Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:18]1[N:23]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[CH:21]=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[S:3][C:2]([NH:1][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[N:23]=3)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)=[CH:11][CH:12]=1
Reactant: NC(=O)c1cc(-c2ccc(Cl)cc2)sc1N
Reactant: CC(O)(CO)c1cccc(Br)n1
Product: CC(O)(CO)c1cccc(Nc2sc(-c3ccc(Cl)cc3)cc2C(N)=O)n1

Procedure:
The title compound was prepared by using the procedure described in Example 1 with 2-amino-5-(4-chlorophenyl)thiophene-3-carboxamide (240 mg, 0.95 mmol) and 2-(6-bromopyridin-2-yl)propane-1,2-diol (200 mg, 0.86 mmol) as the starting materials.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: CCCCCCCOC(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
Under a nitrogen atmosphere, heptyl 4-iodobenzoate (2a) (10.1 g, 29.3 mmol) was dissolved in anhydrous triethylamine (50 mL), Pd(PPh3)2Cl2 (0.0820 g, 0.117 mmol), triphenylphosphine (0.126 g, 0.480 mmol), copper (I) iodide (0.135 g, 0.192 mmol), and trimethylsilylacetylene (TMSA) (4.30 mL, 31.7 mmol) were added, and the mixture was stirred at room temperature for 20 hr. The reaction solution was filtered through celite, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:30) to give heptyl 4-[(trimethylsilyl)ethynyl]benzoate (3a) (9.23 g, yield 98%) as an oily liquid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:53][O:54][CH2:55][C:56]([CH3:61])([CH3:60])[C:57](O)=[O:58]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:57](=[O:58])[C:56]([CH3:61])([CH3:60])[CH2:55][O:54][CH3:53])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: COCC(C)(C)C(=O)O
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.250 g, 0.678 mmol) in THF:DMF (5 mL:1 mL), TBTU (0.653 g, 2.3 mmol), TEA (4.0 mL) were added and the reaction mass was stirred at RT for 1 h. To the reaction mixture, 3-methoxy-2,2-dimethylpropanoic acid (0.134 g, 1.01 mmol) was added and stirring was continued at RT for 2 days. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to obtain crude product. The obtained crude was purified with column chromatography on basic alumina by eluting with 5.0% MeOH:DCM to afford 0.110 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.15 (s, 6H), 1.18 (s, 3H), 3.09 (t, 2H), 4.32 (d, J=11.4 Hz, 2H), 7.43 (dd, J=4.5 Hz, 3.6 Hz, 1H), 7.45 (d, 1H), 7.86 (d, J=5.4 Hz, 2H), 8.15 (t, 1H), 8.20 (d, 2H), 12.50 (br s, 1H); MS (m/z): 483.20 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([O:56][C:55]([NH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[NH:47][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:61])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CCOC(=O)CCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 7-ethoxy-7-oxoheptanoic acid (2.0 g, 10.6 mmol) in DMF (50 mL) were added HBTU (4.4 g, 11.6 mmol), DIEA (4.1 g, 31.8 mmol) at room temperature. The resulting mixture was stirred for 10 min, then tert-butyl (2-aminophenyl)carbamate (2.43 g, 11.7 mmol) was added to the reaction solution. The reaction mixture was stirred for 12 h at room temperature. The reaction was quenched with water (200 mL). The resulting mixture was extracted by EtOAc (200 mL×2). The organic layers were combined, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The resulting solid was purified by column chromatography (elute: EtOAc:PE (petroleum ether)=1:4) to afford the desired compound (3.7 g, yield 92.1%) as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.[F:15][C:16]([F:21])([F:20])[C:17](N)=[O:18]>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][NH:1][C:17](=[O:18])[C:16]([F:21])([F:20])[F:15])[C:8]=2[CH:9]=1
Reactant: COc1ccc2ncn(CCN)c2c1
Reactant: NC(=O)C(F)(F)F
Product: COc1ccc2ncn(CCNC(=O)C(F)(F)F)c2c1

