Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=CC[CH:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19].[C:21]1(C)C=CC=C[CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:16]1([CH2:17][C@H:18]([OH:20])[CH3:19])[CH:22]=[CH:21][C:13]2[CH2:4][O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: C[C@@H](O)CN
Reactant: Cc1ccccc1
Reactant: O=CCC1CC(=O)c2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1ccccc1OC2
Reaction time: 0.58 h
Yield: 83 %

Procedure:
A solution of 1.9 g of (RS)-2-(2-oxoethyl)-4-chromanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 3). 1.9 g (83%) of (R)-1-(1,4-dihydro-[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[N:18]=[C:19]([CH:21]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[NH:44])[NH2:43])=[CH:38][CH:37]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12].CC(N(C)C)=O.[N+](C1C=CC([O:71][C:72](=O)[O:73][CH2:74][C:75]([CH3:78])([CH3:77])[CH3:76])=CC=1)([O-])=O>C(N(CC)CC)C>[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[N:18]=[C:19]([C@H:21]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]([NH2:43])=[N:44][C:72]([O:73][CH2:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:71])=[CH:40][CH:41]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Reactant: CC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid 5-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-metho xyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2,2-dimethylpropyl ester acetate (Example 18e, 70 mg) and DMA (2 mL), carbonic acid 2,2-dimethylpropyl ester 4-nitrophenyl ester [CAS No. 158810-98-1] (70 mg) and triethylamine (0.07 mL) were added, and the resulting mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain a racemate of the captioned compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].C1C=C(C([O-])=[O:37])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[O:37][C:21]4([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CC(C)c1cc(-c2cccc(C=C(C#N)c3ccncc3)c2)c2ncccc2c1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1cc(-c2cccc(C3OC3(C#N)c3ccncc3)c2)c2ncccc2c1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-acrylonitrile from Step 1 (75 mg, 0.3 mmol) in CH2Cl2/MeOH (1:1, 2 mL) was added MMPP (148 mg, 0.3 mmol). The resulting reaction mixture was stirred 18 h at 21° C., then diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with EtOH/ethyl acetate, 10:90) provided the title compounds.
Reaction SMILES: Cl.[CH:2]1([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18](=[O:20])[NH:17][C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C)C=O.O>[CH:2]1([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18](=[O:20])[N:17]([CH3:27])[C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: O=C1Nc2ccccc2C2(CCN(C3CCCCCC3)CC2)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)OC2(CCN(C3CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1′-cycloheptylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one hydrochloride (compound No. 5) (188 mg, 0.54 mmol) was suspended in anhydrous dimethylformamide (4.0 mL), treated with sodium hydride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) and stirred at room temperature for 10 minutes under nitrogen. The reaction mixture was then treated with a solution of methyl iodide (92 mg, 0.65 mmol) in anhydrous dimethylformamide (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL), and the product was extracted in dichloromethane (2×50 mL). The pooled extracts were washed with water (2×10 mL), saturated NaHCO3, (2×10 mL) and saturated brine (2×10 mL); then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-cycloheptyl-1-methylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 65) free base as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:44])=[C:15]([C:19]2[N:20]=[C:21]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[C:14]=1[F:44])(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (60 mg, 0.093 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 μL, 6.49 μmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 32 mg of title compound. MS (ESI): 546.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OC)[O:26]C)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
To a solution of dimethyl 2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (7.5 g) in acetone (75 ml) was added 6 N hydrochloric acid (7.5 ml) and the mixture was stirred at room temperature for 6 hours. The precipitates which were separated out during the reaction course were collected by filtration to give yellowish crystals of dimethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.26 g), and the filtrate was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and the acetone was distilled off under reduced pressure to give additional crops of orange-yellow crystals (3.84 g) of the same product, (total yield, 6.1 g). A small portion of the first crop was recrystallized from methanol to give pure crystals,
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][Si:10]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.CI>O1CCCC1>[CH3:26][Si:10]([CH3:9])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:1])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Into dry tetrahydrofuran (20 ml) at 0° C. under anhydrous conditions was added slowly with stirring lithium diisopropylamide (2 67 g, 25 mmol) and then a solution of 4-(dimethy1-tert-butylsilyloxy)phenylacetic acid (2.66 g, 1.0 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The resultant brown solution was stirred at 20°-25° C. for one hour and at 50° C. for 30 minutes. The solution was then cooled to 0° C. and methyl iodide (3.54 g, 25 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for about 16 hours and then quenched with saturated aqueous ammonium chloride (20 ml) and acidified with 3N hydrochloric acid. The reaction mixture was extracted with diethyl ether (3×100 ml) and the combined extracts washed with saturated aqueous sodium chloride (2×50 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford a tan oil. The oil was chromatographed on a 5× 15 cm column of silica gel eluted with 10 percent isopropanol/hexane to yield the desired product as a solid. m.p. 52°-4° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C1C(=O)N([I:17])C(=O)C1>CC(O)=O>[I:17][C:3]1[C:4]([OH:9])=[N:5][C:6]([OH:8])=[N:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(O)nc(O)n1
Solvent: CC(=O)O
Product: Cc1nc(O)nc(O)c1I
Reaction time: 7 h
Yield: 95 %

