Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:51]=[CH:50][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37](=[O:49])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)N2C=CC=N2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>O1CCCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:49])[NH:1][C@@H:2]([CH3:17])[C:3]([NH:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)=[O:4])=[O:28])=[CH:50][CH:51]=1)([O-:20])=[O:19]
Reactant: C[C@H](N)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Yield: 98.6 %

Procedure:
To a solution of tert-butyl 3-[(2S)-2-amino-2-methylacetylamino]-1-azetidinecarboxylate (557 mg) in anhydrous tetrahydrofuran (10 ml), a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (974 mg) in tetrahydrofuran (20 ml) was added. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(1), whereby 1.32 g of the title compound were obtained as an amorphous substance.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[NH2:23][C:17](=[N:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][NH:3][C:33](=[O:34])[CH2:32][NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[CH:6]=2)[N:12]=1)[NH:18][CH2:19][CH2:20][O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CN)c2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CNC(=O)OC(C)(C)C)c2)cs1
Reaction time: 7 h
Yield: 34.6 %

Procedure:
A suspension of 4-(3-aminomethylphenyl)-2-[[(amino)(2-methoxyethylamino)methylene]amino]thiazole dihydrochloride (3.9 g), N-(t-butoxycarbonyl)glycine (1.85 g), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (2.6 g) and triethylamine (2.3 g) in N,N-dimethylformamide (50 ml) was stirred for 7 hours with cooling on an ice bath. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of water (80 ml) and tetrahydrofuran (20 ml), and the mixture was alkalized with 30% aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate (200 ml) and the extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1) to afford 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-t-butoxycarbonylaminoacetylaminomethylphenyl)thiazole (1.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15](OC)=[CH:14][N:13]=[C:12]([O:18]C)[CH:11]=2)[CH:3]=1.[ClH:20].[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([Cl:20])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: Cl
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(OC)cn1
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1Cl

Procedure:
6.34 g (purity 93%, 21.12 mmol) of 4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 4.23 g (76% of theory)
Reaction SMILES: BrC1C=C([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[N:15]=[CH:14][C:13]([C:20]([NH2:22])=[O:21])=[C:12]3[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)C=CC=1.[Br:32][C:33]1[CH:38]=[CH:37][C:36](S)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[N:15]=[CH:14][C:13]([C:20]([NH2:22])=[O:21])=[C:12]3[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:35][CH:34]=1
Reactant: Sc1ccc(Br)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4cccc(Br)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4ccc(Br)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 59, using 4-bromothiophenol in place of 11-mercapto-1-undecanol. ES/MS calcd. for C24H21BrN3O2S+ 494.1. Found m/z=494.1 (M+H)+
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH:15][C:14]([C:26]2[CH:27]=[C:28]([C:32]([NH:35][S:36]([CH2:39][C:40]([F:43])([F:42])[F:41])(=[O:38])=[O:37])([CH3:34])[CH3:33])[CH:29]=[CH:30][CH:31]=2)=[N:13]1)[CH3:11].C(=O)([O-])O.[Na+]>ClCCl>[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][F:7])=[CH:22][CH:23]=2)=[CH:15][C:14]([C:26]2[CH:27]=[C:28]([C:32]([NH:35][S:36]([CH2:39][C:40]([F:41])([F:43])[F:42])(=[O:38])=[O:37])([CH3:34])[CH3:33])[CH:29]=[CH:30][CH:31]=2)=[N:13]1)[CH3:11]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(CO)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(CF)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (DAST, 0,021 mL, 0.16 mmol, 1.3 equiv) was added to a solution of N-[1-(3-{1-ethyl-5-[4-(hydroxymethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (62 mg, 0.13 mmol, 1 equiv) in dichloromethane (1.2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes, then saturated sodium hydrogencarbonate was added. The crude mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(fluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (22 mg, 35%). Calcd (M+1)+: 500.2. Found: 500.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[O:10]=[C:8]1[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCN)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with MeSO2Cl. LC-MS Method 2 tR=1.525 min, m/z=480.2; 1H NMR (CDCl3) 1.52 (d, 3H), 2.05-2.32 (m, 6H), 2.81 (s, 3H), 2.86 (m, 1H), 2.93-3.04 (m, 1H), 3.06-3.20 (m, 1H), 4.73 (s, 1H), 5.63 (q, 1H), 6.95 (d, 2H), 7.05-7.22 (m, 2H), 7.23-7.40 (m, 6H), 7.71 (d, 1H), 8.50 (d, 1H), 8.66 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:12])=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Yield: 103.6 %

