Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.Cl.[CH3:55][N:56]1[C:60]([C:61](Cl)=[O:62])=[CH:59][N:58]=[CH:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:61]([C:60]2[N:56]([CH3:55])[CH:57]=[N:58][CH:59]=2)=[O:62])[CH2:48]1
Reactant: Cn1cncc1C(=O)Cl
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(=O)N1CC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-imidazole-5-carbonyl chloride hydrochloride as the starting materials in 20% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z=558.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](N)[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.N([O-])=O.[Na+].[FH:29]>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:29])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: F
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccc(N)n2)CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](c2cccc(F)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Batch 1: To a solution of trans-4-(6-amino-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (0.050 g, 0.20 mmol) in 70% hydrogen fluoride in pyridine (0.47 ml, 18 mmol) was added solid sodium nitrite (0.015 g, 0.22 mmol) at 0-5° C. The cooling bath was removed after 20 minutes and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was partitioned between an ice-water mixture (50 ml) and tert-butyl methyl ether (50 ml). The organic layer was collected. The aqueous layer was extracted with two 50-ml portions of tert-butyl methyl ether. The combined organic layers were washed with one 30-ml portion of 2M aqueous sodium hydroxide solution and one 30-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the crude title compound (0.08 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cccnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
Pd(OH)2/C (690 mg) was added to a solution of 3′,6′-dihydro-2′H-[2,4]bipyridinyl-3,1′-dicarboxylic acid 1′-t-butyl ester 3-methyl ester (2.0 g, 6.3 mmol, 1.0 eq.) in PE (220 mL) and EtOAc (50 mL). Hydrogen gas (1 atm) was introduced into the reaction vessel, and the solution was stirred for 20 hours at room temperature. The reaction mixture was filtered and the remaining mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:8) to yield 3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-3,1′-dicarboxylic acid 1′-t-butyl ester 3-methyl ester (1.2 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([O:20]CC)=O.[C:23]([NH:32][NH2:33])(=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([NH:33][NH:32][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:20]
Reactant: C=C(C)C=Cn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: CCCCCCCC(=O)NN
Product: C=C(C)C=Cn1c(=O)c(C(=O)NNC(=O)CCCCCCC)c(O)c2ccccc21

Procedure:
Reagents: Comp 29 (0.66 mmols, 0.2 g); octanoyl hydrazine (0.73 mmols, 0.12 g). Yield: 0.125 g (22%), white solid, m.p.=114° C.-115° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].[F-].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(=Cc2ccc(Br)cc2)CC(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(=Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)CC(C)C)cc1
Yield: 32.6 %

Procedure:
3-{4-[1-(4-bromo-benzylidene)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (2.6 g, 5.86 mmol), 4-t-butyl phenyl boronic acid (2.08 g, 12 mmol), potassium fluoride (1.02 g, 17.6 mmol) and tetrakis(triphenylphosphine)palladium (0.677 g, 0.59 mmol) are placed in a flask. The system is purged with nitrogen. Toluene (40 mL) and water (10 ml) are added and the resulting mixture is refluxed overnight. The reaction is loaded directly onto silica gel and chromatographed using EtOAc/hexanes to yield the titled compound as a yellow oil (0.95 g).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH:14]([C:17](=O)[C:18]4[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=4)[C:15]#[N:16])=[CH:13][C:8]=3[N:7]([CH3:26])[C:6]2=[O:27])[CH2:4][CH2:3][CH2:2]1.[OH:28][CH2:29][CH2:30][NH:31][NH2:32].C(=O)(O)[O-].[Na+]>CC(O)C.C(O)(=O)C>[NH2:16][C:15]1[N:31]([CH2:30][CH2:29][OH:28])[N:32]=[C:17]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[C:14]=1[C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[C:6](=[O:27])[N:7]([CH3:26])[C:8]=2[CH:13]=1
Reactant: NNCCO
Reactant: Cc1cccc(C(=O)C(C#N)c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cccc(-c2nn(CCO)c(N)c2-c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1
Temperature: 70 °C

