Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 866.7 %

Procedure:
To a solution of 0.160 g (0.047 mmol) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid, tert-butyl ester in 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid and the reaction was stirred at room temperature for 19 h. Concentration of the mixture in vacuo provides 0.115 g (86%) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid as a brown glass. Electrospray Mass Spec 281.1 (M−H)−
Reaction SMILES: C[O-].[Na+].[OH:4][N:5]1[C:9](=[O:10])[CH:8]2[CH2:11][CH2:12][CH:13]=[CH:14][CH:7]2[C:6]1=[O:15].[CH2:16](Cl)[CH3:17].O>CO>[CH2:16]([O:4][N:5]1[C:6](=[O:15])[CH:7]2[CH2:14][CH2:13][CH:12]=[CH:11][CH:8]2[C:9]1=[O:10])[CH3:17]
Reactant: CCCl
Reactant: O=C1C2C=CCCC2C(=O)N1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCON1C(=O)C2C=CCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
In an autoclave a solution of 3.5 g of sodium methoxide (0.065 mol) in 40 ml of methanol, 11.0 g of N-hydroxytetra-hydrophthalimide (0.066 mol) and 4.6 g (0.072 mol) of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was held at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction mixture comprised a large quantity of solid material. This was dissolved by the addition of water and the whole was afterwards extracted with toluene to obtain the product. Gas chromatographic analysis of the toluene extract showed that the yield was 74% of N-ethoxytetra-hydrophthalimide (0.049 mol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]O)=[C:6]([Cl:8])[N:7]=1.S(Cl)([Cl:15])=O>>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][Cl:15])=[C:6]([Cl:8])[N:7]=1
Reactant: N#Cc1nc(CO)c(Cl)nc1N
Reactant: O=S(Cl)Cl
Product: N#Cc1nc(CCl)c(Cl)nc1N

Procedure:
The method of synthesizing 7-NR1R2 -MTX wherein either R1 or R2 is hydrogen, and the other is C1 -C5 alkyl, is also outlined in FIGS. 1A and 1B. This method comprises (a) reacting phosphorus oxychloride with 3-amino-6-(chloromethyl)-2-pyrazinecarbonitrile 4-oxide (1) to yield 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile (2); (b) reacting 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile with thionyl chloride to form 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile (4); (c) reacting 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile with ethyl 4-methylaminobenzoate (3) to form ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate (5); (d) reacting ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate with guanidine to form 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate (6); (e) reacting 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate with methylamine to form 4-[N-(2,4-diamino-7-methylamino-y-pteridinylmethyl)-N-methylamino]benzoic acid (7b); and (f) coupling 4-[N-(2,4-diamino-7-methylamino-y-pteridinylmethyl)-N-methylamino]benzoic acid and diethyl L-glutamate to form the diethyl ester of 7-methylamino-MTX.
Reaction SMILES: [SH2:1].[Br-].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8](=[N+]2CCCCC2)[S:9][CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.C(=O)=O>C(O)C>[C:11]([CH2:10][S:9][C:8](=[S:1])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][CH:6]=1)#[N:12]
Reactant: N#CCSC(c1ccc(Cl)cc1)=[N+]1CCCCC1
Reactant: S
Agent: O=C=O
Agent: [Br-]
Solvent: CCO
Product: N#CCSC(=S)c1ccc(Cl)cc1
Temperature: -20 °C

Procedure:
Hydrogen sulfide gas is added to a stirred suspension of 1-[p-chloro-α-(cyanomethylthio)benzylidene]piperidinium bromide (13.7 g; 0.037 mol) in ethanol (50 ml), using a dry ice condenser to contain the gas. The reaction mixture slowly becomes a clear, red solution and the temperature rises to 25° C. The reaction mixture is chilled to -20° C., and an excess of hydrogen sulfide is maintained in the reaction mixture for 3 hours, as evidenced by the condensation of same throughout this period in the dry ice, chilled condenser. The reaction mixture is then allowed to warm up to room temperature, and the excess hydrogen sulfide allowed to evaporate overnight. The reaction mixture is then concentrated in vacuo to yield 8.9 g of a red oil. The red oil is chromatographed on silica gel (300 g) and eluted with a 1:1 mixture of methylene chloride:hexane. Collection of the main fraction affords 4.25 g (50%) of title product, a red oil.
Reaction SMILES: [H-].[Na+].[C:3]1(=[N:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]Cl)([CH3:19])[CH3:18].C(O)(=O)/C=C/C([O-])=O>>[CH:17]([N:20]([CH2:21][CH2:22][O:16][N:15]=[C:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH:24]([CH3:26])[CH3:25])([CH3:19])[CH3:18]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: ON=C1CCCCCCCCCCC1
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)N(CCON=C1CCCCCCCCCCC1)C(C)C

