Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>N1C=CC=CC=1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Reactant: COCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in pyridine (2 mL) and triethylamine (1 mL) at room temperature was treated with 2-methoxyethyl chloroformate (0.2 mmol), stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane) to provide the desired product. MS (ESI(−)) m/e 642 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.55 (d, 1H), 7.89 (dd, 1H), 7.75 (d, 2H), 7.30-7.40 (m, 2H), 7.31-7.25 (m, 2H), 7.21-7.07 (m, 2H), 6.90 (d, 2H), 4.16-4.12 (m, 2H), 3.63 (q, 2H), 3.54-3.43 (m, 4H), 3.31-3.20 (m, 8H), 3.23 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([O:25][C:26]([C:28]1[N:33]2[C:34](=[O:37])[CH:35]([NH2:36])[C@H:32]2[S:31][CH2:30][C:29]=1[OH:38])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:39]([CH2:41][CH2:42][C:43](Cl)=[S:44])#[N:40].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:33]2[C:34](=[O:37])[CH:35]([NH:36][C:43](=[S:44])[CH2:42][CH2:41][C:39]#[N:40])[C@H:32]2[S:31][CH2:30][C:29]=1[OH:38])=[O:27])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCC(=S)Cl
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 3.5 h

Procedure:
7-Amino-3-cephem-3ol-4-carboxylic acid benzhydryl ester p-toluenesulfonate salt [Helv. Chim. Acta 57, 1919 (1974)], (242 mg.) is dissolved in methylene chloride (5 ml.), cooled in an ice bath, and cyanomethylthioacetyl chloride (68 mg.) in methylene chloride (3 ml.) is added, followed by 125 μl of triethylamine. The mixture is stirred for 3.5 hours at 0°-5° and then is allowed to stand overnight in the refrigerator. After diluting with methylene chloride, the reaction mixture is washed with water, then with pH 4 buffer, and dried (Na2SO4). Solvent is removed in vacuo yielding the desired product as a oil (204 mg.); NMR (CDCl3, δ) 3.33 (m,CH2), 3.45 (s, NCCH2SCH2 --) 5.05 (d, J=4.5 Hz, H6), 5.65 (q. J=4.5, 9Hz, H7), 6.93 (s,CHφ2), 7.33 (s, aromatic H's), 7.80 (d, J=9Hz, NH); νmax (CH2Cl2) 3380, 3310, 2225, 1785, 1735, 1690 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9](Cl)=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][CH:5]=1.[CH3:16][O-:17].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([O:17][CH3:16])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(C(=O)OC)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cncc(C(=O)OC)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of 6.3 g (27.5 mmol) of methyl-4-chloro-5-methoxycarbonyl-nicotinate in 100 ml of THF is added 6.48 ml (35 mmol) of a 5.4 m solution of sodium methoxide in methanol. The mixture is stirred for 10 minutes and evaporated. 100 ml of a 0.25M aqueous HCl is added to the residue. The solution is made basic with K2CO3 and extracted with ethyl acetate. The organic phase is dried and evaporated to give an oil which crystallised on cooling. There is obtained 6.2 g (quantitative yield) of a solid (M+1=226).
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([CH2:14][C:15]([O:17]C)=[O:16])[NH:5][C:6]([O:8][C:9]1([CH3:13])[CH2:12][CH2:11][CH2:10]1)=[O:7].CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:13][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:19])=[O:2])[CH2:14][C:15]([OH:17])=[O:16])=[O:7])[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(OC(=O)N[C@@H](CC(=O)O)C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 0.05 moles of aspartic acid dimethyl ester hydrochloride in 50 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 0.10 moles prepared according to the procedure of Example 1 is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-aspartic acid dimethyl ester. Saponification is accomplished by dissolving the ester in 50 ml. of methanol, water 50 ml. is added, and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo to afford N-(1-methylcyclobutyloxycarbonyl) aspartic acid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Cl:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:41]=[CH:40]2.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:15]3([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:19][CH2:20]3)[C:30](=[O:35])[CH2:31]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Triethylamine (253 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (258 mg) in dichloromethane (15 ml), 6-chloronaphthalene-2-sulfonyl chloride (196 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the colorless amorphous title compound (255 mg).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)#[CH:27]>C(#N)C.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>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:26]#[C:27][C:3]2[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[C:12]([CH3:24])[CH:11]=3)[C:4]=2[NH2:25])=[CH:29][CH:30]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4ccc(N)cc4)c3N)cc2C)cn1
Yield: 65.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mL)/triethylamine (7.72 mL), and 4-ethynylaniline (80.3 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (20.8 mg) and copper(I) iodide (7.16 mg) were sequentially added. The title compound (134 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:20])[CH2:17][S:18][CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C(=O)(O)[O-]>C(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([C:16](=[O:20])[CH2:17][S:18]([CH3:19])=[O:29])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CS(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1.75 h

