Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.CN(C=O)C.C(=O)(O)[O-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C1OCCOCCOCCOCCOC1.O>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([O:23][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CCCCCCI
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 g (5.8 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid, 30 ml of DMF, 2 drops of 15-crown-5 and 2 g (23.8 mmol) of sodium bicarbonate are introduced into a round-bottomed flask. 3.1 ml (20.8 mmol) of 1-iodohexane are added and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water and extracted with ethyl acetate and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 2 g (80%) of the expected hexyl ester are collected in the form of a pale red oil.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[O:13][CH:14]=1)=[O:7].[CH2:29](Br)[CH:30]=[CH2:31]>>[CH2:31]([O:23][C:17]1[CH:16]=[C:15]([C:12]2[O:13][CH:14]=[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=3[O:3][CH:2]([F:1])[F:28])[N:11]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH:30]=[CH2:29]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ccccc3OC(F)F)co2)cc1O
Reactant: C=CCBr
Product: C=CCOc1cc(-c2nc(CNC(=O)c3ccccc3OC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 321 and allyl bromide, white powdery N-[2-(3-allyloxy-4-methoxyphenyl)-oxazol-4-ylmethyl]-2-difluoromethoxybenzamide was obtained following the procedure of Example 3.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[H][H]>CCO.C(OCC)(=O)C.[Pd]>[F:24][C:22]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([OH:8])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Yield: 101.3 %

Procedure:
A solution of tert-butyl 2-(benzyloxy)-4-fluorobenzylcarbamate (Example 14; 9 mmol) in EtOH (80 ml) and ethyl acetate (240 ml) was treated with 1 atm of hydrogen at 25° C. over 10% Pd/C (0.4 gr) for 24 hours. The catalyst was removed by filtration through celite, washed with EtOH and the filtrate was concentrated to afford the title compound (2.2 g) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:3].Cl.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:38]([O:40][CH:41]([Cl:43])[CH3:42])=[O:39]>C(Cl)(Cl)Cl>[Cl:43][CH:41]([O:40][C:38]([N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:39])[CH3:42]
Reactant: CC(C)NCC(O)COc1cccc2ccccc12
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)N(CC(O)COc1cccc2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of propanolol hydrochloride (3.0 g) in chloroform (100 ml) was mixed with proton sponge® (4.3 g) and cooled in an ice bath. 1-Chloroethyl chloroformate (1.5 g) was added dropwise to the reaction mixture. The suspension dissolved in about 5 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The chloroform solution was washed with water, 3N HCl and water successively. The organic layer was dried over Na2SO4 and evaporated to a thick oil weighing 3.6 g. NMR (CDCl3) δ1.25 (6H, d, J=7 Hz, CH(Me)2), 1.8 (3H, d, J=7 Hz, CH3CH), 3.3=3.6 (3H, m, ArOCH2 and CH(Me)2), 4.0-4.6 (3H, m, NCH2 and CHOH), 6.61 (1H, q, J=7 Hz, CH3CH) and 6.7-8.4 (7H, m, aromatic). IR (film) ν3450, 1715, 1583, 1270, 1248, 1108 cm-1.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:25])[NH:17][C@H:18]([C:22](F)=[O:23])[CH:19]([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:25])[NH:17][C@H:18]([C:22](=[O:23])[NH:7][CH2:8][CH2:9][SH:10])[CH:19]([CH3:20])[CH3:21])([CH3:12])([CH3:14])[CH3:13]
Reactant: NCCS
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (158.1 mg, 1.88 mmol) in 9.2 mL water was added 2-aminoethanethiol hydrochloride (114.7 mg, 1.01 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25g (201.3 mg, 0.92 mmol) in 9.2 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to afford 222.0 mg (80% from 24g) of clean 26g as a colorless oil. FTIR (neat) 3300, 1681, 1652 cm−1.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:31]5[CH:30]=[CH:29][CH:28]=[C:27]([NH2:26])[CH:32]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc(N)c4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 3-aminophenylboronic acid. Mass spectrum (ESI) 407.3 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:17][CH2:18][CH2:19][C:20]1[C:25](O)=[C:24]([C:27]([CH3:29])=[O:28])[CH:23]=[CH:22][C:21]=1[OH:30].N1CCCC1>C1(C)C=CC=CC=1>[O:28]=[C:27]1[C:24]2[CH:23]=[CH:22][C:21]([OH:30])=[C:20]([CH2:19][CH2:18][CH3:17])[C:25]=2[O:1][C:2]([CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:29]1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reaction time: 4 h

Procedure:
A stirred solution of 12.3 g (53.5 mmol) of diethyl 4-oxopimelate, 10.4 g (53.5 mmol) of 2,4-dihydroxy-3-propylacetophenone, and 3.8 g (55 mmol) of pyrrolidine in 62 ml of toluene was refluxed under a water separator. After 4 hours, the mixture was allowed to cool. The solvent was removed under reduced pressure and the resultant oil was chromatographed on silica gel using ethyl acetate-hexane as eluent. The titled diester (4.98 g) was found to be homogeneous by thin-layer chromatography (20% by volume ethyl acetate/hexane on silica gel plates) and was used in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccc2)cc1F
Temperature: 67.5 °C

Procedure:
4-Bromo-2-fluoro-phenylacetic acid (0.25 gm, 1.1 mmole), phenylboronic acid (0.15 gm, 1.2 mmole) and 50% water wet 10% Palladium carbon (0.07 gm, 0.033 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.14 gm, 1.3 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was acidified using 20% H2SO4, filtered and dried (0.2 gm, 83%) H1-NMR INOVA-500 (DMSO d6) δ 3.675 (s, 2H), 7.382-7.518 (m, 6H), 7.707 (d, J=7.51 Hz, 2H), 12.498 (s, 1H).
Reaction SMILES: [NH:1]([C:3](=[S:6])OC)[NH2:2].[NH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.C(OCC)(=O)C>C(O)C>[NH:1]([C:3]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[S:6])[NH2:2]
Reactant: OC1CCNCC1
Reactant: COC(=S)NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: NNC(=S)N1CCC(O)CC1
Temperature: 90 °C

Procedure:
A solution of methyl hydrazinecarbothioate (1.0 g, 8.2 mmol) and piperidin-4-ol (1.24 g, 12.3 mmol) in ethanol (7 mL) was refluxed with heating at 90° C. for 2 days. After addition of ethyl acetate, the reaction solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the crude desired product. The crude product was used directly for the next reaction.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][NH:40][S:41]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1)(=[O:42])=[O:43]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 33 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with (3-(N-methylsulfamoyl)phenyl)boronic acid (68 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (17 mg, 0.02 mmol) and 1.12 ml 1,2-dimethoxyethane and 0.28 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 40 mg (33% yield, 77% purity) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:68])[N:7]([C@H:34]1[CH2:38][CH2:37][N:36]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:35]1=[O:67])[CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:69]([C:71]1[CH:78]=[CH:77][C:74]([CH2:75]O)=[CH:73][C:72]=1[F:79])#[N:70].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:68])[N:7]([C@H:34]1[CH2:38][CH2:37][N:36]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:35]1=[O:67])[CH2:8][CH2:9][C:10]1[N:11]([CH2:75][C:74]2[CH:77]=[CH:78][C:71]([C:69]#[N:70])=[C:72]([F:79])[CH:73]=2)[CH:12]=[N:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxo-pyrrolidin-3-yl}-{2-[1-(triphenylmethyl)-1H-imidazol-4-yl]ethyl}carbamic acid tert-butyl ester, as described above in Step G, (720 mg, 0.785 mmol) and 4-cyano-3-fluorobenzyl alcohol, as described above in Step H, (142 mg, 0.940 mmol) in dry CH2Cl2 (7 mL) were added N,N-diisopropylethylamine (0.342 mL, 1.96 mmol), followed by trifluoromethanesulfonic anhydride (0.158 mL, 0.940 mmol), dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and was stirred for 18 hours, then concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and the resulting solution was stirred at ambient temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned between saturated aqueous NaHCO3 (5 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with EtOAc—1% MeOH—0.1% NH4OH to yield the desired product as a pale foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:13][C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[H-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[N:16][C:15]=2[NH:21][C:8](=[O:9])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)ethoxycarbonylmethyl-amino]-acetic acid ethyl ester (6.52 g, 17.4 mmol) in DMSO (170 mL) was treated with NaH (0.70 g, 17.5 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (300 mL) and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (6.18 g, quantitative) as an off-white solid: MS (ESI) m/e 328 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Product: CN(C)C=CC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 50.0 g of 3,4-dichloroacetophenone and 75 ml of N,N-dimethylformamide dimethyl acetal was heated under reflux for 6 hours, then allowed to cool for 16 hours. The crystalline precipitate was collected by filtration, washed with hexane and dried. The addition of hexane to the above filtrate precipitated some additional product which was collected by filtration. The precipitates were combined, washed with hexane and dried in vacuo to give 55.0 g of 3',4'-dichloro-3-dimethylaminoacrylophenone as bright yellow crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].CN1CCOCC1>ClCCl>[CH3:8][C@@H:7]([CH2:9][CH3:10])[C@H:5]([NH:6][C:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:14])[C:4]([O:3][CH3:2])=[O:11]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.2 %

Procedure:
A solution of L-iso-leucine methyl ester hydrochloride (2.5 g, 13.75 mmol) in dichloromethane (35 mL) at 0° C. was treated with 4-nitrophenyl chloroformate (3.05, 15.13 mmol) and 4-methylmorpholine (3.2 mL, 29.11 mmol), stirred at 25° C. for 64 hours, and partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (4.19 g, 98% yield).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]([CH:8]=[CH2:9])=[O:7]>>[CH3:5][C:3]1[CH2:4][CH2:9][CH:8]([CH2:6][OH:7])[CH2:1][CH:2]=1
Reactant: C=CC=O
Reactant: C=CC(=C)C
Product: CC1=CCC(CO)CC1

Procedure:
According to the well known Diels-Alder Reaction, using isoprene and acrolein as raw materials, 4-methyl-3-cyclohexenyl aldehyde was synthesized. The reaction was conducted under the conditions described in the literary documents of J. Amer, Chem. Soc., 119, 15, 1997, 3507-3512; and Tetrahedron Lett., 40, 32, 1999, 5817-5822. Subsequently, the compound was reduced to obtain 4-methyl-3-cyclohexenylmethanol at a high yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10](O)=[S:11].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]([Cl:15])=[S:11]
Reactant: OC(=S)Cc1cc(Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: S=C(Cl)Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 2,5-dichlorophenylthioacetic acid (13.0 g, 54.9 mmol) in methylene chloride (55 mL) and thionyl chloride (10 mL, 137 mmol) was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The residue was evaporated two times from toluene to give 14 g of 2,5-dichlorophenyl-thioacetyl chloride (100% yield) as a slightly colored product which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ4.13 (s, 2H), 7.22 (dd, J=2, 9 Hz, 1H), 7.35 (d, J=9 Hz, 1H), 7.39 (d, J=2 Hz, 1H).
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].S(Cl)(Cl)=O.[CH3:18]O>ClCCl>[CH3:18][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([NH:1][C:2]([NH2:4])=[NH:3])=[CH:6][CH:7]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of 4-guanidino benzoic acid (20.0 g, 93 mmol) in methanol (600 mL) was added thionyl chloride (12 mL) drop wise. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give a white powder. The crude material was dissolved in dichloromethane and evaporated to provide the title compound as a white powder (17.95 g, 100% yield): HPLC Retention Time; 1.27 min (Method A). M+1; 193.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]([CH3:3])[CH3:2])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CC(C)N
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 12 %

Procedure:
Isopropylamine (372 μL, 4.37 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (162 mg, 0.437 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Isopropylamine (37.2 μL, 0.437 mmol), sodium cyanoborohydride (82.4 mg, 1.31 mmol) and acetic acid (150 μL, 2.62 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 24 mg of the cis isomer of the title compound (15%) as a pale yellow oily substance and 20 mg of the trans isomer of the title compound (12%) as a pale yellow oily substance.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH:22][C:23]([NH:25][C@@H:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([O:36][C:37]4[CH:38]=[CH:39][C:40]5[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=5)[CH:42]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:20][C:19]([C:49]([CH3:52])([CH3:51])[CH3:50])=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.N.CO>CCO.[Pd]>[C:49]([C:19]1[CH:20]=[C:21]([NH:22][C:23]([NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:29]([O:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=4)[CH:42]=3)[CH2:28][CH2:27]2)=[O:24])[N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:18]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C4CCN(C(=O)OCc5ccccc5)CC4)c4ccccc43)cn12
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: CCO
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C4CCNCC4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A suspension of Intermediate 16d (165 mg, 0.234 mmol), Pd/C (10%, 16 mg), and 2M NH3 in MeOH (0.117 mL, 0.234 mmol) in EtOH (5 mL) under N2 was evacuated and purged with H2 twice, then stirred at rt for 8 h. The suspension was filtered through Celite, then the filter-cake washed with EtOH (10 mL). The combined organics were concentrated in vacuo to ˜0.5 mL volume, then applied to an SCX-2 cartridge (5 g) and washed with MeOH (5 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left a pale yellow solid that was triturated with diethyl ether (10 mL) to leave a buff solid (121 mg). Half of this material was purified by HPLC (XBridge C18, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound as a white solid after freeze-drying (20.0 mg, 15%). LCMS (Method 5): Rt 3.16 min, m/z 571 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.16 (9H, s), 1.33 (3H, d, J 6.8), 1.35 (3H, d, J 6.8), 1.68 (2H, m), 1.79 (2H, m), 1.91 (2H, m), 2.09 (2H, m), 2.47 (2H, m), 2.98 (2H, d, J 12.3), 3.50 (1H, sept, J 6.8), 3.92 (1H, m), 4.82 (1H, m), 5.51 (1H, t, J 4.5), 5.97 (1H, s), 6.88 (1H, d, J 8.6), 7.14 (1H, dd, J 9.9, 2.1), 7.26 (1H, m), 7.31-7.38 (3H, m), 7.65 (1H, dd, J 9.8, 0.8), 8.07 (1H, br s), 8.18 (1H, d, J 2.0).