Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:11][OH:12])[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH3:1][C:2]1([CH2:11][O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1
Reactant: CC1(CO)CCC2(CCCO2)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COCc2ccccc2)CCC2(CCCO2)O1
Yield: 54.1 %

Procedure:
A solution of 1.70 g of 2-methyl-1,6-dioxaspiro[4.4]nonane-2-methanol in 20 ml of dimethylformamide was treated sequentially with 0.60 g of 60% sodium hydride-mineral oil dispersion at 15°-25° C. for 1 hour and then with 1.71 g of benzyl bromide at 0°-25° C. for 1 hour. The resulting mixture was poured into 150 ml of water and extracted with diethyl ether. The ether extract was washed with water, dried and distilled to yield 1.40 g of the desired product as a colorless liquid, b.p. 105°-110° C. (0.3 torr.).
Reaction SMILES: [CH2:1]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(O[Na])(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[CH2:1]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[N:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C1CCNCC1
Reactant: COc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCC(N(C)Cc3ccccc3)CC2)cn1
Temperature: 90 °C
Yield: 36 %

Procedure:
N-Benzyl-N-methylpiperidin-4-amine (3.947 mmol, 1.0 eq.), 5-bromo-2-methoxypyridine (614 μl, 4.737 mmol, 1.2 eq.) and t-BuONa (757 mg, 7.894 mmol, 2.0 eq.) were dissolved in toluene (12 ml) and degassed with argon. Xantphos (136 mg. 0.237 mmol, 0.06 eq.) and Pd2(dba)3 (72 mg, 0.079 mmol, 0.02 eq.) were then added and the mixture was heated for 4 hours at 90° C. After monitoring by TLC, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 3% MeOH in DCM). Yield: 36% (450 mg, 1.447 mmol)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.O.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.C(N(CC)CC)C>[CH3:17][S:18]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.5 g) in dichloromethane (40 ml), triethylamine (2.8 ml) and methanesulfonyl chloride (1.2 ml) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution to separate two layers. Then, the aqueous layer was subjected to extraction with chloroform. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (2.8 g).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([NH:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10])[CH3:7]>C(O)(=O)C>[CH2:6]([NH:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([Cl:4])[C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:26])([F:27])[F:28])=[CH:20][N:19]=2)=[N:12]1)=[O:10])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Solvent: CC(=O)O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.35 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-4-chloro-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.35 g, yield: 92.1%). mp: 111-112° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.66 (s, 3H), 3.41 (dq, J=5.8 and 7.3 Hz, 2H), 6.85-7.10 (m, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.31 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:19](=[O:22])[NH:20][N:21]=2)[CH:8]=[C:9]([C:11]2(C(O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:10]=1)([CH3:3])[CH3:2]>CC(O)=O.O>[CH:11]1([C:9]2[N:10]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:6]3[N:7]([C:19](=[O:22])[NH:20][N:21]=3)[CH:8]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)Nc1nc(C2(C(=O)O)CCCC2)cn2c(=O)[nH]nc12
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1nc(C2CCCC2)cn2c(=O)[nH]nc12
Temperature: 25 °C

Procedure:
A solution of 20 mg of 1-(8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid in AcOH (3.0 mL) was warmed to 120° C. for 30 min. The reaction was cooled to ambient temperature and diluted with water. The mixture was extracted with EtOAc, the organic layer was washed with water (2×), dried over magnesium sulfate, filtered, and concentrated to leave the title compound as a tan solid. MS (M+H+)=262.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:16]2[C:25]3[S:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][C:21](=O)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2].[BH4-].[Na+].C(O)(C)(C)C>CO>[C:1]([C:3]1[CH:4]([C:16]2[C:25]3[S:24][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(-c3ccccc3)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c1SC(c1ccccc1)=CC2
Reaction time: 8 h