Procedure:
The mixture of all materials (6-methylpyrimidine-2,4-diol, 20.00 g, 0.159 mol, 1.0 eq; NIS, 39.25 g, 0.174 mol, 1.1 eq; AcOH, 150 mL) was stirred well for about 7 h. It affords white solid product 5-iodo-6-methylpyrimidine-2,4-diol (37.93 g, 95%), isolated by filtration, washed with ethyl acetate. LC-MS (m/z)=252.9 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]=[CH:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1N=CCN(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(CCN(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-(2-dimethylamino-ethylideneamino)-cyclopentanecarboxylic acid ethyl ester (0.069 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with a 1.0 M solution N,N′-dicyclohexylcarbodiimide in dichloromethane (0.315 mL, 0.315 mmol). The reaction was stirred for 6 h at 25° C., the urea byproduct was filtered off and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, 2-{(2-dimethylamino-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (25.4 mg, 0.047 mmol, 15.6%), as a white solid. LC-MS (ESI) calcd for C22H33N5O7S2 543.18, found 544.4 [M+H+].
Reaction SMILES: C([C@H]1C[O:11][C:10](=[O:13])N1C(=O)/C=C/C)C1C=CC=CC=1.[CH2:19]=[CH:20][C:21](=[CH2:23])[CH3:22].[Al](Cl)(CC)CC.[C:30]1(C)[CH:35]=CC=C[CH:31]=1.Cl>C(Cl)Cl>[CH3:23][C@H:21]1[CH2:22][C@@H:30]([CH3:35])[CH2:31][CH2:19][C@@H:20]1[C:10]([OH:13])=[O:11]
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=CC(=C)C
Reactant: Cc1ccccc1
Agent: CC[Al](Cl)CC
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1CC[C@H](C(=O)O)[C@@H](C)C1
Temperature: -40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of (S,E)-4-benzyl-3-but-2-enoyloxazolidin-2-one (34.5 g, 0.14 mol) and isoprene (250 mL) in DCM was cooled to −78° C. To this solution was added a solution of Et2AlCl in toluene (100 mL, 0.18 mol) dropwise. The solution was warmed to −40° C. and stirred at this temperature overnight. 2 N HCl solution (150 mL) was added. Most of the DCM was removed under vacuum and the mixture was extracted with ether. After drying over Na2SO4, the combined organic layer was concentrated and the residue purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the desired product (39 g, 88% yield) as a crystalline white solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH:4]([F:6])[F:5].[Cl:9][C:10](Cl)([Cl:16])[CH2:11]C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[C:10]([Cl:16])([Cl:9])=[CH2:11].[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([F:6])([F:5])[Cl:9]
Reactant: FC(F)CC(F)(F)F
Reactant: ClC(Cl)(Cl)CC(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(Cl)Cl
Product: FC(F)(F)CC(F)(F)Cl

Procedure:
The known methods of producing 1,1,1,3,3-pentafluoropropane are as follows. Carbon tetrachloride and vinylidene chloride are prepared and an addition reaction is triggered. The reaction product, 1,1,1,3,3,3-hexachloropropane, is fluorinated to produce 1,1,1,3,3-pentafluoro-3-chloropropane which is reduced with hydrogen to produce 1,1,1,3,3-pentafluoropropane (WO 95/04022).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[CH:17][C:16]=1[OH:23].CCCCCC.[C:30](OCC)(=[O:32])[CH3:31]>>[C:1]([O:23][C:16]1[CH:17]=[C:18]([CH3:22])[C:19]([NH:21][C:30](=[O:32])[CH3:31])=[CH:20][C:15]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: Cc1cc(O)c(C)cc1N
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C)c(OC(C)=O)cc1C
Reaction time: 1 h
Yield: 95 %