Procedure:
4-Chloro-3-nitropyridin-2-amine (0.10 g, 0.58 mmol) was dissolved in dry acetonitrile (20 mL). To the stirred solution was then added N-chlorosuccinimide (0.094 g, 0.70 mmol), and the reaction mixture was heated at 80° C. for 1 h. Volatiles were removed in vacuo and the residue purified by silica column chromatography (elution with dichloromethane) to provide the title compound as a pale brown powder (0.125 g, 85%). 1H-NMR (500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.36 (s, 1H, 6-H).
Reaction SMILES: OO.[C:3]1([CH:9]2[O:11][C:10]2([C:17]#[N:18])[C:12]([O:14][CH2:15]C)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.[O-:21]P([O-])([O-])=O.[Na+].[Na+].[Na+]>CCOCC>[NH2:18][C:17]([C:10]1([C:12]([O:14][CH3:15])=[O:13])[CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:11]1)=[O:21]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCOC(=O)C1(C#N)OC1c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(C(N)=O)OC1c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
100 ml of 30% hydrogen peroxide was added over a 20-minute period to a stirred mixture of 67 g of 1-phenyl-2-cyano-2-(ethoxycarbonyl)-1,2-epoxyethane (Reference II), 400 ml of methanol, 20 g of tribasic sodium phosphate (hydrate) and 8 g of 18 crown 6 ether at 25° C. The temperature was allowed to rise to 50° C. during the addition. The mixture then was cooled to 45° C. and 150 ml of the hydrogen peroxide solution was added over a 10-minute period. The temperature rose to 48° C. It was held there for one hour, then was raised to 60° C. and held there for 2 hours. The volatile materials were evaporated under reduced pressure. The residue was recrystallized from chloroform to give 8, mp: 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[N:3]=1.Cl>C(O)C>[NH2:18][C:5]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)=[N:3][C:2]([Cl:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Cl)nc(-c2cccc([N+](=O)[O-])c2)c([N+](=O)[O-])c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Cl)nc(-c2cccc(N)c2)c(N)c1C(=O)OCC
Temperature: 60 °C
Yield: 91.3 %

Procedure:
In 8 ml of ethanol were suspended 0.37 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-(3-nitrophenyl)pyridine and 0.45 g of reduced iron, and the suspension was heated to 60° C. After 1.9 ml of conc. hydrochloric acid was added thereto, the mixture was heated for 30 minutes under reflux. After the reaction mixture was concentrated, the residue was extracted with ethyl acetate, followed by washing with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride and drying over magnesium sulfate. After the extract was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: chloroform/methanol 40:1) to give 0.29 g of the title compound as a yellowish orange viscous oily substance.
Reaction SMILES: [OH:1][C@@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2C[C@H](O)[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC=O)C1.C(C=[P:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(OC)=O>C1C=CC=CC=1>[C:46]1([P:33](=[O:1])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 64.8 g of (0.149) of 3α,12α-dihydroxy-24-cholanal, diformate and 55 g (10% excess) of carbomethoxymethylene triphenylphosphorane 12 in 250 ml of dry benzene was refluxed for 6 hr. The solvent was then removed under reduced pressure and the residue treated with 400 ml of a 3:1 solution of hexane-ether. The resulting precipitate was filtered to give 39 g of crude triphenylphosphine oxide. The filtrate was concentrated, dissolved in a minimum of benzene and washed through 600 g of silica gel with a 2% ethyl acetate-benzene solution. The solvent was removed and the residue crystallized from hexane to give 49 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)-trans-2-pentenoic acid methyl ester mp 112°-115°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=[O:9])N[C:5](=[O:6])[C:4]=1[O:10][CH3:11].[OH-:12].[Na+]>>[CH3:1][O:2][C:3]1=[C:4]([O:10][CH3:11])[C:5]([O:9][C:8]1=[O:12])=[O:6]
Reactant: COC1=C(OC)C(=O)NC1=O
Reactant: [OH-]
Agent: [Na+]
Product: COC1=C(OC)C(=O)OC1=O

Procedure:
555 g of dimethoxymaleimide in 2 l of 5% strength NaOH were stirred for 2 days at room temperature. Thereafter, the mixture was acidified and extracted thoroughly with methylene chloride. After the organic phase had been separated off and the solvent removed in a rotary evaporator, 486 g of a product of melting point 41°-43° C. remained.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:6])[CH:4]=[O:5].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)C(=O)NC=[CH:11]2.CI>O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:4](=[O:5])[N:3]([CH3:6])[CH:2]=[CH:11]2
Reactant: CN(C)C=O
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [Na]
Solvent: CI
Solvent: O
Product: Cn1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 60% sodium hydrogenate (18 mg) was added at 0° C. to 2 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. Then, 0.03 ml of methyl iodide was added at 0° C., stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by preparative thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 24 mg of the above compound as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:20]3[CH:21]=[N:22][O:23][C:19]=3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCc1cnoc1-c1ccccc1)Nc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 4-(1-imidazolyl)aniline (0.85 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (1.21 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.95 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.20 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(1-imidazolyl)phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (1.68 g, yield 86%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.CC(C)=O.[C:37]([O:40][CH2:41]Br)(=[O:39])[CH3:38].CCN(CC)CC.CC(O)=O>>[C:37]([O:40][CH2:41][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:32])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=1)=[O:18])(=[O:39])[CH3:38]
Reactant: CC(=O)OCBr
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCOC(C)=O)on1
Reaction time: 1.5 h
Yield: 26.7 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (40.0 mg, 0.1 mmol) in acetone (1.0 mL, 14 mmol) was added bromomethyl acetate (16.9 μL, 172 μmol) followed by Et3N (24.0 μL, 172 μmol), and resulting mixture was stirred for 90 minutes. The reaction was quenched with AcOH (19.6 μL, 345 μmol) and the mixture was concentrated. The residue was dissolved in AcOH (3 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and lyophilized. The solid was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (14.3 mg, purity 97.8%) as a TFA salt. MS m/z [M+H]+ calc'd for C24H23ClFN3O8, 536.12. found 536.2.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:10]=[C:11](SCC)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCCCCC>C(Cl)Cl>[NH:10]=[C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1c(N)cccc1F
Reactant: CCOC(=O)C(=N)SCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)C(=N)Nc1cccc(F)c1C
Reaction time: 12 h

