Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:16]#[N:17])=[CH:13][NH:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:16]#[N:17])=[CH:13][N:14]([CH3:21])[CH:15]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc(-c2c[nH]cc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cn(C)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred solution of 4-(4-methoxycarbonylphenyl)-1H-pyrrole-3-carbonitrile (3.00 g) in N,N-dimethylformamide (25 ml) was added sodium hydride 60% oil dispersion: 559mg) at ambient temperature and the stirring was continued for half an hour at the same temperature. Iodomethane (1.99 g) was added to the mixture, and was stirred at ambient temperature for two hours. The reaction mixture was poured onto ice water and extracted with ethyl acetate and washed with 7% aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethanol to give 4-(4-methoxycarbonylphenyl)-1-methylpyrrole-3-carbonitrile (2.78 g) as pale yellow needles.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([O:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[C:4]([OH:6])=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.[F:30][C:31]([F:35])([F:34])[CH2:32]O.Cl>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]([O:7][CH:3]([C:4](=[O:6])[O:5][CH2:32][C:31]([F:35])([F:34])[F:30])[C:2]([F:13])([F:14])[F:1])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OC(C(=O)O)C(F)(F)F
Reactant: OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OC(C(=O)OCC(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, 3.18 g (15 mmol) of 3,3,3-trifluoro-2-(methacryloyloxy)propionic acid was added to 60 mL of a solution of 6.8 g (16.5 mmol) of DCC and 0.37 g (0.003 mol) of DMAP in dichloromethane, and 1.78 g (18 mmol) of 2,2,2-trifluoroethanol was added thereto at 0° C. The temperature of the mixture was equilibrated to the room temperature, and the mixture was stirred for 3 hrs. After disappearance of the raw material was confirmed by TLC, the reaction liquid was cooled to 0° C., and the reaction was stopped by adding 1 N hydrochloric acid. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times, and the organic layer thus obtained was washed with water twice. Thereafter, purification by column chromatography gave 2.65 g of intended 1,1,1-trifluoro-3-oxo-3-(2,2,2-trifluoroethoxy)propan-2-yl methacrylate (M-6) (yield: 60%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14][C:15](=O)[CH3:16])=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=[O:3])[CH3:2].[CH3:35][Mg+].[Br-]>C1COCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[C:9]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])=[N:8][C:7]3[N:6]([CH3:33])[C:5](=[O:34])[C:4]4[C:1]([CH3:2])([CH3:35])[O:3][C:15]([CH3:16])=[N:14][C:13]=4[C:12]=3[CH:11]=2)=[CH:23][CH:22]=1
Reactant: C[Mg+]
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1=Nc2c(c(=O)n(C)c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc23)C(C)(C)O1

Procedure:
To the product of Example 1 (59.5 mg) in THF (2 mL) at 0° C. was added 0.52 mL MeMgBr solution (1.4 M, 75% toluene/25% THF). After 10 min the reaction was quenched with saturated aqueous NH4Cl and then diluted with EtOAc. The solution was washed with 10% aqueous NaHSO4 followed by aqueous NaHCO3/NaOH (4:1) before drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with 15% EtOAc in hexane affording the title compound. HPLC/MS: 512.0 (M+1), 514.0 (M+3); Rt=5.14 min.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[CH:16]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[S:14][CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[ClH:25].[N:18]1([CH2:17][C:15]2[S:14][CH:13]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1=NS(=O)N=C1NCCSCc1csc(CN2CCCCC2)c1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCSCc1csc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A suspension of 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (6.1 g; 15.8 mmoles) [prepared according to the procedure of U.S. Pat. No. 4,374,248] in 80 ml of methanol was treated with 10.5 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 50 ml of 1-propanol, filtered and dried to give 5.86 g (83%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 201°-214° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:32])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.3 %

Procedure:
To 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.34 g, 1 mmol) in DCM (5.00 mL) was added 5-(methyloxy)-5-oxopentanoic acid (146.14 g, 1 mmol), HBTU (417.16 g, 1.1 mmol), and TEA (202.38 g, 2 mmol). This was stirred at room temperature for 17 h. The reaction was quenched with H2O (1 mL). The organic layer was loaded onto a Redisep silica gel cartridge (12 g) and purified by CombiFlash Chromatograph to afford the title compound (0.4499 g, 104.26%). LC-MS m/z 432 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(-c2cccnc2N2CCNCC2)nc1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C(=O)CN2CCN(c3ncccc3-c3ccccn3)CC2)c1