Procedure:
Following the procedure of Example 13 but replacing 5-methoxytryptamine with 1-β-aminoethyl-6-methoxybenzimidazole, N-[2-(6-methoxybenzimidazol-1-yl))ethyl]-trifluoroacetamide is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:25])=[N:20][C:21]=1[CH2:22][CH2:23][CH3:24]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:25][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CCCc1nc(N)ccc1OC
Solvent: CC#N
Product: CCCc1nc(Nc2cc(Cl)nnc2C(=O)OCC)ccc1OC
Temperature: 70 °C
Yield: 40.5 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (1.9 g, 8.6 mmol) in acetonitrile (28.7 mL) was added 5-methoxy-6-propylpyridin-2-amine (1.43 g, 8.6 mmol) and the mixture heated at 70° C. for 72 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 10 to 60% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (1.22 g, 3.48 mmol, 41%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.58 (s, 1H), 8.84 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.58 (q, J=7.3 Hz, 2H), 3.88 (s, 3H), 2.87 (t, J=7.5 Hz, 2H), 1.84 (m, 2H), 1.52 (t, J=7.3 Hz, 3H), 1.05 (t, J=7.1 Hz, 3H); MS (EI/CI) m/z: 351.0 [M+H].
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:31])[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:32]1([CH:30]([N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=3[CH3:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])[CH3:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(C2=NN(C(C)c3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(C(C)c3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(1-Phenyl-ethyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 Smog) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.11 (d, 1H), 7.91 (t, 1H), 7.81 (t, 1H), 7.36 (m, 8H), 6.91 (m, 1H), 5.72 (m, 1H), 4.52 (s, 2H), 2.07 (s, 3H), 1.85 (d, 3H) ppm. MS calculated for C26H22FN3O4S—H: 490, observed: 490.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: CNc1ncc(Br)cc1N
Temperature: 70 °C

Procedure:
A suspension of (5-bromo-3-nitro-pyridin-2-yl)-methyl-amine (Stage 67.1.5, 4.58 g, 19.75 mmol) and tin dichloride dihydrate (Acros, Basel, Switzerland, 13.38 g, 59.3 mmol) in 200 ml of THF was heated at 70° C. for 220 min. The solvent was removed by evaporation and the residue taken in CH2Cl2 (100 ml) and 5 M aqueous NaOH (50 ml) and stirred until all the solid was dissolved. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a brown solid. (HPLC: tR 1.69 min (Method A); M+H=202, 204 MS-ES).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=[CH:15][CH:16]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[O:37][CH:38]=[CH:39][N:40]=1)CCC.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:37]1[CH:38]=[CH:39][N:40]=[C:36]1[C:2]1[C:10]2[C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=[CH:15][CH:16]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH:3]=1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(Br)cn3COCC[Si](C)(C)C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2ncco2)cn3COCC[Si](C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of N-(3-(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (249 mg, 0.51 mmol) in toluene (10 mL) under nitrogen, was added 2-(tributylstannyl)-1,3-oxazole (548 mg, 1.53 mmol), Pd2(dba)3 (93 mg, 0.10 mmol), and X-Phos (95 mg, 0.20 mmol). The resulting solution was stirred overnight at 60° C. and then concentrated in vacuo, and the resulting crude reaction was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-100% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-(oxazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C25H30N5O3Si [M+H]+: 476, found 476.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH:17]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[C:26]1([CH:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[N:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCC2c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2c3ccccc3CCC2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (0.6 g, 1.5 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (1.1 ml) was added. The mixture was stirred at ambient temperature for 4 h and excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The mixture was dried (MgSO4) and the solvent evaporated in vacuo to give a residue which was re-evaporated with acetone and recrystallised from acetone. This afforded 0.5 g of the title compound as a solid.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[NH2:16]>>[CH2:2]([C:1]1[NH:16][C:15]2[CH:14]=[CH:13][C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:21][CH2:22]3)=[CH:11][C:10]=2[N:9]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1N
Reactant: CCCCCC(=O)O
Product: CCCCCc1nc2cc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2[nH]1
Yield: 57 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-hexanoic acid in place of butyric acid to react with [4-(3,4-diaminophenyl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a yellow syrup in 57% yield (0.347 g). 1H NMR (300 MHz, CDCl3) δ 8.8 (br., s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64-7.45 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 6.99 (s, 1H), 6.87 (dd, J=1.9, 8.7 Hz, 1H), 4.00-3.91 (m, 2H), 3.33 (t, J=4.8 Hz, 2H), 3.15 (t, J=5.1 Hz, 2H), 3.05-2.95 (m, 2H), 2.82 (t, J=7.7 Hz, 2H), 1.85-1.70 (m, 2H), 1.33-1.16 (m, 4H), 0.79 (t, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 155.3, 147.4, 138.4, 134.5, 134.0, 132.3, 129.3, 127.2, 127.1, 126.8, 126.8, 126.7, 126.6, 125.4, 121.8, 115.4, 115.3, 114.9, 102.3, 51.3, 51.1, 47.3, 41.9, 31.4, 29.1, 27.9, 22.3, 13.9. MS (ES+) m/z 445.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:24]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=2[F:15])(=[O:25])=[O:26])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1ccc(S(=O)(=O)Cl)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cncc(Br)c2)c(F)c1
Yield: 75.9 %

