Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]([C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:56]=[CH:55][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:52]([OH:54])=[O:53])[CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:42])=[O:38])=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.O.[Li+].[Cl-].C1(C)C=CC=CC=1>C(O)(=O)C>[F:63][C:60]1[CH:61]=[CH:62][C:57]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:52]([OH:54])=[O:53])[CH2:45][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]3)=[O:42])=[O:38])=[CH:55][CH:56]=2)=[CH:58][CH:59]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)NCC(=O)N[C@H](CC2CCCCC2)C(=O)O)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](SC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CC3CCCCC3)C(=O)O)cc2)cc1
Reaction time: 8 h

Procedure:
N-({4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine (16.7 mg, 0.018 mmol) (Method 1) was dissolved in acetic acid (1 ml). Water (0.100 ml) and LiCl (50 mg, 1.18 mmol) were added and the reaction mixture was stirred overnight. The acetic acid was co-evaporated with toluene. The residue was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 20 to 60% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and some of MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. H-NMR (500 MHz, DMSO-d6): 0.73-0.92 (m, 2H), 1.05-1.19 (m, 3H), 1.30 (b, 1H), 1.40-1.70 (m, 7H), 2.93 (d, 2H), 2.97 (s, 3H), 3.76 (d, 2H), 4.00 (s, 2H), 4.14 (bs, 1H), 4.31 (d, 1H), 4.52 (s, 2H), 4.71 (t, 1H), 5.10 (d, 1H), 5.74 (bs, 1H), 6.99 (d, 2H), 7.08-7.13 (m, 2H), 7.20 (d, 2H), 7.32-7.41 (m, 6H), 7.60 (b, 1H), 7.94 (b, 1H), 8.26 (t, 1H). M/z: 809 (M+1) and 807 (M−1).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]=[C:15](Cl)[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]=2[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O.C(Cl)Cl>C1COCC1>[CH2:34]([NH:41][C:15]1[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:33])[CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:25]=[CH:24][C:13]=2[N:14]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: CC(C)S(=O)(=O)n1c(Cl)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)n1c(NCc2ccccc2)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Temperature: 40 °C
Yield: 80 %

Procedure:
To a stirred solution of starting 2-(tert-butyl-dimethyl-silyloxy)-1-[2-chloro-3-(propane-2-sulfonyl)-3H-benzimidazol-5-yl]-2-phenyl-ethanone (588 mg, 1.16 mmol, 1 equiv) in 2 mL of dry THF, add benzyl amine (0.4 mL, 3.48 mmol, 3 equiv) dropwise. Heat the resulting yellow solution at 40° C. for 30 minutes, cool down to room temperature, and add water and CH2Cl2. Separate the phases and back extract the organic one with more CH2Cl2 (three times). Dry the combined organic phases over MgSO4, filter, and concentrate in vacuo to afford crude product. Purify by chromatography using CH2Cl2:hexanes (3:1) to provide the title compound (80% yield). MS(ES+): m/z=578.2 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:29]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:29])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(S(=O)(=O)C(F)(F)F)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(S(=O)(=O)C(F)(F)F)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -5-(trifluoromethylsulfonyl)anthranilic acid and POCl3 (30 mL) was heated on a steam bath overnight. The reaction mixture was poured onto ice-water and then was neutralized with NH4OH. The resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried over MgSO4, filtered and stripped. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 1.0 g of 1-ethyl-4-chloro-6-(trifluoromethylsulfonyl)-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:27]([O:29][CH3:30])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O1CCCC1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:27]([O:29][CH3:30])=[O:28])[N:25]=1
Reactant: C=CCO/N=C(\C(=O)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: C1CCOC1
Product: C=CCO/N=C(\C(=O)OC)c1csc(N)n1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
In 32 ml of tetrahydrofuran is dissolved 6.45 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, followed by addition of 32 ml of 50% formic acid. The mixture is stirred at 60° C. for 40 minutes. The reaction mixture is concentrated under reduced pressure and the solid residue is dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in this order, and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by column chromatography [silica gel: 150 g; eluent: hexane-ethyl acetate (1:1)]. The solvent is distilled off and the solid residue is washed with hexane and a small amount of ether in this order, and then dried to give methyl 2-(2-amino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, m.p. 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[C:28]([O:32][C:33](=[O:44])[NH:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[NH2:43])([CH3:31])([CH3:30])[CH3:29]>CCCCCCC.C(OCC)(=O)C>[C:28]([O:32][C:33](=[O:44])[NH:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[NH:43][C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=510.080 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]2[C:11]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][S:9][C:8]=12
Reactant: COCc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(COC)ncn12
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A solution of 925 mg of 7-methoxymethylimidazo[5,1-b]thiazole in anhydrous THF was cooled to −70° C. under the atmosphere of argon and 3.54 ml of a 1.6 N n-butyl lithium/n-hexane solution was slowly added, and the mixture was stirred for 1 hour. To the reaction mixture was slowly added a solution of 1.88 g of tri-n-butylstannyl chloride in 2 ml of anhydrous THF, and the mixture was stirred for further 1.5 hours. After the addition of 100 ml of ethyl acetate, the solvent was removed by distillation to concentrate the mixture to a total volume of about 1 ml. Purification by silica gel chromatography gave 896 mg of 7-methoxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole from a low polar fraction eluted with dichloromethane:ethyl acetate=4:1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CCO>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
Method 1 was followed using 1 eq each of 2,6-difluoronitrobenzene, 4-(N-Boc-amino) piperidine, and TEA in EtOH yielding tert-butyl 1-(3-fluoro-2-nitrophenyl)piperidin-4-ylcarbamate (93%). LCMS (m/z): 340.1 (MH+); LC Rt=3.30 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH:19]([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:26][CH:19]([CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)O
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(C)OC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was added slowly under ice cooling a solution of optically active 2-octanol (0.59 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand until it reached room temperature and was left to stand overnight in order to complete the reaction. The solution was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute hydrochloric acid, water, 1N aqueous sodium carbonate solution and water, in this order, and dried over anhydrous magnesium sulfate. After the extract was distilled to remove the solvent until a crude product was obtained, the product was purified by toluene-silica gel column chromatography and further recrystallized from ethanol to obtain the titled compound (1.48 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].O>C(Cl)Cl>[C:43]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH2:10][CH:9]([N:8]([CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][CH3:35])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:23])=[CH:19][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15]1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.6 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (50 mg) in dry methylene chloride (1 ml) were added triethylamine (21 mg) and acetic anhydride (21 mg), and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 40 mg of 1-acetyl-5-[2-[N-tert-butoxycarbonyl- 2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](N1C=CN=C1)(N1C=CN=C1)=[S:12].C(N(CC)CC)C.Cl>CCCCCCC.C(Cl)Cl>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(O)c1ccc(N=C=S)cc1
Yield: 95 %

