Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl[C:34]1[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:19][C:18]=3[C:29]([F:31])([F:32])[F:30])(=[O:16])=[O:15])[CH2:11][N:10]2[C:34]2[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2)CC1
Reactant: FC(F)(F)c1nnc(Cl)s1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2c2nnc(C(F)(F)F)s2)CC1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 211a) was reacted with 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (CAS Reg. No. 53645-98-0) in a shaking reactor at 55° C. for 12 h to give the title compound as yellow solid. MS (ESI): m/z=638.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[F:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20](O)=O.N>>[F:14][C:15]1[CH:23]=[C:19]([C:20]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)[CH:18]=[N:17][CH:16]=1
Reactant: O=C(O)c1cncc(F)c1
Reactant: NC(=NO)c1ccc2nccn2c1
Agent: N
Product: Fc1cncc(-c2nc(-c3ccc4nccn4c3)no2)c1

Procedure:
The title compound was prepared according to method C using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 5-fluoronicotinic acid (Frontier). 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=1.4 Hz, 1 H), 7.74-7.88 (m, 2 H), 8.20 (s, 1 H), 8.51 (ddd, J=9.0, 2.9, 1.7 Hz, 1 H), 8.97 (d, J=3.1 Hz, 1 H), 9.24 (t, J=1.5 Hz, 1 H), 9.47 (t, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH3:16]I>CN(C=O)C>[CH2:9]([C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([O:13][CH3:16])[CH2:11][CH3:12])[CH3:10]
Reactant: CCC(O)(CC)c1cccnc1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(CC)(OC)c1cccnc1C
Reaction time: 6 h
Yield: 36.7 %

Procedure:
A solution of 3-(2-methyl-pyridin-3-yl)-pentan-3-ol (0.444 g, 2.48 mmol) and NaOH (0.125 g, 5.2 mmol) in DMF (13 mL) was stirred for 16 h. MeI (0.55 g, 3.9 mmol) was added. The mixture was stirred for 6 h, and the solvent was removed by evaporation under vacuum. Brine (25 mL) was added, and the aqueous mixture was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (1:1 Et2O/CH2Cl2), affording 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.176 g, 37%). 1H NMR (CDCl3) δ 0.73 (t, 6H, J=7.5 Hz), 1.87-2.04 (m, 4H), 2.77 (s, 3H), 3.01 (s, 3H), 7.09 (dd, 1H, J=8.1, 4.8 Hz), 7.56 (dd, 1H, J=8.1, 1.5 Hz), 8.40 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:21])(=[O:20])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=2[NH:12][C:11]([CH3:29])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:20])(=[O:21])[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[NH:12][C:11]([CH3:29])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of ethyl 9-(2,3-dichlorophenyl)-4-(t-butyloxycarbonyl)-1,1-dioxo-2,3,4,5,6,9-hexahydro-7-methylpyrido[2,3-f][1,4]thiazepine-8-carboxylate (2.45 g, 4.6 mmole) from Example 7, in ethyl acetate (150 mL) was cooled to 0° C. and saturated with gaseous hydrogen chloride. The mixture was warmed to room temperature. The reaction was then again chilled to 0° C. and shaken with 200 mL of cold 4 N NaOH. The aqueous layer was separated and extracted with 2×100 mL of chloroform. The ethyl acetate layer was dried with brine and the combined organic extracts were dried over Na2SO4. The solvents were evaporated under reduced pressure and the residue triturated with ether to give the product (1.86 g, 94% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][C:13]=2[S:25]([NH2:28])(=[O:27])=[O:26])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][C:13]=3[S:25]([NH2:28])(=[O:26])=[O:27])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: NS(=O)(=O)c1cc(Oc2ccccc2)ccc1NS(=O)(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(Oc2ccccc2)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 15.3 %

