Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.O[C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>>[CH:1]1([O:5][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: OC1CCC1
Product: COC(=O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D14 (first part of synthesis) from cyclobutanol and methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoate (D41).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[C:27]([C:26]1[CH:25]=[C:24]([NH:23][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)[CH:31]=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: N#Cc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminobenzonitrile (29 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-cyanophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 12 mg (12%). 1H-NMR: 10.76 (s, 1H), 8.23-8.20 (m, 1H), 8.07 (d, J=8.5 Hz, 2H), 8.03-7.98 (m, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.23-7.18 (m, 1H), 7.11-7.07 (m, 2H), 3.85-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.68-1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31]CC1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C>[F:1][C:2]([F:39])([F:40])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]
Reactant: FC(F)(F)COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Yield: 95 %

Procedure:
A stirred solution of the product of step (b) (0.97 g) and 10% palladium on carbon (100 mg) in acetic acid:ethanol (1:9, 20 mL) was placed under an atmosphere of hydrogen at 20° C. for 2 hours. The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo to give the title compound (780 mg). LC retention time 2.45 mins
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl.CO>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([S:12][CH3:13])[CH:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2cc(SC)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CSc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Yield: 92 %

Procedure:
A solution of 50 mg of ethyl 4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxylate in 200 μL of 4-chlorobenzylamine is heated at 190° C. under argon for 16 h, then cooled and diluted with CHCl3 and MeOH. The solution is washed with dil. HCl, dried (Na2SO4), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica using 2-4% MeOH in CH2Cl2 affords 62.4 mg (92%) of N-(4-chlorobenzyl)-4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.C[Si](C)(C)N[Si](C)(C)C.[K].[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41].Cl>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:28]([NH:29][C:43]([NH:42][CH2:40][CH3:41])=[O:44])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCN=C=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2nc(NCCCCN(CC)CC)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (5° C.) solution of 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (0.61 g) from Example 53 in THF (6 mL) was added potassium hexamethyldisilazane (0.308 g) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes. Then ethyl isocyanate was added, and the reaction mixture was stirred for an additional 18 hours at ambient temperature. The product was isolated by pouring the reaction mixture into approximately 200 mL of 0.25N aqueous HCl and filtering the resulting solution. The filtrate was made basic with 50% aqueous sodium hydroxide, and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and the filtrate concentrated under vacuum. The product was purified by radial chromatography eluting with a solvent mixture of 90:10:1 EtOAC:MeOH:TEA to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].C[O:11][CH:12](OC)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C(O)C.N>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: COC(CCCCCO)OC
Reactant: CNc1ccncc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: O
Solvent: CCO
Product: Cn1c(CCCCCO)nc2cnccc21
Yield: 30.1 %

Procedure:
3-Amino-4-(methylamino) pyridine (1.23 g), 6,6-dimethoxyhexanol (1.62 g), copper (II) acetate monohydrate (4 g), ethanol (30 ml) and water (30 ml) were mixed and then heated at 150° in a sealed tube for 3 hours. To the cold reaction mixture was added concentrated aqueous ammonia (5 cm3) and the mixture was then filtered through "Hyflo" (Trade Mark), diluted with water (50 ml) and extracted with methylene chloride (3×200 ml). The combined organic extracts were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol. The fractions containing the product were evaporated to leave the title compound, (0.66 g).
Reaction SMILES: [NH2:1][C:2]1[C:27]([Cl:28])=[CH:26][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([O:21]C(C)(C)C)=O)[CH2:13]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:26]=[C:27]([Cl:28])[C:2]([NH2:1])=[CH:3][C:4]=3[O:29][CH3:30])[CH2:13]2)=[O:21])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCCN1CCC(CNC(=O)OC(C)(C)C)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-Amino-N-(3-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-propyl)-5-chloro-2-methoxybenzamide (1.70 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.76 g) to give 4-amino-N-(1-(3-(4-amino-5-chloro-2-methoxybenzoylamino)propyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:21]1([C:24]([NH2:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:32][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (45 mg, 39%); MS (ESI, m/z): 445.5 (M+H+).
Reaction SMILES: FC1C(O[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[Cl:26])=C(F)C(F)=C(F)C=1F.[NH2:32][O:33][CH2:34][CH2:35][OH:36].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:11]1[C:12]([F:17])=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]([NH:32][O:33][CH2:34][CH2:35][OH:36])=[O:27]
Reactant: NOCCO
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Yield: 89.6 %

