Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[CH2:19][NH:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[N:27][N:28]3C(OC)=O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[NH:28]1[C:29]2[C:25](=[C:24]([NH:23][C:21]([NH:20][CH2:19][CH:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]3[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3CCc3ccccc3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCC1CCc2ccccc2N1CCc1ccccc1)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
The product from Example 53A (0.1913 g, 0.40 mmol) was dissolved in methanol (5 mL). A NaOH solution (1.0 mL, 5 M in methanol) was added and stirred for 30 minutes. The reaction mixture was then diluted with water until a precipitate formed. The solid was collected by filtration, washed with water and dried under vacuum to afford the title compound (0.1294 g, 76%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.98 (s, 1H) 8.69 (s, 1H) 8.07 (s, 1H) 7.60 (d, J=7.46 Hz, 1H) 7.24 (m, 6H), 7.04 (m, 2H) 6.94 (d, J=6.44 Hz, 1H) 6.71 (d, J=8.14 Hz, 1H) 6.51 (t, J=6.95 Hz, 2H), 3.71 (m, 1H) 3.37 (m, 3H) 3.11 (m, 1H) 2.83 (m, 3H) 2.62 (m, 1H) 1.87 (m, 1H), 1.54 (m, 1 H). MS (ESI) m/z 426 (M+H)+, 424 (M−H)−. Calcd For C26H27N5O: C 73.39; H 6.40, N 16.46. Found C 73.22; H, 6.36; N, 16.30.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:27][C:28]1[CH:29]=[C:30]([C:33]#N)[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[OH:36].ClCCl.CCCCCC>C1(C)C=CC=CC=1>[CH2:11]([NH:27][C:28]1[CH:29]=[C:30]([CH:33]=[O:36])[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCNc1csc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1csc(C=O)c1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (14 ml., 25% solution in toluene) is added with stirring to a solution of 2.9 g. of 4-hexadecylamino-2-cyanothiophene in toluene under a nitrogen atmosphere. The temperature rises during the addition and the reaction is then stirred for 1 hour. A solution of methanol in toluene (14 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (125 ml., 5%). After 10 minutes diatomaceous earth (7.5 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (25 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give crude product. The product is obtained by recrystallization from dichloromethane-hexane.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[CH:10][C:11]=3[CH2:36][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CC2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1CC1CCCCC1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.04 (d, J=8.3 Hz, 2H), 7.65 (dd. J=8.8, 2.2 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=6.6 Hz, 1H), 6.74 (s, 2H). 6.70 (s, 1H), 4.21 (t, J=6.4 Hz, 2H), 3.00 (t, J=5.9 Hz, 2H), 2.46-2.36 (m, 5H), 1.67-1.51 (m, 11H), 1.47-1.42 (m, 1H), 1.18-1.09 (m, 3H), 0.85-0.83 (m, 2H), MS (ES) m/e 554 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([OH:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:18][C:15]1[S:14][C:13]([C:10]([OH:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1nccs1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(Br)s1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
The product of Step 1 (364 mg, 1.331 mmol) was dissolved in DMF (2 ml). N-bromosuccinimide (284 mg, 1.597 mmol) was added, and the solution was maintained 2 h at rt. Water was added and the mixture extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification via silica gel column chromatography (0%-10% EtOAc:hexanes) afforded 2-(5-bromo-1,3-thiazol-2-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (104 mg, 22%) as a white solid. MS ESI: [M+H]+ m/z 352, 354.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:49]3[CH2:48][CH2:47][CH:46]([N:42]4[CH2:43][CH2:44][CH2:45][CH:40]([CH2:39][OH:38])[CH2:41]4)[CH2:51][CH2:50]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: OCC1CCCN(C2CCNCC2)C1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC(CO)C2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxymethyl-[1,4′]bipiperidine (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C39H51N6O3Cl2 [(M+H)+] 721.3394, observed 721.3392.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12]C)=[O:11].I[CH2:15][CH2:16][CH3:17].C([O-])([O-])=[O:19].[K+].[K+]>CN(C=O)C>[CH2:15]([O:19][C:6]1[CH:7]=[CH:2][C:3]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:5]=1)[CH2:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCCI
Reactant: COC(=O)CCc1ccccc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CCC(=O)O)cc1
Temperature: 60 °C
Yield: 98.1 %

Procedure:
To a solution of methyl 3-(hydroxyphenyl)propionate (15 g, 83.24 mmol) and iodopropane (12.14 mL, 124.5 mmol) in DMF (80 mL) was added K2CO3 (34 g, 249.7 mmol). The resultant slurry was stirred vigorously and heated to 60° C. under argon for 12 h. DMF was evaporated and residue partitioned between EtOAC and 1N HCl. The organic layer was washed with H2O, and brine then dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10% EtOAc in hexanes) to provide the desired product (17 g, 98%) as a clear oil. The resultat oil was dissolved in THF (150 mL), and 2M NaOH (68 mL) was added. The reaction was stirred overnight at room temperature. THF was evaporated and residue acidified with concentrated HCl and extracted 3 times with EtOAC, (100 mL). The organic layer was washed with H2O, dried over Na2SO4 and concentrated to a white solid which was recrystalized from hexanes to provide the desired product (14.06 g 82%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2].[CH2:8]([O:10][C:11](=[O:13])C)[CH3:9]>C(O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:11]([O:10][CH2:8][CH3:9])=[O:13])[CH3:2].[CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2]
Reactant: CCOC(C)=O
Solvent: CCO
Solvent: CCOC(=O)CCl
Product: CCOC(=O)CC(=O)OCC