Procedure:
3 mmol of Ethyl 5-cyano-1,4-dihydro-2,6-dimethyl-4-(4-oxo-2-phenyl-4H-1-benzothiopyran-8-yl)-3-pyridinecarboxylate (DE 33 11 005) and 15 mmol of NaBH4 are initially introduced into 10 ml of t-butanol, 1.8 ml of MeOH are added at 60° C. and the mixture is kept at 65° C. for 8 hours. Customary working up gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@H:11]([NH:22][S:39]([CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:41])=[O:40])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C[C@H](NS(=O)(=O)Cc2ccccc2)c2csc(-c3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (330 mg, 0.80 mmol) in CH2Cl2 (6 mL) at 0° C. is added diisopropylethylamine (0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction mixture is stirred at room temperature for 14 hours. The mixture is diluted with CH2Cl2 and washed with sat. NaHCO3 followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica to afford 210 mg of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([F:25])[CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:25][CH:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)[CH3:24]
Reactant: CC(F)c1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(F)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 112 mg, 0.521 mmol), 4-chloro-6-(1-fluoroethyl)pyrimidine (Intermediate 21, 125 mg, 0.781 mmol) and DIPEA (0.182 mL, 1.041 mmol) were added together in N-methyl-2-pyrrolidone (3 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was heated at 100° C. for 1 hour and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (25 mg);
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:40]2[NH:44][NH:43][C:42](=[O:45])[CH2:41]2)[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH2:56][CH2:57][N:58]([CH2:60][CH2:61][CH2:62]O)[CH3:59])[CH:51]=[CH:52][C:53]=1[O:54][CH3:55]>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH2:56][CH2:57][N:58]([CH2:60][CH2:61][CH2:62][O:45][C:42]2[CH:41]=[C:40]([C:34]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=3)[NH:44][N:43]=2)[CH3:59])[CH:51]=[CH:52][C:53]=1[O:54][CH3:55]
Reactant: COc1ccc(CCN(C)CCCO)cc1OC
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Temperature: 20 °C
Reaction time: 48 h
Yield: 50.6 %

Procedure:
1.31 g of triphenylphosphine were dissolved in 15 ml of tetrahydrofuran. 1.6 ml of a solution of 0.8 ml of ethyl azodicarboxylate in 0.8 ml of toluene were added dropwise to the solution at a temperature of 5° C. After 5 minutes a solution of 1.1 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one in 10 ml of dimethylformamide was added dropwise. After 20 minutes a solution of 1.26 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propanol in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was subsequently stirred at 20° C. for 48 hours. The reaction mixture was then evaporated to dryness. The resulting crude product was purified by flash chromatography in accordance with the method described in Example 1E). 1.14 g of the title compound were obtained as an oily base. This base was converted as described in Example 1E), to the hydrochloride having a melting point of from 189° to 192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13])[O:5]COC.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23](=[S:24])[NH:1][C:2]2[CH:3]=[C:4]([OH:5])[C:9]([O:14][CH3:15])=[CH:10][C:11]=2[O:12][CH3:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCOc1cc(N)c(OC)cc1OC
Reactant: S=C=Nc1ccccc1
Product: COc1cc(OC)c(NC(=S)Nc2ccccc2)cc1O