Procedure:
To a solution of 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (10.0 g, 17.4 mmol) in anhydrous dimethylformamide (36 mL) was added 2-(aminooxy)-ethanol (1.6 g, 20.8 mmol) and N,N-diisopropylethylamine (6.0 mL, 34.8 mmol). The resultant solution was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to 20% volume then diluted with ethyl acetate (360 mL). The resultant solution was washed with water (6×60 mL) and brine (2×60 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a white solid that was purified on silica gel. Elution with ethyl acetate-methanol (9:1) afforded 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (7.31 g, 90%) as a white solid. Recrystallization from methanol afforded analytically pure material, identical in all respects to the material prepared by method A.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH2:36][CH2:35][CH:34]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:19])[F:20])=[C:4]5[C:9]=4[N:8]=[CH:7][CH:6]=[CH:5]5)[CH2:18][CH2:17]3)[CH2:33][CH2:32]2)[CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)c2ncccc12
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: FC(F)(F)c1ccc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-(trifluoromethyl)-8-(piperazin-1-yl)quinoline (Step 3) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a white solid; MP. 202-204° C.; MS (ES) m/z (relative intensity) 492 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH:3]=1.Br[C:26]1[S:34][C:33]2[CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:29][C:28]=2[CH:27]=1>[F-].[K+].C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13]([C:26]3[S:34][C:33]4[CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:29][C:28]=4[CH:27]=3)[CH:14]=2)[CH:3]=1
Reactant: CCN1CCc2sc(Br)cc2C1
Reactant: CC1(C)OB(c2cnc(F)c(-c3cc(Cl)ncc3N)c2)OC1(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCc2sc(-c3cnc(F)c(-c4cc(Cl)ncc4N)c3)cc2C1
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A degassed mixture of 6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4′]bipyridinyl-3′-ylamine (1.99 g, 5.70 mmol), 2-bromo-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.54 g, 6.30 mmol), 1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (466 mg, 0.57 mmol) in 1N aqueous potassium fluoride solution (22.5 mL) and acetonitrile (22.5 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was loaded onto an SCX-2 cartridge (50 g) and eluted with 2N ammonia in methanol to afford impure product as a brown solid. The resultant brown residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as an off-white solid (1.05 g, 47%). 1H NMR (DMSO-D6, 300 MHz): 8.48 (d, J=2.4 Hz, 1H), 8.12 (dd, J=9.0, 2.6 Hz, 1H), 7.89 (s, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 5.54 (s, 2H), 3.45 (s, 2H), 2.86-2.79 (m, 2H), 2.75-2.68 (m, 2H), 2.58-2.51 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(I)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(I)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 60 (0.430 g, 0.77 mmol) and pyridine hydrochloride (2.0 g, 17.30 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [F:1]C1C=CC([N+]([O-])=O)=C(C)C=1.F[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1>>[F:1][C:21]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
The starting 5-fluoro-2-nitrobenzoic acid is prepared from 5-fluoro-2-nitrotoluene using a procedure similar to that for the preparation of 4-fluoro-2-nitrobenzoic acid which follows:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Br[CH:15]([CH3:23])[C:16](=O)[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:16]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)[O:8][C:15]=1[CH3:23]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C
Yield: 2.3 %

Procedure:
A mixture of 3.62 g (19.1 mmol) of 4-trifluoromethylbenzamide and 4.0 g (19 mmol) of methyl 4-bromo-3-oxo-pentanoate in 15 mL of toluene and 10 mL of dioxane (with 2 mL of EtOH) was refluxed for 22 h. The solution was concentrated under reduced pressure. The residue was taken into EtOAc and washed with water, brine, and dried over MgSO4. The crude material was purified by silica gel chromatography (10%-40% EtOAc in hexanes) to yield 130 mg of a yellow solid: 1H NMR (CDCl3, 400 MHz) δ8.1 (d, 2H, J=8.3), 7.65 (d, 2H, J=8.4), 3.75 (s, 3H), 3.58 (s, 2H), 2.39 (s, 3H); low resolution MS (ES+) m/e 300.0 (MH+).
Reaction SMILES: [NH3:1].C(O)C.[O:5]1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6]1>O>[OH:5][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][NH2:1]
Reactant: N
Reactant: CCCCCCC1CO1
Solvent: O
Solvent: CCO
Product: CCCCCCC(O)CN
Reaction time: 1.17 h
Yield: 76.6 %

Procedure:
One-thousand one-hundred grams of ammonia gas was introduced into a mixture of 6 liters of ethanol and 1 liter of water and within 30 minutes there were dropped in at room temperature 320 grams of 1,2-epoxyoctane. The mixture was left at room temperature for 70 minutes under gentle stirring, then the solvent and excess ammonia drawn off and the residue rectified in a vacuu. There were obtained 277.6 grams (77.1% of theory) of 2-hydroxyoctyl amine having a boiling point (0.4 mm Hg) of 80° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][CH3:16].[OH-].[Na+]>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:15][CH3:16])[N:7]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(Cl)nc(-c2ccccc2)n1
Yield: 23 %

