Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([S:14](=[O:18])(=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[CH2:20](N)[CH2:21][NH2:22].C[O-].[Na+]>CO>[NH:2]1[CH2:20][CH2:21][N:22]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([S:14](=[O:17])(=[O:18])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: NCCN
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccccc2S(=O)(=O)c2cc(C3=NCCN3)ccc21

Procedure:
To 13.5 g (0.05 mol) of 3-cyanothioxanthen-9-one 10,10-dioxide was added ethylenediamine, 6.0 g (0.1 mol), and sodium methoxide, 0.5 g (0.01 mol), in 100 ml methanol and the mixture was heated at reflux for 3 days. The reaction mixture was filtered hot and the solid was washed with two 50 ml portions of methanol. The crude product was recrystallized from ethanol to yield 3-(2-imidazolin-2-yl)thioxanthen-9-one 10,10-dioxide, 11.0 g, as bright orange crystals, m.p. 241°-242° C.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[N:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.CCOC(C)=O>[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH:72][C:17]([C:6]3[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=3)=[O:19])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[N:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)n2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (296 mg, 0.970 mmol) (as prepared in Example 3, step (d)) in 8 mL DCM was added DIEA (291 μL, 1.72 mmol) and PyBroP (512 mg, 1.10 mmol), and the reaction was stirred at 25° C. for 15 min. A solution of 5-amino-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (233 mg, 0.65 mmol) (as prepared in the previous step) in 4 mL DCM was added and the reaction stirred overnight at 25° C. The reaction was diluted with EtOAc (25 mL) and washed with NaHCO3 (1×25 mL) and brine (25 mL) and the organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chomatography (silica gel, 5% MeOH—CHCl3) to afford 167 mg (40%) of the title compound as a white solid. Mass Spectrum (ESI, m/z): Calcd. for C32H46N6O4Si, 607.3 (M+H). found 607.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(NC(C)=O)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(C)=O)ccc1OC(C)=O
Reaction time: 48 h
Yield: 84 %

Procedure:
Methyl 2-hydroxy-5-acetamidobenzoate (13.6 g, 68 mmole) was dissolved in pyridine (20 ml), acetic anhydride (7.4 ml) was added, and the reaction mixture was left at room temperature for 48 hours after which time it was evaporated to dryness, in vacuo. The remaining product was recrystallized from ethanol-water (1:3) to give the title compound (14.4 g, 84%), m.p. 133°-135° C. Found (Calc. for C12H13NO5) C 57.11 (57.37), H 5.28 (5.18), N 5.47 (5.58).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:9][C:8](=[CH:10][CH2:11]C(O)=O)[C:7]=2[CH:15]=1.C([N:18](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:9][C:8](=[CH:10][CH2:11][NH2:18])[C:7]=2[CH:15]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)C(=CCC(=O)O)C2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=CCN)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 g (10 mmol) of 3-(5-methoxybenzocyclobuten-1-ylidene)propionic acid and 1.4 ml (10 mmol) of triethylamine are introduced under argon into 20 ml of toluene. 2.2 ml (10 mmol) of diphenylphosphorylazide are added thereto and the whole is heated, while stirring, at 80° for 30 minutes. The mixture is allowed to cool to room temperature, 2.9 ml (20 mmol) of 2-trimethyl- silylethanol are added thereto and the whole is heated at 80° for 7 hours. The reaction mixture is then concentrated to dryness in a rotary evaporator. The oily residue is taken up in diethyl ether, washed with water and 2N sodium hydroxide solution, dried over sodium sulphate and concentrated by evaporation. The crude product is purified by chromatography on a silica gel column, stirred at 50° for 2 hours with 10 ml (10 mmol) of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran and then concentrated to dryness by evaporation. The residue is stirred vigorously with n-pentane/water (1:1). The n-pentane phase is separated off and discarded. The aqueous phase is adjusted to pH 8 with ammonium chloride, whereupon a crystalline product precipitates. The latter is filtered off with suction. The mother liquor is saturated with sodium chloride, whereupon more product crystallises out. The crystallisates are combined, taken up in trichloromethane/methanol (1:1), dried over sodium sulphate and concentrated by evaporation. The crystalline residue is stirred with diethyl ether and then filtered. 2-(5-methoxybenzocyclobuten-1-ylidene)ethylamine of m.p. 238°-240° is obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:16]=1[CH2:17][N:18]1[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]1=[O:25]>ClCCl.O>[CH3:1][S:2]([O:24][CH2:23][CH:21]1[CH2:20][C:19](=[O:25])[N:18]([CH2:17][C:16]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:15]=2[O:14][CH3:13])[CH2:22]1)(=[O:4])=[O:3]
Reactant: COc1ccc(CN2CC(CO)CC2=O)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CC(COS(C)(=O)=O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
MsCl (3.3 g, 28 mmol) and Et3N (3.8 g, 38 mmol) were added to a mixture of 1-(2,4-dimethoxybenzyl)-4-(hydroxymethyl)pyrrolidin-2-one (5.0 g, 19 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 10 hours then diluted with water and extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford [1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl]methyl methanesulfonate. 1H NMR (400 MHz, CDCl3) δ 7.13-7.15 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 4.09-4.14 (m, 2H), 3.79-3.82 (m, 6H), 3.36-3.42 (m, 1H), 3.12-3.19 (m, 1H), 2.98 (s, 3H), 2.62-2.75 (m, 2H), 2.21-2.25 (m, 1H). MS ESI calc'd. for C15H22NO6S [M+H]+ 344. found 344.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23]C(CCl)=[CH:19][CH:18]=1>C(O)C>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(COC(=O)C2CCC(O)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 4-hydroxycyclohexanoate (8.61 g, 50 mmole) in 50 ml ethanol was added a solution of potassium hydroxide 85% (3.63 g, 55 mmole) and the mixture was stirred for 6 hours at 70° C. The mixture was evaporated under reduced pressure, coevaporated two times with N,N-dimethylformamide and reduced to about 100 ml. 4-Methoxybenzyl chloride (9.4 g, 60 mmole) was added and the mixture was stirred for 18 hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acetate was added. The organic phase was washed five times with water, dried with sodium sulfate and evaporated under reduced pressure. Yield: 13.2 g=100% (crude)
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[NH:9][CH2:8][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:28]
Reactant: CCOC(N)=O
Reactant: NCC(CCN1CCCC1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)NCC(CCN1CCCC1)(c1ccccc1)c1ccccc1

