Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][NH:13][CH3:14].C1COCC1>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([N:13]([CH3:14])[CH3:12])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1I
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(F)cccc1I
Reaction time: 16 h

Procedure:
2-Fluoro-6-iodobenzoylchloride 1.0 mL, 6.9 mmol was added dropwise to a solution of dimethylamine in THF (2.0 M 7.0 mL, 10 mmol). The reaction mixture was stirred for 16 h and then transferred into water. The resulting suspension was collected by filtration and dried to afford the title compound as a pale yellow solid. The product was used in the next reaction step without further purification. mp 86-89° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][Cl:23])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)CCCCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)CCCCCl)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a stirred mixture of 3.6 g (16 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 1.3 g (16 mmol) of pyridine in 50 ml of ether cooled to 0° C. there was slowly added 2.5 g (16 mmol) of 5-chlorovalerylchloride. The reaction mixture was allowed to warm to 25° C. and stirred for 15 hours following which the mixture was diluted with 100 ml of ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to 5.8 g of solid. The solid was triturated in hexane and filtered to yield 5.5 g (16 mmol) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-chlorovaleramide.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[CH3:6][C:7]([CH3:14])([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9]>C1(C)C=CC=CC=1>[C:8]([NH:10][C:11]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:12])(=[O:9])[C:7]([CH3:14])([CH3:13])[CH3:6]
Reactant: CC(C)(C)C(=O)N=C=O
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)NC(=O)N1CC1C#N

Procedure:
A solution of 1.61 g. 2-cyanoaziridine in 30 ml. toluene is added dropwise at 20° to 30° C. to a solution of 3 g. trimethyl-acetyl isocyanate in 40 ml. anhydrous toluene and the reaction mixture then stirred for 1 hour at ambient temperature, whereafter the milky solution obtained is evaporated in a vacuum. The evaporation residue is rubbed with a glass rod until crystallization commences and the crystals obtained are triturated with diethyl ether. There is thus obtained 1.82 g. 1-(N-pivaloyl-carbamoyl)-2-cyanoaziridine which, after drying at 60° C. in a vacuum, melts at 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:34]([S:46]SC(=N)N)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(OCC)(=O)C>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:46][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])=[N:11]1
Reactant: COc1cc(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCSSC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCSC1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)N=C1Nc1cc(OC)c(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
15.1 g of 1-(2,4,6-trichlorophenyl)-3-(2,4-dichloro-5-methoxyanilino)-5-pyrazolone was dissolved in 500 ml of 80% ethanol (ratio by volume of ethanol:water=4:1), and 2.5 g of potassium carbonate was added thereto. A solution prepared by dissolving 10.4 g of S-(n-dodecylthio)isothiourea hydrochloride in 100 ml of ethanol was added dropwise thereto over 10 minutes with stirring while heating on a steam bath, and the mixture was stirred for another 10 minutes. After cooled rapidly under a water stream, 300 ml of ethyl acetate was added thereto, and the mixture was washed twice with water. After drying the ethyl acetate layer with anhydrous sodium sulfate, sodium sulfate was removed and the solvent was removed by condensing under a reduced pressure. The residue was crystallized with acetonitrile. The resulting crystals were recrystallized with acetonitrile-ethyl acetate (ratio by volume: 10:1) to obtain 18 g of the coupler having a melting point of 100° to 102° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N[C:35]1[CH:40]=[CH:39][C:38]([NH:41]C(=O)CN(C)C)=[CH:37][CH:36]=1>>[CH2:2]1[C:36]2[C:35](=[CH:40][CH:39]=[C:38]([NH:41][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:37]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CN(C)CC(=O)Nc1ccc(N)cc1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and N-(4-aminophenyl)-N2,N2-dimethylglycinamide by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 6H), 3.09 (s, 2H), 6.46 (d, 1H, J=5.3 Hz), 7.10 (t, 1H, J=6.7 Hz), 7.22 (d, 2H, J=8.0 Hz), 7.34 (d, 1H, J=7.7 Hz), 7.42-7.51 (m, 4H), 7.56 (t, 1H, J=8.2 Hz), 7.61 (d, 2H, J=8.9 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.96 (s, 1H), 8.22 (d, 1H, J=5.3 Hz), 8.46 (bd, 1H, J=8.8 Hz), 8.82 (d, 1H, J=6.8 Hz), 9.47 (s, 1H), 9.60 (s, 1H), 10.91 (s, 1H); ESIMS (M+H)+=619.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:17]([OH:20])[OH:18])=[CH:3][C:4]=2[CH:9]=1)#[N:11]
Reactant: COB(OC)OC
Reactant: N#Cc1ccc2occc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(B(O)O)cc2c1
Reaction time: 0.5 h

