Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]3[N:24]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:23]=[CH:22][CH:21]=3)[N:10]([CH2:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:5]2=[CH:4][CH:3]=1.[NH:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:20]1[N:24]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:23]=[CH:22][CH:21]=1)#[N:16]
Reactant: N#Cc1cccc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2cccc(C#N)c2)n1
Temperature: 140 °C

Procedure:
3-({5-Chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[3,2-b]pyridin-1-yl}methyl)benzonitrile (1.3 g, 3.1 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (1.4 g, 6.2 mmol, Aldrich) and Cs2CO3 (2.0 g, 6.2 mmol) were combined in toluene (20. mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.24 g, 0.31 mmol, Aldrich) was added. The mixture was degassed and heated at 140° C. for 70 minutes. After cooling to room temperature, the mixture was diluted with DCM, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-60% EtOAc in hexanes, afforded purified product. Yield: (1.2 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Na+].[I-].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>CN(C=O)C.O>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][NH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: COCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
Methyl 2-amino-3-nitrobenzoate (3.82 mmol, 0.75 g) in DMF (20 mL) was added NaI (8.40 mmol, 1.26 g). The reaction solution was stirred at 0° C. for 5 min and then added NaH (5.00 mmol, 0.20 g) at 0° C. The reaction solution was stirred at 0° C. for 30 min and then added 1-bromo-3-methoxypropane (5.00 mmol, 0.77 g). The reaction solution was heated to 80° C. and kept stirring at 80° C. for 6 hr. After cooling down the reaction solution was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, EtOAc-hexane: 5:95) to afford methyl 2-(3-methoxypropylamino)-3-nitrobenzoate (44A) (1.49 mmol, 800 mg, yield: 78.1%). ESI-MS: m/z 269.3 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([CH3:34])=[C:22]([C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[CH3:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[NH2:33][CH2:32][C:28]1[S:29][CH:30]=[CH:31][C:27]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:21]=1[CH3:34]
Reactant: Cc1ccc(-c2ccsc2C#N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Product: Cc1ccc(-c2ccsc2CN)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A mixture of 3-(3-tert-butyldiphenylsilyloxymethyl-2,4-dimethylphenyl)-2-cyanothiophene (471 mg) and 1M borane-tetrahydrofuran complex (3 ml) was stirred for 30 minutes at 0° C. under nitrogen atmosphere and allowed to stand at ambient temperature overnight. To the mixture was added 4N hydrochloric acid (1.5 ml) under ice-cooling, and the mixture was stirred for 1 hour. The mixture was partitioned between ethyl acetate and water, and the separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1, V/V) to give 2-aminomethyl-3-(3-tert-butyldiphenylsilyloxymethyl-2,4-dimethylphenyl)thiophene (415 mg) as oil.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOCC.O>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Cc2ccccc2)n1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1csc(Cc2ccccc2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
90 ml of a toluene solution of 2M/liter of diethyl sodium aluminum dihydride were added dropwise at -10° C. to a solution of 20 g of the product of Step A in 100 ml of toluene and the mixture was stirred at -5° C. for one hour. 150 ml of aqueous 2N hydrochloric acid were added dropwise to the mixture at -20° C. and then ether and water were added thereto. The mixture was filtered and the organic phase of the filtrate was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 7-3 methylene chloride-ethyl acetate mixture to obtain 13.6 g of (2-benzyl-4-thiazolyl)-methanol melting about 50° C.
Reaction SMILES: C(OCC=C)C=C.[Na].[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[C:36]=2[Cl:43])[C:15]=1[N:16](C(OC1C=CC=CC=1)=O)[C:17]([O:19][C:20]1C=CC=[CH:22][CH:21]=1)=[O:18])#[N:10].C(=O)=O>C(O)C=C.O1CCCC1>[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[C:36]=2[Cl:43])[C:15]=1[NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])#[N:10]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Agent: C=CCOCC=C
Agent: O=C=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Reaction time: 0.25 h

