Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]1)=S)[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].CCN(CC)CC>CN(C=O)C.Cl[Hg]Cl>[CH2:1]([N:3]1[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]2)=[N:17][N:16]=[N:15]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=S)N1CCC(CCO)CC1
Agent: Cl[Hg]Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1nnnc1N1CCC(CCO)CC1
Reaction time: 10 h
Yield: 40.6 %

Procedure:
To a mixture of N-Ethyl-4-(2-hydroxyethyl)piperidine-1-carbothioamide (200 mg, 0.93 mmol), HgCl2 (277 mg, 1.02 mmol), and NaN3 (181 mg, 2.78 mmol) in DMF (2.5 mL) was added NEt3 (388 μL, 2.78 mmol) at rt. After stirring for 10 h, the reaction mixture was filtered, and the filter cake was washed with CH2Cl2. The combined filtrates and washings were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo, and the residue was purified by SiO2 chromatograph (60% EtOAc/hexane) to afford the titled compound (85 mg, 41%): 1H NMR (CDCl3) δ 4.18 (q, J=7.2 Hz, 2H), 3.75 (td, J=6.8, 5.2 Hz, 2H), 3.51 (brd, J=12.4, 2H), 3.03 (td, J=12.4, 2.8 Hz, 2H), 1.84 (brd, J=14.4 Hz, 2H), 1.71 (m, 1H), 1.59 (q, J=6.8 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H), 1.48-1.38 (m, 2H)
Reaction SMILES: N.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][N:15]=[C:16]([CH2:19][C:20]#[N:21])[C:17]#[N:18]>O.C(O)C>[NH2:21][C:20]1[N:14]([C:4]2[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:6][C:5]=2[Cl:13])[N:15]=[C:16]([C:17]#[N:18])[CH:19]=1
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: N
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
Ammonia (20 microliters of an 8% ammonia solution in water) was added to a mixture of the above 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)-succinonitrile (0.077 g) in ethanol (1 ml) and water (0.2 ml) at 0° C. After 10 minutes, the mixture was extracted (dichloromethane) and evaporated to give 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.076 g, 97% yield). Purity 98% (by hplc).
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH:36]1[CH2:41][CH2:40][SiH:39]([CH2:42][CH2:43][CH3:44])[CH2:38][CH2:37]1>[Cu]I.C1COCC1>[CH2:42]([Si@H:39]1[CH2:40][CH2:41][C@H:36]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:37][CH2:38]1)[CH2:43][CH3:44]
Reactant: Clc1ccc(-c2ccc([C@H]3CC[C@H](CCBr)CC3)cc2)cc1
Reactant: CCC[SiH]1CCC(Br)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(Cl)cc4)cc3)CC2)CC1

Procedure:
37.8 g (0.1 mol) of 4-(trans-4-(2-bromoethyl)cyclohexyl)-4'-chlorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 22.1 g (0.1 mol) of 1-bromo-4-n-propyl-4-silacyclohexane. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-chlorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 10.0 g (yield 22.8%) of the trans isomer.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][C@H:9]([C:31]([O:33][CH3:34])=[O:32])[CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)C=CC=CC=1.[ClH:47]>CO.C(OCC)C>[ClH:47].[CH2:28]([NH:27][C:25]([NH:24][C:20]1[CH:19]=[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C@@H:9]([C:31]([O:33][CH3:34])=[O:32])[NH2:8])[CH:13]=2)[CH:23]=[CH:22][CH:21]=1)=[O:26])[CH2:29][CH3:30]
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)c2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](N)C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl N-triphenylmethyl-O-(3′-{[(propylamino)carbonyl]amino}-1,1′-biphenyl-3-yl)-L-serinate (Example 4) (291.2 mg, 0.48 mmol, 1 equiv) was dissolved in MeOH and treated with a 1 M solution of HCl in diethylether at rt. The solution was stirred for 2 h at rt and then the solvents were removed in vacuuo. The crude product was titurated with ether to give a yellow precipitate which was filtered off and dried in vacuo. Yield 195.0 mg, 99%. 1H NMR (DMSO, 200 MHz) δ 8.85 (brs, 2H); 7.82 (s, 1H); 7.55 (d, 2H); 7.49-7.22 (m, 3H); 7.05 (d, 2H); 4.85-4.55 (m, 1H); 4.49-4.29 (m, 2H); 3.80 (s, 3H); 2.92 (dd, 1H); 1.60-1.29 (m, 3H); 0.96 (t, 3H).
Reaction SMILES: CO.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br-:20].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.C(=O)([O-])O.[Na+]>O>[Br:20][CH2:18][C:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:10]=1)=[O:19]
Reactant: [Br-]
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)CBr)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.7 %