Procedure:
From 2,2-diphenyl-4-pyrrolidin-1-yl-butyl amine in analogy to 3a. The urethane was further reacted in a crude state.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[CH3:11][CH2:12][O:13][C:14]([C:16]([CH2:18][C:19]([CH3:21])=O)=O)=[O:15]>C(O)C>[CH2:7]([N:9]1[C:19]([CH3:21])=[CH:18][C:16]([C:14]([O:13][CH2:12][CH3:11])=[O:15])=[N:10]1)[CH3:8]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
Ethylhydrazine oxalate (23.7 g, 158 mmol) was added slowly to an 11° C. solution of ethyl acetopyruvate (50.0 g, 316 mmol) in ethanol so that the internal temperature did not exceed 14° C. The reaction was allowed to warm to ambient temperature and was stirred overnight. The reaction was concentrated under reduced pressure and 2 M sodium carbonate was added to adjust the mixture to pH 9. The mixture was transferred to a separatory funnel. The aqueous phase was extracted with methyl tert-butyl ether (3×600 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 28.94 g of ethyl 1-ethyl-5-methyl-1H-pyrazole-3-carboxylate as an orange oil that was used without purification in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CSc1cccc2c(Cl)cc(C)nc12
Product: CSc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylsulfanylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a round bottom flask was placed a solution of intermediate 21a (0.0580 mmol, 1 equiv), 4-mercaptobenzoic acid (11 mg, 0.0696 mmol, 1.2 equiv), potassium carbonate (24 mg, 3 equiv), and DMF (1 mL). The solution was stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was dried (Na2SO4). The solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 34 mg of product. 1H-NMR (400 MHz, DMSO, ppm): δ 11.55(s, 1H), 11.48(s, 1H), 8.67(d, J=2.6 Hz, 1H), 8.32(d, J=8.3 Hz, 1H), 8.19(S, 1H), 8.16(d, J=7.8 Hz, 1H), 8.01(s, 1H), 7.85-7.71(m, 5H), 7.65(d, J=7.5 Hz, 3H), 7.52(t, J=7.7 Hz, 1H), 7.44(d, J=8.7 Hz, 2H), 7.04(d, J=2.7 Hz, 1H), 4.46(s, 2H), 3.30(s, 4H), 1.70(s, 4H), 1.59(s, 2H). MS (ES, m/z) 700 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12]Br>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12][O:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][OH:6]
Reactant: OCC=CCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC/C=C\COCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 500 ml flask, 1,4dihydroxybut-2-ene (6.13 ml, 74.5 mmol) was dissolved in N,N-dimethylformamide (150 ml) under a nitrogen atmosphere. Sodium hydride (60%, 2.98 g, 74.5 mmol) was added and the resulting mixture was stirred at ambient temperature for thirty minutes. The reaction mixture was cooled to 0° C. and 2-fluoro-5-bromobenzyl bromide (3.99 g, 14.9 mmol) was added dropwise. The resulting mixture was warmed to ambient temperature and stirred for four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH:18]3[CH2:19][CH2:20][CH:15]2[CH2:16][CH2:17]3)=[O:10])=[CH:7][N:8]=1)[CH3:2].[OH:21]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH:18]3[CH2:19][CH2:20][CH:15]2[CH2:16][CH2:17]3)=[O:10])=[CH:7][N:8]=1)=[O:21])[CH3:2]
Reactant: OO
Reactant: CCSc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Solvent: CC(=O)O
Product: CCS(=O)c1ncc(C(=O)NCCC2C3CCC2CC3)s1

