Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:77][CH2:76][CH2:75][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][CH2:60][CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH2:74])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[H][H]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:77][CH2:76][CH2:75][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][CH2:60][CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH2:74])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
98 mg of Z-Arg-Arg-Pro-Phe-His-Sta-β-Ala-His-NH2 (from Example 20) are dissolved in 2 ml of 95% strength MeOH and hydrogenated with 20 mg of Pd-on-carbon (10% Pd), while stirring with a magnet and passing hydrogen through, until the starting material has disappeared. The catalyst is then filtered off, the filtrate is concentrated to dryness and the vitreous residue is dissolved in 2 ml of H2O and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-β-Ala-His-NH2 in the form of an amorphous powder; Rf (D)=0.05; Rf (M)=0.06; Rf (O)=0.06.
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:5]1[C:10]2[C:16](=[CH:17][CH:13]=[CH:12][CH:11]=2)[CH:15]=[CH:14]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1

Procedure:
To a stirred solution of Intermediate 6 (250 mg, 0.4 mmol) in THF (10 mL) was a TBAF solution (1.0 M in THF, 10 mL, 10 mmol) and the resulting solution was heated to reflux for 22 hrs. Upon cooling, the reaction was diluted with EtOAc (250 mL), washed with H2O (7×15 mL) and brine, dried over Na2SO4, filtered, and concentrated to give the intermediate deprotected indole as a brown foam (252 mg, LC/MS (ESI) retention time: 2.01 min, m/z 501 (MH+)) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[C:23]1([CH2:29][C:30]([Cl:32])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[ClH:32].[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)N1CCC(Nc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)N1CCC(N(C(=O)Cc2ccccc2)c2ccccc2)CC1
Product: Cl
Reaction time: 8 h

Procedure:
To a stirred mixture of 4.4 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine, 5.3 parts of sodium carbonate and 180 parts of benzene are added dropwise 5 parts of benzeneacetyl chloride. Upon completion, stirring is continued overnight at reflux. The reaction mixture is cooled, washed successively with water, a sodium hydrogen carbonate solution and again with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The formed salt is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 2.5 parts of N-[1-(1-methylethyl)-4-piperidinyl]-N-phenylbenzeneacetamide hydrochloride; mp. 184.4° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Thionyl chloride (6.5 g, 0.055 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (8.0 g, 0.050 mole) and methylene chloride (50 ml). The mixture was warmed to 35°-40° C. for 4 hours and the resulting dark solution evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml). On the following day, the solution was treated dropwise at 15°-20° C. over 2 hours with a solution of ethyl 3-aminobenzoate (8.2 g, 0.050 mole) and triethylamine (5.5 g, 0.054 mole) in methylene chloride (50 ml). The reaction mixture was stirred at room temperature for a further 5 hours and worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml). Evaporation of the solvent left an oil, which slowly solidified. Recrystallization from ethanol (75 ml) gave yellow-tan crystals, m.p. 100°-102° C. (11.2 g, 73% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][CH:10](O)[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:10]([CH3:11])[CH3:9])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CC(C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1cc(I)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 2.30 g (10.4 mmol) 4-iodo-1H-pyridin-2-one in 130 mL DCM are added 0.88 mL (11.4 mmol) 2-propanol and 3.00 (11.4 mmol) triphenylphosphine. After cooling down to 0° C. 2.23 mL (11.4 mmol) DIAD are added dropwise. After 5 min the cooling is removed and the mixture is stirred at r.t. for 2 h. The reaction mixture is washed with water and brine, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 90/10).
Reaction SMILES: [C:1]1([CH2:7][C:8](NC2C(=O)N3C2CCOC3(C)C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:31]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]([NH2:41])[C:29]1=[O:42]>>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:31]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]([NH:41][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:29]1=[O:42]
Reactant: NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1
Reactant: CC1(C)OCCC2C(NC(=O)Cc3ccccc3)C(=O)N21
Product: O=C(Cc1ccccc1)NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1

Procedure:
Following the procedure described for the preparation of 7-phenylacetamido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 7-amino-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 6) and using 1-(2-tetrahydropyranyl)-3-amino-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone there is obtained 1-(2-tetrahydropyranyl)-3-phenylacetamido-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12](O)=[O:13].[H]1[BH2][H][BH2]1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: N#Cc1ccc(CCC(=O)O)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCCO)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(2-chloro-4-cyanophenyl)-propanoic acid (14.3 g, 0.068 mol) in 70 mL of dry THF at -18° C. was added B2H6 (72 ml, 0.068 mol) in THF. The mixture was stirred at room temperature overnight. After addition of water, the layers were separated and the aqueous phase was extracted with ether. Evaporation and distillation gave 3-(2-chloro-4-cyanophenyl)propanol as an oil: 11.0 g; bp 55°-60° C. (0.005 mm Hg). Anal. calcd for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.02; H, 5.19; N, 6.76. ##STR31##
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:12]=1[C:20](Cl)=[O:21]>>[CH2:1]([NH:8][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[C:12]([C:20]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1C(=O)Cl
Reactant: NCc1ccccc1
Product: COc1ccc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1