Procedure:
5-Bromopyridin-3-amine (500 mg, 2.89 mmol) was dissolved in dichloromethane (14 ml) and pyridine (4 ml) was added. To this mixture 2-fluoro-4-methoxybenzene-1-sulfonyl chloride (1 g, 4.45 mmol) was added dropwise and the mixture stirred at reflux for 5 h. Once at room temperature, the reaction mixture was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 50% DCM/AcOEt) to give 792 mg (76% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][S:30][CH2:31][CH3:32])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:43])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][S:30]([CH2:31][CH3:32])=[O:43])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCSCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCS(=O)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 60 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystallization from acetonitrile to afford 0.05 gm of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[N:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=3)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:30]1[N:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([NH2:14])[CH2:20][CH2:19]1)=[CH:33]2
Reactant: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)cc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](N)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (6.33 mL, 82.2 mmol, 20 eq) is added at room temperature to a stirred solution of {trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.65 g, 4.11 mmol, 1.0 eq) in dichloromethane (100 mL). After 2 hours stirring at room temperature, the reaction mixture is partitioned between saturated sodium hydrogen carbonate aqueous solution and dichloromethane and the pH value is about 10. The combined organic layers are dried over sodium sulfate and concentrated to afford trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine as a yellow solid (1.24 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(F)cc1
Reaction time: 15 h

Procedure:
The ester from step 1 was reduced by dissolving in THF (0.15 M) and treating with LiBH4 (5 eq.) and stirring for 15 hours. The reaction mixture was quenched with water and extracted with DCM, the organic layer dried (Na2SO4) and concentrated to provide oily 2-(4-fluorophenyl)-2-methylpropan-1-ol: 1H NMR (600 MHz, CDCl3) δ 7.31-7.34 (m, 2 H), 6.99-7.02 (m, 2 H), 3.58 (d, J=5.8 Hz, 2 H), 1.30 (s, 6 H).
Reaction SMILES: C[N:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]1=[O:12].Cl[Si](C)(C)[CH3:15]>CO>[CH3:15][O:11][C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[NH:2][C:3](=[O:12])[CH:4]=1)=[O:10]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(C(=O)O)cc(=O)n1C
Solvent: CO
Product: COC(=O)c1cc(C)[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 75.5 %

Procedure:
1,6-Dimethyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (1.0 g, 6.5 mmol) was suspended in dry methanol (8 mL) and chlorotrimethylsilane (2.8 g, 26 mmol) was added at room temperature. The reaction was stirred for 36 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of dichloromethane/methanol (25 mL) and saturated aqueous sodium bicarbonate (25 mL) was added. A precipitate formed which was filtered off and washed with water and MTBE and air-dried. The filtrate was diluted with methanol/dichloromethane and water and the layers were separated. The aqueous layer was extracted once more with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered and concentrated. Both the previously precipitated material and the concentrated organic layer consisted of product and were combined to afford of the title compound (820 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[NH:8][C:9]2[C:13]([C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[N:8]([CH2:38][C:35]2[CH:34]=[CH:33][C:32]([C:31]([O:30][CH3:29])=[O:40])=[CH:37][CH:36]=2)[C:9]2[C:13]([C:14]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(Cc2ccc(C(=O)OC)cc2)c1=O
Yield: 51 %

Procedure:
The compound was prepared from 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (40) and methyl-4-bromomethylbenzoate by applying general procedure A. Yield 51%; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 3.30 (m, 4H), 3.82 (m, 7H), 4.27 (q, J=7.2 Hz, 2H), 5.28 (s, 2H), 7.12 (d, J=3.2 Hz, 1H), 7.16 (dd, J=5.2, 3.2 Hz, 1H), 7.37 (m, 2H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 5.2 Hz, 1H), 7.91 (m, 2H), 8.13 (d, J=3.2 Hz, 1H) ppm; MS m/z=565 amu (M++1). Anal. (C28H27N3O6S2) C, H, N.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[C:20]1([Mg]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)(=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (8.0 g, 29.4 mmol) in THF (25 mL) was added PhMgCl (8.0 g, 58.8 mmol) dropwise at 0° C. After stirring at rt for 2 h, the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to afford tert-butyl 4-benzoylpiperidine-1-carboxylate (5 g, 59% yield) as a pale yellow solid which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:5]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:4]2[NH:3]1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>ClCCl>[NH:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C@H:5]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:4]3[NH:3][C:2]2=[O:1])[CH2:12][CH2:11]1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)NC3CCCCC32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H]2CCCC[C@@H]2N1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution tert-butyl 4-(2-oxooctahydro-1H-benzimidazol-1-yl)piperidine-1-carboxylate (1 g) in dichloromethane (20 mL) was added with TFA (5 mL) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to provide the titled compound as its TFA salt. The salt was then transformed to freebase by MP-carbonate and used without any purification. MS (M+1): 224.25