Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]O)=[N:4][C:3]=1[CH2:9][CH3:10].S(Cl)([Cl:13])=O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][Cl:13])=[N:4][C:3]=1[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCc1nc(CO)sc1Br
Solvent: C1CCOC1
Product: CCc1nc(CCl)sc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of (5-bromo-4-ethylthiazol-2-yl)methanol (313 mg 1.41 mmol) in THF (15 ml) under nitrogen at room temperature was added thionyl chloride (0.206 ml 2.82 mmol) and stirred overnight. LCMS indicated the completion of the reaction. A saturated ice cold aqueous NaHCO3 solution was added to the reaction solution with gas evolution. The mixture was extracted with EtOAc (4×20 ml), dried over sodium sulfate and concentrated to give a brown oil 301 mg, 89% which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:20]=[C:21](\[O:25][CH3:26])/[C:22]([OH:24])=[O:23])[CH:9]=[CH:10][C:11]=1OS(C(F)(F)F)(=O)=O)[CH2:2][CH2:3][CH3:4].[CH2:27]([NH:34][C:35](=[O:53])[N:36]([CH3:52])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:20]=[C:21](\[O:25][CH3:26])/[C:22]([OH:24])=[O:23])[CH:9]=[CH:10][C:11]=1[C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([N:36]([CH3:52])[C:35]([NH:34][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:53])[CH:42]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
870 g (2.2 mmol) of (Z)-3-(3-butoxy-4-(trifluoromethanesulphonyloxy)phenyl)-2-methoxyacrylic acid (XII), 981 mg (2.62 mmol) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (III) [prepared according to International Application WO2007/049158], 14 mg (3 mol %) of palladium acetate and 46 mg (6 mol %) of dicyclohexylbiphenylphosphine are dissolved in 8 ml of dimethylformamide, 1.5 ml of a 2M potassium phosphate solution are added and the medium is degassed several times. The reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted with a 2M hydrochloric acid solution and then the mixture is extracted with ethyl acetate. The organic phases are washed with a sodium chloride solution and then dried over Na2SO4. The solvents are evaporated and then the residue is taken up in 10 ml of heptane/AcOEt 1/1. Filtration is carried out through a silica patch (1 cm). The solvents are evaporated. The residue is precipitated from pentane. The solid is recrystallized from isopropyl ether/heptane. 510 mg of (Z)-3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the solid form.
Reaction SMILES: [NH:1]([C:25]([O:27]C(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33](C(O)=O)[CH3:34]>>[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33]([C:25]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:27])[CH3:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 82.9 %

Procedure:
By using 7.53 g of Boc-Ser(Bzl)-Leu-OEt and 3.50 g of Boc-Ala-OH, and the same procedure as in Reference Example 15 was repeated to obtain 7.26 g (yield: 82.9%) of the above-mentioned objective product.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])[CH:12]=1.C([O-])(O)=O.[Na+]>CC#N.C(OCC)(=O)C>[C:17]([NH:16][S:13]([C:11]1[CH:12]=[C:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[CH:8]=[CH:9][C:10]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])(=[O:15])=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)Cl
Reactant: CN(C)C(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(C(=O)N(C)C)c(S(=O)(=O)NC(C)(C)C)c1
Yield: 83.3 %

Procedure:
0.47 g of methyl chloroformate is added dropwise to a suspension of 1.50 g of 5-amino-N-tert.-butyl-2-dimethylaminocarbonyl-benzenesulfonamide (Example e) and 1.46 g of NaHCO3 in 50 ml of CH3CN at 0° C. When the reaction has ended, the reaction mixture is taken up in ethyl acetate and the mixture is washed with 1N hydrochloric acid, dried over MgSO4 and concentrated. 1.48 g of N-tert.-butyl-2-dimethylaminocarbonyl-5-methoxycarbonylamino-benzenesulfonamide are thus obtained; m.p.: 184-188° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1(O)CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, white solid (15 mg, 48.7%), MS (ISP) m/z=430.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclobutancarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:26]([C:28]1[N:29]=[C:30]([C:41]([O-])=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27]>>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:41]([C:30]3[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=3)=[O:42])=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: COC(=O)C1(c2ccc(N)c(N3CCC(C)CC3)c2)CCOCC1
Agent: [K+]
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(N3CCC(C)CC3)c2)CCOCC1

Procedure:
The title compound is prepared by the procedure of Example 16, step (e) using 4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)).
Reaction SMILES: C(OC([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[C:7]=1[OH:22])=O)C>[OH-].[Na+]>[OH:22][C:7]1[C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][S:13][C:9]=2[NH:10][C:11](=[O:12])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c(-c3ccccc3)csc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(O)c2c(-c3ccccc3)csc2[nH]1
Temperature: 0 °C