Procedure:
By following the general method of Example 1, benzyl amine was reacted with 4-methoxy-1,3-benzenedicarbonyl dichloride to give the titled compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.[CH:12]([O-])([O-])[O:13]C.[CH3:17][O-].[Na+]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:17][O:10][CH:9]([O:13][CH3:12])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:11]
Reactant: C[O-]
Reactant: COC([O-])[O-]
Reactant: CC(C=O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C)c1ccc(I)cc1
Reaction time: 0.17 h
Yield: 762.3 %

Procedure:
To a solution of 39.2 g of 2-(4-iodophenyl)propionaldehyde in 39.2 ml of methanol was added 0.2 g of p-toluenesulfonic acid, and the mixture was stirred for 10 minutes. After addition of 19.2 g of methyl orthoformate, stirring was continued for 30 minutes. After completion of the reaction, 1.0 g of sodium methylate was added to the reaction mixture and the solvent was removed by distillation under reduced pressure. On distillation of the residue, there was obtained 43.2 g of 2-(4-iodophenyl)propionaldehyde dimethyl acetal, b.p. 155°-160° C./15 mmHg.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2O.P(Br)(Br)([Br:20])=O>C1(C)C=CC=CC=1.CC#N>[Br:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[C:3]([CH3:17])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1cc(O)c2ccc(C)c(F)c2n1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)c2ccc(C)c(F)c2n1
Temperature: 75 °C
Yield: 66.5 %

Procedure:
A mixture of (methyl 8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate (7-15, 842.1 mg, 3.58 mmol) and POBr3 (1129 mg, 3.94 mmol) in Toluene (8.14 mL) and CH3CN (0.81 mL) was heated at 75° C. for 1 h. After cooling to room temperature, the mixture was poured to a mixture of ice-H2O, followed by CH2Cl2 extraction (twice). The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient 0-50% EtOAc/Hexanes) to afford methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 710 mg). LRMS m/z (M+H)+ 298.1 found, 298.0 required.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2)[CH2:2][CH2:3][CH3:4].[Na].[F:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][Cl:32])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(O)(C)C>[ClH:32].[ClH:32].[CH2:1]([NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:20]2[CH:33]=[CH:34][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:24][CH2:25]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncnc2nc[nH]c12
Reactant: Fc1ccc(OCC2CCN(CCCCl)CC2)cc1
Agent: [Na]
Solvent: CC(C)O
Product: CCCCNc1ncnc2c1ncn2CCCN1CCC(COc2ccc(F)cc2)CC1
Product: Cl
Yield: 71.1 %

Procedure:
9.55 g (0.05 mole) of N6 -n-butyladenine are added to a solution of 1.15 g (0.05 mole) of sodium in 200 ml of isopropanol and the reaction mixture is heated under reflux for 10 minutes. After cooling, 22.8 g (0.08 mole) of 3-[4-(4-fluorophenoxymethyl)-piperidino]-propyl chloride in 50 ml of isopropanol are added thereto. After boiling under reflux for 6 hours, the reaction mixture is evaporated in a vacuum and the residue is taken up in methylene chloride, washed with 2N aqueous sodium hydroxide solution and subsequently with water, dried over anhydrous sodium sulfate, evaporated and the residue is taken up in acetone and mixed with excess saturated ethereal hydrogen chloride solution. The salt which precipitates out is filtered off and recrystallized from isopropanol. There are obtained 14.6 g (57% of theory) of N6 -n-butyl-9-{3-[4-(4-fluorophenoxymethyl)-piperidino]-propyl}-adenine dihydrochloride; m.p. 180° - 182° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:21]([CH3:30])[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>C(O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:21]([CH3:30])[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)c1ccccc1)N1CCC(Cc2ccccc2)CC1

Procedure:
17.5 g (0.1 mol) of 4-benzylpiperidine and then 12 g of sodium carbonate are added to a solution of 21.3 g (0.1 mol) of 2-bromopropiophenone in 100 ml of ethanol, and the mixture is heated under reflux for 2 hours. It is then filtered and the solvent is driven off. An oil remains, which is used as such in the subsequent reduction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:35](CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:24])[NH2:35])=[CH:19][CH:20]=2)=[CH:26][CH:27]=1)[C:28](=[O:32])[N:29]([CH3:30])[CH3:31])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
Acid compound 33 (0.7 g, 1.58 mmol) was dissolved in DCM (25 mL). Triethylamine (0.26 mL, 1.89 mmol) and BOP reagent (0.77 g, 1.74 mmol) were added and the reaction mixture stirred at room temp for 15 min under an atmosphere of argon. Ammonia gas was then bubbled gently through the solution for 15-20 min to complete the reaction. Excess ammonia was degassed, the solvent was removed under reduced pressure and the residue was suspended in EtOAc (75 mL). The organic layer was washed with 0.5 N NaOH (2×10 mL), water (2×25 mL), and brine (1×30 mL), dried and concentrated under reduced pressure to yield the amide compound 38 (0.7 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6): 7.33 (d, J=8.4 Hz, 2H), 7.30 (br, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.93 (overlapped d, J=8.8 Hz, 2H0, 6.92 (overlapped d, J=8.8 Hz, 2H), 6.78 (br, 1H), 5.50 (d, J=8.0 Hz, 1H), 2.90 (s, 3H), 2.84 (s, 3H), 2.79 (t, J=8.0 Hz, 2H), 2.35 (t, J=8.0 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(C)c1C(=O)O
Reaction time: 20 h