Procedure:
(3-Amino-4,6-dimethoxyphenoxy)methoxymethane and phenyl isothiocyanate were treated in the same manner as described in Example 1 to give 3-(3-phenylthioureido)-4,6-dimethoxyphenol (melting point: 152°-154° C.).
Reaction SMILES: [Br:1][CH:2]([CH2:8][Br:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:6]([NH:5][C:3](=[O:4])[CH:2]([Br:1])[CH2:8][Br:9])=[O:7])=[CH:13][CH:12]=1
Reactant: O=C=NC(=O)C(Br)CBr
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 54 g of 2,3-dibromopropionyl isocyanate in 100 ml of benzene is added dropwise with cooling at 20° C. to a solution of 25 g of 4-chloroaniline in 250 ml of dry benzene. After stirring for 3 hours at 20° C., the suspension is diluted with 200 ml of petroleum ether, filtered and dried. Yield: 71.0 g, m.p.: 162° - 163° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[OH-].[Na+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[C:41]([O:50][CH2:51][CH3:52])(=[O:49])/[CH:42]=[CH:43]\[C:44]([O:46][CH2:47][CH3:48])=[O:45].C(O)C.NO>C(O)C>[OH:7][NH:6][C@H:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42][C:41]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NO
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 394.4 g (0.60 mols; 1.20 eq) of 25% aqueous hydroxylamine sulfate was placed in a 2-liter round-bottom flask equipped with a reflux condenser, thermometer, dropping funnel, mechanical stirrer, and cooling bath. To this was added, over about a thirty minute period, 94.1 g (1.20 mole) of 50% aqueous sodium hydroxide. Phenolphthalein indicator was added and the last of the caustic was added dropwise to the end point (pH of ~9.5). The temperature was kept below 40° C. Then 400 ml of ethanol was added; the sodium sulfate reaction product, which precipitated upon addition of the ethanol, was removed by filtration. Then 172.0 g (1 mole) of diethyl maleate was added to the ethanol-hydroxylamine solution, and the resulting homogeneous solution was stirred for 30 minutes. This latter reaction produced diethyl N-hydroxyaspartate in quantitative yield (>99%).
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([CH2:51][O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[NH:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:79]1(=[O:85])[O:84][C:82](=[O:83])[CH2:81][CH2:80]1>C1COCC1>[C:1]([O:20][CH2:21][C:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:51][O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[N:23]([CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])[C:79](=[O:85])[CH2:80][CH2:81][C:82]([OH:84])=[O:83])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)(COC(=O)CCCCCCC/C=C\CCCCCCCC)NCCS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)(COC(=O)CCCCCCC/C=C\CCCCCCCC)N(CCS(=O)(=O)O)C(=O)CCC(=O)O
Reaction time: 18 h