Procedure:
Starting from 2.4 g. (0.1 moles) of sodium hydride, 19.73 g. (0.1 moles) of cyclododecanone oxime and 17.95 g. (0.11 moles) of 1-diisopropylamino-2-chloroethane the title compound is prepared as in Example 1. Yield: 22.1 g. (68.20%); b.p.: 164°-166° C./0.6 torr. Hydrogen fumarate, m.p.: 120°-121° C.
Reaction SMILES: [OH2:1].[OH2:2].C[N+]([O-])(C)C.[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]2([CH2:20][CH:19]=[CH:18][CH2:17]2)[C:9]1=O>ClCCl.[Os](=O)(=O)(=O)=O>[OH:1][CH:18]1[CH:19]([OH:2])[CH2:20][C:10]2([C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]=[CH:9]2)[CH2:17]1
Reactant: O
Reactant: O=C1Nc2ncccc2C12CC=CC2
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: OC1CC2(C=Nc3ncccc32)CC1O
Yield: 92.4 %

Procedure:
To a mixture of trimethylamine-N-oxide dihydrate (408 mg, 3.67 mmol) and spiro[cyclopent-3-ene-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (622 mg, 3.34 mmol) in dichloromethane (115 mL) was added osmium tetroxide (25 uL of 2.5% solution in 2-methyl-2-propanol). After 24 h the reaction mixture was concentrated. The crude product was loaded onto a silica gel chromatography column with a minimal amount of methanol and eluted with a gradient of 5 to 20% methanol:dichloromethane to give the title compound (0.63 g). MS: m/z=221.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-:15].[K+].Cl.[CH3:18][CH2:19][OH:20]>>[CH3:1][C:2]1[N:7]=[C:18]([C:19]([OH:15])=[O:20])[C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1ccc(N2CCCC2)c(C#N)n1
Agent: Cl
Agent: [K+]
Product: Cc1ccc(N2CCCC2)c(C(=O)O)n1
Temperature: 90 °C

Procedure:
To the title compound of Step A (162 mg, 0.9 mmol) in EtOH (2.6 mL) was added 4M KOH (650 μL, 2.6 mmol). The reaction was then heated at 90° C. for 18 h. Additional 4M KOH (1.5 mL, 6 mmol) was added and heating continued overnight. The reaction was then cooled to rt, acidified with 1N HCl (aq), concentrated and used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[CH2:19][CH:18]([CH2:20][O:21]C(=O)C)[O:17][C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28].C[O-].[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[CH2:19][CH:18]([CH2:20][OH:21])[O:17][C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28]
Reactant: CC(=O)OCC1Cn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C1OC(CO)Cn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione (46 mg, 0.10 mmol) and 30% sodium methoxide in methanol (39 mg) in dioxane (1.5 mL) was stirred at room temperature for 2 hours. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)Cl
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)NCc1cccc(Br)c1
Yield: 87 %

Procedure:
10.00 g of 3-bromobenzylamine hydrochloride suspended in chloroform (100 ml) was mixed with 9.55 g of triethylamine at room temperature. The resulting solution was stirred under cooling with ice while 4.67 g of methyl chloroformate was added dropwise and then stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into saturated aqueous sodium chloride, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated at ordinary pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 9.54 g of methyl N-(3-bromobenzyl)carbamate as white crystals. m.p. 41-44° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[NH2:9][CH:10]1[CH2:22][C:21]2[C:13](=[CH:14][C:15]3[CH2:19][CH2:18][O:17][C:16]=3[CH:20]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>C1C=CC=CC=1.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:9][CH:10]1[CH2:22][C:21]2[C:13](=[CH:14][C:15]3[CH2:19][CH2:18][O:17][C:16]=3[CH:20]=2)[CH2:12][CH2:11]1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCCCl)NC1CCc2cc3c(cc2C1)OCC3
Reaction time: 1 h

Procedure:
4.2 g of 4-chlorobutyryl chloride are added at room temperature to a mixture of 5 g of the compound of Example 2 and 4.2 g of triethylamine in 60 ml of benzene. After 1 hour at room temperature, the medium is diluted with water and filtered and the aqueous phase is extracted with benzene. The filtrate and the precipitate are combined and the benzene is evaporated off under vacuum. The dry residue is solidified in ether.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:39]1[CH:43]=[C:42]([CH2:44][OH:45])[NH:41][N:40]=1)CCC>O1CCOCC1.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>[OH:45][CH2:44][C:42]1[NH:41][N:40]=[C:39]([C:2]2[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]5[N:24]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[N:23]=[N:22][N:21]=5)[CH2:16][CH2:15]4)=[O:13])=[CH:9][NH:8][C:7]=23)[CH:43]=1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(CO)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1cnc(-c2cc(CO)[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 120 °C
Yield: 21.8 %