Procedure:
4-Aminobenzoic acid (5.00 g, 36.5 mmol) was added to a methylene chloride solution (51 mL) of thiocarbonyldiimidazole (8.45 g, 47.4 mmol) and triethylamine (5.6 mL, 40.2 mmol) at an internal temperature of at most 5° C., followed by stirring under cooling with ice for one hour. The mixture was dropped to a separately prepared mixed solution of concentrated hydrochloric acid (12.2 mL, 140.5 mmol) and n-heptane (51 mL) so that the internal temperature became from 25° C. to 30° C., whereupon a pale yellow suspension was obtained. This was stirred under cooling with ice for 3 hours, and the solid was collected by filtration and washed with water (50 mL) to obtain a pale yellow crude product. The obtained crude product was subjected to an operation of washing with water (50 mL) with stirring and collection by filtration twice, followed by drying under reduced pressure to obtain 4-isothiocyanatobenzoic acid as a pale yellow solid (6.23 g, yield: 95%, HPLC purity: 100.0%).
Reaction SMILES: C(OC(C)C)(=O)CCCCCCCCCCCCCCCCC.C([O:43][CH:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH3:45])(=O)CCCCCCCCCCCCCCCCC>O>[CH3:45][C@H:44]([OH:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)CCCCCCCC
Agent: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Solvent: O
Product: CCCCCCCC[C@H](C)O
Temperature: 85 °C
Reaction time: 0.02 h
Yield: 73.5 %

Procedure:
In a 300 ml separable flask were put 1 g of Lipase PL and 40 g of (R,S)-2-decanol, and the mixture was subjected to ultrasonication with the same ultrasonic wave generating equipment as used in Example 1 at room temperature and 90 kHz for 1 minute. To the mixture was added 60 g of isopropyl stearate, followed by stirring at 85° C. at 250 rpm for 30 hours to carry out interesterification. The water content of the reaction system was 0.02% by weight, and 96% of the lipase particles had a particle size of 10 to 40 μm. Gas chromatographic analysis of the reaction mixture revealed that 57 mol % of (R,S)-2-decanol had been converted to 2-decyl stearate. Lipase was separated by filtration in the same manner as in Example 12, and the filtrate was subjected to simple distillation at 70° C. and 5 mmHg to give unreacted (S)-(+)-2-decanol (yield: 73.5%; chemical purity: 99.9%; optical purity: 95% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](C(F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.C1(N=C=O)CCCCC1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: O=C=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol), diisopropyl(ethyl)amine (125 mg, 0.97 mmol), and cyclohexyl isocyanate (121 mg, 0.97 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])(=O)=O.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][NH2:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[C:22]([O:26][C:27](=[O:28])[NH:29][CH2:30][CH2:31][NH:32][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1[N+](=O)[O-]
Yield: 90.5 %

