Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:23]=[CH:22][C:7]([NH:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)[C:10]#N)=[CH:6][CH:5]=1)[CH3:2].O=[CH:25][C:26](=C)[CH3:27]>>[CH2:1]([S:3][C:4]1[CH:23]=[CH:22][C:7]([N:8]2[CH:25]=[C:26]([CH3:27])[CH:10]=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=C(C)C=O
Reactant: CCSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Product: CCSc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-ethylthioanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 69%), melting at 139-141° C.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:13]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1cccc2ccccc12
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOc1cccc2ccccc12
Temperature: 25 °C
Yield: 98.4 %

Procedure:
1-naphthol (5 g, 34.7 mmol), iodohexane (8.82 g, 41.6 mmol) and K2CO3 (7.2 g, 50 mmol) in acetonitrile (150 ml) were refluxed overnight under N2. After being cooled to room temperature, water (10 ml) was added and acetonitrile was evaporated. Water (150 ml) and Et2O (150 ml) were added. The ethereal layer was extracted and washed with water (2×100 ml), brine (100 ml), dried over MgSO4, filtered and evaporated to dryness to afford 7.8 g (98%) of compound 2 as an orange oil after drying at 80° C. under vacuum.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1
Reactant: CN1C(=O)C(CCO)Sc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)C(CCCl)Sc2ccccc21
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 4.90 g of 2-(2-hydroxyethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one in 20 ml of dichloromethane, was added dropwise 5 ml of thionyl chloride with stirring at room temperature. The mixture was stirred for one hour and then concentrated. The concentrate was subjected to a column chromatography on silica-gel (35 g). From the eluate with hexane-ethyl acetate (4:1, v/v) was obtained 5.05 g (95.3%) of 2-(2-chloroethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:36]1[CH2:41][CH2:40][CH2:39][C@H:38]([O:42][C:43]2[C:44]3[CH:51]=[CH:50][NH:49][C:45]=3[N:46]=[CH:47][N:48]=2)[CH2:37]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[N:46]1[C:45]2[NH:49][CH:50]=[CH:51][C:44]=2[C:43]([O:42][C@H:38]2[CH2:39][CH2:40][CH2:41][N:36]([C:11](=[O:13])[CH2:10][NH:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:37]2)=[N:48][CH:47]=1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Reactant: c1nc(O[C@H]2CCCNC2)c2cc[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1cc(F)cc(Cl)c1)N1CCC[C@H](Oc2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a cooled solution of 2-(3-chloro-5-fluorophenylamino)acetic acid (139 mg, 0.68 mmol) at 0° C. in DMF (5 mL) was added HOBt (136 mg, 0.10 mmol), EDCI (197 mg, 0.10 mmol), (S)-4-(piperidin-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (150 mg, 0.7 mmol) and Et3N (0.2 mL, 1.37 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3×20 mL). The combined EtOAc layer was dried over Na2SO4 and concentrated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (45 mg, 17%) the titled compound. 1H NMR (400 MHz, DMSO-d6): δ 12.08 and 12.05 (2s, 1H), 8.41 and 8.39 (2s, 1H), 7.35 (s, 1H), 6.62-6.25 (m, 4H), 5.39-5.24 (m, 1H), 4.05-3.62 (m, 5H), 3.55-3.42 (m, 2H), 1.89-1.45 (m, 4H). LC-MS: m/z [M+1]=404.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:26]([C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)[C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 3.75 g of 4-t-butylphenol in 40 ml of tetrahydrofuran was added 0.88 g of sodium hydride (oil dispersion). After stirring 30 minutes, 1 ml of hexamethylphosphoramide was added and a solution of 7.36 g of methyl α-bromo-α-[p-(p-nitrophenoxy)phenyl]acetate in 25 ml of tetrahydrofuran was added over a period of 30 minutes. The mixture was stirred at room temperature for 30 minutes and refluxed for 30 minutes. The mixture was poured into 130 ml of ice-water and extracted with dichloromethane. The extracts were washed with saturated sodium chloride solution and chilled. Filtration gave 2.1 g of product. The filtrate was concentrated to an oil under vacuum and chromatographed over silica gel (eluent-CCl4). From the first fractions there was obtained 4.3 g of solid which was dissolved in hot methanol and the volume reduced. Chilling gave 3.7 g of product as pale yellow crystals, mp 101° -103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[F:20])[CH3:12].O.[C:25]([OH:29])(=[O:28])[CH:26]=O>C(#N)C.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:26]([C:16]2[CH:17]=[CH:18][C:19]([F:20])=[C:14]([O:13][CH2:11][CH3:12])[CH:15]=2)[C:25]([OH:29])=[O:28])[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: O=CC(=O)O
Reactant: CCOc1cc(B(O)O)ccc1F
Reactant: NC(=O)c1cccc(N)c1
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1F
Temperature: 55 °C
Yield: 60.2 %