Procedure:
As described in Example 1, but with 160 g of an 8.85% solution of Co2 (CO)8 in ethanol, 2.7 moles out of 4 moles of chloroacetic acid ethyl ester are reacted at 7.5 at. CO and 55° C. in 51/4 hours. 400 g of malonic acid diethyl ester is obtained (93% yield) and 3.5 g of acetic acid ethyl ester plus 160 g of chloroacetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH2:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,5S)-2-aminomethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (200 mg), and Et3N (77 μL, 0.55 mmol) in CH2Cl2 (3 mL) was added under nitrogen atmosphere at 0° C. acetyl chloride (39 μL, 0.55 mmol) and the mixture was stirred at 0° C. for 1 h. CH2Cl2 and 1N aqueous HCl were added, the layers were separated and the aqueous one back-extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 0:100) to give the title compound. MS (LC/MS): 480.1 [M+H]+; tR (HPLC conditions b): 4.69 min.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21].O>C1(C)C=CC=CC=1>[CH3:21][C:20]([NH:25][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:22])[CH2:23][CH3:24]
Reactant: CCC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.5 %

Procedure:
To a solution of 10 g of 4-bromomethylbenzenesulfonyl chloride and 10 ml of triethylamine in 50 ml of toluene is added, dropwise at RT, a solution of 3.2 g of tert-amylamine in 10 ml of toluene, and the mixture is left stirring for 3 hours at RT. Water is then added to the reaction mixture and, after separation by settling, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/heptane mixture (50/50; v/v). 1 g of the expected product is obtained after crystallization from iso ether, mp=100° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.[S:13](Cl)([OH:16])(=O)=[O:14].[F:18][C:19]([F:27])([F:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:12][CH2:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][N:2]([CH3:1])[S:13]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:27])([F:26])[F:18])=[CH:21][CH:22]=2)(=[O:16])=[O:14])[CH2:5][CH2:6]1
Reactant: CNC[C@H]1CC[C@H](CCO)CC1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccccc1
Product: CN(C[C@H]1CC[C@H](CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 1.6, trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol was acylated with 4-trifluoromethyl-benzene sulfochloride to yield trans-N-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 380 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[N:11]([CH3:19])[N:10]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16]([Br:20])=[CH:17][CH:18]=2)[N:11]([CH3:19])[N:10]=1
Reactant: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1cccs1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2,6-dichlorophenyl)-5-(thien-2-yl)-1-methyl-[1,2,4]triazole (75 mg, 0.242 mmol) and bromine (39 mg, 0.242 mmol) were combined in glacial acetic acid (3 mL) and the mixture was stirred overnight at room temperature, then heated to 95° C. for five hours. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with ether, and dried over magnesium sulfate. Chromatography (SiO2, 25% Hex-CH2Cl2) delivered the title product as a waxy white solid. MP 130-132° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[C:4]([S:23][CH3:24])[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:34]([CH2:36][NH2:37])[OH:35]>O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:6]3[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH2:36][CH2:34][OH:35])[N:3]=[C:4]([S:23][CH3:24])[N:5]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc(NCCO)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Yield: 83.6 %

Procedure:
A dispersion of 200 mg (0.55 mmol) of 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-pyrimidine-5-carbonitrile and 84 mg (0.6 mmol) of N-ethyl-diisopropylamine in 4 ml of dioxane was treated at 65° C. with 37 mg (0.6 mmol) of ethanolamine during 18 h. For the working-up, the reaction mixture was evaporated, and, thereafter, the residue obtained was directly chromatographed on silica gel using a 5:1 mixture of toluene and ethyl acetate as the eluent yielding 177 mg (0.46 mmol, 83% of theory) of the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile as a yellowish oil which crystallized on standing. MS: [M+H]+=388.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]([C:17](=[O:19])[NH2:18])[F:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[Li+].[OH-].Cl>CO.C1COCC1>[C:17]([CH:15]([F:16])[C:12]1[CH:13]=[CH:14][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=1)(=[O:19])[NH2:18]
Reactant: CCOC(=O)c1cc2ccc(C(F)C(N)=O)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)C(F)c1ccc2cc(C(=O)O)sc2c1