Procedure:
1-Nitro-2-naphthyl trifluoromethanesulfonate (1.61 g, 5 mmol), N-(tert-butoxycarbonyl)ethylenediamine (0.80 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol), and toluene (20 mL) were mixed, and the mixture was refluxed by heating for 16 hours. This reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give yellow crystals, and the crystals were washed twice with hexane (20 mL) to obtain the title compound (1.50 g, yield 91%) as yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](Cl)(=[O:26])[O:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([Cl:25])[CH:21]=1)[CH2:17][O:16][C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A reaction mixture comprising tert-butyl 4-aminopiperidine-1-carboxylate (1 g, 4.99 mmol), 3,5-dichlorobenzyl carbonochloridate (1.196 g, 4.99 mmol) and sodium hydroxide (250 ml, 499 mmol) in DCM (16.64 ml) was stirred at room temperature for 18 hours. The reaction mixture separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. No further purification was carried out and the material was taken crude to the next step.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O-:12])(=[O:11])=[S:10].[K+]>C(O)C.CCCCCC>[CH2:1]([O:12][S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[S:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=S)OCc2ccccc2)cc1
Yield: 77.6 %

Procedure:
The title compound was prepared as described in General Method 2 using 0.05 mol of benzyl chloride, 0.05 moles of potassium thiotosylate in 150 mL of ethanol. The residue was dissolved in hexane and seeded with a crystal of the product to afford 10.8 g (77%) of benzyl-p-toluenethiosulfonate (m.p. 52-56.5° C.). 1H NMR (CDCl3) δ 2.45 (s, 3 H), 4.26 (s, 2 H), 7.18-7.30 (m, 7 H), 7.74 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22](O)=[O:23])[CH:18]=4)[N:13]=3)=[CH:10][C:9]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:67]([O:69][C:70](=[O:85])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][CH:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)=[C:73]([NH2:84])[CH:72]=1)[CH3:68]>CN(C=O)C>[CH2:67]([O:69][C:70](=[O:85])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][CH:78]2[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83]2)=[C:73]([NH:84][C:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:11]2[C:6]([C:5]4[CH:32]=[CH:33][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:7][CH:8]=[C:9]([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[CH:10]=2)[CH:21]=[CH:20]3)=[O:23])[CH:72]=1)[CH3:68]
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Reaction time: 8 h

Procedure:
Compound 24 (270 mg, 0.59 mmol) in 4 mL of DMF was activated with 246.6 mg (0.65 mmol) of HATU and 226 μL (1.30 mmol) of DIEA at room temperature for 15 minutes. Compound 11 (170 mg, 0.65 mmol) was added as solid and the mixture was stirred overnight. The DMF was evaporated; the remaining oil was solidified by trituration with water. The solid Compound 25 was filtered off, dried and used without further purification. MS: 701.34 (M+H+).
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]2[CH3:13].CO.Cl>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]2[CH3:13]
Reactant: CC1C(=O)Nc2ccc(F)cc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1CNc2ccc(F)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 18 mL (18 mmol) of a 1M borane in THF solution was added dropwise to 1.5 g (9.1 mmol) 5-fluoro-3-methyl-1,3-dihydro-indol-2-one in 50 mL THF. The reaction mixture was stirred for 2 h at 70° C., cooled to 0° C. and combined with 10 mL methanol and then with 30 mL semi-concentrated hydrochloric acid solution. The reaction mixture was refluxed for 1 h with stirring, cooled and the organic phase was eliminated using the rotary evaporator. The aqueous phase was extracted with ethyl acetate. The aqueous phase was made alkaline with an aqueous 4M sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried on sodium sulphate, filtered off and evaporated down.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][CH2:13][CH:14]=O)[CH:7]=[CH:8][CH:9]=1)=[CH:2][CH3:3].[Cl-].[CH2:17]([N:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:22](=[O:24])[CH3:23])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([NH:21][C:22](=[O:24])/[CH:23]=[CH:14]/[CH2:13][CH2:12][C:11]#[C:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]=[CH:2][CH3:3])[CH:5]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC=Cc1cccc(C#CCCC=O)c1
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: CC=Cc1cccc(C#CCC/C=C/C(=O)NCC(C)C)c1

Procedure:
N-isobutyl 7-(3'-propenylphenyl)-(2E)-hepten-6-ynamide was prepared from 5-(3'-propenylphenyl)-4-pentyn-1-al and N-isobutyl acetamidotriphenylphosphonium chloride as in Example 9 and semi-hydrogenated as in Example 9 to give N-isobutyl 7-(3'-propenylphenyl)-(2E,6Z)-heptadienamide.