Procedure:
To a solution of 2-(3-bromophenylsulfonamido)-5-phenoxybenzenesulfonamide (241.5 mg, 0.5 mmol), 3,4-dichlorobenzeneboronic acid (190.8 mg, 1.0 mmol), tricyclohexyl phosphine (50 mg, 0.18 mmol) and potassium phosphate (340 mg, 1.6 mmol) in DMF (10 mL), was added Pd(OAc)2 (20 mg, 0.09 mmol). The reaction mixture was stirred at 80° C. for 7 h, diluted with 1N HCl and the product was extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to afford the title compound (42 mg, 15%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[C:13](=[CH:18][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])(OCC)=O)C.[CH2:24]([C:26]1([C:31]2[S:35][C:34]([CH:36]=O)=[CH:33][CH:32]=2)[O:30][CH2:29][CH2:28][O:27]1)[CH3:25].CC(C)([O-])C.[K+]>C1COCC1>[CH2:24]([C:26]1([C:31]2[S:35][C:34](/[CH:36]=[CH:9]/[C:10]3[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[C:13](=[CH:18][CH:19]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:33][CH:32]=2)[O:27][CH2:28][CH2:29][O:30]1)[CH3:25]
Reactant: CCC1(c2ccc(C=O)s2)OCCO1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(C(=O)OC)c1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1(c2ccc(/C=C/c3ccc(C(=O)OC)c(C(=O)OC)c3)s2)OCCO1
Reaction time: 24 h

Procedure:
18.5 g (53.7 mmol) of dimethyl 4-(diethoxyphosphorylmethyl)phthalate and 9.5 g (44.7 mmol) of 5-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-2-carbaldehyde (described in Example 6(b)) are dissolved in 200 mL of anhydrous THF. 6.02 g (53.7 mmol) of potassium tert-butoxide are added and the mixture is stirred for 24 h. After the usual treatment and chromatography on silica gel (eluent: 8 heptane/2 ethyl acetate), the desired product is obtained in the form of a yellow oil (m=9.53 g, Y=53%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)[CH:5]=[C:6]([CH3:16])[C:7]=1OS(C(F)(F)F)(=O)=O.[CH3:30][N:31](C)C=O>CCOCC.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)=[CH:5][C:6]=1[CH3:16])#[N:31]
Reactant: CN(C)C=O
Reactant: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1C#N
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 4-(3,5-dimethyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.80 g, 0.00643 mol) and zinc cyanide (1.51 g, 0.0128 mol) in N,N-dimethylformamide (15.0 mL, 0.194 mol)was degassed with nitrogen for 15 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.74 g, 0.00064 mol). The reaction mixture was heated at 100 Celsius for 4 h. The mixture was diluted with ether, washed with aq. sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified on silica gel, eluting with 0 to 10% EtOAc in hexane, to generate the titled compound (1.08 g, 53.66%). LCMS (M+H) 313.1
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:13]([CH2:27][N:28]2[CH:32]=[C:31]([C:33](OC)=[O:34])[N:30]=[N:29]2)=[C:14]2[C:19](=[CH:20][C:21]=1[Cl:22])[N:18]=[C:17]([O:23][CH3:24])[C:16]([O:25][CH3:26])=[N:15]2.[Cl-].[NH4+]>CO>[Cl:11][C:12]1[C:13]([CH2:27][N:28]2[CH:32]=[C:31]([CH:33]=[O:34])[N:30]=[N:29]2)=[C:14]2[C:19](=[CH:20][C:21]=1[Cl:22])[N:18]=[C:17]([O:23][CH3:24])[C:16]([O:25][CH3:26])=[N:15]2
Reactant: COC(=O)c1cn(Cc2c(Cl)c(Cl)cc3nc(OC)c(OC)nc23)nn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)c(Cn3cc(C=O)nn3)c2nc1OC
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 97.6 %

