Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:14]([CH3:15])[C:13](=[O:16])[N:12]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@:10]1([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH:14]([CH3:15])[C:13](=[O:16])[N:12]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:11]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Tert-butyl (3S)-3-{[tert-butyl (dimethyl) silyloxy]methyl}-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (3.72 g, 8.31 mmol) was dissolved in tetrahydrofuran (70 mL), and tetrabutylammonium fluoride (12.5 mL, 1.0 mol/l solution in tetrahydrofuran, 12.5 mmol) was added dropwise in an ice bath. The mixture was stirred at the same temperature for 1 hour. After concentrating the mixture, saturated aqueous solution of ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (elusion by hexane:ethyl acetate=3:1→1:2) to obtain 1.87 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([P:3]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:35]>C1(C)C=CC=CC=1>[Ti+4:35].[CH2:1]([P:3]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:5][CH2:6][C:7]([O-:9])=[O:8])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][CH2:6][C:7]([O-:9])=[O:8])([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][CH2:6][C:7]([O-:9])=[O:8])([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][CH2:6][C:7]([O-:9])=[O:8])([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:4])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCC(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC(=O)[O-]
Yield: 97.4 %

Procedure:
222 g (1 mol) of 3-(ethylbutoxyphosphinyl)propionic acid (produced as in Example 13) and 85 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 227 g of 3-(ethylbutoxyphosphinyl)propionic acid titanium salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[C:23]([NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:34][CH2:33][CH2:32][CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:22])=[CH:12][N:11]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C5, 328 mg), N-Boc-1,3-propanediamine (289 μL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (846 mg), and 1-hydroxybenzotriazole monohydrate (676 mg), N,N-dimethylformamide (10 mL) and triethylamine (306 μL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 50 to 30% hexane in ethyl acetate) to obtain tert-butyl (3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D1, 224 mg) as white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=2)=[CH:15][C:14]=1[C:30]1[CH:39]=[CH:38][C:37]2[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[C:32]=2[CH:31]=1>C(C(C)=O)C>[Br:1][CH2:2][CH2:3][CH2:4][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=2)=[CH:15][C:14]=1[C:30]1[CH:39]=[CH:38][C:37]2[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[C:32]=2[CH:31]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
320 μl (3.14 mmol) of 1,3-dibromopropane and 440 mg (3.18 mmol) of potassium carbonate are added to a solution of 900 mg (2.1 mmol, 1 eq) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 30 ml of methyl ethyl ketone. The reaction mixture is stirred overnight at room temperature and then for 1 day at reflux. The medium is cooled to room temperature and then filtered. The filtrate is evaporated and the residue is purified by chromatography on silica gel (eluent: 90/10 heptane/ethyl acetate). 640 mg of ethyl 4′-(3-bromopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=55%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.9 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(tert-butoxycarbonyl)amino-thiophene-2-carboxylic acid methyl ester (4.344 g, 9.58 mmol) in CH2Cl2 (30 mL) is added trifluoroacetic acid (30 mL), and the mixture is stirred at room temperature overnight. Then it is evaporated to dryness, obtained residue is redissolved in CH2Cl2 and washed with aqueous NaHCO3 and brine. Organic fraction is separated, dried over Na2SO4, and concentrated to give 3.135 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-amino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11](Br)[CH:12]=[CH:13][C:14]=2[F:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:27]3[CH:26]=[C:25]([CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:42])[CH:30]=[CH:29][C:28]=3[O:31][CH3:32])[CH:12]=[CH:13][C:14]=2[F:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(F)ccc(Br)c2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)c3c2CN(C(=O)OC(C)(C)C)CC3)c1
Temperature: 100 °C