Procedure:
4-Hydroxy-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.5 g, 4.76 mmol) was refluxed in 2M sodium hydroxide (50 ml) for 5 hr, filtered while still hot, then cooled to 0° C. and acidified to pH 1 by addition of conc. HCl. The resultant white precipitate was filtered and dried to give 4-hydroxy-3-phenyl-7H-thieno[2,3-b]pyridin-6-one as a white solid. Yield=1.05 g (90.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-nitrophenol (5.2 g, 23.8 mmol) in 2-butanone (100 ml) was added potassium carbonate (9.0 g, 65.1 mmol) followed by benzyl bromide (2.6 ml, 21.8 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux overnight. The solids were then removed by filtration, washing with acetone, and the filtrate reduced in vacuo. The residue was dissolved in ethyl acetate and washed with 2M aqueous sodium hydroxide solution (×3) and then brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and reduced in vacuo to afford the title product. 1H-NMR (d6-DMSO) δ 8.14 (1H, d, J 3.5 Hz), 7.84 (1H, dd, J 11.0, 3.5 Hz), 7.45-7.39 (5H, m), 7.37-7.33 (2H, m), 5.32 (2H, s).
Reaction SMILES: [CH:1]([C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1)=[O:2].Cl([O-])=[O:44].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>O.O1CCCC1.C(O)CCC>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:19]2[C:20](=[O:21])[N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:3]4([C:1]([OH:44])=[O:2])[CH2:6][CH2:5][CH2:4]4)[CH2:10][CH2:11]3)[C:16]3[N:17]([N:40]=[CH:41][N:42]=3)[C:18]=2[CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=1)#[N:36]
Reactant: [O-][Cl+][O-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C=O)CCC3)CC2)c2ncnn12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(=O)O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-[(4-{trans-4-[(1-formylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.7 g), sodium chlorite (0.21 g), sodium dihydrogen phosphate (0.15 g), 2-methyl-2-butene (0.53 mL), n-butanol (10 mL), tetrahydrofuran (5 mL) and water (5 mL) was stirred at room temperature for 16 hr. The reaction mixture was extracted with 1 N hydrochloric acid and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.47 g, 65%).
Reaction SMILES: N(CCNC(C1NC2C(C=1)=CC(NC(C1OC3C=CC(NC(=O)CNC(N)=N)=CC=3C=1)=O)=CC=2)=O)C(N)=N.[N+](C1C=C2C(=CC=1)NC(C(O)=O)=C2)([O-])=O.[N+](C1C=CC2OC(C(O)=O)=CC=2C=1)([O-])=O.[NH:69]([CH2:73][CH2:74][NH:75][C:76]([C:78]1[NH:79][C:80]2[C:85]([CH:86]=1)=[CH:84][C:83]([NH:87][C:88]([C:90]1[NH:91][C:92]3[C:97]([CH:98]=1)=[CH:96][C:95]([NH:99][C:100](=[O:106])[CH2:101][NH:102][C:103]([NH2:105])=[NH:104])=[CH:94][CH:93]=3)=[O:89])=[CH:82][CH:81]=2)=[O:77])C(N)=N>>[NH2:69][CH2:73][CH2:74][NH:75][C:76]([C:78]1[NH:79][C:80]2[C:85]([CH:86]=1)=[CH:84][C:83]([NH:87][C:88]([C:90]1[NH:91][C:92]3[C:97]([CH:98]=1)=[CH:96][C:95]([NH:99][C:100](=[O:106])[CH2:101][NH:102][C:103]([NH2:105])=[NH:104])=[CH:94][CH:93]=3)=[O:89])=[CH:82][CH:81]=2)=[O:77]
Reactant: N=C(N)NCCNC(=O)c1cc2cc(NC(=O)c3cc4cc(NC(=O)CNC(=N)N)ccc4[nH]3)ccc2[nH]1
Agent: N=C(N)NCCNC(=O)c1cc2cc(NC(=O)c3cc4cc(NC(=O)CNC(=N)N)ccc4o3)ccc2[nH]1
Agent: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Product: N=C(N)NCC(=O)Nc1ccc2[nH]c(C(=O)Nc3ccc4[nH]c(C(=O)NCCN)cc4c3)cc2c1