Procedure:
To benzofuran-5-carbonitrile (500 mg, 3.49 mmol) in THF (9.98 mL) at −78° C. was added nBuLi 1.6M in hexanes (2.401 mL, 3.84 mmol) dropwise. The mixture was stirred for 30 min at this temperature, and then trimethyl borate (0.858 mL, 7.68 mmol) was added dropwise. The mixture was stirred for 20 min, and then HCl 2N (11.52 mL, 23.05 mmol) was added. The bath was removed, and stirring continued for 30 min. The mixture was diluted with water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated. Crude 5-cyanobenzofuran-2-ylboronic acid (623 mg, 87%) was then dried and used as is for the next step.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1[N:23]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[N:24]=[N:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][CH:27]([N:23]5[N:24]=[N:25][CH:26]=[N:22]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1nnn(C2CCNC2)n1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ncnn4)C3)c(F)cc2c1=O

Procedure:
A solution of 1-cyclopropyl-6,7,8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid (28.3 mg, 0.1 mmol), 3-(1,2,3,4-tetrazol-2-yl) pyrrolidine hydrochloride (35.1 mg, 0.2 mmol) and DBU (45.6 mg, 0.3 mmol) in acetonitrile (2 ml) was refluxed under nitrogen for 23 hrs. The solvent was then evaporated to dryness. The residue was diluted with water and extracted with chloroform. The organic extract was dried over Na2SO4, concentrated and the residue was crystallized from methanol-water. Yield: 12 mg, m.p. 192°-199° C. 1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.5 (s, 1H), 7.8 (dd, 1H), 5.6-5.4 (m, 1H), 4.46-3.76 (m, 5H), 2.9-2.45 (m, 2H), 1.35-1.02 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:11])=[O:10]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Br)cc1F
Temperature: 5 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
1-(4-Bromo-2-fluorophenyl)ethanone (2.59 g, 11.9 mmol, 1.00 equiv) was dissolved in chloroform (5 mL) and cooled to 5° C. Bromine (0.613 mL, 11.9 mmol, 1.00 equiv) was added dropwise via syringe. On completion of the addition, the bath was removed and the reaction was allowed to warm to room temperature. After two hours, the reaction was poured onto ice and diluted with EtOAc. The mixture was washed sequentially with saturated NaHCO3, water, and saturated NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to afford 3.14 g (89%) of a white solid. 1H NMR (CDCl3) δ 17.92-7.83 (m, 1H), 7.51-40 (m, 2H), 4.50 (s, 2H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[O:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Br[CH2:21][C:22]#[N:23]>O1CCCC1>[C:22]([CH2:21][CH2:19][C:12](=[O:11])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])#[N:23]
Reactant: CC(=O)CCCC(=O)O
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCC(=O)CCCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of potassium hexamethyldisilazide (66 ml, 60 mmol) in dry tetrahydrofuran (140 ml) at -70° is added slowly 5-oxohexanoic acid (36 ml, 30 mmol). The resulting yellow suspension is stirred at -70° for 1 h and bromoacetonitrile (2.2 ml, 32 mmol) is added slowly. The reaction mixture is stirred at -70° for 1 h and then at room temperature for 0.5 h. The reaction is quenched by addition of 1N aqueous hydrochloric acid (100 ml). The aqueous layer is extracted twice with ether. Combined organic layer is dried, filtered and evaporated to obtain a dark oil which is purified by silica gel chromatography using 9:1 ether/hexane with 1% acetic acid as eluent to give 7-cyano-5-oxoheptanoic acid as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[NH:27][C:26](=[O:28])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.CO.[C:32]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:32][N:27]1[C:26](=[O:28])[O:25][N:24]=[C:23]1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:14]2[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]3[N:29]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[C:15]2=[O:16])[CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)n3C)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
(S)-3-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.37 mmol) obtained in Step 1 was suspended in THF (2.0 mL), and the mixture was stirred at room temperature for 2 hours after adding methanol (0.022 mL, 0.55 mmol), triphenylphosphine (144 mg, 0.55 mmol), and diethyl azodicarboxylate (40% toluene solution, 0.25 mL, 0.55 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-4-methyl-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (127 mg, 82%).
Reaction SMILES: C[O-].[Na+].[C:4]1([SH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[C:4]1([S:10][CH2:14][CH2:13][CH2:12][C:11]([OH:16])=[O:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCO1
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCSc1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Sodium methoxide (1.2 equivalent) was added to 60 ml of ethanol, in one portion, and the suspension was stirred at room temperature. Thiophenol (1 equivalent) was added to the above suspension and stirred at room temperature for an additional 30 minutes. Butyrolactone (1.1 equivalent) was then added and the resulting mixture was stirred at reflux temperature for 6 hours, cooled to room temperature and concentrated in vacuo. The residual solid was washed with 200 ml hexane/ether 2:1, v/v. The solid was suspended in ice cold 2N HCl and stirred for 15 minutes. The solid was then filtered, washed with 100 ml hexane/ether and dried under reduced pressure at room temperature to give 4-(phenylsulfanyl)butanoic acid as a tan solid: 52% yield; 1H NMR (CDCl3) δ 7.32-7.12 (m, 5H), 2.94 (t, 2H, J=7.2 Hz), 2.41 (t, 2H, J=7.2 Hz), 1.85 (p, 2H, J=7.2 Hz); Anal. Calc. For C10H12S1O2: C, 61.22; H, 6.12. Found: C, 61.16; H, 6.28.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(CCl)n1
Temperature: 25 °C