Procedure:
In a sealable, flask a mixture of 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.150 g, 0.321 mmol) in 1,4-dioxane (5 mL) was prepared. (3-(tributylstannyl)-1H-pyrazol-5-yl)methanol (0.137 g, 0.353 mmol) was added followed by tetrakis(triphenylphosphine)palladium (0) (0.150 g, 0.130 mmol). The mixture was flushed with N2, and flask was sealed. The mixture was then heated to 120° C. for 14 h. After cooling to rt, the mixture was diluted with DMF, and filtered through a plug of celite to remove any solids. The liquid was concentrated under reduced pressure, and the residue was dissolved in DMF. The DMF solution was purified by prep HPLC to give 0.037 g of an off-white solid as the 1-(7-(5-(hydroxymethyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione. LCMS: m/e 529.2 (M+H)+, ret time 1.78 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.65 (s, 1 H) 7.98 (s, 1 H) 7.56-7.80 (m, 5 H) 7.16 (s, 1 H) 4.81 (s, 2 H) 4.15 (s, 3 H) 3.83-3.87 (m, 2 H) 3.63-3.68 (m, 2 H) 3.40-3.44 (m, 2 H) 3.34-3.39 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[C:4]([Br:9])[C:3]=1[Br:10].[N:11]1[C:18](Cl)=[N:17][C:15](Cl)=[N:14][C:12]=1Cl.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Br:28])[C:22]=1[Br:29]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[N:14]=[C:15]([O:27][C:24]3[CH:25]=[CH:26][C:21]([Br:20])=[C:22]([Br:29])[C:23]=3[Br:28])[N:17]=[C:18]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Br:10])[C:4]=3[Br:9])[N:11]=2)=[C:4]([Br:9])[C:3]=1[Br:10]
Reactant: [O-]c1ccc(Br)c(Br)c1Br
Reactant: Oc1ccc(Br)c(Br)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Brc1ccc(Oc2nc(Oc3ccc(Br)c(Br)c3Br)nc(Oc3ccc(Br)c(Br)c3Br)n2)c(Br)c1Br