Procedure:
A solution of diisobutylaluminium hydride (1M in dichloromethane, 9 mL, 9 mmol) was added dropwise to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-[(4-methoxycarbonyl-1,2,3-triazol-1-yl)methyl]quinoxaline (1.087 g, 2.73 mmol) under nitrogen at -78° C. After 2.25 hours, methanol (5 mL) was added, followed by saturated aqueous ammonium chloride (25 mL) 5 minutes later. The mixture was allowed to warm to room temperature, filtered through Arbocel filter aid, washing the filter cake with dichloromethane. The organic solution was dried (MgSO4) and concentrated under reduced pressure to give 6,7-dichloro-2,3-dimethoxy-5[(4-formyl-1,2,3-triazol-1-yl)methyl]quinoxaline (981 mg, 98%), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)C1(CCCNCc2ccccc2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(CCCNCc2ccccc2)CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 132.7 %

Procedure:
To a solution of 2-(3-benzylaminopropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.69 g) in chloroform (38 ml) cooled to 0° C. was added 4M hydrochloric acid-ethyl acetate (18 ml), and the mixture was stirred at room temperature for 3 hours. To the mixture was added additional 4M hydrochloric acidethyl acetate (20 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure, and then thereto was added saturated aqueous sodium bicarbonate solution (150 ml). The mixture was extracted with chloroform (100 ml×2, 75 ml×2) 4 times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (7.49 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[C:10]([CH2:31][CH3:32])([CH2:29][CH3:30])[NH:9]1)=[O:7])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[C:10]([CH2:29][CH3:30])([CH2:31][CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC1(CC)NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC)NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 48c (0.33 g, 0.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white foam (0.35 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([OH:16])[C:13]([C:17]#[N:18])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:12]=[C:13]([C:17]#[N:18])[C:14]([O:16][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(-n2cc(O)c(C#N)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(OCc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22.8 %

Procedure:
To a solution of 4-(3-cyano-4-methoxypyrrole-1-yl)benzoic acid ethyl ester (0.081 g) in dichloromethane (3 mL) was added boron tribromide (0.33 mL, 1 mol/L dichloromethane solution) under ice-cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water, and this mixture was extracted with diethyl ether. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) to give 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g). To a solution of 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g) in N,N-dimethylformamide (4 mL) were added benzylbromide (0.038 g) and cesium carbonate (0.13 g) at room temperature, and this mixture was stirred at 80° C. for 5 hours. To this reaction mixture was added water at room temperature, and the precipitated solid was collected by filtration, and washed with methanol (5 mL) to give the title compound (0.016 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[N:24]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:23]2(=[O:35])=[O:34])=[C:18]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:17]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:37]([O:36][C:18]1[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)[CH:21]=[CH:20][C:19]=1[N:22]1[S:23](=[O:34])(=[O:35])[N:24]([CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:25](=[O:27])[CH2:26]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of 2-((E)-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-vinyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 62, step B) (240 mg, 0.353 mmol) in TFA/methylene chloride (3:8) is stirred at RT for 75 min. The solvent is removed under reduced pressure and the residue purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[CH2:11][N:12]([CH2:20][CH3:21])[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH2:20]([N:12]([CH2:11][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:7]=2)[CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:21]
Reactant: CCN(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCN(Cc1cccnc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 23 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 440. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.63 (s, 1H) 8.49 (m, 1H) 8.26 (m, 1H) 8.15 (s, 1H) 8.05 (s, 1H) 7.45 (m, 2H) 7.25 (m, 1H) 7.05 (m, 3H) 6.99 (d, 1H) 6.75 (m, 4H) 3.4-3.8 (m, 4H) 2.88 (t, 2H) 2.75 (t, 2H) 2.55 (m, 2H) 1.05 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[NH:16])[NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]([SH:21])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[C:18]([Cl:17])[S:21][N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCN(Cc3ccccc3)CC2)ns1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
To a solution of 4-benzylpiperazine-1-carboximidamide (2.50 g, 11.5 mmol) and perchloromethyl mercaptan (1.24 ml, mmol) in methylene chloride (12 ml) was added dropwise a solution of sodium hydroxide (1.84 g, 46.0 mmol) in water (5 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The reaction mixture was poured to water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.00 g (29.6%) of the desired product as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH:16][CH:17]([CH2:29][NH:30]C(OC(C)(C)C)=O)[C:18]([N:20]([CH3:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].Cl>CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH:16][CH:17]([CH2:29][NH2:30])[C:18]([N:20]([CH3:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:38][CH:39]=1)#[N:2]
Reactant: CN(Cc1ccccc1)C(=O)C(CNC(=O)OC(C)(C)C)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)C(CN)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
A solution of the product from Example 27 (86.3 mg, 0.163 mmol) in EtOAc (5 ml) at 0° C. was saturated with gaseous HCl and stirred for 15 min. The solvent was evaporated and the title compound was dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:45])[O:23][CH2:24][CH2:25][O:26][P:27]([O:37]CC2C=CC=CC=2)([O:29]CC2C=CC=CC=2)=[O:28])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:10]=1.C1CC=CCC=1>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:45])[O:23][CH2:24][CH2:25][O:26][P:27]([OH:37])([OH:29])=[O:28])[C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[C@H:11]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:10]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: CC(C)(C)[C@H](NC(=O)OCCOP(=O)(O)O)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1