Procedure:
A mixture of ethyl 6-methyl-2-methoxybenzoate (642.0 g, 3.3 mol), water (2.5 l), ethanol (4.0 l) and sodium hydroxide (270 g, 6.6 mol) is heated under reflux with stirring for 20 hours. Subsequently, ethanol is distilled off and the reaction mixture is diluted with water, acidified with concentrated hydrochloric acid. The solid material is collected by vacuum filtration, washed with water and dried yielding off-white crystals, 460.0 g (83.9%).
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([C:25]([F:28])([F:27])[F:26])=[CH:12][C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=2)=O)[CH:7]=[C:8]([Cl:10])[CH:9]=1.C1(C)C=CC=CC=1.[OH2:36].S(O)(O)(=O)=O.[NH2:42]O>[OH-].[Na+]>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:25]([F:28])([F:27])[F:26])[O:36][N:42]=[C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Reactant: O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 0 °C

Procedure:
3.2 g of methyl alcohol was added to a solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 8.51 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was added to the mixture, and a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 1.11 g of water was slowly added in dropwise with care not to generate heat. After reacting the mixture for 3 hours with stirring while keeping the reaction temperature at 0° C., the resultant solution was analyzed by high-performance liquid chromatography (wavelength 254 nm). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 85.49% of relative area.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH:45]=O)=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:49])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:49])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:45][CH2:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O=CCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(CCCc2ccc(Cl)cc2)C[C@@H]1CCCB(O)O
Reaction time: 2.5 h
Yield: 45.7 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and 3-(4-chlorophenyl)propionaldehyde (118 mg, 0.7 mmol), stirred for 2.5 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(3-(4-chlorophenyl)propyl)pyrrolidine-3-carboxylic acid (84.3 mg, 38%) as a white powder. NMR (D2O) 7.25 (d, J=8 Hz, 2 H), 7.13 (d, J=8 Hz, 2 H), 3.75-4.10 (m, 2 H), 3.40-3.60 (m, 1 H), 3.10-3.30 (m, 3 H), 2.60 (t, J=7 Hz, 2 H), 2.40-2.55 (m, 1 H), 1.85-2.00 (m, 2 H), 1.50-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 369.1; MS (m−H2O+1): 351.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C1(C)C=CC=CC=1.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reaction time: 24 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 hours. The solution was then filtered through a Celite pad and concentrated to give 6.92 g of crude tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellow syrup.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[NH:13][CH:12]=[C:11](CCNC(=O)C)[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:21]=1.[OH-:22].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[N:13]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH3:10])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:21]=1
Reactant: COc1ccc2c(c1)CCc1c(CCNC(C)=O)c[nH]c1-2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1ccc(O)cc1CC2
Temperature: -15 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
N-[2-(4,5-Dihydro-7-methoxy-1H-benzo[g]indol-3-yl)ethyl]acetamide (48.8 g) was dissolved in 1000 ml of methylene chloride under argon, cooled to -15° C. and treated at this temperature while stirring with a solution of 50 ml of borontribromide in 300 ml of methylene chloride. The mixture was stirred at -15° C. for 1 hour, at 0° C. for 5 hours at room temperature overnight. The reaction mixture was treated at -10° C. with 1000 ml of 2N sodium hydroxide solution and stirred at room temperature for 1 hour. 500 ml of methylene chloride were added to this mixture and the resulting mixture was adjusted to pH=8 with 250 ml of 2N hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with 500 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 33.2 g of yellow-brown, amorphous material, was chromatographed on 500 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1) as the eluent. There were obtained 30.2 g (65%) of N-[2-[4,5-dihydro-7-hydroxy-1H-benzo[g]indol-1-yl)ethyl]acetamide which was processed without further purification. MS: (m/e)=270 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=O)[CH3:11].[C:18]([O-])(=[O:20])[CH3:19].[Na+].C(OC(=O)C)(=O)C>>[C:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[C:15](=[O:16])[O:17][C:10]([CH3:11])=[N:13]2)=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)[O-]
Reactant: CC(=O)NCC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C=C2N=C(C)OC2=O)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde, 13.9 g of N-acetylglycine, 15.6 g of sodium acetate, and 51.0 g of acetic anhydride were mixed, and the mixture was stirred at 120° C. for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, and 50 ml of ice-water was added thereto, followed by stirring for 1 hour. The precipitated crystals were collected by filtration and washed with 100 ml of water. The resulting crystals were vacuum dried to give 22.0 g of 4-(4-acetoxybenzylidene)-2-methyloxazol-5(4H)-one as yellow crystals.