Procedure:
2-(1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-oxo-3-m-tolyl-propionitrile (66.5 mg, 0.19 mmol) was diluted with 2-propanol (0.4 mL) and acetic acid (0.8 mL). Hydroxyethyl hydrazine was then added (0.1 mL) and the mixture was heated to 70° C. for 8 hours. The reaction was cooled, poured onto saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated. Preparative thin layer chromatography gave 5-[5-Amino-1-(2-hydroxy-ethyl)-3-m-tolyl-1H-pyrazol-4-yl]-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (27.6 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: CCOC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-2-(3-chlorobenzoyl)-1H-indole (step 2) and ethyl chloroformate.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:10]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[N:9]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[Cl:27][C:24]1[S:23][C:22]([C:10]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([NH:2][S:40]([CH3:39])(=[O:42])=[O:41])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:36])([F:37])[F:38])=[O:28])[N:9]=2)=[CH:26][CH:25]=1
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure of Example 68, 35 mg (52 μmol) of the compound of Example 61A were reacted with methanesulphonyl chloride. This gave 14 mg (41% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][OH:24].C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:23][OH:24])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCC[C@H]2CO)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 69.9 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.287 mmol), (S)-(+)-2-pyrrolidinemethanol (Aldrich Chemical Company) (0.14 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL) to give 61.9 mg (70%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. Mp: 255-256° C. 1H NMR (CDCl3; 500 MHz): δ 2.06-2.14 (m, 4), 2.54 (s, 3), 3.76 (d, 1, J=9.23), 3.84 (dd, 1, J=2.0, 11.1), 3.96-3.98 (m, 1), 4.11 (q, 1, J=7.6, 7.9), 4.55-4.57 (m, 1), 6.68 (s, 1), 7.35-7.45 (m, 3), 7.61 (d, 2, J=7.4), 9.17 (br s, 1). MS m/z: 167 (base), 307 (M−1). Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 70.00; H, 6.59; N, 18.11.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[C:10]3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1>>[N:11]1[C:10]2=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:9]2=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccnc(Cl)n1
Reactant: c1ccc2nc(N3CCNCC3)nc-2cc1
Product: Nc1ccnc(N2CCN(c3nc4cccccc-4n3)CC2)n1

Procedure:
Similarly, by condensing 2-(1-piperazinyl)cycloheptimidazole with 2-chloro-4-aminopyrimidine, there was obtained 2-[4-(2-cycloheptimidazolyl)-1-piperazinyl]-4-pyrimidinamine (I: R1, R2, R4 and R5 =H; R3 =2-cycloheptimidazolyl; and n=1) as the di-(Z)-2-butenedioate salt: mp 205°-208° C. (crystallized from methanol-diethyl ether); and Anal. Calcd for C16H17N7.2C4H4O4 : C, 53.43% H, 4.63% N, 18.18% and Found: C, 53.66% H, 4.81% N, 18.34%.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:31])[CH2:15][CH2:16][C@@:17]34[CH2:23][C@:22]53[CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([CH3:29])([CH3:28])[C@@H:21]5[CH2:20][CH2:19][C@H:18]4[C@:13]2([CH3:32])[CH2:12][CH2:11]1)[CH2:3][CH2:4][C:5]([CH:7]([CH3:9])[CH3:8])=[CH2:6].C([O:36][C:37]1[CH:47]=[CH:46][C:40]([CH:41]=[CH:42][C:43]([O-:45])=[O:44])=[CH:39][C:38]=1[O:48][CH3:49])(=O)C.C(OC(=O)C)(=O)/C=C/C1C=CC(O)=C(OC)C=1>>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:31])[CH2:15][CH2:16][C@@:17]34[CH2:23][C@:22]53[CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([CH3:29])([CH3:28])[C@@H:21]5[CH2:20][CH2:19][C@H:18]4[C@:13]2([CH3:32])[CH2:12][CH2:11]1)[CH2:3][CH2:4][C:5]([CH:7]([CH3:8])[CH3:9])=[CH2:6].[OH:36][C:37]1[CH:47]=[CH:46][C:40]([CH:41]=[CH:42][C:43]([O-:45])=[O:44])=[CH:39][C:38]=1[O:48][CH3:49]
Reactant: COc1cc(C=CC(=O)[O-])ccc1OC(C)=O
Agent: C=C(CC[C@@H](C)[C@H]1CC[C@@]2(C)[C@@H]3CC[C@H]4C(C)(C)[C@@H](O)CC[C@@]45C[C@@]35CC[C@]12C)C(C)C
Agent: COc1cc(/C=C/C(=O)OC(C)=O)ccc1O
Product: COc1cc(C=CC(=O)[O-])ccc1O

