catalyst was removed by filtration and the solvent was concentrated to dryness. The residue was recrystallized from chloroformpetroleum ether to give 2-(2-aminophenyl)oxazolo[5,4-b]pyridine, m.p. 142°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12].FC1C=CC([Cl:34])=CC=1CBr>>[F:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:34])=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)N(CCCCOCc1ccccc1F)C(=O)OC(C)(C)C
Reactant: Fc1ccc(Cl)cc1CBr
Product: CC(C)N(CCCCOCc1cc(Cl)ccc1F)C(=O)OC(C)(C)C

Procedure:
The title intermediate was prepared essentially as described supra for 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine, except that an equimolar amount of 2-fluoro-5-chlorobenzyl bromide was employed instead of the 2-fluorobenzyl bromide employed therein.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide (Stage 32.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=4.18 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=451.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.89 (m, 2H) 2.94 (d, J=11.73 Hz, 1H) 3.18-3.33 (m, 2H) 3.36-3.49 (m, 1H) 4.18 (br. s, 1H) 4.81 (d, J=3.13 Hz, 1H) 6.38 (s, 1H) 7.68-7.85 (m, 2H) 8.02 (d, J=1.95 Hz, 1H) 8.32 (dd, J=8.60, 2.35 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 8.98 (d, J=2.35 Hz, 1H) 10.42 (s, 1H) 12.89-13.12 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>ClCCl>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(=O)O)c1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
2-amino-3-methoxybenzoic acid 97 (1 g, 6.0 mmol) and pyridine (0.97 mL, 12.0 mmol) were dissolved in dry dichloromethane (30 mL). The resulting mixture was cooled and Troc—Cl (0.9 mL, 6.6 mmol) was added drop wise. The reaction mixture was allowed to stir overnight at room temperature, then washed with HCl (1N, 50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and evaporated to yield 1.42 g of crude product, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:14]([NH:16][N:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:19][N:17]([CH3:18])[NH:16][C:14]([C:11]1([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCNCC1
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 2.02 mmol) in methylene chloride (2 ml) at 0° C. was added trifluoroacetic acid (5 ml) and the mixture was stirred for 60 min. The mixture was quenched with ethanol (20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: Cn1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccn(C)n6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 3-(chloromethyl)-1-methyl-1H-pyrazole (39.2 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 44.5 mg; LC (method 23): tR=2.09 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1)=[C:10]([CH3:27])[CH:9]=2)=[O:5])C.[OH-].[K+]>CO.O.O>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[C:12]([CH3:15])=[C:13]3[C:8](=[CH:9][C:10]=2[CH3:27])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:18][C:19]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(C)C)c3)c(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2[nH]c(C(=O)O)cc2c(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 5-(4-hydroxy-3-isopropyl-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (60 mg, 0.16 mmol) in methanol/water (1:1, 3.2 mL) at room temperature was added 3N potassium hydroxide (324 μL). After stirring at room temperature for 2 hours, the mixture was diluted with water (10 mL) and washed with ethyl acetate. The aqueous solution was acidified with 1 M hydrochloric acid and then extracted with ethyl acetate (3 times 25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the title compound (30 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ11.07 (s, 1H), 7.16 (s, 2H), 6.62 (d, 1H), 6.57 (d, 1H), 6.25-6.22 (dd, 1H), 3.24-3.19 (m, 1H), 2.27 (s, 3H), 2.17 (s, 3H), 1.12 (d, 6H). MS (APCI−) Calc: 339.1, Found: 338.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)sc2ccc(Cl)cc12
Yield: 68 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and benzyl alcohol (10.8 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107, using a slightly modified reaction time (2 days). The title compound was obtained in 68% yield (17.6 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.44 (s, 3 H) 5.31 (s, 2 H) 6.96 (s, 1 H) 7.33-7.40 (m, 5 H) 7.36 (dd, J=8.05, 7.70 Hz, 1 H) 7.43 (ddd, J=8.05, 2.36, 1.20 Hz, 1 H) 7.43 (dd, J=8.63, 2.06 Hz, 1 H) 7.68 (dd, J=8.63, 0.58 Hz, 1 H) 7.69 (dd, J=2.06, 0.58 Hz, 1 H) 7.74 (dd, J=2.36, 1.58 Hz, 1 H) 7.86 (ddd, J=7.70, 1.58, 1.20 Hz, 1 H). MS (ESI+) m/z 472 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1.[Cl:19][C:20]1[C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN1C(=O)CCC1>[ClH:19].