Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCNCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
49 g 4-chlorobenzyl cyanide 1 (323 mmol, 1.00 equiv) and 58 g of bis[2-chloroethyl]amine (323 mmol, 1.00 equiv) were dissolved in 325 mL of anhydrous DMF in a 2 L round bottom flask fitted with a magnetic stir bar, reflux condenser, and N2 inlet. The mixture was cooled in an ice water bath, then 52 g of 60% NaH in mineral oil (1293 mmol, 4.00 equiv) was added to the stirring solution at a rate such that the exothermic reaction did not become violent. After the addition was complete, the apparatus was transferred to an oil bath and the mixture heated to 60° C. and stirred for 48 h under N2 atmosphere. The mixture was cooled to room temperature and the remaining hydride carefully quenched under N2 by dropwise addition of a small amount of H2O. The resultant slurry was poured into 2 L of rapidly stirring H2O and the pH adjusted to ˜1 with concentrated HCl. The mixture was transferred to a 4L separatory funnel and extracted with 3×500 mL of hexane. The organic extracts were discarded and the aqueous extracts was adjusted pH to ˜9 by the addition of solid K2CO3. The resultant precipitate was collected by vacuum filtration and washed with small portions of H2O, followed by hexane. The tan solid was dried under vacuum to yield 4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=221.7, found=221.1.
Reaction SMILES: Cl[C:2](OC)=[O:3].[NH2:6][CH2:7][C:8]1[C:14]([O:15][CH2:16][CH:17]([OH:31])[CH2:18][N:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(O)(C)C.O>[CH2:20]([N:19]([C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:18][CH:17]([OH:31])[CH2:16][O:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:9]2[C:8]=1[CH2:7][NH:6][C:2](=[O:3])[NH:10]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc(N)c1CN
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc2c1CNC(=O)N2

Procedure:
5.3 g of methyl chloroformate are added dropwise to a solution of 16.2 g of 2-aminomethyl-3-[2-hydroxy-3-(N-benzyl-tert.-butylamino)-propoxy]-aniline in a mixture of 150 ml of isopropanol and 150 ml of water, at 15°-20°, whilst stirring and cooling with ice. The reaction mixture is stirred at room temperature for a further 2 hours and then evaporated. The residue is dissolved in 100 ml of water, the solution is extracted with 50 ml of ether and the aqueous phase is rendered alkaline with concentrated ammonia and extracted 3 times with, in each case, 200 ml of ethyl acetate. The residue which remains after evaporating the organic phase is dissolved in 50 ml of methanol and boiled with 4.86 g of sodium methylate under reflux for 3 hours. The crystalline precipitate which gradually forms is filtered off after cooling the reaction mixture in an ice bath, whereupon 5-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-3,4-dihydro-1H-quinazolin-2-one with a melting point of 215°-217° is obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].[C:8]([O:14][CH3:15])(=[O:13])[C:9](OC)=[O:10].S(=O)(=O)(O)O>C(OCC)C>[CH3:15][O:14][C:8](=[O:13])[C:9]([OH:10])([C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(=O)OC
Reactant: Brc1cccs1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C(O)(c1cccs1)c1cccs1
Temperature: 35 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
2-Bromothiophene (9.68 mL, 0.1 mol) was slowly added to a stirred mixture of magnesium turnings (2.7 g, 0.11 mol) in diethyl ether (100 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 35° C. for 3 h and then dimethyl oxalate (5.9 g, 0.05 mol) in diethyl ether (150 mL) was added dropwise. The reaction mixture was heated at reflux (45° C.) for 45 min and then the mixture was allowed to cool to ambient temperature and 1.25 M sulfuric acid (150 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h and then the organic layer was separated and washed with dilute aqueous sodium bicarbonate solution (100 mL), water (100 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid residue was recrystallized from tetrachloromethane (˜1 g/3 mL) to yield the title compound (7.68 g, 30 mmol, 60%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=O)[CH2:3][CH2:2]1.[CH3:17][NH:18][NH2:19]>CN(C)C=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:18]([CH3:17])[N:19]=2)[CH2:3][CH2:2]1