Procedure:
To 200 ml of methanol solution containing 11.6 g (49.5 mmol) of 1-(3-cyclopentoxy-4-methoxyphenyl)ethanone (see Bioorg. Med. Chem. Lett. 2003, 13, 2355) was added 20.47 g (54.5 mmol) of trimethylphenylammonium tribromide at room temperature, and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, water was added to the reaction mixture, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and then extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained concentrate was added 50 ml of a mixed solvent (diisopropyl ether/hexane=1/2 (V/V)), and precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether, and dried under reduced pressure to obtain 6.47 g of the title compound as a white solid. (Yield: 41%)
Reaction SMILES: C(OC([NH:11][C@H:12]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[C:56]([F:58])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@H:47]([OH:59])[C@@H:46]1[OH:60])=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:34])[CH3:32])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[ClH:61].C(O)C.[H][H]>C(O)C.CO.[C].[Pd]>[ClH:61].[ClH:61].[NH2:11][C@H:12]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[C:56]([F:58])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@H:47]([OH:59])[C@@H:46]1[OH:60])=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:34])[CH3:32])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: [H][H]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 98.8 %

Procedure:
0.94 Gram (1.11 mmol) of the ester obtained as described above was dissolved in ethanol (100 ml) and methanol (20 ml), and 0.40 g of 10% palladium-carbon and 0.50 g (4.93 mmol) of 36% hydrogen chloride-ethanol were added. The mixture was stirred in a stream of hydrogen under normal pressure for 2 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with ether (20 ml) to obtain 0.71 g (99%) of the desired 5'-O-{N-(N-lysylalanyl)isoleucyl}-5-fluorouridine dihydrochloride as a colorless powdery solid.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:22]([N-]C1CCCCC1)(C)C.[Li+].CI.Cl>O1CCCC1>[CH3:22][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([O:20][CH3:21])=[O:19]
Reactant: CC(C)[N-]C1CCCCC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCC(C)C(=O)OC

Procedure:
A solution of methyl oleoate (0.054 mole) in tetrahydrofuran (100 ml) was added dropwise to a freshly prepared cold solution of lithium isopropyl cyclohexyl amide (1.2 eq.) in tetrahydrofuran (400 ml) over 4.75 hrs. Methyl iodide (1.5 eq.) was added dropwise rapidly and the reaction was allowed to come to room temperature. The reaction was stripped of solvent to give an orange oil. The material was added to 1N hydrochloric acid (100 ml) and extracted into ethyl ether. The ethyl ether was washed with water (100 ml), dried over sodium sulfate, filtered and stripped to an oil which was identified as the title compound by spectral analysis and used in Example 67.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].ClNC(=O)CCC(N)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:48]=[C:49]1[CH2:54][CH2:53][CH:52]([C:55](O)=[O:56])[CH2:51][CH2:50]1>ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:55]([CH:52]1[CH2:53][CH2:54][C:49](=[O:48])[CH2:50][CH2:51]1)=[O:56])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: O=C1CCC(C(=O)O)CC1
Agent: NC(=O)CCC(=O)NCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(=O)CC1)C(C)C

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.5 g, 5.45 mmol) in 1,2-dichloroethane, N-chlorosuccinamide (0.940 g, 7.091 mmol), triphenylphosphine (1.9 g, 7.091 mmol) and 4-oxo-cyclohexanecarboxylic acid (800 mg, 5.455 mmol) were added. The reaction mixture was stirred at reflux for overnight under an atmosphere of N2. The reaction mixture was diluted with CH2Cl2 and extracted with saturated solution oh NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified using silica gel column chromatography using ethyl acetate: hexane (1:4) as eluent to obtain 3-[Isopropyl-(4-oxo-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. (1.2 g, 55%) as syrup. 1H NMR (CDCl3, 400 MHz): δ7.75-7.50 (m, 2H), 7.70-7.38 (m, 3H), 7.12 (s, 1H), 4.95 (m, 1H), 3.87 (s, 3H), 2.75-0.83 (m, 15H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:21]=3)[CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[N:21]=3)[CH2:15]2)=[CH:12][CH:13]=1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccc(C2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 29.3 %

Procedure:
N,N-Dimethylcarbamoyl chloride (0.24 g, 2.23 mmol) was added to a solution of 2-[(2S)-2-(4-aminophenyl)morpholin-4-yl]-3-methyl-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (0.40 g, 1.10 mmol) and triethylamine (1.1 g, 10.9 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at 50° C. for 48 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 1,1-Dimethyl-3-{4-[4-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl) morpholin-2-yl]-phenyl}-urea (0.14 g, 30%) as white crystals.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH3:26])[CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].[F:27][CH:28]([F:43])[O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]OS(C)(=O)=O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:37][CH2:36][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:27])[F:43])=[CH:35][CH:34]=4)[CH2:22]3)[CH2:18]2)[CH3:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: CS(=O)(=O)OCCc1ccc(OC(F)F)cc1
Reactant: CN(CCN1CC2CNCC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCN1CC2CN(CCc3ccc(OC(F)F)cc3)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Yield: 56.7 %