Procedure:
To a mixture under N2 of 8-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.24 g, 3.75 mmol, 1.00 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.69 g, 3.75 mmol, 1.00 eq.) and sodium carbonate (1.59 g, 15.00 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (75 mL), tetrakis(triphenylphosphine) palladium (0) (217 mg, 0.19 mmol, 0.05 eq.) was added and the mixture was stirred under reflux at 100° C. for 70 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (150 mL) and water (150 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×75 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 40 mL, Heptane+10% AcOEt to Heptane+25% AcOEt) to yield the desired ester as a pale yellow oil.
Reaction SMILES: B(F)(F)F.CCOCC.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH2:19][C:20]2([CH2:24][CH3:25])[CH2:23][O:22][CH2:21]2)=[O:17])[CH:11]=1.C(N(CC)CC)C.O>ClCCl>[CH2:24]([C:20]12[CH2:21][O:17][C:16]([C:12]3[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=3)([O:18][CH2:19]1)[O:22][CH2:23]2)[CH3:25]
Reactant: CCC1(COC(=O)c2cccnc2)COC1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC12COC(c3cccnc3)(OC1)OC2
Temperature: 25 °C

Procedure:
Boron trifluoride etherate (1.50 ml.) was added to a stirred solution of (3-ethyl-oxetan-3-yl)methyl 3pyridinecarboxylate) (1.10 gm.) in dry dichloromethane at -70°, under a current of dry nitrogen. The stirred mixture was allowed to warm up to room temperature over a period of six hours. Triethylamine (5 ml) was added and the mixture was poured into water. The aqueous mixture was extracted with dichloromethane. The extracts were washed with water, dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC) eluting with 1:1 dichloromethane:hexane, saturated with ammonia. 4-Ethyl-1-(3-pyridyl)-2,6,7-trioxabicyclo[2.2.2]octane was obtained as colourless crystals (Mpt. 58°-60°, from ether, hexane).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: CC(C)(C)OC(=O)NCCNc1cccc[n+]1[O-]
Reaction time: 47 h
Yield: 89.3 %

Procedure:
A mixture of mono-Boc-1,2-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, 43.67 mmole), NaHCO3 (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture was cooled, diluted with CH2Cl2 (100 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene. Silica gel chromatography (10% MeOH/CHCl3) gave impure title compound (8.23 g, 89%) as a yellow solid which was used without further purification: TLC (10% MeOH/CHCl3) Rf 0.42; 1H NMR (250, CDCl3) δ 8.16 (dd, J=6.5, 1.3 Hz, 1 H), 7.05-7.30 (m, 2 H), 6.68 (br d, J=8.6 Hz, 1 H), 6.50-6.65 (m, 1 H), 5.70-5.95 (m, 1 H), 3.35-3.60 (m, 4 H), 1.44 (s, 9 H); MS (ES) m/e 254 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH2:18][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21]
Reactant: C1COCCN1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2OCCCO)cc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2OCCCN2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 198 (100 mg, 0.25 mmol) was dissolved in dry pyridine (130 μL) under an argon atmosphere. The solution was cooled on an ice bath and 4-toluenesulfonyl chloride (48 mg, 0.25 mmol) was added. The reaction mixture was quenched with water after 45 min at room temperature. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/EtOAc 4:1 as the eluent. The tosylate was dissolved in dry DMF (2.0 mL) and morpholine (17 μL, 0.19 mmol) was added. The reaction mixture was stirred for 48 h at room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM/MeOH 100:4 as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][N:17]=1>>[CH:23]1([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=3)=[N:17][CH:18]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Clc1ccc(OC2CCCC2)cn1
Reactant: CC(=O)NCCCc1ccc(O)cc1
Product: CC(=O)NCCCc1ccc(Oc2ccc(OC3CCCC3)cn2)cc1