Reactant: CNN
Reactant: O=C(C#CC1CC1)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C2CC2)cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Cyclopropyl-1-(4-nitrophenyl)prop-2-yn-1-one (500 mg, 2.323 mmol) was dissolved in N,N-dimethylformamide (7.75 mL), and the solution was chilled to 0° C. Methylhydrazine (118 mg, 2.56 mmol) was added dropwise. The mixture was stirred overnight at room temperature then diluted with water (25 mL) and stirred for 45 minutes. The resulting precipitate was collected by filtration to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:37])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([Cl:37])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of step A (0.33 mmol) in dichloromethane (3 mL) was added a drop of N,N-dimethylformamide followed by oxalyl chloride (0.532 mmol). After stirring for 0.5 hour at room temperature, the solution was heated to reflux for three hours. The solvent and excess oxalyl chloride were evaporated to yield the crude product, which was used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[C:23]2=[O:30])=[CH:18][C:17]=1[F:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([F:31])[CH:18]=2)[C:23]1=[O:30])=[O:28]
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
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: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(Cl)c(F)c2)C1=O
Yield: 41.8 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(4-chloro-3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.115 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (42%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chloro-3-fluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1
Reactant: C1CSCCN1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccccc1)N1CCSCC1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 120 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 6.7 g (66.0 mmol) of thiomorpholine. The reaction mixture was refluxed for four hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using a methanol/chloroform gradient as eluent. A second purification was performed using chloroform as eluent and was concentrated to dryness to yield 5.36 g (97%) of the desired mixture of isomers as a yellow oil. MS (ion spray) 252.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([CH:21]=[C:22](Br)Br)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:30]#[N:31].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([CH2:21][C:22]2[NH:35][C:34]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=3[N:26]=2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(Cl)c32)cc1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(Cl)c32)cc1
Reaction time: 8 h

Procedure:
A solution of 7-chloro-4-(2,2-dibromovinyl)-5-methyl-1-tosyl-1H-indole (67 mg, 0.133 mmol), 3,4-diaminobenzonitrile (26.6 mg, 0.200 mmol) and DABCO (44.8 mg, 0.399 mmol) in NMP (0.5 mL) was stirred at 110° C. After stirring overnight, the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-100% EtOAc in heptanes) to provide 2-((7-chloro-5-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile. The obtained compound was dissolved in EtOH (5.0 mL), and KOH (0.118 g, 2.105 mmol) and isoamylamine (0.489 mL, 4.21 mmol) were added, and the mixture was stirred at 100° C. in the microwave for 30 minutes. The reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (s, 1H) 11.33 (br. s., 1H) 7.93 (s, 1H) 7.57 (d, J=8.84 Hz, 1H) 7.47 (dd, J=8.34, 1.52 Hz, 1H) 7.33 (t, J=2.78 Hz, 1H) 7.06 (s, 1H) 6.52-6.63 (m, 1H) 4.45 (s, 2H) 2.39 (s, 3H). HRMS calcd. for C18H13ClN4 (M+H)+ 321.0902. found 321.0906.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14]1.[I:20]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([I:20])[C:15]([CH3:19])=[N:14]1
Reactant: Cc1cc(C)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C)c1I