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]4[C:25]([C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=5[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.039 g, 0.16 mmol), 4-chloro-N-(2,4-difluorophenyl)nicotinamide (0.043 g, 0.16 mmol) and p-toluenesulfonic acid monohydrate (Aldrich, 0.024 g, 0.13 mmol), in anhydrous NMP (1 mL), was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 160° C. After one hour, the reaction mixture was partitioned between chloroform and brine. The aqueous layer was extracted twice with chloroform, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to an off-white solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4 N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.015 g, 18%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32](=[O:35])[NH:33][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32](=[O:35])[NH:33][CH:34]=4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(=O)[nH]c1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NCc2ccc(=O)[nH]c2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 57.5 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(10 mg, 0.028 mmol) described in example 92 and 5-(aminomethyl)-2(1H)-pyridinone (50 mg, 0.403 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-N-[(6-oxo-1,6-dihydro-3-pyridinyl)methyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (7 mg, 58% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.51 (br s, 1 H), 8.59 (s, 1 H), 7.49 (d, J=9.6 Hz, 1 H), 7.39 (s, 2 H), 7.17-7.13 (m, 2 H), 7.04-6.94 (m, 2 H), 6.56 (d, J=9.6 Hz, 1 H), 4.38 (d, J=6 Hz, 2 H), 4.13 (s, 2 H), 3.56 (s, 3 H); HRMS m/z calcd for C23H20N4O4F: 435.1469 Found: 435.1470.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[NH2:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: NCc1ccccc1N
Solvent: CC(C)O
Product: Nc1cc2ncnc(NCc3ccccc3N)c2cn1
Yield: 47.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (136 mg, 0.71 mmol) (described in a previous experimental) and 2-aminobenzylamine (1.70 g, 13.8 mmol) in isopropanol (5 mL) is stirred at reflux for 1 h, and the resulting product is chromatographed on silica gel (7-20% EtOH/EtOAc) and alumina (6-10% EtOH/CHCl3) to give 7-amino-4-(2-aminobenzylamino)pyrido[4,3-d]pyrimidine (89 mg, 47%) as a white solid. 1H NMR (DMSO) δ 9.08 (1H, s), 8.68 (1H, t, J=5.8 Hz), 8.26 (1H, s), 7.05 (1H, d, J=7.4 Hz), 6.96 (1H, t, J=7.6 Hz), 6.63 (1H, d, J=7.9 Hz), 6.51 (1H, t, J=7.4 Hz), 6.46 (2H, brs), 6.35 (1H, s), 5.20 (2 H, brs), 4.56 (2H, d, J=5.8 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][NH:31]C(OC(C)(C)C)=O)[CH:26]=[CH:27][C:28]=1[F:29].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:30]([C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=3)[N:31]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 46.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.300 g), tert-butyl 2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.300 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([C:17]([O:19]CC)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([C:9]([OH:16])([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([OH:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
A 250 mL round-bottom flask was charged with anhydrous THF (120 mL) at room temperature and then cooled to 0° C. with water/ice bath. Cyclohexylmagnesium chloride solution (2.0 M in ethyl ether) (56 mL, 112 mmol) was added. A solution of ethyl benzoylformate (14.89 g, 79.41 mmol) in THF (20 mL) was added dropwise over 30 minutes. More of THF (10 mL) was added to wash the addition funnel. The resulting mixture was stirred at 0° C. for 15 minutes, and then at room temperature for three hours. The reaction mixture was poured into saturated aqueous ammonium chloride (150 mL). Water (15 mL) was added. The mixture was concentrated to remove the organic solvents. The remaining solution was extracted with EtOAc (2×100 mL). The extraction was washed with brine, dried over sodium sulfate, concentrated to afford a slight green residue. The residue was purified with flash column chromatography on silica gel using 0-8% EtOAc/hexane (20 CV, 40 M column, biotage) to afford 14.955 g of product in 72% yield. 1H-NMR (400 MHz, CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:35][S:36]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Yield: 49 %

Procedure:
7-Amino-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (3 g, 8.6 mmol) was dissolved in dichloromethane (100 ml), and 2,6-lutidine (1.2 ml, 10.32 mmol) was added. To this methylsulfonyl chloride (0.73 ml, 9.46 mmol) was added dropwise. A further portion of 2,6-lutidine (0.6 ml, 5.16 mmol) and methylsulfonyl chloride (0.37 ml, 4.78 mmol) were later added. The mixture was partitioned between sodium bicarbonate solution (100 ml) and dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue on alumina with ethyl acetate +0-1% methanol gradient elution gave the title compound as an oil (1.8 g, 49%).