Procedure:
A mixture of 3-aminobenzamide (68 mg, 0.5 mmol), 9B (92 mg, 0.5 mmol) and glyoxylic acid monohydrate (46 mg, 0.5 mmol) in acetonitrile (3.0 mL) and DMF (0.8 mL) was heated at 55° C. for 18 h. After removal of solvent, the crude was purified by silica gel column chromatography eluting with gradient methanol in methylene chloride to give 9C as a solid (100 mg, 60% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.25 (t, J=6.81 Hz, 3H) 3.96 (m, 2H) 5.03 (s, 1H) 6.70 (d, J=7.91 Hz, 1H) 6.96-7.08 (m, 5H) 7.15 (dd, J=8.35, 1.76 Hz, 1H); LC-MS 333 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[C:6]([O:11]C)(=O)[C:7]([CH3:9])=[O:8].C(O)(=O)C>O>[OH:8][C:7]1([CH3:9])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]1=[O:11]
Reactant: COC(=O)C(C)=O
Reactant: CNC(N)=O
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C1(C)O
Yield: 31.5 %

Procedure:
155 g of N-methylurea were added to 214 g of methyl pyruvate in a 3 1 eggplant type flask. 800 ml of acetic acid and 200 ml of water were added to dissolve them and the solution was refluxed for 2.5 hours. Then, the reaction mixture was evaporated to dryness and acetic acid was removed by azeotropic distillation with toluene. The obtained crude product was purified by chromatography on silica gel (ethyl acetate and 5% methanol/chloroform) to give 95 g of 5-hydroxy-1,5-dimethylhydantoin (compound 10).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[CH2:27]([N:30]=[C:31]=[O:32])[CH2:28][CH3:29]>C1(C)C=CC=CC=1>[CH2:27]([NH:30][C:31]([N:4]1[C:5]2[CH:6]=[C:7]3[N:22]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[NH:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:26])([CH3:1])[C:3]1=[O:25])=[O:32])[CH2:28][CH3:29]
Reactant: CCCN=C=O
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Solvent: Cc1ccccc1
Product: CCCNC(=O)N1C(=O)C(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methoxy-benzamide (200 mg) and propyl isocyanate (59 μl) in dry toluene (2 ml) is stirred in a microwave apparatus at 150° C. for 900 s. The resulting solid is collected by filtration, dissolved in acetic acid (3 ml) and iron (200 mg; powder) is added and the mixture is again stirred in a microwave apparatus at 150° C. for 900 s to achieve reduction of the nitro function and ring closure. The mixture is filtered and concentrated in vacuo. The desired compound (65 mg) is obtained by preparative RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1.C1COCC1.[CH2:22]([O:24][CH:25]([O:34][CH2:35][CH3:36])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[CH3:23]>CCCCCC.O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:26]([OH:27])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]([O:24][CH2:22][CH3:23])[O:34][CH2:35][CH3:36])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: Cc1c(NC(=O)C(C)(C)C)cnc(Cl)c1C
Reactant: CCOC(OCC)C(=O)c1ccccc1
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)C(O)(Cc1c(NC(=O)C(C)(C)C)cnc(Cl)c1C)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
144.3 g (0.6 mol) of 2-chloro-3,4-dimethyl-5-pivaloylaminopyridine are dissolved in 2.9 1 of abs. THF and the solution is treated under argon at -78° C. with 127 ml of a 10.4N solution of n-BuLl in n-hexane (1.32 mmol). The mixture is stirred at 0° C. for 3 h, 129.8 ml (0.6 mol) of 2,2-diethoxyacetophenone are slowly added at -78° C. and the mixture is stirred at room temperature overnight. It is then added to water and extracted 3 times with ethyl acetate, dried and concentrated on a rotary evaporator. The purity is sufficient for further reaction. After chromatography, 180.5 g (67%) of the title compound are obtained. M.p.: 133° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:23])=[O:22])#[N:14]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: Fc1ccc(C2CCCN2)cc1
Product: N#Cc1ccccc1S(=O)(=O)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, light green solid, m.p. 101° C. and MS: m/e=330 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2-cyano-benzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][C:10]1(C)[C:14](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[CH2:9]=[C:10]([C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1)[CH3:14]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Nc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cncc(N)c1
Temperature: 90 °C
Yield: 230.4 %