Procedure:
A mixture of 4-cyano-N-methyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.169 g, 0.40 mmol, prep. I above), methanesulfonic acid 2-(4-difluoromethoxy-phenyl)-ethyl ester (0.107 g, 0.40 mmol, prep W above ), potassium carbonate (0.177 g, 1.28 mmol), and water (0.1 mL) in acetonitrile (4 mL) was heated in an oil bath (60° C.) for 20 h. Solid material was filtered off and the filtrate was loaded onto a cation-exchange column (SCX-2, Isolute™, 2 g/15 mL). The column was washed with a solution of methylene chloride/acetonitrile/methanol (2:1:1, 40 mL) and eluted with 20% methanol saturated with ammonia in methylene chloride (30 mL). The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane eluent. Concentration in vacuo afforded 118 mg (57%) of the title compound as a solid white material.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:29]=[C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[N:28]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)Nc1ccc(F)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3)n2)s1
Yield: 89.6 %

Procedure:
To a mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(4-fluoro-phenyl)-guanidine nitrate (2.0 mmol, 0.44 g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixture was refluxed under N2 for 24 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as brown crystals (269 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.03 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: OO[S:3]([O-:5])=O.[K+].S1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:39])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1>O.CO>[O:5]=[S:3]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:39])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1
Reactant: O=S([O-])OO
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Reaction time: 0.33 h
Yield: 128.7 %

Procedure:
To a solution of oxone (120 mg, 0.200 mmol) in water (0.7 mL) which was cooled below 0° C. in an ice bath, was added a solution of tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate (155 mg, 0.333 mmol) in methanol (3 mL) dropwise. The mixture was stirred below 0° C. about 20 minutes. The formed precipitate was collected by filtration, washed with water and purified by flash column chromatography to afford 124 mg of the product as a white solid (yield was 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1cnc2ccccc2c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromoquinoline (10.40 g, 0.05 mol), trimethylsilylacetylene (8.48 mL, 0.06 mol), cuprous iodide (0.5 g) and trans-dichlorobis(triphenylphosphine)palladium (1 g) and TEA (15 mL) was heated at 70° C. in a sealed tube for 1 h. H2O (150 mL) was added, followed by Et2O (300 mL). The organic layer was separated and the aqueous layer extracted with Et2O (200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give 3-(trimethylsilylethynyl) quinoline as a brown oil. 3-(Trimethylsilylethynyl) quinoline was dissolved in anhydrous MeOH (100 mL) and K2CO3 (0.69 g, 5 mmol) was added. The mixture was stirred at rt for 1 h and DCM (250 mL) was added. The mixture was filtered over celite. The filtrate was evaporated and the residue was purified by flash column chromatography to give Compound 13b as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[C:21]([NH2:23])=[O:22])C1C=CC=CC=1.[H][H]>CO.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:21]([NH2:23])=[O:22])[CH2:10]1
Reactant: [H][H]
Reactant: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1N1CCNC(C(N)=O)C1

Procedure:
1-benzyl-4-(2-methylphenyl)piperazine-2-carboxamide (2.64 g, 8.53 mmol) and palladium hydroxide/carbon (430 mg) were combined in a mixture of methanol (35 ml) and ethanol (35 ml) and shaken in an atmosphere of hydrogen at 55 psi for 6 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was reconcentrated in vacuo from ether three times to provide 4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NOCc1ccccc1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (150 mg, 0.44 mmol) in dry THF (3 mL) under argon was added O-benzylhydroxylamine hydrochloride (421.5 mg, 2.64 mmol), potassium cyanide (1.43 mg, 0.02 mmol) and triethylamine (0.36 mL, 2.64 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1.5/1) to give 182 mg of the desired compound (89% yield).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C:31]2[C:32]([OH:38])=[CH:33][CH:34]=[C:35]([F:37])[CH:36]=2)[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[C@@H:40]([CH3:42])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C@@H:40]([CH3:42])[C:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxylate (0.19 ml) was added to a solution of the product of example 2 part (iii) (250 mg), tert-butyl (R)-(+)-lactate (141 mg) and triphenylphosphine (252 mg) in tetrahydrofuran (10 ml) at 0° C. After 20 minutes the ice bath was removed and the reaction stirred at room temperature overnight. The reaction mixture was then adsorbed onto silica and purified using flash column chromatography (eluent 10% ethylacetate/hexane) to give the subtitle compound as an oil, yield 140 mg.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 87.3 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (250 mg, 0.61 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (969 mg, 9.11 mmol) followed by pyrrolidine (0.51 mL, 6.1 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml) and washed with water (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (233 mg, 0.48 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.42 mL, 0.53 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (240 mg, 76%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.5, 2.0 Hz, 1H), 4.57-4.53 (m, 1H), 4.49-4.46 (m, 1H), 4.27 (br s, 1H), 3.25-2.75 (br m, 6H), 1.85 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=15.1 min; [α]23D −11.3° (c 0.11, Methanol).