Procedure:
A solution of sodium 2-propenyloxide in allyl alcohol [30 ml; prepared by dissolving sodium metal (1.0 g) in allyl alcohol (40 ml)] was added to a stirred solution of 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (15 g) in tetrahydrofuran (300 ml). The mixture was stirred for 15 minutes at laboratory temperature then solid carbon dioxide pellets added to adjust the pH of the solution to pH7. The neutralized solution was filtered through diatomaceous earth and then evaporated under reduced pressure and the residue crystallised from a mixture of ethyl acetate and hexane to give 4-cyano-5-(2-propenyloxycarbonylamino)-1-(2,3,4-trichlorophenyl)pyrazole, m.p. 154°-155° C., in the form of colourless crystals.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(CO)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Serinol (3.42 g) was added to a solution of trityl chloride (8.36 g) and triethylamine in 75 mL of dry DMF. After stirring at room temperature overnight, the reaction was poured into water and extracted twice with toluene. The combined organic layers were dried over potassium carbonate and concentrated to dryness. Recrystallization from boiling 1:1 benzene/hexane (two crops) afforded N-triphenylmethylserinol (7.59 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([N:15]1[CH2:109][CH2:108][CH2:107][C@H:16]1[C:17]([NH:19][C@H:20]([C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH:50][C@H:51]([C:62]([NH:64][CH2:65][C:66]([NH:68][C@H:69]([C:79]([NH:81][CH2:82][C:83]([NH:85][C@H:86]([C:97]([N:99]1[CH2:106][CH2:105][CH2:104][C@H:100]1[C:101]([NH2:103])=[O:102])=[O:98])[C@@H:87]([CH3:96])[O:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)=[O:84])=[O:80])[CH2:70][O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:67])=[O:63])[C@@H:52]([CH3:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[C@@H:30]([CH3:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])[CH2:21][CH2:22][C:23](=[O:25])[NH2:24])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:117]([C:136]([O:138][C:139]([CH3:142])([CH3:141])[CH3:140])=[O:137])[C@H:118]([C:124](OC1C=CC([N+]([O-])=O)=CC=1)=[O:125])[CH2:119][CH2:120][C:121](=[O:123])[NH2:122]>>[NH:117]([C:136]([O:138][C:139]([CH3:142])([CH3:141])[CH3:140])=[O:137])[C@H:118]([C:124]([NH:1][C@H:2]([C:13]([N:15]1[CH2:109][CH2:108][CH2:107][C@H:16]1[C:17]([NH:19][C@H:20]([C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH:50][C@H:51]([C:62]([NH:64][CH2:65][C:66]([NH:68][C@H:69]([C:79]([NH:81][CH2:82][C:83]([NH:85][C@H:86]([C:97]([N:99]1[CH2:106][CH2:105][CH2:104][C@H:100]1[C:101]([NH2:103])=[O:102])=[O:98])[C@@H:87]([CH3:96])[O:88][CH2:89][C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=1)=[O:84])=[O:80])[CH2:70][O:71][CH2:72][C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)=[O:67])=[O:63])[C@@H:52]([CH3:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[C@@H:30]([CH3:39])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:27])[CH2:21][CH2:22][C:23](=[O:25])[NH2:24])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:125])[CH2:119][CH2:120][C:121](=[O:123])[NH2:122]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Yield: 95.8 %

Procedure:
By using 2.65 g of Boc-Thr(Bzl)-Pro-Gln-Thr(Bzl)-Asn-Thr(Bzl)-Gly-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 907 mg of Boc-Gln-ONp, and the same procedure as in Reference Example 18 was repeated to obtain 2.74 g (yield: 95.5%) of the above-mentioned objective product.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([CH3:19])[CH:10]=2)[CH2:5][CH2:4]1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][O:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[C:11]([CH3:19])[CH:10]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@H](OC)CC2)cc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](c2ccc(CO)c(C)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of the title compound from Example 13 Step F (90.0 mg, 0.343 mmol) in THF (1.7 mL) was added DIBAL-H (1.03 mL, 1.0 M in toluene, 1.03 mmol). After 30 min, the reaction mixture was allowed to warm to 0° C. After 2 h, the reaction mixture was quenched by addition of MeOH (0.140 mL). The resulting mixture was diluted with diethyl ether and saturated aqueous sodium/potassium tartrate, and the mixture was stirred rapidly until a clear phase separation was achieved. The organic phase was then separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[N:30]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:27][CH:28]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 408.99 g/mol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[C:10]([O:29][CH3:30])=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[N:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:3][CH:2]=1>[Pt].CCOCC>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]2[C:10]([O:29][CH3:30])=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[N:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:5][CH:6]=1
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccccc2Cl)cc1C=Cc1ccncc1
Agent: [Pt]
Solvent: CCOCC
Product: COc1cc(OC)c(-c2ccnn2-c2ccccc2Cl)cc1CCc1ccncc1

Procedure:
11.C.2 Hydrogenation of “E7” using 5% Pt/C as catalyst gives the compound 5-{5-[2-(pyridin-4-yl)ethyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole and ether cleavage thereof gives the compound 5-{5-[2-(pyridin-4-yl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole, retention time [min] 1.397, M+H+[m/e] 392.86.
Reaction SMILES: C([NH:8][C@H:9]1[C@@H:15]([F:16])[CH2:14][C@@H:13]2[N:17](CC3C=CC=CC=3)[C@@:10]1([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C@H:12]2[CH2:25][OH:26])C1C=CC=CC=1>C(O)C.C1CC=CCC=1.[Pd]>[NH2:8][C@H:9]1[C@@H:15]([F:16])[CH2:14][C@@H:13]2[NH:17][C@@:10]1([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C@H:12]2[CH2:25][OH:26]
Reactant: OC[C@@H]1C[C@@]2(c3ccccc3)[C@@H](NCc3ccccc3)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: N[C@H]1[C@@H](F)C[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2CO
Yield: 88.5 %