Procedure:
5-Bromopyridin-3-amine (0.433 g, 2.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.630 g, 3.75 mmol), Cs2CO3 (3.10 g, 9.5 mmol) and Pd(PPh3)4 (0.289 g, 0.25 mmol) were suspended in DMF/H2O (3:1, 20 mL). The reaction mixture was degassed with N2 and heated at 90° C. for 16 h. Solvent was removed under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried, concentrated in vacuo and purified by chromatography to afford 5-(prop-1-en-2-yl)pyridin-3-amine (0.773 g, 230%) as a dark yellow oil. MS (ESI) m/z: 135.0 (M+H+).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].N#N.O=O.[C:9]([OH:12])(=[O:11])[CH3:10]>>[C:9]([O:12][C:1]([O:12][C:9](=[O:11])[CH3:10])=[CH:2][CH2:3][CH3:4])(=[O:11])[CH3:10]
Reactant: C=CC=C
Reactant: CC(=O)O
Agent: N#N
Agent: O=O
Product: CCC=C(OC(C)=O)OC(C)=O

Procedure:
Butadiene, acetic acid, air and N2 were passed at rates of 100 l./hr, 200 l./hr, 150 l./hr and 550 l./hr, respectively, by using the same catalyst as in Example 1. That is, the reaction was performed under the same conditions as in Example 1, except that air is oxygen source was used. As a result, diacetoxybutene was obtained at a space time yield of 0.73 mol/l.cat·hr and CO2 at a space time yield of 0.049 mol/l.cat·hr.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C@:16]([CH3:30])([CH2:19][N:20]1[CH:29]=[C:23]2[N:24]=[CH:25][C:26]([Br:28])=[CH:27][C:22]2=[N:21]1)[C:17]#[N:18]>C1COCC1>[Br:28][C:26]1[CH:25]=[N:24][C:23]2=[CH:29][N:20]([CH2:19][C@@:16]([NH:15][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)([C:17]#[N:18])[CH3:30])[N:21]=[C:22]2[CH:27]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@](N)(C#N)Cn1cc2ncc(Br)cc2n1
Solvent: C1CCOC1
Product: C[C@](C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Trifluoromethoxybenzoyl chloride (14.5 mL) was added at around 0° C. to a cold solution of (R)-2-amino-3-(6-bromo-pyrazolo[4,3-b]pyridin-2-yl)-2-methyl-propionitrile (23.4 g, 95% ee) in dry THF (600 mL) mixed with TEA (13.4 mL). The reaction mixture was stirred for around 4 hours at around 0° C. The cold reaction mixture was then filtered through a short plug of Celite® and basic alumina and solvent evaporated under reduced pressure. The resulting residue was triturated with DCM to afford a solid that was isolated by filtration to give the title compound as a white solid (28.6 g, 73.1%, 99.6% analytical purity, 99% ee). The filtrate was collected and solvent evaporated under reduced pressure. The residue was loaded on silica gel and purified by chromatography (SiO2, heptane/EA) to afford a second crop of title compound as a white solid (4.1 g, 10.5%). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, CHLOROFORM-d): 1.94 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.02 (d, J=14.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.83-7.92 (m, 2H), 8.02 (s, 1H), 8.21 (dd, J=2.0, 0.7 Hz, 1H), 8.40 (d, J=0.7 Hz, 1H) and 8.62 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>CN(C)C=O>[CH:30]([N:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C(C)C)C(C)C)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1g) and diisopropylamine (0.1ml) in dimethylformamide (10ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((diisopropylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 119) (0.11g) as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>>[Cl:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CO
Reactant: O=C(O)CSCCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)CSCCCl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (10 ml) was added to a solution of the title compound of Example 9 (9.7 g, 0.06 mole) in methyl alcohol (100 ml) cooled to 5° C. via an ice bath. The ice bath was removed and the reaction stirred for 2.5 hours at room temperature. The methyl alcohol and excess thionyl chloride were removed using a rotary evaporator to give 9.8 g, of an oil which was identified by NMR as the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[OH2:24].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])(=[O:21])=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: CSCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCS(C)(=O)=O
Reaction time: 1 h
Yield: 38.7 %