Procedure:
In this preparation a mixture of 20 g. of 2-ethylthio-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole (0.064 mole); 40 ml. of 30% aqueous hydrogen peroxide and 200 ml. of acetic acid is stirred at a temperature of from 40° to 50° C for 4 hours. The mixture is concentrated by evaporation of a large portion of the acetic acid, under vacuum, at room temperature (about 20° C) and the resulting residue poured into 500 ml. of ethyl acetate and then washed with aqueous sodium bicarbonate solution until no acetic acid is present in the organic layer. The ethyl acetate layer is then separated, dried with anhydrous magnesium sulfate, filtered, and the resulting filtrate evaporated to dryness, under vacuum, affording 2-ethylsulfinyl-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C(#N)C>[NH2:13][C:14]1[C:19]([NH:8][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[S:2])=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1
Reactant: Nc1ccc(Br)cn1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Nc1ncc(Br)cc1NC(=S)n1ccnc1

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (17.8 G, 0.1 m) and 2-amino-5-bromopyridine (17.3 g, 0.1 m) in acetonitrile (150 mL) was stirred at room temperature for 2 hours. To this suspension was added the material described below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1cc(C=O)ccc1O
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)c(OC)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 4-hydroxy-3-methoxybenzaldehyde gave the title compound as a cream solid m.p.:195° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O[C@H]1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 150 °C

Procedure:
A stirred mixture of 2,6-dichlorobenzo[d]thiazole (CAS #3622-23-9, 0.314 g, 3.00 mmol), (S)-pyrrolidin-3-ol (0.314 g, 3.60 mmol), and potassium carbonate (1.24 g, 9.00 mmol) in water/ethanol (10 mL/8 mL) was heated at 150° C. under microwave irradiation for 5 minutes. The reaction mixture was cooled to room temperature then partitioned between dichloromethane and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude solid that was purified by crystallization from ethyl acetate/hexane. Crystals were collected by filtration, then dried under vacuum to provide (S)-1-(6-chlorobenzo[d]thiazol-2-yl)pyrrolidin-3-ol. 1H NMR (300 MHz, CD3OD) δ ppm 2.04-2.14 (m, 1H), 2.16-2.29 (m, 1H), 3.48-3.55 (m, 1H), 3.59-3.75 (m, 3H), 4.54-4.59 (m, 1H), 7.26 (dd, J=2, 8 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.67 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC(=O)[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1)(C)(C)C.C(OC(=O)NC1CCCC(B2OC(C)(C)C(C)(C)O2)=C1)(C)(C)C>>[NH2:30][CH:31]1[CH2:32][C:33]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[C:5]=3[O:4][CH:3]=2)=[CH:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)(C)OC(=O)NC1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCCC(N)C3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting material 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine and the mixture of [3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester and [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-2-enyl]-carbamic acid tert-butyl ester. 1H-NMR (CD3OD, 400 MHz): δ=1.43-1.59 (m, 1H), 1.86 (d, J=6.8 Hz, 3H), 1.89-1.98 (m, 1H), 2.08-2.22 (m, 1H), 2.28-2.45 (m, 2H), 2.59 (dd, J=16.3, 4.93 Hz, 1H), 2.98-3.14 (m, 1H), 6.25 (br. s., 1H), 6.48 (q, J=6.7 Hz, 1H), 7.15-7.24 (m, 1H), 7.38 (dd, J=9.0, 4.9 Hz, 1H), 7.54 (s, 1H), 8.15 (s, 1H). MS (ES+): m/z 436.03 (MH+, 35Cl, 37Cl), 437.97 (MH+, 35Cl, 37Cl). HPLC: tR=2.20 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCCC1Cc1ccccc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 2-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (9.4 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1136.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>O1CCOCC1>[OH:15][CH2:14][C:13]1[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1
Reactant: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2CO)o1

Procedure:
To obtain the starting material, stir 1.2 ml of a 70% solution of sodium dihydro-bis-(2-methoxyethoxy)aluminate together with 0.6 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid and 15 ml of dioxane at 70° C for 1.5 hours. Then add thereto 0.16 ml of 15% caustic soda and 0.5 ml of water at room temperature before filtering the thus-prepared product while warm. Extract the filtered precipitate with dioxane, concentrate the combined dioxane solutions and crystallize from ethanol to obtain 4-hydroxymethyl-3-(5-nitro-2-furyl)-1-phenylpyrazole [m.p. 148° to 149° C].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:21])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-pyroglutamate (11.5 g, 40 mmol) in THF (200 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in THF (42 mL, 42 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (3.11 mL, 50 mmol) was added. After an additional 2 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed with 1:1 ethylacetate/hexanes to give Boc-PyroGlu(4-methyl)-OtBu (10.6 grams, 35.4 mmol, 88%) as a mixture of isomers (2:1 cis to trans). Step 2. Synthesis of Tert-butyl N-tert-butoxycarbonyl-4,4-dimethyl-L-pyroglutamate (Boc-PyroGlu(4,4-dimethyl)-OtBu):