Procedure:
1-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(methylsulfanyl)ethanone (15.00 g, 50.94 mmol) is dissolved in CH2Cl2 (100 mL) in a flame-dried flask under argon then cooled in an ice/H2O bath. mCPBA (85%, 10.45 g, 51.47 mmol) is added carefully, generating some gas evolution of H2. The reaction is stirred for 1.75 h while maintaining the bath temperature until the last 20 minutes when the bath is allowed to warm. The reaction is then poured into saturated bicarbonate, separated and extracted with 2× CH2Cl2. The organics are concentrated on a rotavap then dried under vacuum (being careful of foaming). This gives a light tan foam which is purified by flash chromatography on silica with 1.6 L 27.5% acetone in hexanes then 100% acetone. A white solid is obtained which can be crystallized with EtOAc/hexanes with refrigeration to give white crystals, mp=143.6°-144.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: BrCCCCCOc1cccc2ncccc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a stirred suspension of 5-hydroxyquinoline (10.0 g, 69.0 mmol) and 1,5-dibromo-pentane (23.9 g, 103.5 mmol) in N-methylpyrrolidinone (100 mL) was added potassium carbonate (14.7 g, 103.5 mmol). The resulting mixture was stirred at 90° C. for 4 h and then quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and then concentrated under vacuum. The residue was purified by silica gel chromatography to give 5-(5-bromo-pentyloxy)-quinoline (12.6 g, 42.8 mmol, 62%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].[N+:18]([O-])([OH:20])=[O:19]>FC(F)(F)C(O)=O>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1)=[O:4]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 30 g (0.121 mole) of the amide in 254 ml of trifluoroacetic acid at 0° under an argon atmosphere was added dropwise with stirring a solution of 7.5 ml (0.12 mole) of conc. nitric acid in 56 ml of trifluoroacetic acid. The reaction mixture was stirred at 0° for 1/2 hour and at room temperature for 2 hours. The solvents were evaporated. The residue was dissolved in ethyl acetate which was extracted with 5% hydrochloric acid, dilute sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate and activated charcoal. After filtering, the solvents were removed to give 34.8 g (98%) of crude (2-trifluoroacetamidoethyl)-3-nitro-4-methoxybenzene which was an amber-colored solid. This material was recrystallized from 400 ml of 1:3 ethyl acetate-hexane to give 25.3 g (71.5%) of the product, m.p. 92.5°-93.0°. The mother liquors were concentrated and recrystallized to give a second crop, 4.59 g (13%), m.p. 90°-92° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2)[CH:4]=1.[OH-].[K+]>O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: COC(=O)Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 12.40 g of methyl [p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate, 30 ml of 20% KOH and 10 ml of water is refluxed overnight. After dilution with 250 ml of water, the clear orange solution is acidified and extracted with two 50 ml portions of chloroform. The combined organic extracts are washed with two 50 ml portions of water, saturated brine, and dried over MgSO4. Evaporation of the solvent affords white crystals, mp 61°-63° C (from petroleum ether). Recrystallization from petroleum ether affords colorless blades, mp 61°-62.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]C(OC(C)(C)C)=O)[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(C)c([N+](=O)[O-])cc1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (62.5 g, 276 mmol), K2CO3 (20.0 g, 145 mmol), and DMF (100 mL) was heated with stirring in a hot water bath to 90° C. for 1 h. Gas evolution was noted during the heating period and had ceased after 1 hour. The mixture was poured into stirred ice water (600 mL), with washing of the reaction flask with a small volume of acetone. The resulting precipitate was collected by filtration and air dried to give 2-methoxy-3,6-dimethyl-5-nitropyridine (48.5 g, 96% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.08 (S, 1H), 4.02 (s, 3H), 2.76 (d, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.37, 151.63, 139.44, 135.02, 119.39, 54.45, 24.18, 15.16. An analytical sample was recrystallized from hexanes to give tan needles: mp 85.9-90.5° C. Anal. calcd. for C8H10N2O3: C, 52.74, H, 5.53, N, 15.37. Found: C, 52.82, H, 5.28, N, 15.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][N:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:34][C:33]4[CH:32]=[N:31][C:30]([O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:37][CH:36]=4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: COCCOc1ccc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCOc1ccc(CN2CCC[C@@H](CN3CCN(C(=O)Nc4ccc(Cl)c(Cl)c4)CC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a suspension of the hydrochloride salt of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (442 mg, 1.00 mmol) in dichloromethane (40 ml) was added 6-(2-methoxyethoxy)nicotinaldehyde (199 mg, 1.00 mmol) and the cloudy mixture stirred at room temperature for 10 minutes. Polymer supported sodium triacetoxyborohydride (555 mg, 1.50 mmol) was added and the reaction stirred at room temperature overnight. The mixture was filtered, the filtrate washed with water (20 ml), organic extract dried (Na2SO4), filtered and evaporated to an oil. Flash column chromatography (10 gram Isolute silica column eluting; CH2Cl2 to 10% MeOH/CH2Cl2) yielded N-(3,4-dichlorophenyl)-4-[((3R)-1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}piperidin-3-yl)methyl]piperazine-1-carboxamide (145 mg, 27%) as a white foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]([CH3:18])[CH:11]=[C:10]2[C:19]1[N:29]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2=[N:23][CH:24]=[CH:25][C:26]([CH2:27]O)=[C:21]2[CH:20]=1.C(=O)([O-])O.[Na+]>CN(C=O)C.ClCCl>[Cl:3][CH2:27][C:26]1[CH:25]=[CH:24][N:23]=[C:22]2[N:29]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:19]([C:10]3[C:9]4[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH3:5])[CH:8]=4)[N:12]([CH3:18])[CH:11]=3)=[CH:20][C:21]=12
Reactant: COc1cc2c(-c3cc4c(CO)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(CCl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 4 h