Procedure:
Compound 137 was synthesized as described for Compound 135 in Example 116 through Example 122, except instead of 5-nitrobenzofuran-2-carboxylic acid 5-nitroindole-2-carboxylic acid was used. Yield: 15.4 mg (59%) of compound 138. MS: 518.24 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[H][H]>C1COCC1.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:39])[CH3:40])(=[O:36])=[O:37])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)[CH2:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C=C(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (45 mg, 0.08 mMol) was dissolved in 3.8 mL of THF and 0.9 mL of methanol added. 10% palladium on carbon (13 mg) was added and the reaction placed under 1 atm (balloon) of hydrogen atmosphere and stirred at room temperature for 18 hrs. The reaction was filtered through a plug of celite and the celite rinsed using dichloromethane. Removal of volatiles from the filtrate in vacuuo yield 47 mg of material which was purified by prep. HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=20 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=10.09 min to 10.88 min. Obtained 33.7 mg (75%) of the title compound as a colorless solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20-1.31 (m, 1.1 H) 1.31-1.52 (m, 2.1 H) 1.66 (d, J=13.12 Hz, 1.1 H) 1.78 (d, J=9.16 Hz, 2.0 H) 1.93 (d, J=13.12 Hz, 1.1 H) 1.96-2.09 (m, 2.9 H) 2.82-2.98 (m, 2.2 H) 3.03-3.08 (m, 6.0 H) 3.11-3.19 (m, 1.0 H) 3.73-3.81 (m, 1.0 H) 3.84 (s, 1.3 H) 3.90 (s, 1.8 H) 3.97-4.02 (m, 0.9 H) 4.05 (dd, J=14.95, 5.80 Hz, 0.7 H) 4.75-4.85 (m, 0.4 H) 4.90 (d, J=14.95 Hz, 0.6 H) 6.84 (d, J=2.44 Hz, 0.4 H) 6.94 (dd, J=8.55, 2.44 Hz, 0.5 H) 6.97-7.01 (m, 1.2 H) 7.09-7.17 (m, 1.0 H) 7.32-7.49 (m, 2.0 H) 7.64 (s, 0.6 H) 7.69 (s, 0.4 H) 7.78-7.87 (m, 1.2 H) 7.90 (d, J=8.55 Hz, 0.4 H) 8.02 (s, 0.4 H) 8.42 (s, 0.5 H) 8.59 (s, 0.4H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.02 min, purity 99%; Flow injection Mass Spectrometry: MS m/z 563(MH+), m/z 561(M-H)−.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15]
Reactant: COc1cc(C(C)=O)cnc1OCC(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (1.05 g, a white solid) from 1-(6-(2,2-difluoroethoxy)-5-methoxypyridin-3-yl)ethanone (0.94 g, 4.04 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])(=[O:3])[NH2:2].[C:30]([SH:33])(=[O:32])[CH3:31].[H-].[Na+].O>CN(C)C=O>[C:30]([S:33][C@@H:10]1[CH2:9][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:7]([CH2:6][O:5][CH2:4][C:1](=[O:3])[NH2:2])[CH2:11]1)(=[O:32])[CH3:31]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of (2S,4R)-2-(carbamoylmethyl)oxymethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.98 g) in dimethylformamide (2 ml) was added to a reaction mixture of thioacetic S-acid (0.25 ml) and sodium hydride (62.8% in oil suspension) (0.11 g) in dimethylformamide (10 ml) in a nitrogen stream and the mixture was heated at 70°-75° C. for 3 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml×3), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 v/v) to give (2S,4S)-4-acetylthio-2-(carbamoylmethyl)oxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.72 g).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH:30]([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N(CCC(C)C)c2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Yield: 45.8 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino]benzoate (Compound 8, 37 mg, 0.10 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (1.5 mL). The solution was treated with isovaleraldehyde (0.08 mL, 0.74 mmol) and then sodium cyanoborohydride (13 mg, 0.20 mmol) and the reaction mixture was stirred at room temperature for 5 hours. 1M aqueous NaOH was added until pH=6 and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified by silica gel chromatography (5% ethyl acetate in hexanes) to give the title compound (20 mg, 45%) as an oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]3[C:24](=[O:32])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:33][O:34][C:35]1[CH:56]=[CH:55][C:38]([C:39](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]3[C:24](=[O:32])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:39]([C:38]3[CH:55]=[CH:56][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCOCCO)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCCOCCNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
(2S,4R)-4-Hydroxy-2-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound 72) (1.69 g, 3.83 mmol) and 4,4′-dimethoxytrityl chloride (2.47 g, 7.66 mmol) were dissolved in pyridine (5.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by reverse-phase silica (0.1% ammonium acetate, H2O, CH3OH, gradient) to afford the title compound (Compound 73) (2.24 g, 79%) as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O.C(Cl)Cl.O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:36]=[N+:37]=[N-:38])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Temperature: 80 °C

Procedure:
A mixture of methanesulfonic acid 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridine-2-ylmethyl ester (505 mg, 1.03 mmol) and sodium azide (201 mg, 3.12 mmol) in DMSO (5 mL) is heated at 80° C. for 2 h. The mixture is then diluted with DCM (100 mL) and water. The organic layer is washed further with brine and then dried over anhydrous Na2SO4. Following concentration the residue is separated via FCC (20-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 453.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCCCCCC#Cc1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CO
Product: OCCCCCCCCc1ccc(Cl)c(Cl)c1
Yield: 97.1 %

Procedure:
To a solution of 8-(3,4-dichlorophenyl)-oct-7-yn-1-ol (0.70 g) in methanol (20 ml) was added platinum dioxide (0.05 g) and the mixture reacted under an atmosphere of hydrogen (initial pressure 50 psi). After 1 h. the catalyst was filtered through Hyflo and washed with methanol. The combined methanol layers were evaporated under reduced pressure to give 8-(3,4-dichlorophenyl)octan-1-ol (0.69 g). 1H-NMR (CDCl3) δ 1.1-1.8 (12H, m), 2.55 (2H, t), 3.64 (2H, m), 6.99 (1H, dd) and 7.2-7.4 (2H, m).