Procedure:
Commercial available γ-oryzanol (100 g, 24-methylenecycloartanol content 45%) was acetylated with acetic anhydride in pyridine. This acetylated γ-oryzanol was recrystallized repeatedly from chloroform-ethyl acetate-ethanol (4:3:2, V/V), giving acetyl ferulate (18 g) of 24-methylenecycloartanol content 95%. This acetyl ferulate was completely saponified in the solution of 2N NaOH-ethanol, then the obtained alcohol was converted into the benzoate. This benzoate was recrystallized repeatedly, and completely saponified to give 24-methylenecycloartanol (5 g). A portion (2 g, 0.0045 mole) thereof wa converted into 24-methylenecycloartanol-4-acetoxy-3-methoxycinnamate according to following the procedure of Example 65. This ester was then deacetylated according to following the procedure of Example 100-2, giving 24-methylenecycloartanol-4-hydroxy-3-methoxycinnamate (2.58 g), in a 90% yield. m.p. 166°-167° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1.[C:25](#[N:27])[CH3:26].[H-].[Na+]>CN(C)C=O.O1CCCC1>[O:2]=[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1)[CH2:26][C:25]#[N:27]
Reactant: COC(=O)c1ccc(CCc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(CCc2ccc(C(=O)CC#N)cc2)cc(OC)c1OC
Temperature: 65 °C

Procedure:
To a solution of 10 g (30 mmol) of methyl-4-[2-(3,4,5-trimethoxyphenyl)ethyl]benzoate and 1.74 ml (33 mmol) of acetonitrile in a mixture of 30 ml of dry N,N-dimethylformamide and 20 ml of dry tetrahydrofuran was added, portionwise under a nitrogen atmosphere at 0° C., 3 g (76 mmol) of a 60% suspension of sodium hydride in mineral oil. The resulting suspension was heated under a flow of nitrogen to 65° C. and maintained at this temperature for 2 hours. After cooling to 25° C., the resultant mixture was quenched with 3 ml of methanol and the solvent was removed in vacuo. The resultant residue was dissolved in 60 ml of water, acidified with 2N hydrochloric acid to a pH between 4 and 5 and then extracted with ethyl acetate. The combined organic phase was then washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate, after which time the solvent was removed under reduced pressure. The crude product was then purified on silica gel employing a mixture of ethyl acetate and hexane in a 1:1 ratio as the eluent to yield a white crystalline solid.
Reaction SMILES: Br[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[NH3:14]>S([O-])([O-])(=O)=O.[Cu+2]>[NH2:14][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(C(=O)O)c(Br)cn1
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: Nc1cnc(C(=O)O)cc1C(=O)O
Temperature: 160 °C
Reaction time: 20 h