Procedure:
A mixture of 2,4-dichloro-6-phenyl-1,3,5-triazine (16.0 g, 70.8 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (80 mL) was cooled (0° C.), and a solution of NH2Me (8.00 g, 27.5% solution in H2O, 70.8 mmol, 1.00 equiv) was added. The pH of the reaction mixture was adjusted to 9-10 by treating with 1 N NaOH. The pH was maintained at 9-10 for 15 min (product formation monitored by LCMS). The mixture was diluted with water, and filtered to provide 12 g of crude product (filtered solid was washed with additional water). A portion of this material (8 g) was purified by HPLC to afford 3.6 g of the title compound. MS (ES+): m/e 221.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:24])=[N:14][CH:15]=[C:16]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[N:17]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[CH2:32]([S:34]([N:21]1[CH2:20][CH:19]=[C:18]([C:16]2[N:17]=[C:12]([C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][N:9]=3)[C:13]([NH2:24])=[N:14][CH:15]=2)[CH2:23][CH2:22]1)(=[O:36])=[O:35])[CH3:33]
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.1151 mmol) was dissolved in DCM (3 mL) and Et3N (34.94 mg, 48.13 μL, 0.3453 mmol) followed by ethanesulfonyl chloride (16.28 mg, 12.00 μL, 0.1266 mmol) were added. The reaction was allowed to stir for 30 mins and then diluted with dichloromethane and washed with water. The aqueous layer was extracted further with dichloromethane and the organics washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (47.47 mg, 60% Yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2
Reactant: CCCCCCC(O)c1ccc2cc(OC)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a stirred solution of the 1-(6-methoxy-2-naphthyl)heptan-1-ol (101.1 g, 371 mmol) in CH2Cl2 (1000 mL) under N2 was added pyridinium chlorochromate (120.02 g, 556.74 mmol). The reaction was stirred for a total of 3 h and then poured onto an alumina column (2000 g, basic Brockman activity, 60-325 mesh). Column was eluted with CH2Cl2. Product was collected, filtered, rotovap'd and dried in vacuo to give the product as a white solid (81.5 g, 301.44 mmol, 81%) with mp 69-72° C. 177 mg of crude ketone was recrystallized from methanol to give the desired product as a white solid (105 mg) mp 70-72° C.; 1H NMR (DMSO-d6) δ 0.86 (m, 3H), 1.25-1.40 (m, 6H), 1.60-1.70 (m, 2H), 3.07 (t, J=7.3 Hz, 2H), 3.90 (s, 3H), 7.24 (d, J=9 Hz, 1H), 739 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 8.02 (d, J=8.9, 1H), 8.58 (s, 1H); IR (solid) 2910, 2870,1660, 1630, 1470, and 1180 cm−1; mass spectrum [EI], m/z 271 (M+H)+;
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]1[CH2:10][N:9]([CH3:11])[CH2:8][CH:7]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][N:9]1[CH2:10][CH2:6][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1
Reactant: CCOC(=O)C1CN(C)CC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(C)C1

Procedure:
The ethyl 1-methyl-3-pyrrolidinecarboxylate was prepared by the reaction of thionyl chloride with ethyl 4-hydroxy-1-methyl-3-pyrrolidinecarboxylate followed by basifying with potassium carbonate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2Cl)(=[O:3])[NH2:2].[F:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[N:25]([CH3:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27].[H-].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:24][C:22]1[CH:21]=[CH:20][C:19]([N:25]([CH3:36])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[C:18]([F:17])[CH:23]=1)(=[O:3])[NH2:2]
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N(C)C(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C(N)=O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
6-Carbamoyl-4-chloro-7-methoxyquinoline (41 mg, 0.1744 mmol) and N-(2-fluoro-4-hydroxyphenyl)-N′-(4-fluorophenyl)-N-methylurea (57 mg, 0.2048 mmol) were dissolved in dimethylsulfoxide (1.0 ml), and then sodium hydride (8.4 mg, 0.2093 mmol) was added and the mixture was heated and stirred at 85° C. for 30 minutes. After cooling the reaction solution to room temperature, water was added and the precipitated crystals were filtered out. The crystals were then suspended in acetone: diethyl ether=1:2 and refiltered out, washed with diethyl ether and dried by aspiration to obtain the title compound (46 mg, 0.0961 mmol, 55.13%) as yellow crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1C(=O)O
Product: Cc1c(C(=O)O)ccc(F)c1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To fuming nitric acid (20.3 mL, 409 mmol) was slowly added dropwise 4-fluoro-2-methylbenzoic acid (4.50 g, 29.2 mmol) while maintaining the temperature of the reaction mixture at 5-10° C. The reaction solution was stirred at 0-5° C. for 1 hr, and poured into ice. The precipitated solid was recovered, washed with water, and dried under reduced pressure to give 4-fluoro-2-methyl-3-nitrobenzoic acid (5.70 g, purity 25%) as a crudely purified product.