Procedure:
Acetic anhydride (0.894 ml, 9.48 mmol) and pyridine (1 ml) were added to a solution of 2,5-dimethy-4-aminophenol (500 mg, 3.64 mmol) in ethyl acetate (5 ml), and the resulting mixture was refluxed. After 1 hour, hexane (50 ml) was poured into the reaction solution and the crystals formed were filtered under reduced pressure and then dried to obtain 4-(acetylamino)-2,5-dimethylphenyl acetate (763 mg, 95%).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.[Si:21]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[O:14]=[C:1]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:30]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OC1CCCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N1CCCC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve lauric acid (0.77 g) in methylene chloride (50mL) and cool to 0° C. Add oxalyl chloride (0.37 mL) and dimethylformamide (3 drops). Allow to warm to room temperature and stir for 1 hour. Add, by dropwise addition, to a solution of 3-(O-tert-butyldimethylsilyloxy)piperidine (0.76 g, 3.5 mmol) and triethylamine (1 mL) in methylene chloride (20 mL). Stir overnight. Dilute with methylene chloride (50 mL) and separate the organic phase. Wash twice with 10% sodium hydroxide, once with 10% hydrochloric acid, and once with saturated sodium hydrogen carbonate and once with brine. Dry (Na2SO4) and evaporate the solvent in vacuo to give 1-oxododecyl-3-(O-tert-butyldimethylsilyoxy)piperidine.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)C1C=CC(O)=CC=1.CN([CH:19]=[O:20])C>>[O:20]([C:19]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:1])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:1]
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: CN(C)C=O
Product: Sc1ccccc1Oc1ccccc1S
Reaction time: 24 h
Yield: 75 %

Procedure:
4.91 g (0.0225 mol) of 4,4′-thiodiphenol was dissolved in DMF, and then an aqueous solution of 1.26 g (0.0225 mol) of NaSH was added thereto. The mixture was stirred for 24 hours. The mixture was washed with water several times and filtered, and thus oxydibenzenethiol was obtained. The oxydibenzenethiol thus obtained was dissolved in methylene chloride, and then 1.50 g (0.0148 mol) of triethylamine (TEA) was added thereto. The mixture was stirred for 10 minutes. Subsequently, 1.34 g (0.0148 mol) of acyloyl chloride was added thereto, and the mixture was stirred. After 24 hours, the mixture was washed several times with distilled water and several times with a 1 wt % aqueous hydrochloric acid solution, the organic layer was separated, and the solvent was eliminated. A residue remaining thereafter was purified by a chromatographic method and using hexane and ethyl acetate. An aqueous solution containing 0.89 g (0.0158 mol) of KOH was added thereto, 1.462 g (0.0158 mol) of epichlorohydrin was added thereto, and the mixture was stirred at normal temperature. After 36 hours, chloroform was added to the mixture to extract the product, and then the extract was washed several times with distilled water. Epichlorohydrin and the solvent were evaporated, and then a compound represented by the Formula (1-8) was separated by a chromatographic method and using hexane and ethyl acetate at a weight ratio of 2:1. The compound was purified to a purity of 99% or higher (yield: 75%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])=[CH:20][CH:19]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Product: O=C(NCc1ccncc1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 43.8 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 37 μL (0.36 mmol) of pyridin-4-ylmethylamine. The precipitate that forms during the reaction is filtered then washed with dimethylformamide and diethyl ether to give 46 mg (44%) of N-(pyridin-4-ylmethyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide in the form of a white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.C1(C(C2C=CC=CC=2)[N:25]2[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26]2)C=CC=CC=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:25]1[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCOC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 9.1 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL), 1-(diphenylmethyl)-3-(pentyloxy)azetidine (34 mg, 0.19 mmol; which may be prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) and EDAC (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 48 h and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 9/1) to give a beige solid. This solid was triturated in acetone to give the title compound (5 mg, 9%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][C:13]([F:18])=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN1C(=O)CCC1>[Cl:9][C:10]1[N:11]=[C:12]([NH:2][C@H:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5])[C:13]([F:18])=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CC[C@@H](N)C(N)=O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To the mixture of (R)-(−)-2-aminobutanamide hydrochloride (1.00 g, 7.2 mmol) and 2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (0.92 g, 4.8 mmol) in 40 mL NMP added DIEA (2.5 mL, 14.4 mmol). The mixture was then sent to 100° C. for stirring for 1 h. The mixture was cooled to RT, and to it was poured 300 mL EtOAc. The mixture was washed with brine four times. The organic phase was dried, concentrated and purified using silica flash column (70% EtOAc-30% DCM) to isolate (R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide (1.21 g, 98% yield).
Reaction SMILES: [CH2:1](O)[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].N1C=CC=CC=1.S(Cl)([Cl:28])=O.S(=O)=O>C1C=CC=CC=1>[CH2:1]([Cl:28])[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: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=S(Cl)Cl
Agent: O=S=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCl
Temperature: 0 °C
Yield: 81 %

Procedure:
67 gms of oleyl alcohol was dissolved in 75 mls of benzene, 0.15 ml of pyridine were added. The solution was cooled to 0° C. and 46 gms of thionyl chloride was added over 5 minutes with stirring. The solution was heated to reflux temperature for 10 minutes until all sulphur dioxide evolution ceased. It was cooled and extracted with 150 ml of 10% saline solution then with 50 ml of 10% sodium carbonate solution and finally with 100 ml of 10% saline solution. The organic layer was dried over sodium sulphate, evaporated and distilled. The product distilled at 166°-169° C., at 3 torr and yielded 58 gms of oleyl chloride.