Procedure:
2-{[bis(benzyloxy)phosphoryl]oxy}ethyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (9-2, 11 mg, 0.015 mmol, 1 equiv), 1,4-cyclohexadiene (1 mL, excess) and 10% Pd/C (5 mg) were added to methanol (4 mL) and the mixture was stirred under a nitrogen atmosphere. After 30 minutes another 5 mg of 10% Pd/C was added and stirring was continued for an additional hour. The reaction was filtered and the filtrate concentrated. The residue was purified by reverse phase LC (H2O/CH3CN gradient w/0.1% TFA present) to give 2-(phosphonooxy)ethyl (1S)-1-{[(2S)-4-2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (9-3) as a colorless foam. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.34-7.20 (m, 5H), 7.12-6.92 (m, 3H), 6.38 (s, 1H), 5.93 (bs, 1H), 5.21 (d, 1H, J=14 Hz), 4.91 (d, 1H, J=14 Hz), 4.41 (d, 1H, J=10 Hz), 4.38-3.97 (m, 7H), 0.91 (s, 9H). LRMS m/z (M+H) 539.5 found, 538.2 required.
Reaction SMILES: O1CCCC1.[H-].[Na+].Cl[CH2:9][C:10]([CH3:12])=[CH2:11].[CH2:13]([O:15][CH2:16][CH2:17][OH:18])[CH3:14]>O.C(O)C>[CH2:9]([O:18][CH2:17][CH2:16][O:15][CH2:13][CH3:14])[C:10](=[CH2:11])[CH3:12]
Reactant: CCOCCO
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C=C(C)COCCOCC
Temperature: 25 °C

Procedure:
Into a 22 liter flask equipped with a reflux condenser, mechanical stirrer, addition funnel and nitrogen gas inlet, was placed 12.5 liters of dry tetrahydrofuran and 1958 grams of a 60% oil dispersion of sodium hydride. The mixture was stirred and heated to a gentle reflux, then 2.99 Kg of 3-chloro-2-methyl propene was added as one portion. Next, 2.79 Kg of 2-ethoxyethanol was added dropwise during 3.5 hours with no external heating of the resulting exothermic reaction. Refluxing was continued for two additional hours, then the solution was cooled to room temperature. Excess sodium hydride was decomposed by carefully adding ethanol then enough water to dissolve the resulting salts. The organic layer was separated and distilled through a vigreaux column at 156°-158° C. The yield of product was 3490 grams and was 99.4% pure by G.L.P.C. analysis.