Procedure:
An exemplary production process according to this invention comprises preparing an aqueous tribromophenolate solution and dripping this aqueous solution to a dispersion or solution of cyanuric chloride and tertiary amine in a non-hydrophilic solvent or adding said tertiary amine and a powder of cyanuric chloride to said aqueous solution. The preferred molar ratio of cyanuric chloride to tribromophenol is 1:2.94-3.60. Where both a tertiary amine and a phase transfer catalyst are employed, an exemplary procedure comprises preparing an aqueous tribromophenolate solution, adding a tertiary amine thereto and dripping the mixture to a solution or dispersion of cyanuric chloride and phase transfer catalyst in a non-hydrophilic solvent or adding said phase transfer catalyst, said tertiary amine and a powder of cyanuric chloride to the aqueous tribromophenolate solution. After the above dripping or addition, the reaction system is aged where necessary and the non-hydrophilic solvent is removed from the reaction system at atmospheric or subatmospheric pressure. In this manner, tris(tribromophenoxy)-s-triazine of high purity can be obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36].O>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cc(F)cc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (24 g, 0.062 mol) in dry CH2Cl2 (300 mL) and Et3N (31.4 g, 43 mL) was cooled to 0° C. in ice-water bath, a solution of methyl chloroformate (11.8 g, 0.124 mol) in dry CH2Cl2 (100 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Water (200 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×100 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to give (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (19 g, 0.043 mol). 1H NMR (CD3OD) δ 7.17 (s, 1H), 7.16-7.08 (m, 1H), 7.07-7.00 (m, 1H), 4.20-4.00 (m, 2H), 3.90-3.78 (d, 1H), 3.61 (s, 3H), 3.28-3.20 (m, 2H), 2.92-2.68 (dd, 2H), 1.52-1.74 (m, 2H), 1.42 (s, 9H), 1.35-1.10 (m, 3H),
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([O:11]C(=O)C)[CH:9]([O:15]C(=O)C)[CH:8]([O:19]C(=O)C)[CH:7]([O:23][C:24](=[O:49])[NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([S:37]([C:40]3[N:47]4[C:43]([S:44][CH:45]=[CH:46]4)=[N:42][C:41]=3[Cl:48])(=[O:39])=[O:38])[CH:29]=2)[O:6]1)=[O:4].CO.O[Li].O>C1COCC1.O>[Cl:48][C:41]1[N:42]=[C:43]2[N:47]([C:40]=1[S:37]([N:30]1[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([CH2:27][CH2:26][NH:25][C:24]([O:23][C@@H:7]3[O:6][C@H:5]([C:3]([OH:4])=[O:2])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@H:8]3[OH:19])=[O:49])=[CH:29]1)(=[O:38])=[O:39])[CH:46]=[CH:45][S:44]2
Reactant: COC(=O)C1OC(OC(=O)NCCc2cn(S(=O)(=O)c3c(Cl)nc4sccn34)c3ccccc23)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12)O[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of 3,4,5-triacetoxy-6-(2-{1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indol-3-yl}ethycarbamoyloxy)tetrahydropyran-2-carboxylic acid methyl ester (1.0 g, 1.35 mmol) in THF is treated with CH3OH (38.8 mL) and H2O (10 mL), cooled to 0° C. (ice-water bath), treated with a solution of LiOH.H2O (340 mg, 8.1 mmol, 6 eq) in H2O (5.5 mL) [0.1 N LiOH/MeOH/THF/H2O] and stirred at 0° C. for 2 h under N2 atmosphere. Progress of the deprotection is monitored via reversed-phase TLC (SiO2—C18 MeCN/H2O, 3/7). The reaction mixture is diluted with 150 mL of H2O, neutralized by the addition of 10 g of amberlite-120 (plus) cation exchange material (H+ form) and filtered. The filtrate is concentrated under reduced pressure to an aqueous suspension. This suspension is freeze dried and lyophilized to give the title product, 700 mg (86% yield). Further purification by silica gel column chromatography [CHCl3/CH3OH/H2O (7:3:0.5) as a eluent] provides the title product, 310 mg, 98% pure, identified by mass spectral and NMR analyses. 1H NMR (300 MHz, DMSO-d6): 8.31 (d, 1H, J=4.5 Hz), 7.94-7.91 (m, 1H), 7.82 (s, 1H), 7.69 (d, 1H, J=4.2 Hz), 7.64-7.57 (m, 2H), 7.39-7.27 (m, 2H), 5.31 (d, 1H, J=8.1 Hz), 3.69 (d, 1H, J=9.0 Hz), 3.37-3.13 (m, 5H), 2.82 (t, 2H, J=7.0 Hz); 13C (75 MHz, DMSO-d6): 170.6, 155.4, 155.3, 152.3, 139.2, 134.9, 131.6, 125.7, 124.5, 124.4, 121.1, 121.1, 120.7, 118.8, 116.6, 113.8, 95.5, 76.6, 76.5, 72.8, 72.0, 25.2; LC/MS (ESI) retention time=35.12, [M+H]+=600.7.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[N:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Sc1ccncc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: O=c1[nH]nc(Sc2ccncc2)c2ccccc12

Procedure:
4-chlorophthalazin-1(2H)-one and pyridine-4-thiol were processed using a method similar to that described in Example 57A to afford the title compound. MS (APCI) M/Z 256 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.[CH3:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[CH:33]=O>>[CH3:25][C:22]1([CH3:26])[CH2:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH:1][CH2:27][C:28]5[NH:29][CH:30]=[N:31][C:32]=5[CH3:33])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:24]=2[O:23]1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1nc[nH]c1C=O
Product: Cc1nc[nH]c1CNc1cccc2nc(Nc3cccc4c3OC(C)(C)C4)ccc12

Procedure:
The title compound, MS: m/e=400.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and 4-methyl-1H-imidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: [C:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br-].[Mg+2].[Br-].Cl>C1COCC1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH:5]=[C:4]([CH3:7])[CH3:6])[C:14]([OH:16])=[O:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C)=CC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-Boc-pyroglutamic acid (0.23 g 1.0 mmol) in 10.0 ml of anhydrous THF was added 2-methylprop-1-enyl)magnesium bromide (0.5 M in THF, 5 mL, 2.5 mmol) at −78° C. slowly. The reaction mixture was stirred for 1 h at −78° C. 1 N HCl (2.5 ml) aqueous solution was added and the mixture was slowly warmed up to RT. The pH was adjusted to ˜3 by 1 N HCl. The THF was then removed under vacuum and the remaining aqueous was extracted by DCM (3×20 mL). The organic layer was dried over Na2SO4, filterd and the solvent was removed to provide the crude product.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15](OCC)=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:29][C:30]([F:47])([F:46])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38](Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:21][C:11]1[NH:12][C:13]2[CH:20]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30]([F:47])([F:46])[F:29])[C:15](=[O:16])[C:14]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: FC(F)(F)c1ccccc1N=C(Cl)c1ccccc1
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccc3C(F)(F)F)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(2-trifluoromethylphenyl)-benzimidoyl chloride (4.7 g, 15.5%).