Procedure:
N-[3-(4-Hydroxyphenyl)propyl]acetamide was reacted with 2-chloro-5-cyclopentyloxypyridine in analogy to example 2c. M+H+: 355.18.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(Cl)c2)cc1
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A solution of tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate (Intermediate H, 3 g, 9.6 mmol), 3-chlorophenylboronic acid (1.8 g, 11.5 mmol) and K2CO3 (3.9 g, 28.8 mmol) in acetonitrile:water (4:1) was degassed for 20 min. Tetrakis triphenylphosphine palladium (300 mg) was added and heated at reflux for 18 h. After completion, the reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4 filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using EtOAc: Pet ether to give (3 g, 91%) tert-butyl (trans)-2-(3′-chlorobiphenyl-4-yl)cyclopropylcarbamate as a white solid.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Product: COc1cccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1OC
Yield: 70 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2,3-dimethoxycinnamic acid under the conditions described in example 86 to yield 70% of the desired product.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:15][NH:14][C@H:13]([C:16]#[N:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][NH:9][CH:10]1[CH2:15][NH:14][C@H:13]([C:16]#[N:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCC(NOCc2ccccc2)CN1

Procedure:
The compound of Formula (IX) was reacted with sulphuric acid and sodium triacetoxy borohydride, in presence of suitable solvent such as ethyl acetate and at temperature below −5° C., to provide (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine (X). The compound of Formula (X) was purified by forming oxalate salt. The compound of Formula (X) was reacted with oxalic acid in a mixture of ethylacetate and acetone to provide (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine ethanedioate (1:1) (XI), which was further treated with sodium hydrogen carbonate to obtain purified (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine (XII). The racemic compound (XI) was treated with methanol to obtain pure (2S,5R)-5-[(benzyloxy)amino]-2-cyanopiperidine ethanedioate.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Br[CH:22]1[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[S:23]1>C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]([CH:22]2[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=3)[S:23]2)[C:2](=[O:3])[N:4]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: F[C@@H]1C(Br)S[C@H](COCc2ccc(Cl)cc2)[C@H]1OCc1ccc(Cl)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](COCc3ccc(Cl)cc3)[C@@H](OCc3ccc(Cl)cc3)[C@@H]2F)c(=O)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To another reaction vessel, 0.12 g of cytosine and 0.53 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80° C. for 2 hours. After cooling in air, a methylene chloride solution containing (3S,4S,5R)-2-bromo-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane was added to the reaction mixture, and the obtained mixture was then stirred 60° C. for 2 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was washed with a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 80/20), so as to obtain 0.18 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane in the form of a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[C:49]([CH3:55])=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][CH:54]=[C:48]([F:47])[C:49]=4[CH3:55])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1c(N)cccc1F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(F)c2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoro-2-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 772 [(M+H)+].
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC(=O)OCC.O>[CH3:22][N:6]1[C:5]2[S:23][C:2]([O:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:36])[F:37])[CH:30]=3)=[C:3]([CH:24]=[O:25])[C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(OC(F)(F)F)c3)sc21
Temperature: 80 °C
Yield: 40.8 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2, 3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (See Compound 2, Step 4, 100 mg, 0.232 mmol) in DMSO (2 mL) was added 3-(trifluoromethoxy)phenol (82.6 mg, 0.464 mmol) and K2CO3 (96.1 mg, 0.696 mmol). The reaction was heated to 80° C. for 18 h, cooled to RT then diluted with EA (10 mL) and water (10 mL). The organic layer was washed with aq. 1N LiCl (3×5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 3:1) to give 1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (50 mg, 40.8% yield) as a solid. LCMS: [MH+-THP] 445 and TR=1.834 min.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]([CH:29]1[CH2:31][CH2:30]1)([CH3:28])[CH2:24][C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[CH2:24][C:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]2[CH2:5][C:2]([F:21])([F:1])[CH2:3]2)=[CH:11][N:10]=1)=[O:14])([CH:29]1[CH2:31][CH2:30]1)[CH3:28]
Reactant: CC(N)(CC(N)=O)C1CC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 223b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (70 mg, 63%) as a racemate; MS (ESI, m/z): 437.3 (M+H+).