Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.8 g (30 mmol) of N,N-dimethylethylenediamine are placed in 100 ml of dichloromethane and 8.3 ml (60 mmol) of triethylamine. While cooling with ice a solution of 3.9 ml (30 mmol) of benzenesulphonic acid chloride in 100 ml of dichloromethane is added dropwise and the mixture is stirred overnight at ambient temperature. Water is added and the mixture is extracted with dichloromethane. The organic phase is dried and evaporated down.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[N:16](C4CCCCO4)[N:15]=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([F:37])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[C:32]([C:33]([F:35])([F:36])[F:34])=[C:31]([F:37])[CH:30]=[CH:29][C:25]=1[C:26]([N:3]1[CH2:4][CH2:5][C:6]2[C:11]([C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:2]1[CH3:1])=[O:27]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1Cl
Reactant: CC1NCCc2c(-c3ccnn3C3CCCCO3)ncnc21
Agent: CCN=C=NCCCN(C)C
Agent: CC[SiH](CC)CC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1c2ncnc(-c3ccn[nH]3)c2CCN1C(=O)c1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of the product of Example 112, step g (60 mg, 0.20 mmol) in DCM (2 mL) was added 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid (49 mg, 0.20 mmol), followed by EDCI (116 mg, 0.607 mmol), HOBt (19 mg, 0.14 mmol) and TEA (2.0 mL, 0.607 mmol). The reaction was stirred at room temperature overnight. The crude mixture was treated directly with TFA (0.8 mL) and triethylsilane (81 L, 0.20 mmol) and stirred for 3 h. The solvents were removed in vacuo and the residue was azeotroped with toluene (1×). Chromatography on SiO2 eluted with EtOAc/Hex afforded the desired product (59 mg, 66%). MS (ESI) mass calcd. C19H14ClF4N5O, 439.1. m/z found 440.1 [M+H]+. 1H NMR (500 MHz, MeOD): 9.08-8.87 (m, 1H), 7.92-7.68 (m, 2H), 7.57-7.44 (m, 1H), 7.10-6.92 (m, 1H), 5.71-5.63 (m, 1H), 3.68-3.33 (m, 3H), 3.19-3.08 (m, 1H), 1.77-1.56 (m, 3H).
Reaction SMILES: CO[C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.FC1C(OC)=CC=CC=1[CH:15]=[O:16].[S].[NH4+].[OH-]>COCCO>[CH3:15][O:16][C:6]1[C:7]2[S:11][N:10]=[CH:9][C:8]=2[CH:3]=[CH:4][CH:5]=1
Reactant: COc1cccc2sncc12
Reactant: COc1cccc(C=O)c1F
Agent: [NH4+]
Agent: [OH-]
Agent: [S]
Solvent: COCCO
Product: COc1cccc2cnsc12
Yield: 14 %

Procedure:
A method similar to 4-methoxy-benzo[d]isothiazole using 2-fluoro-3-methoxy-benzaldehyde (410 mg, 2.66 mmol), sulfur (85 mg, 2.66 mmol), NH4OH (5 mL), and 2-methoxyethanol (5 mL) gave the title compound (60 mg, 14%); Mass spectrum (ion-spray): m/z=165.8 (m+1).
Reaction SMILES: [K].[CH3:2][C:3]1[O:7][C:6]([CH:8]=[CH:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.[Cl-].[Na+].[OH2:15]>>[CH2:9]([C:8]1[C:6](=[O:7])[CH2:5][CH:4]([OH:15])[C:3]=1[CH3:2])[CH:10]=[CH2:11]
Reactant: O
Reactant: Cc1ccc(C=CCCO)o1
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 0.58 h

Procedure:
Potassium secondary phosphate (1.12 g) and potassium primary phosphate (3.54 g) were dissolved in water (800 ml) to prepare a buffer solution (pH 6.2, 20° C.). In a reaction vessel, 5-methyl-2-furylallylcarbinol (20 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 150° C. in 35 minutes while stirring. The mixture was stirred at the same temperature for 4 hours, the inner pressure at this time being 3.8 kg/cm2. After cooling with ice, sodium chloride (100 g) was added thereto, and the mixture was extracted with methyl isobutyl ketone (200 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, whereby an oily substance (18.2 g) was obtained. The crude product was purified by distillation (130°-132° C./1.2 mmHg) to obtain 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (16.6 g). Yield, 83%.
Reaction SMILES: [CH3:1][S:2]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([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)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[O:30]1[CH2:34]CC[CH2:31]1.[OH-:35].[Na+]>CO>[CH3:31][O:30][C:34]([CH2:1][S:2][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([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)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:35]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CO
Product: COC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone in 250 ml of methanol is added 100 ml of tetrahydrofuran, followed by addition of 3.45 g of methyl thioglycollate and 32.5 ml of 1N sodium hydroxide under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The solvent is then distilled off under reduced pressure and 100 ml of ethyl acetate is added. The ethyl acetate layer is separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using n-hexane-ethyl acetate (3:2). The earlier eluate fractions are combined and concentrated under reduced pressure to give 4.35 g of (3R,4R)-4-[[(methoxycarbonyl)methyl]thio]-3-tritylamino-2-azetidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:13])[CH2:10][CH2:11]O.S(Cl)([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH2:1])[C:3]([N:9]([CH2:10][CH2:11][Cl:16])[CH3:13])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)c1ccc(Br)cc1N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCl)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
2-((2-amino-4-bromophenyl)(methyl)amino)ethanol (3.09 g, 0.013 mol) was dissolved in DCM (100 mL) with DMF (10 drop), Thionyl chloride (1.8 g, 0.015 mol in 10 ml DCM) was added dropwise at 0° C. The reaction was stirred at rt for 10 min then 80° C. for 30 min, rt for 16 h. The mixture was partitioned between 1N NaOH and DCM (2×30 ml). The combined organic layers was concentrated to give 3.2 g, (96.3%) of 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine LCMS-ESI+ (m/z): [M+H]+ calcd for C9H12BrClN2:261.99; found 262.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8](OC2CCCCO2)[C:9]([C:11]2[O:12][C:13]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2O)=[NH:10])[CH:5]=[CH:6][CH:7]=1.C[OH:30]>>[NH2:21][C:20]1[C:13]2[O:12][C:11]([C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10][OH:30])=[CH:15][C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CO
Reactant: N=C(c1oc2c(N)cccc2c1O)N(OC1CCCCO1)c1cccc(Cl)c1
Product: Nc1cccc2cc(C(=NO)Nc3cccc(Cl)c3)oc12
Yield: 62 %

Procedure:
To a methanol solution of 32 mg of N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine was 200 mg of acidic Dowex resin. The resulted solution was stirred at reflux temperature for 1 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified using a chromatotron and eluting with 5–10% methanol/dichloromethane to give 18 mg of 7-amino-N-(3-chloro-phenyl)-N′-hydroxy-benzofuran-2-carboxamidine in 62% yield.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[O:6]1[C:17]2[C:9](=[CH:10][C:11](=[CH:15][CH:16]=2)[CH2:12][CH:13]=[CH2:14])[O:8][CH2:7]1.[ClH:18]>C(OCC)(=O)C>[Cl:18][CH:13]([CH3:14])[CH2:12][C:11]1[CH:15]=[CH:16][C:17]2[O:6][CH2:7][O:8][C:9]=2[CH:10]=1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Cl)Cc1ccc2c(c1)OCO2

Procedure:
5 g of anhydrous tin chloride was added to 100 g of safrole. Hydrochloric acid gas was passed though the mixture under cooling with ice for 1.5 hours. 2 l of ethyl acetate was added to the reaction mixture, followed by the dissolution. The obtained mixture was washed with water twice, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/benzene=10:1) to obtain 41.7 g of 5-(2-chloropropyl)-1,3-benzodioxole as a colorless oil. This oil was dissolved in 150 ml of ethanol, followed by the addition of 48 g of thiourea. The obtained mixture was heated under reflux for 7 days, cooled and filtered. A solution of 12.8 g of sodium hydroxide in 100 ml of water was added to the filtrate. The obtained mixture was heated under reflux for 2 hours, cooled and acidified with dilute sulfuric acid. 1 l of benzene and 1 l of water were added to the mixture to carry out the phase separation. The benzene layer was washed with water twice, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/benzene=10:1) to obtain 8.5 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].[NH2:23]/[C:24](/[CH3:28])=[CH:25]\[C:26]#[N:27]>C(O)(C)C>[CH3:4][C:2]1[NH:23][C:24]([CH3:28])=[C:25]([C:26]#[N:27])[CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:1]=1[C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1
Reactant: C/C(N)=C/C#N
Reactant: CC(=O)Cc1nc(CCl)no1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CCl)no2)=C(C)N1
Yield: 42.3 %

Procedure:
A stirred solution of 1.0 g of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole, 0.95 g of 3-nitrobenzaldehyde and 0.52 g of 3-aminocrotononitrile in 10 ml of isopropyl alcohol was heated under reflux for 4 hours and then concentrated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (40:1) as eluent to give 0.90 g of 1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carbonitrile, m.p. 204.5°-206.5° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:35]([C:37]1[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:35][C:37]4[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=4)[CH2:16][CH2:17]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C#N)Cc1cccc(C=O)c1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C#N)Cc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reaction time: 0.17 h

Procedure:
To a 20 mL dichloroethane solution of 0.35 g (0.92 mmol) 4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one and 0.25 mL (1.4 mmol) DIEA went 0.16 g (0.92 mmol) 3-(3-formylphenyl)-2-methylpropanenitrile (9-3). The suspension was allowed to stir for 10 min then 0.4 g (1.9 mmol) sodium triacetoxyborohydride was added and the reaction was allowed to stir at rt overnight. HPLC/MS showed no starting material so the reaction was quenched with 100 mL sat NaHCO3 and diluted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The remaining oil was purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 5% MeOH+0.5M NH3 in CH2Cl2 at 25 mL/min over 30 min. The product eluted second.
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[CH:6]=[N:5][CH:4]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:1][C:11]1[C:7]2[CH:6]=[N:5][CH:4]=[N:3][C:8]=2[NH:9][CH:10]=1
Reactant: BrBr
Reactant: c1ncc2cc[nH]c2n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c[nH]c2ncncc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of bromine (0.086 mL, 1.68 mmol) in DMF (5.5 mL) was added to a solution of 7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.68 mmol) in DMF (5.5 mL). The reaction mixture was stirred at RT for 4 h and poured into a mixture of ice and water containing Na2S2O3. A saturated aqueous solution of NaHCO3 was added (until basic pH), the layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The material thus obtained was used without further purification in the next step. TLC, Rf (CH2Cl2/MeOH 9:1)=0.45; MS (UPLC/MS): 198.1/200.1 [M+H]+, 196.1/198.1 [M−H]−.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N+:35]([O-:37])=[O:36])[N:5]([CH2:7][C:8]2([CH2:16][O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]2)[CH:6]=1.[CH2:38](C([Sn])=C(CCCC)CCCC)[CH2:39]CC>CN(C)C=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>[O:17]([CH2:16][C:8]1([CH2:7][N:5]2[CH:6]=[C:2]([CH:38]=[CH2:39])[N:3]=[C:4]2[N+:35]([O-:37])=[O:36])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)[Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(Br)nc2[N+](=O)[O-])CO1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
280 mg (0.48 mmol equivalents) of 5-{(4-bromo-2-nitro-1H-imidazol-1-yl)methyl}-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane was dissolved in 4.7 mL of dimethylformamide, 278 μL (0.95 mmol equivalents) of tributylvinyltin and 55 mg (0.05 mmol equivalents) of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was heated to 80° C. in an oil bath and then stirred for 5 hours. After completion of the reaction, the reaction liquid was concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 163 mg (0.30 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-vinyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:16]2[O:30][C@H:29]([CH2:31][O:32]C(C3C=CC(C)=CC=3)=O)[C@@H:18]([O:19]C(C3C=CC(C)=CC=3)=O)[CH2:17]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:13])[CH3:12])=[CH:8][C:7]([Cl:14])=[C:6]([Cl:15])[CH:5]=2.C[O-].[Na+]>CO>[Cl:1][C:2]1[N:3]([C@@H:16]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:18]([OH:19])[CH2:17]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:13])[CH3:12])=[CH:8][C:7]([Cl:14])=[C:6]([Cl:15])[CH:5]=2
Reactant: CC(=O)c1c(Cl)n([C@H]2C[C@H](OC(=O)c3ccc(C)cc3)[C@@H](COC(=O)c3ccc(C)cc3)O2)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1c(Cl)n([C@H]2C[C@H](O)[C@@H](CO)O2)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
2,5,6-Trichloro-3-acetyl-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.116, 0.62 g, 1.0 mmol) was suspended in dry MeOH (50 mL) to which was added sodium methoxide (220 mg, 4.1 mmol). The suspension was stirred at room temperature for 16 h, after which time the solution first clarified and a precipitate then formed. The suspension was allowed to stand at 4° C. for 4 h, and was then filtered, and the solids rinsed with cold MeOH (10 mL). The solid was recrystallized from warm MeOH to yield 0.28 g (74%) of 4.117 as a white crystalline solid: mp dec. >200 C; Rf 0.4 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.37 (s, 1H), 6.49 (dd, 1H), 5.43 (s, 1H, D2O exch.), 5.26 (s, 1H, D2O exch.), 4.45 (m, 1H), 3.89 (d, 1H), 3.72 (m, 2H), 2.60 (s, 3H), 2.49 (m, 1H), 2.13 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 192.13, 132.15, 131.99, 126.12, 125.50, 125.65, 121.96, 115.25, 112.85, 87.55, 85.43, 69.81, 60.67, 47.10, 30.68. HRMS (EI) m/z calcd. for C15H14Cl3NO4 376.9988. found 376.9982. Anal calcd for C15H14Cl3NO4: C, 47.58; H, 3.73; N, 3.70. Found: C, 47.52; H, 3.95; N, 3.59.
Reaction SMILES: CS(O[N:6]=[C:7](Cl)[C@H:8]1[CH2:12][O:11][C:10]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9]1)(=O)=O.N1C=CC=CC=1.[S-:25][C:26]#[N:27].[Na+].[CH2:29]([C:31]1[C:36]([O:37][C:38]2[C:39]([NH2:51])=[N:40][CH:41]=[C:42]([S:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:43]=2)=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:30]>C(#N)C>[CH2:29]([C:31]1[C:36]([O:37][C:38]2[C:39]([NH:51][C:26]3[S:25][N:6]=[C:7]([C@H:8]4[CH2:12][O:11][C:10]5([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]5)[O:9]4)[N:27]=3)=[N:40][CH:41]=[C:42]([S:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:43]=2)=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:30]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1N
Reactant: N#C[S-]
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 60 °C
Yield: 57.1 %

