Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]([N:10]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH-].[K+]>C(O)C.O>[CH2:1]([C:4]1[C:9]([N:10]([CH2:29][C:30]([OH:32])=[O:31])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncccc1N(CC(=O)OCC)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1ncccc1N(CC(=O)O)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The compound resulting from Example 153E is dissolved in 1 part methylene chloride and 1.5 parts formic acid and stirred at ambient temperature to give 2-propyl-3-{N-ethoxycarbonylmethyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyridine. This ester is hydrolyzed with potassium hydroxide in ethanol/water to give the title compound.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1([CH2:40]CO)[O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][O:33]1>>[Na:1].[CH3:30][C:13]1[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])=[N:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:31][C:32]1([CH3:40])[O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][O:33]1
Reactant: CC1(C)COC(C)(CCO)OC1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 7.2 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethanol obtained in the step (34a) to obtain the title compound (196 mg, total yield: 7.2%) as a light yellow solid.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([C:16](=[CH2:19])[CH:17]=[O:18])[CH2:13][CH2:14][CH3:15]>C(O)(=O)C.O>[CH3:11][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:19][CH:16]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:17]=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=C(C=O)CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a stirred solution of 4-toluenesulfinate sodium salt (10.10 g, 56.68 mmol) in 35 mL of acetic acid at 50° C. is added 2-butylacrolein (10.6 mL, 79.66 mmol) slowly. The reaction mixture is kept at 50° C. for 3 hours. After cooling to room temperature, the mixture is diluted with 50 mL of water and extracted with ethyl acetate (2×25 mL). The combined extract is washed with saturated NaHCO3, water, brine, and dried with MgSO4. After removing solvents, the product is obtained as a yellow liquid in 75% yield.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:22]=[C:23]=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:8]([NH:22][C:23](=[O:24])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCN=C=O
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 91 %

Procedure:
Triethylamine (1.06 ml) and tetradecyl isocyanate (1.64 g) were added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (1.70 g) obtained in Example 3(4) in methylene chloride (17 ml). After being stirred for 18.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=60:1 to 30:1), thereby yielding the entitled compound (3.04 g) as white solid.
Reaction SMILES: [C:1]([CH:3]([C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1)[NH:4]S(C(C)(C)C)=O)#[N:2].Cl.O1CCOCC1.C(N(CC)CC)C>CO>[NH2:4][CH:3]([C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1)[C:1]#[N:2]
Reactant: CC1(C(C#N)NS(=O)C(C)(C)C)COC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C(N)C#N)COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
To a solution of N-[cyano-(3-methyloxetan-3-yl)methyl]-2-methyl-propane-2-sulfinamide (example 251a, 1.5 g, 6.51 mmol) in methanol (40 ml) cooled at 0° C. was added a solution of hydrochloric acid in dioxane (2.44 ml, 9.77 mmol) and the reaction mixture was stirred at 0° C. for 2 hours. Triethylamine (1.32 g, 1.82 ml, 13.0 mmol) was added to the reaction mixture which was then concentrated in vacuo. The residue was directly purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (854 mg) as a yellow oil which was not totally pure and was used without any further purification. MS (ESI, m/z): 127.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 150 °C
Yield: 24.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (700 mg, 3.4 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (1.5 g, 10.2 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.1 mmol). The mixture was heated in a sealed tube at 150° C. in microwave (Model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (340 mg, 26%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@H:17]([C:22]([N:24]([C@@H:26]([CH:33]([CH3:35])[CH3:34])/[CH:27]=[C:28](/[C:30]([OH:32])=O)\[CH3:29])[CH3:25])=[O:23])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[C:4]([CH3:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[CH:6]=1.O[C:37]1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70].[NH:74]1[CH2:95][CH2:94][CH2:93][C@H:75]1[C:76]([N:78]1[CH2:92][CH2:91][CH2:90][C@H:79]1[C:80]([NH:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)=[O:81])=[O:77]>C(#N)C>[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70].[CH3:29]/[C:28](=[CH:27]\[C@@H:26]([N:24]([CH3:25])[C:22](=[O:23])[C@H:17]([C:18]([CH3:20])([CH3:19])[CH3:21])[NH:16][C:14](=[O:15])[C@H:3]([C:4]([CH3:12])([CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:37])[CH:6]=1)[NH:2][CH3:1])[CH:33]([CH3:34])[CH3:35])/[C:30]([N:74]1[CH2:95][CH2:94][CH2:93][C@@H:75]1[C:76]([N:78]1[CH2:92][CH2:91][CH2:90][C@@H:79]1[C:80]([NH:82][CH2:83][C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)=[O:81])=[O:77])=[O:32]
Reactant: O=C(NCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1cccc(C)c1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N1CCC[C@@H]1C(=O)N1CCC[C@@H]1C(=O)NCc1ccccc1)C(C)C)C(C)(C)C)C(C)(C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
By using an analogous procedure described in General Procedure I Method A, N,β,β,3-tetramethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropyl-2-butenyl]-N1,3-dimethyl-L-valinamide (100 mg, 0.205 mmol) is treated with hydroxybenzotriazole (36 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) in anhydrous acetonitrile (10 ml) at room temperature for 40 hours, followed by addition of diisopropylethylamine (0.143 ml, 0.82 mmol) and a solution of L-prolyl-N-benzyl-L-prolinamide trifluoroacetic acid salt (255 mg, 0.615 mmol) in anhydrous acetonitrile (3 ml). After stirring at room temperature for 4 hours, the product is purified by preparative HPLC, to provide the trifluoroacetic acid salt of the title compound (126.6 mg, 69%) as a white amorphous solid. MS (ES): m/z 771.5 (M+H). IR cm−1: 3306.94, 2969.17, 1673.9, 1642.27, 1203.38. Analytical HPLC: (4.6×150 mm YMC Pack Pro C18 column eluted with 10 to 100% acetonitrile in water containing 0.02% formic acid over 35 minutes): 92.56% (at 17.7 minutes) of 1-{(2E,4S)-2,5-dimethyl-4-[methyl(N,β,β,3-tetramethyl-L-phenylalanyl-3-methyl-L-valyl)amino]hex-2-enoyl}-D-prolyl-N-benzyl-D-prolinamide, and 6.92% (at 18.5 minutes) of the other diastereomer.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)(=[O:5])=[O:4])[CH3:2].[ClH:16].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:16].[CH2:1]([S:3]([CH2:6][CH2:7][NH2:8])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)CCN
Yield: 69 %

Procedure:
To a mixture of tert-butyl 2-(ethylsulfonyl)ethylcarbamate (1.5 g) and ethyl acetate (15 mL) was added dropwise 4N hydrochloric acid•ethyl acetate solution (4 mL) with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hrs., and the precipitated crystals were collected by filtration and washed with ethyl acetate to give 2-(ethylsulfonyl)ethylamine hydrochloride as crystals. (0.76 g, yield 69%). Recrystallization from ethanol gave colorless prism crystals. melting point: 103–104° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[BrH:12].C([O-])(=O)C>C(O)(=O)C>[NH2:2][C:1]1[N:11]=[C:10]([Br:12])[C:5]2[C:4]([CH:3]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Br
Reactant: N#CCc1ccccc1C#N
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Nc1cc2ccccc2c(Br)n1
Yield: 90.8 %

Procedure:
To a suspension of α-cyanotolunitrile (20.0 g) in acetic acid (50 ml) was added 25% hydrogen bromide/acetate solution (150 ml), and the mixture was reacted at room temperature overnight. The resulting precipitates were collected by filtration and then added to a 10% aqueous solution of potassium carbonate. The yellow powder was changed to a pale yellow powder. The resulting powder was collected by filtration, washed with water and hexane, and dried at 50° C. under reduced pressure, to give 3-amino-1-bromoisoquinoline (28.5 g; 90.8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:56][CH3:57])=[C:21]([CH:55]=1)[CH2:22][C@H:23]1[C:29](=[O:30])[N:28]([C:31](OC2C=CC=CC=2Cl)=[O:32])[CH2:27][C:26](=[O:41])[N:25](CC2C(OC)=CC(OC)=CC=2OC)[CH2:24]1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:56][CH3:57])=[C:21]([CH:55]=1)[CH2:22][C@H:23]1[C:29](=[O:30])[N:28]([C:31]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:14][CH:15]=2)=[O:32])[CH2:27][C:26](=[O:41])[NH:25][CH2:24]1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CN)cc1
Product: COc1ccc(Cl)cc1C[C@@H]1CNC(=O)CN(C(=O)NCc2ccc(C(=O)OC(C)(C)C)cc2)C1=O

Procedure:
Instead of the starting material, that is, the compound S11, of Reference Example 43, tert-butyl 4-(aminomethyl)benzoate was used, and instead of (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate, the compound S45 was used for a similar reaction as in Reference Example 43 to obtain tert-butyl 4-{[({(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoate (compound S47a).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][C@H:6]([OH:8])[CH2:5][N:4]1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[ClH:30]>N1C=CC=CC=1.C(O)C>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([N:4]2[CH2:5][C@H:6]([O:8][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH3:29])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:7][C@H:3]2[CH2:2][Cl:30])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@@H]2CO)cc1
Reactant: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CCl)N(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Temperature: 50 °C
Yield: 70 %

Procedure:
To an ice-cold solution of 170 g (626.5 mmol) of (2R, 4S)-2-hydroxymethyl-4-hydroxy-1-(4-toluenesulfonyl)-pyrrolidine in 0.5 l of pyridine was added 250 g (1.32 mol) of p-toluenesulfonyl chloride in one portion and the reaction was warmed to 50° C. After 6 hours the mixture was cooled with an ice bath and 3 l of 10% aqueous hydrogen chloride solution was carefully added. A white precipitate formed which was isolated via filtration and then taken in 1 l of ethanol and heated to reflux for 30 minutes. The mixture was then cooled and the solids were filtered and dried under reduced pressure to give 195 g of product in 70% yield. M.P.=145°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8](OC)[O:9]C.Cl>CO>[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:9])([O:2][CH3:1])=[O:13]
Reactant: COC(=O)CCCCC(OC)OC
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After the reaction, MeOH was recovered, following by the same treatment as above to give 9.47 g. of crude 6,6-dimethoxycaproic acid methyl ester. Then, a 10 wt.% aqueous hydrochloric acid solution was added to this crude product, followed by stirring for 6 hours at room temperature. The reaction mixture was treated by usual method to give crude products. Pure 3.20 g. of 5-carbomethoxy-1-pentanal was obtained by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1([CH2:55][C@H:56]([NH2:65])/[CH:57]=[CH:58]/[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:65][C@H:56](/[CH:57]=[CH:58]/[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@H](/C=C/c1ccccc1)Cc1ccccc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]-pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 7.1 mg (32 μmol) (2S,3E)-1,4-diphenylbut-3-en-2-amine (intermediate 13).
Reaction SMILES: F[C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH2:20][C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:22]=1.[C:39](OCC)(=O)C=C>C(Cl)(Cl)Cl>[F:27][C:26]1[C:21]([N:20]2[C:2]3[C:3](=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=3[F:16])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:39]2)=[N:22][C:23]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[C:24]([F:28])[CH:25]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(CNc2nc(N)c(F)cc2F)cc1
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 20 ml of chloroform solution of ethyl 3-ethoxy-2-pentafluorobenzoylacrylate prepared from 5.6 g of ethyl 2,3,4,5,6-pentafluorobenzoylacetate by normal process was added 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine until the disappearance of the ethyl acrylate spot in TLC analysis. The solution was concentrated under reduced pressure. To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water, and the chloroform layer was washed twice with 1 liter of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 6.15 g of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([N:15](CC2C=CC(OC)=CC=2OC)[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])([CH3:14])[CH2:9][S:10][CH2:11][C:12]#[N:13])[CH:7]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([NH:15][C:16](=[O:21])[C:17]([F:18])([F:20])[F:19])([CH3:14])[CH2:9][S:10][CH2:11][C:12]#[N:13])[CH:7]=1
Reactant: COc1ccc(CN(C(=O)C(F)(F)F)[C@@](C)(CSCC#N)c2cc(Br)ccc2F)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](CSCC#N)(NC(=O)C(F)(F)F)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
A mixture of (R)—N-(2-(5-bromo-2-fluorophenyl)-1-(cyanomethylthio)propan-2-yl)-N-(2,4-dimethoxybenzyl)-2,2,2-trifluoroacetamide (5.9 g, 10.7 mmol, Eq: 1.00) and trifluoroacetic acid (73.5 g, 49.6 ml, 644 mmol, Eq: 60) was stirred at 23° C. for 16 hours resulting in a dark red solution. Poured into sat. NaHCO3-sol. and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography 0 to 50% ethyl acetate in heptane to give the (R)—N-(2-(5-bromo-2-fluorophenyl)-1-(cyanomethylthio)propan-2-yl)-2,2,2-trifluoroacetamide (3.1 g, 6.99 mmol, 65.1% yield) as a light brown oil. MS (ISN): m/z=396.7 [M−H]− and 399.0 [M+2H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](Cl)(C)C.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>ClCCl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:10]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of Example 125B (2 g, 9.2 mmol) and dichloromethane (56 mL) was treated sequentially with 1M trimethylsilyl chloride (20.4 mL, 20.4 mmol) and pyridine (3.4 mL, 41.7 mmol), stirred for 3 hours, treated with benzenesulfonyl chloride (1.4 mL, 11.1 mmol), stirred for 48 hours, diluted with dichloromethane (100 mL), acidified to pH 1 with 1M HCl and stirred for 15 minutes. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired product as an off-white solid. MS (ESI(−)) m/e 354, 356 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 11.36 (br s, 1H), 7.84 (m, 3H), 7.66 (m, 4H), 7.33 (dd, 1H), 3.38 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:25]3[CH2:26][CH2:27][C:22]([F:28])([F:21])[CH2:23][CH2:24]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: FC1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1c(CCN2CCC(F)(F)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (60 mg, 0.20 mmol) in DCE (10 mL) was added 4,4-difluoropiperidine.HCl (42 mg, 0.26 mmol), triethylamine (0.04 mL, 0.26 mmol), powdered 4 Å molecular sieves and sodium triacetoxyborohydride (86 mg, 0.41 mmol). The reaction mixture was stirred at room temperature for 5 h, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-5% MeOH in DCM) to give the title compound as a pale yellow oil (30 mg, 37%). LCMS (Method H): RT=2.61 min, [M+H]+ 401.5
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][CH:8]([C:15]([C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:16][C:15]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)=[C:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccoc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)oc1-c1ccoc1
Yield: 46.6 %

Procedure:
10.0 g of ethyl 3-(3,4-dichlorobenzoylamino)-3-(3-furylcarbonyl)propionate, 50 ml of chloroform and 20.0 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.44 g of ethyl 2-[2-(3,4-dichlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 46.5%