Procedure:
A mixture of 500 mg of 5-bromo-pyridine-2,4-dicarboxylic acid from Example 2, 100 mg of copper sulfate and 20 ml of ammonia solution (d=0.91) is heated at 160° C. in an autoclave for 4 hours. The solution is evaporated to dryness, the solid is heated with a little methanol and the insoluble material is removed from the solution. After 20 hours, a white solid precipitates out at 0° C. and is filtered off and dried.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=[O:5])[CH3:2].[BH4-].[Li+]>CO.CO.O.C1COCC1>[CH2:17]([C:16]1[C:15]([CH3:19])=[C:14]2[C:10](=[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:8]=1[CH2:7][CH:6]=[C:3]([CH2:4][OH:5])[CH2:1][CH3:2])[C:11](=[O:20])[O:12][CH2:13]2)[CH3:18]
Reactant: CCC(C=O)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (50.3 mg, 0.129 mmol) was dissolved in MeOH (3 mL). A solution of CeCl3 (31.9 mg, 0.129 mmol) in MeOH/water (9/1, 0.66 mL) was added and the solution was cooled to 0° C. A solution of lithium borohydride in THF (2M, 0.065 mL) was added dropwise. After 10 minutes, the reaction was quenched with 1N HCl (0.5 mL). The methanol was removed in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and were dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded a crude oil, which was purified by silica gel chromatography to provide 35.4 mg (70%) of the desired product. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.10-1.19 (m, 6H), 1.26 (m, 2H), 2.19 (s, 3H), 2.32 (q, J=7.5 Hz, 2H), 2.72 (q, J=7.5 Hz, 2H), 3.54 (d, J=6.6 Hz, 2H), 4.05 (s, 2H), 4.26 (m, 2H), 5.14 (s, 2H), 5.27 (m, 1H) ppm.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[S:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:7][CH:6]=1)#[N:4]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[S:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)C(C)(C)Sc1cnccc1-c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1cnccc1-c1ccc(C#N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
Methanol (1 mL) and aqueous sodium hydroxide solution (2M, 1 mL) were added to ethyl 2-(4-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.25 g, 0.77 mmol) and stirred at ambient temperature for 2 hours. The volume was reduced (˜1 mL) by rotary evaporation and the resulting residue treated with aqueous HCl (6N) with stirring to pH 6, resulting in formation of a white precipitate, which was isolated by filtration. The solid was washed with water (6×1 mL), air dried for 1 hour and dried under vacuum over P2O5 overnight to give a white powder (0.072 g, 32%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6](=[O:24])[C@H:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[OH-].[Na+].Cl>CC(C)=O>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
The product of N-pyrazineformyl-L-phenylalanyl-L-phenylalanine methyl ester (1.52 g, 3.52 mmol) in Preparation example 4 was dissolved with 10 ml of acetone, 2N NaOH was added dropwise slowly under the condition of ice water bath until a pH value of 12˜13 was obtained, and the solution was kept reacting under the condition of an ice water bath, the reaction was monitored by TLC and completed after 2 h. Hydrochloric acid was added dropwise under the condition of ice water bath until a pH value of 2˜3 was obtained, a large amount of white solid was produced, the generated precipitate was filtered, washed with diethyl ether followed by airing to dry, 1.33 g of white product was obtained with a yield of 90.5%, the melting point of the white solid: 194-196° C.; 1H-NMR (DMSO-d6, 300 MHz): δ 12.88 (s, 1H), 9.10 (s, 1H), 8.90-8.87 (m, 1H), 8.77-8.73 (m, 1H), 8.75-8.65 (m, 2H), 7.24-7.14 (m, 10H), 4.84-4.80 (m, 1H), 4.53-4.50 (m, 1H), 3.14-2.89 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:10]#[C:11][CH3:12]>>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([NH:6][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:9][C:10]#[C:11][CH3:12])=[CH:19][CH:18]=1)(=[O:22])=[O:21])[CH3:7]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H](C)C(=O)OC)cc1

Procedure:
According to the procedure of Example 20, 0.500 g (3.58 mmol) of D-alanine methyl ester hydrochloride and 0.877 g (3.58 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride provided 0.532 g of the NH-sulfonamide ester, (2R)-2-(4-but-2-ynyloxy-benzenesulfonylamino)-propionic acid methyl ester, as a white solid. Electrospray Mass Spec 312.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]3OCOC[C:30]=3[CH:35]=2)[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[N:19]=[CH:20][S:21][C:22]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH3:38][O:39]C(=O)N=C(SC)C(C1C=C(OC)C=C(OC)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:26]2[CH:27]=[C:28]([O:36][CH3:37])[CH:29]=[C:30]([O:39][CH3:38])[CH:35]=2)[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[N:19]=[CH:20][S:21][C:22]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OC)c1
Reactant: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)cc2c1OCOC2
Product: COc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (166a) to (166c), except that {2-(3,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (225a)) was used instead of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (166a), to give the first eluting enantiomer of the title compound.