Procedure:
To a solution of 3-fluoro-2-methylaniline (200 mmol, 25 g) in methylene chloride (70 ml) was added a solution of ethyl imino(ethylthio)acetate hydrogentetrafluorobarate (200 mmol) prepared by a method disclosed in Japanese Patent Laid-open Publication No. 56-39092 in methylene chloride (100 ml), and the mixture was thoroughly shaken and allowed to stand at room temperature for 12 hours. At the end of the period, n-hexane (300 ml) was added to the reaction mixture and the mixture was allowed to stand for 2 hours. After removal of a supernatant by decantation, methylene chloride (200 ml) was added to the remaining mixture, which was then neutralized by addition of an aqueous solution of sodium bicarbonate with thorough stirring. From the resulting mixture an organic phase (a solution in methylene chloride) was separated and dried over anhydrous magnesium sulfate overnight. After removal of inorganic materials by filtration, the filtrate was concentrated under reduced pressure to obtain ethyl imino[(3-fluoro-2-methylphenyl)amino]acetate. The product was dissolved in ethanol (80 ml), and to the resulting solution 37% formalin (30 ml) was added and the mixture was thoroughly shaken and allowed to stand overnight. The crystalline product so produced was filtered and recrystallized from ethanol. A white crystalline product (86 mmol, 18 g) was obtained in a yield of 43%.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
A mixture of di-tert-butyl 4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrazolidine-1,2-dicarboxylate 144 (0.43 g, 0.80 mmol) and Pd/C (0.14 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 145 (0.39 g, quant.) as a light brown foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][C@H:32]([CH3:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=2)=[CH:21][CH:22]=1)[C:13]([NH:31][C@@H:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:40])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccc(-c2ncc(Br)cn2)cc1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 89.3 %

Procedure:
Prepared using General Procedure 7: To a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoic acid (962 mg, 2.11 mmol) and (R)-tert-butyl 2-aminopropanoate hydrochloride (383 mg, 2.11 mmol) in DMF (20 mL) was added DIEA (1.2 mL, 6.32 mmol). The mixture was cooled to 0° C. and HATU (802 mg, 2.11 mmol) was added portionwise. The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 h the mixture was poured onto citric acid (100 mL of a 0.1 M aqueous solution) and iso-hexanes (20 mL) and the resulting precipitate collected by filtration, washing successively with water (2×10 mL), ACN (3 mL) and iso-hexanes (2×5 mL) to afford 1.1 g (89%) of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-42 as a white solid. LCMS-ESI (m/z) calculated for C28H31BrN4O5: 582.2. found 605.2 [M+Na]+, tR=7.94 min (Method 10).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]3([CH2:21][CH2:20][CH:19]([NH:22]C(=O)OCC4C=CC=CC=4)[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=1>[Pd].[OH-].[OH-].[Pd+2].CO>[NH2:22][CH:19]1[CH2:20][CH2:21][C:11]2([NH:10][C:9]3[CH:8]=[C:7]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])[S:15][C:14]=3[C:13](=[O:16])[NH:12]2)[CH2:17][CH2:18]1
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(NC(=O)OCc3ccccc3)CC1)N2
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(N)CC1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzyl [6′-(5-methyl-1H-pyrazol-4-yl)-4′-oxo-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-thieno[3,2-d]pyrimidin]-4-yl]carbamate (the isomer ratio was 1:1, 78 mg, 0.173 mmol), 10% Pd/C (20 mg, 50% wet) and MeOH (5 mL) was stirred for 1 h at room temperature under H2 atmosphere. Then, 20% palladium hydroxide on carbon (200 mg, 50% wet) was added. After 1 h, the mixture was filtered through a pad of celite, and the celite was washed with MeOH well. The filtrate was concentrated under reduced pressure, and the residue was triturated with MeOH/EtOAc. The precipitate was collected by filtration to afford the title compound (35.3 mg, 64%, a mixture of 1:1 cis/trans isomers) as a white solid: