Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccc(Cl)c(Cl)c2)CS1)c1ccccc1
Yield: 29.7 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (as prepared in example 1) (8.99 g, 39.8 mmol) was reacted with 8.3 g (39.6 mmol) of 3,4-dichlorobenzoylchloride in dichloromethane (30 mL) and pyridine (9.6 mL) as described in Example 2 to yield 4.86 g of the desired compounds in 1:1 ratio.
Reaction SMILES: Cl.[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[S:16][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([CH2:30][C:31](O)=[O:32])[N:28]=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH2:19][CH2:20][N:21]([C:31](=[O:32])[CH2:30][N:29]5[C:25]([CH3:24])=[CH:26][C:27]([C:34]([F:37])([F:36])[F:35])=[N:28]5)[CH2:22][CH:23]=4)[S:16][CH:17]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CCNC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CC=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1,2,3,6-tetrahydropyridine hydrochloride (i.e. the product of Example 13, Step C) (0.250 g, 0.720 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.150 g, 0.720 mmol) in dichloromethane (10 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.138 g, 0.720 mmol), 1-hydroxybenzotriazole (0.024 g, 0.177 mmol), and triethylamine (0.145 g, 1.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 3% methanol in chloroform as eluant to give 200 mg of the title product as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([O-:33])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:40]([C:37]1[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:39][CH:38]=1)(=[O:41])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 4-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol), diisoproylethylamine (0.084 mL, 0.474 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydrogen sulfate (1N). The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (254 mg, 88%) as a foam. H1-NMR (chloroform-D3): 0.90 (m, 6H), 1.60 (m, 7H), 2.90 (m, 5H), 3.68 (m, 2H), 3.87 (m, 4H), 4.17 (m, 1H), 4.83 (d, 1H), 5.02 (m, 1H), 5.64 (d, 1H), 7.23 (m, 5H), 7.99 (d, 2H), 8.38 (d, 2H). MS(ESI): 630(M+Na).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[CH:9]([CH3:11])[CH3:10].[Br:16][CH2:17][CH2:18][CH2:19]Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][CH2:17][CH2:18][CH2:19][C:9]([CH3:11])([CH3:10])[C:8]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 126 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise. The mixture was stirred for 1 hour, after which 41.8 g of 1,3-dibromopropane was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and then at room temperature for 2 hours. The mixture was then poured in aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was then distilled off and the residue was subjected to vacuum distillation to provide 40.3 g of the title compound as colorless oil. b.p. 76°-78° C./0.27 mmHg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Yield: 79 %

Procedure:
2-Amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one. 1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 116 part a to d except using 3,5-dichloro-2-nitrobenzaldehyde (2.1 g) and decaborane (0.41 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(3,5-dichloro-2-nitrobenzyl)amine (1.2 g, 32%). 3,5-Dichloro-2-nitrobenzaldehyde (2.2 g, 79%) was prepared by nitration of 3,5-dichlorobenzaldehyde (2.2 g) in a mixture of nitric acid (1.5 mL) and sulfuric acid (8 mL) at 0° C. for 30 minutes.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]([CH2:23][CH3:24])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.O.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>[C:1]1([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)[CH:6]=[CH:5][C:4]([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)=[CH:3][CH:2]=1
Reactant: CCn1nc(Br)c2ncccc21
Reactant: OB(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc(-c2ccc(-c3nn(CC)c4cccnc34)cc2)c2ncccc21
Yield: 7.3 %

Procedure:
A mixture of 1,4-phenylenediboronic acid (37.0 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (101 mg), Pd(PPh3)4 (25.8 mg) and Cs2CO3 (0.280 g) in DME/water (3/1, 4 mL) was exposed to microwave irradiation (120° C., 40 min), treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). Crystallization from AcOEt/hexane gave the title compound (6.00 mg).
Reaction SMILES: [C:1]1([S:7][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>ClCCl>[C:12]1([S:16]([OH:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([S:8][S:7][C:1]2[CH:2]=[CH:3][C:4]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(SSc2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(SSc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of phenyl disulfide (4.36 g, 20 mmol) in dichloromethane (40 mL) at 0° C. is added a solution of chlorosulfonic acid (4.64 g, 2.95 mL, 40 mmol) in dichloromethane (60 mL) dropwise. The mixture is stirred at 0° C. for 1 hour followed by 1.5 hours at room temperature. The reaction mixture is concentrated to dryness in vacuo and the residue is partitioned between diethyl ether and water. The water phase is separated, made basic with 2N aqueous sodium hydroxide and concentrated in vacuo to half the volume. The resulting solution is refrigerated overnight. The precipitate formed overnight is discarded, the filtrate is concentrated further in vacuo until a solid started to appear. The mixture is placed in the refrigerator for 2 hours. The mixture is treated with ethanol, the solid formed is filtered, washed with ethanol twice and dried under high vacuum overnight at room temperature to give 6.0 g of 4,4′-dithiobisbenzenesulfonic acid as a white solid: [M−1]−=398.8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O.[OH-].[Na+]>O>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1cncnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccccc1-c1nc2ncncc2[nH]1
Temperature: 180 °C
Yield: 88.5 %

Procedure:
A mixture of 4,5-diaminopyrimidine (0.500 g), 2-fluorobenzoic acid (0.700 g) and polyphosphoric acid (25 mL) was heated at 180° C. for 3 hours. Then the reaction mixture was cooled and poured into water (500 mL). The solution was adjusted to pH=8-9 by addition of solid NaOH and the resulting precipitate was collected by filtration, washed with water and dried to give 8-(2-fluorophenyl)-purine (off-white powder, 88.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].CN(C)C=O.[H-].[Na+].[CH3:30][O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34]>O>[CH3:30][O:31][C:32](=[O:37])[C:33]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2)([CH3:35])[CH3:34]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1c(Cc2ccc(Cl)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1H-quinolin-2-one (0.14 g), N,N-dimethylformamide (10 mL), sodium hydride (60% in oil, 0.020 g) and 2-bromo-2-methylpropionic acid methyl ester (0.11 g) was stirred at 100° C. for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford title compound, 0.056 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=C(Cl)C=CC=1C1NC2C=C(F)C(F)=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3Br)[nH]c2cc1F
Agent: BrCC1CCCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3Br)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Off-white solid (60%). MS (Turbo Spray): m/z=440.2 (M+H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C:10]1([F:15])[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C:10]1([F:15])[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: [C-]#[N+]CC(=O)N1CCC(F)(F)C1
Yield: 60 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 345 mg, 3.48 mmol) was slowly added 3,3-difluoropyrrolidine hydrochloride (500 mg, 3.48 mmol), triethylamine (487 μL, 3.48 mmol) and MeOH (1 mL). The mixture was stirred for 15 h at RT and then concentrated. The resulting oil was coevaporated twice from EtOAc. 1-(3,3-Difluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01158 was obtained as a yellow oil (305 mg, 60% yield) and used in the next step without purification.
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2].[C:27](=O)([O-])[O-].[K+].[K+]>CC(C)=O.CI>[C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([O:25][CH3:27])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(C)=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
11-Acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (55 mg) was dissolved in a mixture of acetone (2 ml) and methyl iodide (2 ml). To the solution was added potassium carbonate (150 mg), and the mixture was stirred at 45° C. overnight under nitrogen atmosphere. The mixture was cooled to room temperature and filtered, and the filter cake was washed with a mixture of chloroform and acetone (1:1, v/v, 10 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to column chromatography on silica gel, and elution was carried out with a mixture of chloroform and acetone (4:1, v/v). The desired fractions were collected and evaporated to dryness. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (1:1, v/v) to afford 11-acetyl-4-formyl-9-hydroxy-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (11 mg).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])O.[Na+].O.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>CO>[CH2:19]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])[CH:20]([CH2:22][OH:23])[OH:21]
Reactant: OCC1CO1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1OCC(O)CO
Temperature: 60 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
Under an argon atmosphere, L-ascorbic acid (10.0 g) and sodium hydrogen carbonate (9.54 g) were added to water and the resultant mixture was stirred at room temperature for 30 minutes, then, glycidol (8.41 g) was added thereto. Thereafter, the mixture was heated up to 60° C. and stirred for 5 hours. Thereto, methanol was added and filtration was performed. The filtrate was concentrated under reduced pressure, and 19.0 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:6/4/1), and concentration was performed under reduced pressure to obtain 2-O-glyceryl ascorbic acid (1.21 g).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)=[CH:22][CH:21]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: ClCc1ccc(Cl)cc1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(Cl)cc4)CC3)cccc2n1
Yield: 67 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-Chlorobenzyl Chloride (59.6 mg; 0.37 mmol) to obtain 49.5 mg. (67% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 9.94 (s, 1H), 8.88 (s, 1H), 7.69 (m, 2H), 7.38 (m, 4H), 7.25 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 3.57 (s, 2H), 3.03 (br d, J=10.8 Hz, 3H), 2.91 (m, 3H), 2.29 (m, 2H). ESIMS+369.2 m/z
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][SH:14])=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]([C:19]1[C:20](S(C)(=O)=O)=[N:21][S:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[C:20]([S:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)=[N:21][S:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]
Reactant: SCc1ccc(Cl)cc1
Reactant: COC(=O)c1c(S(C)(=O)=O)nsc1NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of n-BuLi (2.5M, 11.5 mL, 28.8 mmol) in THF (20 mL) at 0° C. is added (4-Chloro-phenyl)-methanethiol (4 mL, 30 mmol) dropwise over 15 min. After 1 hr., a solution of 18 (2 g, 6 mmol) in THF (15 mL) is added. The reaction is then stirred at 0° C. for 1 hour and 2 hrs. at room temperature. The reaction was then quenched with water and extracted with EtOAc (3×50 mL). The combined organics are then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (3% EtOAc/hexane) provides 19 (1.98 g, 80%) as a white solid. 1H NMR (CDCl3): δ 10.00 (1H, br. s), 7.29 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 4.36 (2H, s), 3.89 (3H, s), 1.53 (9H, s).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C>[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:22][CH:21]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Triethylamine (0.77 ml) and 4-chlorobenzenesulfonyl chloride (1.2 g) were added to a solution of 4-hydroxybenzylamine (0.68 g) in ethanol(10 ml), respectively. The reaction mixture was stirred at room temperature for 4 hours and evaporated in vacuo to remove the solvent. The residual solid was washed with water then recrystallized from ethanol to give N-(4-hydroxybenzyl)-4-chlorobenzenesulfonamide (1.2 g), mp 187-189° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([Cl:24])=[O:21])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Solvent: c1ccccc1
Product: Cn1c(C(=O)Cl)cc2c(OCc3ccccc3)cccc21
Temperature: 80 °C