Procedure:
To 566 mg (0.553 mmol) of 2-[tris(oleoyloxymethyl)methylamino]-1-ethanesulfonic acid in 10 mL THF was added 410 mg (4.06 mmol) of triethylamine. After 5 min 96 mg (0.960 mmol) of succinic anhydride was added. The yellow solution was stirred for 18 h under reflux. The solvent was removed under reduced pressure. The residual oil was purified by chromatography on silica gel, eluted with an ethyl acetate/methanol gradient (25:75 vol/vol to 0:100 vol/vol). N-[tris(oleoyloxymethyl)methyl]-N-(2-sulfoethyl)succinic acid monoamide was isolated as a yellow heavy viscous oil with a yield of 240 mg (38%).
Reaction SMILES: [NH:1]([C:33](OC(C)(C)C)=[O:34])[CH2:2][C:3]([N:5]1[CH2:32][CH2:31][CH2:30][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])=[O:4].C(Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O>>[NH:1]([C:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:34])[CH2:2][C:3]([N:5]1[CH2:32][CH2:31][CH2:30][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([NH:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)c1ccccc1)C(=O)NCC(=O)NOCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To Boc-Gly-Pro-Leu-Gly-NHOBzl (0.55 g; 1.00 mmol) obtained in Example 1 (F) was added under ice cooling 4.5N HCl/AcOEt (2 ml), and the mixture was brought back to room temperature. The reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure and the residue was dissolved in DMF (5 ml). The solution was cooled with a coolant at -20° C. and TEA (0.14 ml; 1.00 mmol) was added dropwise. Bz-Cl (0.17 g; 1.21 mmol) was then added dropwise and TEA was used to adjust the pH to 8-9. The reaction was carried out for 1 hour and insolubles were filtered off. The solvent was distilled off under reduced pressure. The residue was dissolved in AcOEt, and the solution was washed successively with water, 1N-HCl, water, 10% Na2CO3 and water and then dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on silica gel (Fuji Davison BW 200, 25 g; eluted with CHCl3 :MeOH (=20:1) mixed solvent) to give Bz-Gly-Pro-Leu-Gly-NHOBzl (0.43 g; 78%) as a colorless powder. m.p. 79°-84° C.,specific rotation [α]D28 -69.0 (c=1.0, EtOH).
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=2)[CH:6]=1.Cl.[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]2[C:46](=[O:55])[NH:47][C:48]3[C:53]([CH:54]=2)=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>>[O:55]=[C:46]1[C:45]([CH:42]2[CH2:43][CH2:44][N:39]([C:1]([O:2][C@H:3]([CH2:4][C:5]3[CH:13]=[C:12]([CH3:14])[C:11]4[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:22])[CH3:20])[N:10]=4)[CH:6]=3)[C:23]([O:25][CH3:26])=[O:24])=[O:27])[CH2:40][CH2:41]2)=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47]1
Reactant: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of 1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)ethyl 4-nitrophenyl carbonate (0.859 mmol) was added 3-(piperidin-4-yl)quinolin-2(1H)-one-hydrochloride (682 mg, 2.58 mmol), in one portion, followed by dropwise addition of diisopropylethylamine (0.37 mL, 2.15 mmol) at room temperature. The resulting yellow suspension was stirred at room temperature overnight. The mixture was extracted with ethyl acetate (2×2 mL) and the organic phase was washed with brine and dried over sodium sulfate. The crude product was purified using preparative HPLC to afford (R)-1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (157 mg, 30%). Mass spec. 619.24 (MH+). 1H-NMR (CDCl3, 400 MHz) δ 8.0 (s, 1H), 7.53 (br s, 2H), 7.47-7.43 (m, 1H), 7.34-7.31 (m, 1H), 7.21-7.18 (m, 1H), 6.96 (s, 1H), 5.7 (s, 2H), 5.23 (dd, J=8.6, 4.6 Hz, 1H), 4.28 (br s, 2H), 3.74 (s, 3H), 3.61 (m, 2H), 3.13 (m, 3H), 2.93 (m, 2H), 2.59 (s, 3H), 1.94 (m, 2H), 0.92 (m, 2H), −0.064 (s, 9H).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[CH:14][N:13]=[C:12]3[NH2:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[CH:14][N:13]=[C:12]3[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncnn2cc(C#CCN3CCCC3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ncnn2cc(CCCN3CCCC3)cc12
Reaction time: 18 h
Yield: 91.9 %

Procedure:
In a round-bottom flask, the compound (269 mg, 1.14 mmol) prepared in Example 11, palladium/carbon (10%, 20 mg) and methanol (10 mL) was added and the atmosphere was replaced with hydrogen gas at 1 atm. After 18 hours, the mixture was filtered through celite and the celite pad was washed with methanol. The methanol was removed in vacuo to obtain the title compound (257 mg) having the following physical data.
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH:22](N)(C)C>>[CH:5]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:21])[N:7]=1)([CH3:22])[CH3:4]
Reactant: CC(C)N
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Product: CC(C)NC1=NS(=O)(=O)c2cc(C(F)(F)F)ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with isopropylamine according to the general procedure Method A to give the title compound; m.p. 287-289° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:14])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:13])=[CH:8][CH:7]=2.[P:15]([O:20]C)([O:18][CH3:19])[O:16][CH3:17]>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:14])[C:3]([CH2:2][P:15]([O:18][CH3:19])([O:16][CH3:17])=[O:20])=[CH:12]2
Reactant: Cc1nc2ccc(Cl)cc2cc1CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc2cc(Cl)ccc2nc1C)OC
Yield: 100.1 %

Procedure:
A mixture of 3-bromomethyl-6-chloro-2-methylquinoline (0.85 g, 3.0 mmol) and trimethyl phosphite (1.2 ml, 9.6 mmol) was refluxed in toluene (20 ml) for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was flash chromatographed on silica gel. Elution with ethyl acetate afforded 0.90 g of 6-chloro-3-(dimethylphosphonomethyl)-2-methylquinoline.