Procedure:
To a solution of 6-(carbamoyl-fluoro-methyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (295 mg, 1.05 mmol) in MeOH/THF (1.5/6 mL) was added 1M LiOH (1.16 mL). The resultant solution was stirred overnight and 1N HCl was added dropwise to acidify (˜2 mL). The solvent was removed in vacuo and the solid was used without further purification. cal'd 254 (MH+), exp 254 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:46](=[O:47])[N:14]2[C:15]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:16](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:17][S:18][C@H:13]12)=[O:10])C1C=CC=CC=1.[CH:48](/[Sn](CCCC)(CCCC)CCCC)=[CH:49]/[CH3:50].Br[C:65]1[CH:70]=[CH:69][C:68](S(Cl)(=O)=O)=[CH:67][CH:66]=1>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:46](=[O:47])[N:14]2[C:15]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:16](/[CH:48]=[CH:49]\[CH3:50])[CH2:17][S:18][C@H:13]12)=[O:10])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)c3ccc(Br)cc3)CS[C@H]12
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 0.184 g (0.00025 mole) of the product of Procedure 6, 0.103 g (0.0003215 mole) of Z-1-propenyl-tri-n-butylstannane and 0.0064 g (0.000025 mole) of 4-bromobenzenesulfonyl chloride in 2.5 mL of 1-methyl-2-pyrrolidinone, under a nitrogen atmosphere, at room temperature was added 0.006 g (0.000025 mole) of palladium (II) acetate. The reaction mix was stirred at room temperature for 20 hours. High pressure liquid chromatography (HPLC) analysis of the reaction mixture showed a peak for the title compound with retention time identical to an authentic sample of the title compound. The HPLC area percent for this peak was 21.2%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:34])[F:35])[CH:18]=1
Reactant: COC(=O)C1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of compound 8.0 6-bromo-4-chloro-3-nitroquinoline (0.29 g, 1.0 mmol, 1 equiv.) in dioxane (5 mL) at room temperature was added 8.1 methyl 1-(4-amino-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.3 g, 1.0 mmol, 1 equiv.). The resulting mixture was heated overnight to 85° C. under argon. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3, diluted with EtOAc (50 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (Hexanes:EtOAc=4:1) to afford desired product 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.50 g; 90%). LC-MS (M+H): 555.10
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[Br-:1].[O:7]=[C:3]1[CH:2]([P+:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4]1
Reactant: O=C1OCCC1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C1OCCC1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
3-Bromo-2-oxotetrahydrofuran (5 g) and triphenylphosphine (7.94 g) in dry benzene (50 mls) were left at room temperature for 4 days. The solution was decanted from the orange gum. This was dissolved in dichloromethane and concentrated to give a pale brown foam.
Reaction SMILES: [F:1][CH:2]([F:11])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N-:12]=[N+:13]=[N-:14].[Na+].[CH:16](OCC)(OCC)OCC>C(O)(=O)C>[F:11][CH:2]([F:1])[S:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:16]=[N:14][N:13]=[N:12]2)=[CH:6][CH:5]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(SC(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)Sc1ccc(-n2cnnn2)cc1
Temperature: 95 °C

Procedure:
A mixture of p-(difluoromethylthio)aniline (4.0 g.), sodium azide (4.0 g.), triethyl orthoformate (25 ml.), and acetic acid (25 ml.) was heated at 95° C. for 4.5 hours and then evaporated at reduced pressure. The residue was diluted with water, filtered, dried and recrystallized from ethyl acetate:hexane to give crystals, m.p. 94°-97° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=O.[CH2:15]([SH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[O-:29].[Na+]>CO>[CH2:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:29])=[S:27])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: CCCCCCCCCCCCS
Reactant: C[O-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1000 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 26.6 g of 11-bromoundecanoic acid, 21.2 g of 1-dodecanthiol, 42.4 ml of sodium methoxide (28% methanol solution) and 300 ml of methanol, and the mixture was refluxed for 6 hours on an oil bath. After cooling the reaction mixture to room temperature, the precipitated crystals were collected by filtration under reduced pressure and washed with methanol. The resulting crystals were suspended in 1000 ml of distilled water, and the suspension was made pH 2 by adding a conc. hydrochloric acid, and suspension was stirred on an oil bath at 60° C. for 30 minutes to carry out neutraliza tion. Crystals after neutralization were collected by filtration under reduced pressure and washed with distilled water. The residue was recrystallized from ethanol to obtain 35.2 g of the title compound.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C@@H:27]([C:40](=[O:45])[N:41](OC)C)[CH2:26]1)(C)(C)C.[O:58]1CCC[CH2:59]1>>[OH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@@:27]([C:40](=[O:45])[NH2:41])([O:58][CH3:59])[CH:26]1[CH3:2]
Reactant: CON(C)C(=O)[C@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)OCc1ccccc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Product: CO[C@@]1(C(N)=O)C(C)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
7.46 ml of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) was added to a tetrahydrofuran (30 ml) solution of 2.04 g of benzyl (2R,4R)-4-(tert-butyl-diphenyl-silanyloxy)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylate obtained in (step 2), and the reaction liquid was stirred at room temperature for 20 minutes. The solvent of the reaction liquid was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/3) to obtain the entitled compound.