Procedure:
0.089 cm3 of thionyl chloride and five drops of DMF are added to a solution of 0.4 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol in 4 cm3 of dichloromethane, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 4 hours. Ice is added and the reaction medium is then neutralized with saturated sodium hydrogen carbonate solution. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/ethyl acetate 97.5/2.5 by volume as eluent), 0.234 g of 4-chloromethyl-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:18])=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:25]1([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37](=[O:40])[CH2:38]Br)=[O:31])[CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:38][C:37]([N:33]2[CH2:34][CH2:35][CH2:36][C@H:32]2[C:30](=[O:31])[NH:29][CH:25]2[CH2:28][CH2:27][CH2:26]2)=[O:40])[C:13]2[C:8](=[CH:9][C:10]([CH3:18])=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1C(=O)CBr
Reactant: CCOC(=O)c1cc(O)c2cc(Cl)c(C)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2cc(Cl)c(C)cc2n1

Procedure:
To a solution of 1.1 g 6-Chloro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 25 ml DMF were added 2.7 g of cesium carbonate followed by dropwise addition of a solution of 1.8 g (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclobutylamide in 25 ml DMF over a period of 3 h. After this time another portion of cesium carbonate (700 mg) and (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclobutylamide (700 mg) were added over 1.5 h. The mixture was evaporated, diluted with DCM and washed with aqueous LiCl (4%). The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation. Yield: 3.3 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:16][C:17](OC(C)(C)C)=O)=[CH:11][CH:10]=2.[C:24]1([C:30]2[N:35]=[N:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:16][C:17]1[N:34]3[N:35]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:31]=[CH:32][C:33]3=[N:36][N:37]=1)=[CH:11][CH:10]=2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (0.080 g, 0.25 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.094 g, 0.50 mmol), HYDROCHLORIC ACID (0.063 ml, 0.76 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 15 min. at 140° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the precipitate was collected via filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=60%:37%:3%, Flow=30 mL/min) to afford the desired product as light yellowish solid. MS m/z: 412.3 (M+H). Calc'd. for C24H21N5O2—411.45.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCCCCC(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 66.7 %

Procedure:
In a vessel sufficiently replaced with nitrogen, 0.40 g (3.0 mmol) of (-)-2-fluoroheptanol and 1.00 g (13 mmol) of dry pyridine were placed and dried for 30 min. under cooling on an ice bath. Into the solution, 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride was added, and the mixture was stirred for 5 hours. After the reaction, 10 ml of 1N-HCl was added, and the resultant mixture was subjected to two times of extraction with 10 ml of methylene chloride. The extract liquid was washed once with 10 ml of distilled water and dried with an appropriate amount of anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 0.59 g (2.0 mmol) of (+)-2-fluoroheptyl p-toluenesulfonate.