Procedure:
(1R*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-1-phenyl-6-(hydroxymethyl)-8-azabicyclo[3.2.1]octane (Description 38; 486 mg, 1.13 mmol) was dissolved in ethanol (20 mL) and 1,4-cyclohexadiene (2 mL). 10% Palladium on activated charcoal (500 mg) was added and the suspension was heated at reflux for 24 hours. After cooling and filtration, the filtrate was concentrated in vacuo to give the title compound as a gum (257 mg, 1.0 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[O:22]1[C:26]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])=[CH:25][N:24]=[CH:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>C(#N)C.O>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[C:5]([O:20][CH3:21])=[CH:4][N:3]=[C:2]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:27]([C:26]5[O:22][CH:23]=[N:24][CH:25]=5)[CH:28]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: COc1cnc(Nc2cccc(-c3cnco3)c2)nc1-c1cnn(C(CC#N)C2CC2)c1

Procedure:
A mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopropylpropanenitrile (20 mg, 0.00008 mol), 3-(1,3-oxazol-5-yl)aniline (18.1 mg, 0.000113 mol), and p-toluenesulfonic acid (11 mg, 0.000064 mol) in dry 1,4-dioxane (0.5 mL, 0.006 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as a racemic mixture (free base). LCMS (M+H) 428.1.
Reaction SMILES: C([NH:11][C:12](=[N:47]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH3:38])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:62]>[Pd].CO>[ClH:62].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@H:17]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[CH3:38])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:47])=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc([C@@H](C)NC(=O)[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc([C@@H](C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(S)-N-[1-(4-methoxyphenyl)ethyl]-arginine amide (2.8 g; from step (e) above), 10% Pd/C (1.5 g), and, instead of HOAc, MeOH (225 mL) and concentrated HCl (21 mL) under hydrogen, 18 hours reaction time, which gave the crude product (1.8 g). Crystallization from MeOH:diethyl ether then from isopropanol:diethyl ether afforded the sub-title compound as a white solid (0.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)=[O:8].O1[CH2:36][CH2:35]OCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([N:10]2[CH2:36][CH2:35][N:6]([CH3:5])[CH2:7][CH2:9]2)[N:10]=1)=[O:8]
Reactant: Cc1ccccc1-c1cnc(S(C)(=O)=O)nc1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Reactant: C1COCCO1
Product: Cc1ccccc1-c1cnc(N2CCN(C)CC2)nc1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 0.25 g (0.538 mmol) 2-methylsulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide in 5 ml dioxane 0.15 ml (1.34 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 25 ml CH2Cl2 and 25 ml H2O. The aqueous layer was extracted with 20 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH) 9:1) to give 0.116 g (44%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a colorless oil, MS (ISP): 484.3, 486.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([O:21]CC)=[O:20])[C:12]=2[N:11]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1.[Li+].[OH-]>O1CCOCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[C:12]=2[N:11]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][CH:34]=2)[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1
Reactant: CCOC(=O)CC1CCCc2c(-c3ccc(Cl)cc3Cl)cn(C(CCc3ccccc3)c3ccc(C(F)(F)F)cc3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)CC1CCCc2c(-c3ccc(Cl)cc3Cl)cn(C(CCc3ccccc3)c3ccc(C(F)(F)F)cc3)c21
Temperature: 60 °C

Procedure:
The ester from the foregoing step (0.03 g, 0.05 mmol) was dissolved in a mixture of dioxane (7 ml)/water (2 ml). Then LiOH (12 mg, 0.5 mmol) was added and the solution heated to 60° C. for 14 h. The reaction mixture was then diluted with AcOEt (20 ml), washed with 2.0N HCl (20 ml), brine (20 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 20% AcOEt/Hexane and consequently by HPLC (gradient 60-98% CH3CN/0.1% TFA-H20) to afford 1.2 mg of the title compound; m/z (ES+) 586 (MH+); m/z (ES−) 584 (M−H+).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:41])[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:40])[CH2:16][C@@H:17]([NH:29][C:30]([O:32]CC1C=CC=CC=1)=[O:31])[CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[CH2:2]([N:29]([C@H:17]([CH2:16][C:15]([NH:14][CH2:13][CH2:12][NH:11][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:41])=[O:40])[CH2:18][CH2:19][CH2:20][NH2:21])[C:30](=[O:31])[OH:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)N(Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
8 ml of a 4M solution of hydrogen chloride in dioxane are added to a solution of 320 mg (0.287 mmol) of benzyl[2-({(3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoyl}amino)ethyl]carbamate (Example 104A) in 2 ml of dioxane at 0° C. After 1 h at RT, the reaction solution is concentrated in vacuo, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cccc2cccnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ccc(Br)c2cccnc12
Reaction time: 0.25 h

Procedure:
To a solution of 8-aminoquinoline (4.0 g, 28 mmol) in CH3CN (185 mL) was added N-bromosuccinimide (2.47 g, 13.9 mmol). After stirring for 15 minutes, a second portion of N-bromosuccinimide (2.71 g, 15.2 mmol) was added. After stirring for an additional 30 minutes, the mixture was concentrated. The residue was dissolved in EtOAc, then washed with water (2×100 mL) and saturated NaCl (aq) (100 mL). The organics were dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10-15% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.79 (dd, J=1.5, 4.1 Hz, 1H), 8.46 (dd, J=1.5, 8.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.52 (dd, J=4.1, 8.5 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H); LC7: 2.48 min. (M+H) 225.