Procedure:
In a dried reaction flask, the crude tert-butyl 2-(methylthio)ethylcarbamate (2.464 g, about 11.0 mmol) was dissolved in tetrahydrofuran (22 mL). To the mixture was added 77% mCPBA (5.698 g, 25.42 mmol) in portion at 0° C. The mixture was stirred for 1 hr. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and was purified by silica gel column chromatography with ethyl acetate to obtain a white solid (0.95 g) in 38.7% yield.
Reaction SMILES: C1COCC1.[C:6]12([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=3)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-].[Na+].Cl>C(O)C>[C:6]12([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:20][CH:21]=3)[CH2:7][CH:8]3[CH2:9][CH:10]([CH2:11][CH:12]([CH2:14]3)[CH2:13]1)[CH2:15]2
Reactant: CCOC(=O)C(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 70 °C
Yield: 89.8 %

Procedure:
THF (18 mL) and ethanol (6 mL) were added to 600 mg (1.83 mmol) of ethyl {[4-(adamantan-1-yl)phenyl]amino}(oxo)acetate. Thereafter, 2.7 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was heated at 70° C. for 2 hours. Next, 1N hydrochloric acid was added to acidify the mixture, and the organic solvent was distilled off under reduced pressure. The resulting solids were filtered and washed with H2O and n-hexane, followed by drying, thereby giving 492 mg of {[4-(adamantan-1-yl)phenyl]amino}(oxo)acetic acid (yield: 90%).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.CN(C)[CH2:26][CH2:27]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([O:15][CH2:26][CH3:27])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C

Procedure:
5 g of Boc-Phe(4-NO2)-OH, 3.09 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5 ml of ethanol and 2 g of dimethylaminopyridine were stirred in dichloromethane for 3 days. The obtained substance was washed with 1N hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and saturated NaCl solution, and dried with magnesium sulfate. The solvent was removed to obtain the title compound.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:58][CH2:57][CH2:56][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:24]([N:26]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:27]1[C:28]([NH:30][C@H:31]([C:42]([O:44]CC1C=CC=CC=1)=[O:43])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:41])[NH:37][N+]([O-])=O)=[O:29])=[O:25])[CH2:15][O:16]CC1C=CC=CC=1)=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4]>[C].[Pd]>[NH:1]1[CH2:58][CH2:57][CH2:56][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:24]([N:26]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:27]1[C:28]([NH:30][C@H:31]([C:42]([OH:44])=[O:43])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:41])=[O:29])=[O:25])[CH2:15][OH:16])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4].[CH3:31][C:42]([OH:44])=[O:43]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Agent: [Pd]
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1)C(=O)O

Procedure:
150 mg of Z-Pro-Asn-Ser(Bzl)-Pip-Arg(NO2)-OBzl was reduced in the presence of palladium-carbon in the same manner as in Example 12-(4). The resulting product was purified by high-performance liquid chromatography at 12 ml/min. (flow rate), 0 to 10% (B) 20 min. linear gradient (A) (mobile phase), subjected to Dowex 1×2 (acetate type) treatment and freeze-dried to obtain the desired compound.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:35])/[CH:22]=[CH:23]/[C:24]3[CH:25]=[N:26][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2[N:48]([OH:49])N=NC=2C=1.NOC1CCCCO1>CN(C=O)C.C1COCC1>[OH:49][NH:48][C:32](=[O:34])/[CH:31]=[CH:30]/[C:27]1[CH:28]=[CH:29][C:24](/[CH:23]=[CH:22]/[C:21](=[O:35])[C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[CH:20][CH:19]=2)=[CH:25][N:26]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCNCC3)cc2)cn1)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester hydrochloride (184 mg, 0.363 mmol) was dissolved in DMF (5 ml), THF (5 ml) and TEA (0.190 ml, 1.47 mmol). Then EDC (140 mg, 0.736 mmol), HOBT (99 mg, 0.736 mmol) and NH2OTHP (51.6 mg, 0.441 mmol) were added to the resulting solution. The mixture was stirred at room temperature overnight and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 98:2:0.2) and the resulting compound was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off and washed with DCM. The hygroscopic powder was dissolved in water and freeze dried to give 53 mg of (E)-N-hydroxy-3-{5-[(E)-3-oxo-3-(4-piperazin-1-yl-phenyl)-propenyl]-pyridin-2-yl}-acrylamide as its bis-hydrochloride salt.