Procedure:
N-(6-Hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (2.03 g) in CH2Cl2 (75 mL) was treated at RT with thionyl chloride (1.785 mL) and then heated to reflux for 1.5 h. The reaction mixture was cooled to RT and partitioned between water and AcOEt, the layers were separated, the organic layer dried over MgSO4, filtered and evaporated to give N-(6-chloromethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.66 g) as a brown liquid. MS (ESI): 227.2 (MH+).
Reaction SMILES: FC1C=C2C(=CC=1F)N([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])C=C2I.[I:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=2)[NH:25][CH:24]=1>>[I:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:33])([F:35])[F:34])=[CH:29][CH:30]=2)[N:25]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)c(F)cc21
Reactant: FC(F)(F)c1ccc2c(I)c[nH]c2c1
Product: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(C(F)(F)F)cc21
Yield: 45 %

Procedure:
Following the general method as outlined in Intermediate 28, starting from 3-iodo-6-(trifluoromethyl)-1H-indole (Intermediate 39; 1.60 g; 5.14 mmol), 1.06 g (45%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>CN(C=O)C>[CH2:39]([O:38][C:35](=[O:37])[CH2:36][N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])[CH3:40]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 44.2 %

Procedure:
To a solution of rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.1 mg, 0.10 mmol) in DMF (3 mL) was added potassium carbonate (43.3 mg, 0.313 mmol) and the reaction mixture was stirred at rt under argon for 21 hrs. The reaction mixture was diluted with ethyl acetate and washed with water (2×) and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by flash chromatography to give rac [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid ethyl ester (22.3 mg, 44.2%,) as a white amorphous solid. HRMS (ES+) m/z Calcd for C26H28Cl2F2N2O2+H [(M+H)+]: 509.1569; Found: 509.1569.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5](OC)=[O:6].[NH2:13][NH2:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:13][NH2:14])=[O:6]
Reactant: NN
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Solvent: CCO
Product: NNC(=O)c1ccc(O)c(Cl)c1
Yield: 60 %

Procedure:
To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was added hydrazine (1.8 mL). The reaction was refluxed overnight under nitrogen. Upon cooling the reaction vessel, the desired product crystallized out of solution. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[NH:5][CH:4]=[C:3]1[C:11]([O:13]CC)=[O:12].[OH-].[Na+].Cl>>[O:1]=[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[NH:5][CH:4]=[C:3]1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1c[nH]c2ccnn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccnn2c1=O
Temperature: 25 °C

Procedure:
A suspension of ethyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (1.9 g, 9.2 mmol) in 10% aq. NaOH (12 mL, 30.0 mmol) was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature; the solution was acidified to pH 3-4 with 6 M HCl. The forming precipitate was filtered, washed with water and dried to afford 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid; 1.6 g (97%). 1H NMR (300 MHz, DMSO) δ 8.53 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 6.32 (d, J=1.8 Hz, 1H). MS (ESI) m/z: 177.9 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Reactant: C1CCNC1
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCCC4)c3)ccc2C)cc1
Temperature: 80 °C