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3,5-dimethylpyrazole (0.218 g) in acetonitrile (3 ml) at room temperature was added dropwise a solution of N-iodosuccinimide (0.158 g) in acetonitrile (2 ml). After 27 hours the mixture was evaporated to dryness and the residue purified by column chromatography on silica gel (5 g) eluted with dichloromethane. Combination and evaporation of suitable fractions provided the title compound as yellow oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:34][OH:35])[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1.O>CN(C=O)C>[CH3:14][S:11]([C:7]1[CH:6]=[C:5]([C@@H:4]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:3][CH:2]2[CH2:34][O:35][C:41](=[O:42])[O:1]2)[CH:10]=[CH:9][N:8]=1)(=[O:12])=[O:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1cc([C@H](C[C@H](O)CO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc([C@H](CC2COC(=O)O2)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a chilled (0° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(1S,3S)-3,4-dihydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-butyl]-amide (50.0 mg, 0.100 mmol) in DMF (1 mL) was added CDI (32.4 mg, 0.200 mmol). The mixture was then allowed to warm to room temperature. After 12 hours, the reaction was poured in to water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with aqueous ammonium chloride (3×10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-6% methanol in methylene chloride. The solid from the column chromatography was crystallized from methylene chloride to afford the title compound as white needle-shaped crystals. MS m/z 526.64 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[Li].[CH3:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:11]1[S:10][C:9]([CH3:8])=[CH:13][CH:12]=1
Reactant: Cc1cccs1
Reactant: BrCCCCBr
Agent: [Li]
Solvent: O
Product: Cc1ccc(CCCCBr)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
This procedure was used to synthesize the disubstituted synthetic intermediate 2-(n-bromoalkyl)-5-R-thiophene (2, wherein R is not H). The synthesis of 2h was accomplished by first synthesizing the 2-methylthienyllithium intermediate. A solution of n-butyllithium (2.5 M in hexane) (Aldrich Chemical Co.) (4.4 mL, 0.011 moles) was added dropwise to 2-methylthiophene (0.98 gm, 0.01 moles) (Lancaster Synthesis, Windham, N.H.) in THF (50 mL) at 0° C. to yield the lithium salt of 2-methylthiophene. The solution was stirred at room temperature for one hour. 1,4-Dibromobutane (3.24 gm, 0.015 moles) was added in one lot to the lithium salt of 2-methylthiophene at 0° C. The solution was allowed to warm to room temperature and stirred for 12 hours. Water (20 mL) was added and the layers were separated. The organic layer was diluted with ethyl acetate (50 mL) and washed with water (3×10 mL), dried over MgSO4 (anhydrous), filtered and evaporated under reduced pressure. Purification by column chromatography (silica gel, hexanes) gave 2 gm of 2-(4-bromobutyl)-5-methylthiophene (2h) (85.8%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:11]=2)[NH:6][C:5]=1C(O)=O.C(=O)=O.C(O)(=O)CCC(O)=O.[N:33]1[C:42]2C(=CC=CC=2)C=C[CH:34]=1>>[CH3:34][N:33]([CH2:2][CH2:3][C:4]1[C:12]2[CH:11]=[C:10]([CH2:13][N:14]3[N:15]=[CH:16][N:17]=[CH:18]3)[CH:9]=[CH:8][C:7]=2[NH:6][CH:5]=1)[CH3:42]
Reactant: c1ccc2ncccc2c1
Reactant: O=C(O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Agent: O=C(O)CCC(=O)O
Agent: O=C=O
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Temperature: 25 °C
Yield: 86 %

Procedure:
700 mg (2,2 mmoles) of 3-(2-hydroxyethyl)-5-[1,2,4-triazol-1-ylmethyl]-1H-indol-2-carboxylic acid was suspended in 7 ml of dry quinoline. 14 mg of cuprous oxide was added and the stirred suspension heated, under dry nitrogen stream, to 200° C. The reaction mixture was kept at this temperature until no more CO2 was released (15-20 min.). It was left to cool to room temperature and the reaction mixture was filtered through decalite. The filtrate was concentrated by vacuum distillation of the solvent, providing a residue which was dissolved with a succinic acid solution and washed three times with 10 ml of dichloromethane. The washed aqueous phase was cooled and adjusted to pH 12 with a 40% sodium hydroxide solution and extracted three times with 20 ml of dichloromethane. The combined organic phases were dried on anhydrous sodium sulphate and evaporated to dryness. The residue was recrystallised from heptane/isopropyl acetate to give 510 mg (86%) of rizatriptan as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:13]=O)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[OH:15][C@@H:16]([C@H:44]([OH:59])[C@H:45]([OH:58])[C@@H:46]([NH:49][C:50](=[O:57])[C@H:51]([CH2:53][CH:54]([CH3:56])[CH3:55])[NH2:52])[CH2:47][OH:48])[C:17]([NH:19][C@H:20]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:21][C:22]([O:24]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23])=[O:18].C([BH3-])#N.[Na+]>CO>[NH2:8][C@@H:9]([CH:10]([CH3:12])[CH3:11])[CH2:13][NH:52][C@H:51]([C:50]([NH:49][C@@H:46]([CH2:47][OH:48])[C@@H:45]([OH:58])[C@@H:44]([OH:59])[C@H:16]([OH:15])[C:17]([NH:19][C@H:20]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[O:57])[CH2:53][CH:54]([CH3:56])[CH3:55]
