Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:24]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
1-(4-Fluorophenyl) piperazine (2.8 mmol) was dissolved in 10 mL of CH2Cl2. Triethylamine (5.5 mmol) was added to it and the reaction was cooled to 0° C. Chloroacetylchloride (4.2 mmol) was added to it slowly, and the reaction was warmed to room temperature overnight. After completion, the reaction was quenched with brine solution and reaction mixture was extracted with methylene chloride. The combined organic phases were washed with brine and water and dried over magnesium sulfate. The solvent was evaporated and the compound purified by column chromatography (hexane/ethyl acetate=1.5/1) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.9–7.2 (m, 2H), 6.82–6.92 (m, 2H), 4.1 (s, 2H), 6.62–3.8 (m, 4H), 3.46–3.6 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 158, 156.2, 148.5, 118.2, 116.8, 52.6, 52.2, 48, 46, 42.1, 40.6.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[N:15]1([CH2:21][CH2:22][C:23]2[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[C:25]([C:32](Cl)=[O:33])[N:24]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[N:1]1([C:32]([C:25]2[N:24]=[C:23]([CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=23)=[O:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nc(CCN2CCOCC2)n2ccccc12)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of morpholine (0.050 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (85 mg, 55%). 1H NMR (DMSO-d6) δ 8.35 (1H), 8.05 (1H), 7.08 (1H), 6.85 (1H), 3.65 (4H), 4.05 (4H), 3.53 (4H), 3.18 (2H), 2.75 (2H), 2.45 (4H); m/z (M+H)=345.21.
Reaction SMILES: C(NCC(C)C)C(C)C.[CH3:10][C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C1(C)C=CC=CC=1>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH:13]([CH:14]=[O:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH3:10]
Reactant: CC(C)(C)CCC=O
Reactant: COC(=O)CBr
Agent: CC(C)CNCC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(C=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked flask fitted with a Dean-Stark apparatus under argon, a solution of diisobutylamine (4.62 ml from Acros), 4,4-dimethyl pentanal 362 (2.5 g, 0.021 mol.) in toluene (20 ml) is heated at 130° C. for 2 h and water is extracted. The yellow solution is cooled down to room temperature and methyl bromoacetate (3.7 g, 0.024 mol.) is added in one time. The pink solution is stirred at room temperature overnight and 1 h at 90° C. Water (10 ml) is added at this temperature and after 1 h, the solution is cooled down to room temperature. The organic layer is washed with HCl 1N, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford an oil which is distilled under reduced pressure (1 mmHg) to afford 5,5-dimethyl-3-formyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mol, Teb (1 mmHg): 69-71° C.). The aldehyde esters are then used in the reductive amination step. Alternatively, alkylation with ethyl bromoacetate can be conducted in the presence of toluene-acetonitrile 1/1 (v/v) as solvent. The final aldehyde can also be distilled under reduced pressure.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:30]([Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O:6][Si:36]([C:30]([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31])([CH:41]([CH3:42])[CH3:43])[CH:38]([CH3:39])[CH3:40])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 17.2 g (0.2 mol) of methacrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 47.0 g (0.20 mol) of thexyldiisopropylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 43.2 g of a fraction having a boiling point of 92-97° C./0.13 kPa.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH2:18](Br)[CH3:19]>>[CH2:18]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH3:19]
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Reactant: CCBr
Product: CCOCCCc1cc(C(=O)O)cc(OC)c1OC
Yield: 72 %

Procedure:
3-(3-Ethoxypropyl)-4,5-dimethoxybenzoic acid was prepared from 3-(3-hydroxypropyl)-4,5-Dimethoxybenzoic acid (Example 10, Step 1) and ethyl bromide by following Method I in 72% yield. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1N2CCN(CC2)C1.CN(C=O)C>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2
Reactant: C1CN2CCN1CC2
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 92.5 °C
Yield: 989.4 %

Procedure:
To a solution of 5-bromoindole (1.0 g, 5.10 mmol) in DMC (10 mL), DABCO (0.057 g, 0.51 mmol) is added followed by DMF (1 mL). The resulting solution is heated to 90-95° C. for 5 h. The reaction is cooled to RT, and diluted with ethyl acetate (EtOAc, 50 mL) and H2O (50 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×50 mL) and H2O (4×50 mL). The organic layer is dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under vacuum to give 5-bromo-1-methylindole (about 1.06 g, 99%) as a golden colored solid: 1H NMR (CDCl3) δ7.72 (d, 1H), 7.26 (dd, 1H), 7.13 (d, 1H), 7.00 (d, 1H), 6.39 (d, 1H), 3.71 (s, 3H); 13C NMR (CDCl3) δ135.3, 130.1, 129.9, 124.2, 123.2, 112.6, 110.6, 100.5, 32.9; MS m/z 209 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Br:30][CH:31](C)[C:32](Cl)=O.[CH3:36][OH:37]>CCOCC>[Br:30][CH2:31][CH2:32][C:36]([NH:28][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:26](=[O:27])[N:18]([CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]2=[O:29])=[O:37]
Reactant: CO
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: CC(Br)C(=O)Cl
Solvent: CCOCC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCBr)c3C2=O)ccc1OC
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (0.80 g, 1.9 mmol) and 2-bromopropionyl chloride (0.8 mL, 7.9 mmol) was heated at 100° C. for 30 min. The mixture was cooled to room temperature. Methanol (10 mL) was added to the mixture. The solvent was removed in vacuo to give an oil. The oil was stirred in ether (10 mL) for 1 day. The resulting suspension was filtered and the solid washed with ether to give 3-bromo-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide as a yellow solid (0.84 g, 80% yield). A portion of the isolated bromide (620 mg, 1.2 mmol) and dimethylamine (2 mL, 2M in methanol, 4 mmol) was stirred at room temperature for 3 h. The resulting suspension was filtered and washed with methanol to yield the crude product as a yellow solid. The solid was purified by column chromatography to give 3-(dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide as a white solid (180 mg, 30% yield): mp, 163-165° C.; 1H NMR (CDCl3) δ 1.47 (t, J=6.9 Hz, 3H, CH3), 2.38 (s, 6H, CH3), 2.59 (t, J=5.7 Hz, 2H, CH2), 2.70 (t, J=5.9 Hz, 2H, CH2), 2.82 (s, 3H, CH3), 3.78-3.85 (m, 1H, CHH), 3.86 (s, 3H, CH3), 4.10 (q, J=7.0 Hz, 2H, CH2), 4.49 (dd, J=9.8, 14.6 Hz, 1H, CHH), 5.86 (dd, J=4.9, 9.7 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.10-7.13 (m, 2H, Ar), 7.48 (d, J=7.2 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.82 (d, J=8.4 Hz, 1H, Ar), 11.36 (s, 1H, NH); 13C NMR (CDCl3) δ 14.62, 34.85, 41.49, 44.65, 48.74, 54.31, 55.01, 55.88, 64.44, 111.43, 112.52, 115.99, 117.93, 120.39, 120.08, 129.52, 131.42, 135.59, 137.33, 148.55, 149.67, 168.00, 168.16, 171.86; Anal Calcd for C25H31N3O7S: C, 58.01; H, 6.04; N, 8.12. Found: C, 57.75; H, 5.86; N, 7.91.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:30])[CH2:14][C:15]([O:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:30])[CH2:14][C:15]([O:17][CH2:18][O:19][C:20]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:21])=[O:16]
Reactant: CC(C)CC(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CC(=O)OCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl 3-methylbutanoate (547 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 5 (310 mg, 49% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.86-0.94 (br. m, 8H), 1.17-1.38 (br. m, 3H), 1.64-1.72 (br. m, 2H), 1.83-1.91 (br. m, 2H), 1.96 (hept., J=7.2 Hz, 1H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.21 (d, J=6.8 Hz, 2H), 2.78-2.86 (br. m, 2H), 5.61 (s, 2H), 7.55 (t, J=5.6 Hz, 1H), 11.99 (br. s, 1H). MS (ESI) m/z 316.11 (M+H)+; 314.07 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=[N:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28](=[O:29])[C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[N:26][CH:25]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cncc(C(=O)O)c1
Product: Cc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-3-pyridinecarboxylic acid (CAN 3222-49-9) as starting materials; MS (EI) 422.1 (M+H)+.
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[C:11]3[CH2:28][S:27](=[O:30])(=[O:29])[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:12]=3[N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:14]=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:31][CH2:32][CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:31][CH2:32][CH2:33][N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[C:12]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[S:27](=[O:30])(=[O:29])[CH2:28][C:11]=3[C:10]([C:8]([N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)=[O:9])=[N:14]2)[CH2:16][CH2:17]1
Reactant: O=C(c1nn(C2CCNCC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: O=CCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(c1nn(C2CCN(CCCl)CC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(morpholin-4-ylcarbonyl)-1-piperidin-4-yl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide hydrochloride (100 mg; 0.23 mmol; 1 eq.), chloroacetaldehyde (31.13 mg; 0.24 mmol; 1.1 eq.) in DCE (4.2 ml) is added sodium triacetoxyborohydride (229.27 mg; 1.08 mmol; 1.4 eq) and the reaction mixture is stirred at 65° C. overnight. The reaction mixture is diluted with DCM and the organic phase is washed with a saturated aqueous solution of NaHCO3 then dried on MgSO4 and concentrated. The residue is purified by flash chromatography eluting from 100% to 30% AcOEt and MeOH to afford after concentration of the desired fractions of the title compound as a brown oil. HPLC (max plot) 89.6%; Rt 2.33 min.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])(O)=[O:2].P(C#N)(OCC)(OCC)=O.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CN(C)C=O.C(N(CC)CC)C>[CH2:38]([N:40]([CH2:41][CH3:42])[C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:26][CH:27]=1)=[O:7])=[O:2])[CH3:39]
Reactant: O=C(O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: CCNCC
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1-[4-(3-Carboxypropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) is dissolved in dimethylformamide (1 ml) and thereto is added dropwise diethyl cyanophosphate (0.25 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then cooled again with ice. Thereto are added dropwise a solution of diethylamine (0.11 g) in dimethylformamide (1 ml) and triethylamine (0.34 g). The mixture is stirred at room temperature for 16 hours. The solvent is distilled off under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethane. The organic layer is washed successively with diluted hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate), and recrystallized from n-hexane/ethyl acetate to give 1-[4-(3-diethylaminocarbonylpropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) as colorless scales, m.p. 165°-167° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(4-nitrophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-nitrophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [O:1]=[O+][O-].CC(C)=[CH:6][CH2:7][C:8]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1.CSC.C(N(CC)CC)C>C(Cl)Cl>[O:1]=[CH:6][CH2:7][C:8]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1
Reactant: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC=O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ozone was passed through a solution of 1-benzyl 3-ethyl 3-(3-methylbut-2-en-1-yl)piperidine-1,3-dicarboxylate (35.2 g, 0.0979 mol) in methylene chloride (800 mL) at −78° C. until the color of the solution turned blue. The reaction mixture was then flushed with nitrogen until the blue color dissipated. Dimethylsulfide (Aldrich, cat #: 274380) (14 mL, 0.19 mol) and triethylamine (26.5 mL, 0.19 mol) were added and the mixture was stirred at ambient temperature overnight. The volatile solvent were removed under reduced pressure and purified directly by flash chromatography on a silica gel column with 20% ethyl acetate in hexanes to afford the desired product in quantitative yield. LC/MS 334.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:40]([C:36]4[S:35][CH:39]=[CH:38][CH:37]=4)(=[O:42])=[O:41])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(=O)(=O)c4cccs4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A30 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), thiophene-2-sulfonyl chloride (9 mg, 0.049 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.07 (m,4H), 3.08 (s, 3H), 3.14 (m, 2H), 3.41 (m, 2H), 5.53 (m, 1H), 7.31 (m, 1H), 7.50 (m, 1H), 7.55 (m,1H), 7.83 (m, 2H), 7.95 (m, 2H), 8.37 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C20H21N5O7S3 539.06, found 540.2 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.Cl.[CH3:11][NH:12][O:13][CH3:14].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.CCOC(C)=O>[CH3:14][O:13][N:12]([CH3:11])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: O=C(O)C1CCOCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid 1 (4.0 g, 31 mmol) in DCM (65 mL) was added sequentially N,O-dimethylhydroxylamine hydrochloride (3.3 g, 34 mmol), 4-methylmorpholine (7.4 mL, 68 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.5 g, 34 mmol). The resulting mixture was stirred at RT for 18 h. At that time, the reaction was diluted with 1N HCl and EtOAc and stirred vigorously until both phases cleared. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120 g silica, 80 ml/min, 0% to 100% EtOAc/hexanes) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (4.3 g, 24.8 mmol, 81%). LCMS for 2 (conditions D): tR=1.12 min, m/e=174.3 (M+H, base).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].I[CH3:26].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:26])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 5.98 g) was added in portions to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 30, 10 g, 30 mmol) in dimethylformamide (100 mL) and the mixture was stirred at 0° C. for 30 min. Iodomethane (9 mL) was added in one portion and the mixture was stirred at room temperature for 30 min. Water (1.5 L) was added and the mixture was extracted with ether (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (240 mL) and aqueous sodium hydroxide (4M, 60 mL) was added. The mixture was heated under reflux for 1 h., cooled and the pH was adjusted to 1.0 with hydrochloric acid (2M). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the title compound (7.5 g, 72%). 1H NMR (360 MHz, CDCl3) δ 7.58 (1H, d, J 1.8 Hz), 7.44-7.48 (2H, m), 7.18-7.30 (4H, m), 3.53 (3H, s), 2.96-3.00 (2H, m), and 2.54-2.59 (2H, m).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.[N:32]1[C:41]2[C:36](=[CH:37][C:38]([NH2:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[C:26]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:27]=[CH:28][C:29]([C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:42][C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:32]=[CH:33][CH:34]=[CH:35]3)=[O:12])=[O:7])=[CH:30][CH:31]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=434.2.