Procedure:
A stirred mixture of 2-bromo-1-(3-methoxyphenyl)ethanone (0.5 g, 2.2 mmol), 1-[3-(2-pyridyl)-2-pyridyl]piperazine (0.6 g, 2.6 mmol) and K2CO3 (3 mmol) in acetonitrile was refluxed overnight. After cooling, the mixture was evaporated to dryness and H2O (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2×30 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 9:1, as eluent) to afford pure compound in quantitative yield. 1H NMR (CDCl3): δ 2.52 (br s, 4H), 2.93 (app t, 4H), 3.78 (s, 2H), 3.80 (s, 3H), 6.84-6.90 (m, 3H), 7.04-7.10 (m, 2H) 7.20-7.26 (m, 1H), 7.71 (dd, 1H, J=1.6, 7.4 Hz), 7.83 (dt, 1H, J=1.9, 7.4 Hz), 7.88-7.92 (m, 1H), 8.27 (dd, 1H, J=1.9, 4.9 Hz), 8.69-8.72 (m, 1H). GC-MS m/z 387 (M+1, 2), 390 (M+, 8), 254 (100), 184 (63).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:26]([N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][CH2:35]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][CH2:35][O:16][C:15]([C:6]1[C:5](=[O:18])[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH:7]=1)[CH:11]=[C:2]([O:1][CH2:35][CH2:34][N:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:3]=2)=[O:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cn2c3c(cc(O)cc3c1=O)CCC2
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCCN(Cc1ccccc1)Cc1ccccc1)c1cn2c3c(cc(OCCN(Cc4ccccc4)Cc4ccccc4)cc3c1=O)CCC2
Temperature: 60 °C
Yield: 88.1 %

Procedure:
9-Hydroxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (GB1417129) (0.905 g, 3.69 mmol) was suspended in dry DMF (50 mL). To this was added potassium carbonate (3.06 g, 22 mmol) and dibenzyl-(2-chloroethyl)amine hydrochloride (2.37 g, 8 mmol). The mixture was heated at 60° C. for 16 h, then more potassium carbonate (0.55 g) and dibenzyl-(2-chloroethyl)amine hydrochloride (1.18 g, 4 mmol) were added. After a further 25 h at 75° C. the mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried and evaporated under reduced pressure. The crude product (4.0 g) was purified by chromatography on silica gel (100 g), eluting with 0-4% methanol in dichloromethane, to give the title compound (2.25 g, 89%); ESMS m/z 692 [M+H]+ (100%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)COc1cccc2c1CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCN(S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of ethyl 2-((1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetate (300 mg, 1.28 mmol) and Et3N (387 mg, 3.83 mmol) in DCM (25 mL) cooled in an ice-water bath was added MsCl (176.6 mg, 1.54 mmol) drop wise. The mixture was stirred at 25° C. for 16 h and then quenched with aq.NH4Cl. The mixture was extracted with ethyl acetate and the combined organic layers were concentrated under vacuum to give the crude product (312 mg, 78%) which was used to the next step without purification.
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:21][CH2:20]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 63.7 %

Procedure:
To a flask containing a suspension of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.202 g, 0.344 mmol) in 1,4-dioxane (3 mL) was added Hunig's base (0.421 mL, 2.408 mmol) followed by morpholine (0.150 mL, 1.720 mmol). The mixture was heated to 100° C. for 15.5 h then was cooled to rt. The mixture was directly purified by flash chromatography using a 0-40% ethyl acetate in hexanes gradient and a 25 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-morpholinoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.148 g, 0.219 mmol, 63.7% yield) as a white foam. LCMS: m/e 675.8 (M+H)+, 2.06 min (method 1).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[ClH:19]>>[ClH:19].[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCN1CCN(c2ccc(C(=O)OC)cc2)CC1
Agent: Cl
Product: CCN1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 2 °C

Procedure:
4-(4-Ethyl-piperazin-1-yl)-benzoic acid methyl ester (15 mmol) is dissolved in 4N HCl (35 ml) and heated under reflux for 8 hours. The mixture is cooled in an ice bath to 0-4° C. and the solid material formed is filtered off, washed with acetone and dried (vacuum). A grey powder with mp. >270° C., Rf=0.08 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH3:14])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:15]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:18][O:17][C:15](=[O:16])/[CH:19]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH3:14]
Reactant: CC/C(=C\C=O)c1ccc(OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-pentenal (7.1 g) was treated with (carbomethoxymethylene)triphenylphosphorane (14 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) overnight at room temperature. The ester was isolated in the normal fashion to afford 8 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadienoic acid methyl ester as an oil.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[CH2:35]([SH:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>C1(C)C(C)=CC=CC=1>[CH2:35]([S:43][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCS
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: CCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 172.5 °C
Reaction time: 4.5 h

Procedure:
To a 500-mL, round-bottomed flask are charged 30 g (0.083 mol) of 5-chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, 65 g (0.65 mol) of N-methyl-pyrrolidinone, 13.5 g (0.21 mol) of potassium hydroxide pellets and 25 g (0.16 mol) of n-octyl mercaptan are added. The mixture is agitated and the resultant slurry is heated to 170-175° C. and held at that temperature for 4.5 hours. The reaction mixture is then cooled to 120° C. at which time 150 g of xylene and 90 g of 10% aqueous hydrochloric acid are added. The brine layer is split off and the xylene phase at 90° C. is washed three times with water. Xylene is partially distilled under vacuum and then 80 g of methanol are added. The temperature of the reaction mixture is reduced to ambient temperature to induce crystallization. The yellow slurry formed is further cooled to 0-5° C. and filtered. The wetcake is washed with 100 g of cold methanol and dried to constant weight. The title compound is obtained as yellow needles in a yield of 37.7 g (97%). The structure of the product is verified by 1HNMR and mass spectroscopy.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.Cl.Cl.[CH2:36]([NH:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([NH:43][NH:44][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNCc1ccccc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NNCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added first 2.5 g triethylamine and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 5.0 g triethylamine followed by 4.9 g benzylhydrazine dihydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide solution and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried with anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions* are collected, and evaporated i.v. to dryness to yield the title product as a viscous oil.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([C:33](O)=[O:34])[C:12]2[CH2:13][C:14]([CH3:32])([CH3:31])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[C:12]2[CH2:13][C:14]([CH3:31])([CH3:32])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2c(cc(Cl)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cc(Cl)cc2C(=O)NS(C)(=O)=O)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (494 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (48 mg, 20%) as a white solid: LC/MS m/e calcd for C23H28ClN3O4S (M+H)+: 478.01, observed: 478.1.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)(=[O:6])=[O:5])[CH3:2].[CH3:17][C:18]([C:26]1[S:30][C:29]([NH2:31])=[N:28][N:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>>[CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([NH:31][C:29]1[S:30][C:26]([C:18]([CH3:19])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])=[N:27][N:28]=1)=[O:14])(=[O:5])=[O:6])[CH3:2]
Reactant: CC(C)(c1ccccc1)c1nnc(N)s1
Reactant: CCNS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1ccc(F)c(C(=O)Nc2nnc(C(C)(C)c3ccccc3)s2)c1
Yield: 15.6 %

Procedure:
To the mixture of 5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid (24.7 mg, 0.1 mmol), prepared according to Scheme 4, and above crude 5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-amine (21.9 mg, 0.1 mmol) in 2.0 mL of mixed solvents (DCM:DMF=10:1) was added EDC (19.2 mg, 0.1 mmol) and HOAt (13.6 mg, 0.1 mmol). The resultant mixture was stirred at room temperature for overnight, and then concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 10% B to 90% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-[(ethylamino)sulfonyl]-2-fluoro-N-[5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-yl]benzamide (7.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[CH:6]=1)=[O:4].[Br:16]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([Br:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[CH:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1cc2c(OC)cccc2s1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2c(OC)ccc(Br)c2s1

Procedure:
The title compound was prepared as an off-white solid (m.p. 112° C.) according to the literature by treatment of 4-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester with bromine in chloroform at 0° C. to 20° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:21]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-fluoro-4-(trifluoromethyl)benzoic acid (1.5 g), THF (25 mL), oxalyl chloride (0.5 mL) and ammonia gas to afford 1.35 g of the product. 1H NMR (300 MHz, DMSO d6): δ 7.65 (d, J=8.4 Hz, 1H), 7.77-7.84 (m, 3H), 7.96 (br s, 1H); MS (m/z): 208.06 (M+).