Procedure:
(R)—N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (0.854 g, 2.87 mmol), pyridine (0.618 ml, 7.64 mmol), and sodium thiocyanate (0.310 g, 3.82 mmol) were dissolved in acetonitrile (10 mL). The solution was heated to 60° C. for 30 minutes. 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.620 g, 1.91 mmol) was added and the reaction was heated at 60° C. overnight. The solution was quenched with saturated aqueous NaHCO3 solution, extracted with EtOAc (3×100 mL), washed with brine, dried over MgSO4, and concentrated. The material was purified over silica gel (25 to 100% ethyl acetate in hexanes) to afford (S)—N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.600 g, 1.09 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:22]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccncc3)CC1)O2

Procedure:
Compound 57 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, isonicotinoyl chloride and conditions outlined in procedure AC. M.p.=267-269° C.; 400 MHz 1H NMR (CDCl3) δ: 8.74-8.70 (m, 2H), 8.06-8.10 (m, 1H), 7.73-7.76 (m, 1H), 7.66-7.70 (m, 1H), 7.49-7.55 (m, 1H), 7.30-7.33 (m, 2H), 4.65-4.71 (m, 1H), 3.62-3.69 (m, 1H), 3.45-3.56 (m, 1H), 3.34-3.45 (m, 1H), 2.96-3.04 (m, 2H), 2.26-2.32 (m, 1H), 2.12-2.18 (m, 1H), 1.85-1.97 (m, 1H), 1.68-1.78 (m, 1H); LCMS: 407 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH2:19][CH3:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCCN=C=O
Product: CCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 28.2 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) propyl isocyanate, 5.8 mg of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:32][C@H:33]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([NH:32][C@H:33]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)=[O:28])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
3.05 g of N,N'-carbonyldiimidazole were added to a solution of 7.99 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 80 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was cooled to 0° C., after which a solution of 3.34 g of (3S)-3-amino-1-t-butoxycarbonylpyrrolidine in 30 ml of dry acetonitrile was added, and the mixture was stirred an the same temperature for 20 minutes; it was then stirred at room temperature for a further 1.4 hours and at 32° C. for 45 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the concentrate was diluted with 200 ml of ethyl acetate. The resulting ethyl acetate solution was washed twice with water and then once with a saturated aqueous solution of sodium chloride. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was recrystallized from diethyl ether, to give 9.11 g of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=[O:18])C.C(O)C>ClC1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:14])[CH2:16][C:17]([CH3:19])=[O:18])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Solvent: Clc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated in 50 ml of chlorobenzene together with 20 gm of acetoacetic acid ethyl ester, with the simultaneous distillation of ethanol, formed in the reaction. From the cold reaction mixture the precipitate was suctioned off, washed with dilute methanol and recrystallized from dilute acetic acid. The product had a melting point of 146°-147°C.