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC[C@@H](N)C(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of N-tert-butoxycarbonyl-L-valinal (240 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionate (278 mg) in methanol (10 ml) was added sodium cyanoborohydride (63 mg) at 0° C. and the mixture was stirred at 0° C. for 2 hours and at room temperature for 18 hours. After concentration under reduced pressure, the residue was subjected to flush silica gel column chromatography, followed by elution with ethyl acetate-methanol(20:1). The effective fractions were combined and concentrated under reduced pressure. To the residue was added 4N hydrogen chloride solution in ethyl acetate (10 ml) and the whole was stirred at room temperature for 1 hour. Removal of the organic solvent gave a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-diethylether to afford the title compound (25 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH3:9])[CH2:4][N:3]1[CH2:10][C:11]1[N:15]([CH2:16][C:17]([OH:19])=O)[CH:14]=[N:13][CH:12]=1.C(N(CC)CC)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:27]([NH:34][C:17](=[O:19])[CH2:16][N:15]1[C:11]([CH2:10][N:3]2[CH2:4][CH:5]([CH2:7][CH2:8][CH3:9])[CH2:6][C:2]2=[O:1])=[CH:12][N:13]=[CH:14]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC1CC(=O)N(Cc2cncn2CC(=O)O)C1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(Cc2cncn2CC(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
In a 10 ml, three necked flask fitted with a magnetic stirrer, under inert atmosphere, {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic acid x50 (0.1 g, 0.33 mmol) is dissolved in DMF (1 ml). Triethylamine (0.1 ml, 0.66 mmol), benzylamine (37 μl, 0.33 mmol) and TBTU (0.16 g, 0.33 mmol) are added and the mixture is stirred for 0.5 h at room temperature. An additional amount of benzylamine (0.0165 mmol) is added and stirring is continued overnight. The solvent is evaporated and the residue is purified by chromatography on silicagel (AcOEt/MeOH/NH4OH: 90/9/1 (v/v/v)). The product is treated with a methanolic solution of HCl and the obtained solid is recrystallized from acetonitrile to afford N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide 124.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:21])=CC=1.C(#N)C.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O>[CH3:19][C:16]1([CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:21])[NH:8][C:17]1=[O:18]
Reactant: COc1ccc(CN2C(=O)c3ccccc3C(C)(C)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1(C)C(=O)NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 297 %

Procedure:
The compound (6.0 g) obtained in step (b) just above was dissolved in a mixed solvent (acetonitrile:water=4:1) (40 ml). Diammonium cerium nitrate (26.6 g) was added to the solution. The mixture was stirred at room temperature for 3 hr. The reaction solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give 4,4-dimethyl-4H-isoquinoline-1,3-dione (10.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[NH2:45][CH2:46][C:47]([NH2:49])=[O:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a cooled (0° C.) solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.25 g, 0.61 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.96 mL stock solution prepared 0.1 mL in 0.9 mL DCM, 0.74 mmol) and 4-methylmorpholine (0.88 mL stock solution prepared 0.1 mL in 0.9 mL DMA, 0.80 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added NMM (0.1 mL, 0.92 mmol), glycineamide HCl (0.10 g, 0.92 mmol), and DMAP (0.01 g, 0.06 mmol) and stirred at ambient temperature for 1.5 h. Removed DMA under reduced pressure. Purified crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=463) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.01 (m, 2H), 5.60 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 463.0990 (M+H calculated for C21H18ClF2N4O4 requires 463.0979).