Procedure:
Using an analogous procedure to that described in Example 3, a mixture of N-[3-(4-diethylaminomethylbenzamido)-4-methylphenyl]-2-chloropyridine-4-carboxamide (0.5 g) and pyrrolidine (5 ml) was stirred and heated to 80° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 40° C. There was thus obtained the title compound (0.021 g); NMR Spectrum: (DMSOd6) 1.0 (t, 6H), 1.95 (m, 4H), 2.2 (s, 3H), 2.44-2.49 (m, 4H), 3.42-3.5 (m, 4H), 3.6 (s, 2H), 6.86 (s, 1H), 6.96 (d, 1H), 7.22 (d, 1H), 7.58 (d, 1H), 7.79 (s, 1H), 7.92 (d, 2H), 8.18 (d, 1H), 9.83 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 486.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Si:5]([Cl:8])([Cl:7])Cl.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:3][CH2:4][Si:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([Cl:7])[Cl:8]
Reactant: CCCCCC[Mg]Br
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Tetrahydrofuran (50 ml) and 3,7-dimethyloctyl trichlorosilane (11.0 g, 40.0 mmol) were placed in a 200 mL four-necked flask in a nitrogen atmosphere, and cooled to −20° C. n-hexyl magnesium bromide (Sigma-Aldrich Co. LLC., 2.0 M, 21 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and distillation under reduced pressure was performed to obtain the target 3,7-dimethyloctyl-n-hexyl-dichlorosilane (Compound G18) (127-130° C./0.26 Torr, 9.5 g, yield 73%).
Reaction SMILES: [C:1]([O:5][C:6](/[N:8]=[C:9](\[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])/[NH:10][C@H:11]1[CH2:16][C:15]([C:17]([O:19]CC)=[O:18])=[CH:14][C@@H:13]([O:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C@@H:12]1[NH:28][C:29](=[O:33])[CH:30]([F:32])[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>O1CCOCC1>[C:1]([O:5][C:6](/[N:8]=[C:9](\[NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])/[NH:10][C@H:11]1[CH2:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C@@H:13]([O:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C@@H:12]1[NH:28][C:29](=[O:33])[CH:30]([F:32])[F:31])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(=O)C(F)F)[C@@H](N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a solution of (3R,4R,5S)-ethyl 5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 6b (250 mg) in dioxane (5 ml) 5% solution of lithium hydroxide (2.5 ml) was added and the reaction mixture was stirred at room temperature for 45 min. Then lithium hydroxide was passivated by adding acetic acid (300 mcl), the solvents were evaporated in vacuo. The solid was extracted with isopropyl alcohol, the extract was dried over Na2SO4 and evaporated in vacuo. It gives (3R,4R,5S)-5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 8b (200 mg, 84%). LCMS (M+H): found 563; calculated 562.62. The obtained acid 8b (200 mg) was dissolved in 10% solution of trifluoroacetic acid in methylene chloride (2 ml) and stirred at room temperature for 12 h. Then the solvents were evaporated in vacuo. (3R,4R,5S)-4-(2,2-Difluoroacetamido)-5-guanidino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 1.4 was separated by HPLC method. LCMS (M+H): found 363; calculated 362.28. 1H NMR (DMSO-d6), 400 MHz: 8.68 (d, J=8.4 Hz, 1H), 7.6 (d, J=10 Hz, 1H), 7.26 (br, 2H), 6.91 (br, 2H), 6.63 (s, 1H), 6.27 (t, J=53.6 Hz, 1H), 4.18 (d, J=8 Hz, 2H), 4.09 (m, 1H), 3.54 (q, J=10 Hz, 1H), 3.39 (m, 2H), 2.57 (dd, J1=18 Hz, J2=6 Hz, 1H), 2.31 (m, 1H), 1.44 (m, 4H), 0.85 (t, J=8 Hz, 3H), 0.795(t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(F)cc1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (340 mg, 1.75 mmol) in CH2Cl2 (8 mL), SnCl4 (1.0M solution in CH2Cl2 ; 3.5 mL, 3.5 mmol) and 4-fluorobenzoyl chloride (270 μL, 2.28 mmol) as a solid (350 mg, 63%). 1H NMR (CDCl3) 7.81 (m, 2H), 7.13 (m, 2H), 6.85 (s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.79 (s, 2H), 3.61 (s, 3H).