Procedure:
To a stirred suspension of 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (0.75 g) in benzene (5 mL) was added thionyl chloride (2.8 mL) in benzene (5 mL) followed by heated at 80° C. for 45 min to give a clear orange solution. Evaporation to dryness gave 0.80 g of the title compound as an orange solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCCC1>[O:23]=[C:22]1[N:8]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccncc2n1C1CCNCC1
Yield: 129.6 %

Procedure:
A solution of 4-amino-3-[(1-benzylpiperidin-4-yl)amino)pyridine (2.8 g, 9.9 mmol) and carbonyldiimidazole (3.0 g, 18.5 mmol) in tetrahydrofuran (100 mL) was refluxed overnight. The reaction was cooled, concentrated and partitioned between chloroform (500 mL) and saturated sodium carbonate (100 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 209 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].N1C=CN=C1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].O>CN(C=O)C>[Si:41]([O:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3.72 g (7.88 mmol) of the crude product of Example 21 dissolved in 10 mL of DMF was added 2.68 g (0.039 mol) of imidazole followed by 2.85 g (0.019 mol) of t-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature for 2 h and then poured into 200 mL of H2O. The resulting solution was extracted with ether and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 10mL of methanol/THF (1:1) and 5.0 mL of 1N NaOH solution was added. After stirring for 0.75 h at room temperature the reaction mixture was acidified with 5% HCl solution to pH 5 and then extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.76 g (100%) of the desired product as a colorless oil. Electrospray Mass Spec: 603.5 (M-H)-.