Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.O.[CH3:20][N:21]([CH3:31])[C:22]([CH2:24][C:25]1[S:26][C:27]([SH:30])=[N:28][N:29]=1)=[O:23].P(Cl)(Cl)(OP(Cl)(Cl)=O)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:30][C:27]3[S:26][C:25]([CH2:24][C:22]([N:21]([CH3:20])[CH3:31])=[O:23])=[N:29][N:28]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN(C)C(=O)Cc1nnc(S)s1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 10 °C
Yield: 87.7 %

Procedure:
Mixed were 1.36 g of 7-ACA, 0.36 g of water and 1.32 g of 2-dimethylaminocarbonylmethyl-5-mercapto-1,3,4-thiadiazole, and 6.5 ml of acetonitrile was added. 5.04 g of diphosphoryl tetrachloride was added through a dropping funnel to the mixture at -20° to -30° C., followed by rinsing the funnel with 1.5 ml of acetonitrile. The reaction mixture was warmed at 10° C. over a period of 5 minutes with stirring, placed in a warm water bath of 40° C. and stirred at the same temperature for 20 minutes. The reaction solution was cooled with ice and adjusted to pH 4.1 with aqueous concentrated ammonia after the addition of 10 ml of cold water. The precipitate was recovered by filtration, washed with water and dried, thereby affording 1.82 g (87.6%) of 7-amino-3-(2-dimethylaminocarbonylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=O.[OH:13][C:14]1[C:15]([CH3:34])=[C:16]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)[CH:17]=[CH:18][CH:19]=1.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:3][O:13][C:14]1[C:15]([CH3:34])=[C:16]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]4)[CH2:30]2)[CH2:24]3)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (0.20 ml) was added to a solution of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.20 g, Example 26), methanol (0.10 ml) and triphenylphosphine (0.41 g) in toluene (10 ml) and tetrahydrofuran (5 ml). After 2 hours stirring at room temperature further triphenylphosphine (0.20 g) and diethyl azodicarboxylate (0.10 ml) were added and the solution stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel to chromatography eluting with dichloromethane:ethyl acetate (19:1) to give the title compound as a colourless solid (0.20 g).
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[CH:10]=[C:11]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])[C:12](=[O:26])[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14]=1[CH3:15])=[CH2:8])CCC.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:7]([C:9]1[CH:10]=[C:11]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])[C:12](=[O:26])[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14]=1[CH3:15])(=[O:6])[CH3:8]
Reactant: C=C(OCCCC)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Yield: 51.5 %

Procedure:
Aqueous hydrochloric acid (2.0M, 50 μl) was added to a solution of 5-(1-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (38 mg, 67.5 μmol) in DMF (0.5 ml). After 20 min. the solution was neutralized with aqueous sodium hydrogen carbonate. The reaction mixture was purified by preparative HPLC to give the title compound as a white solid (17.6 mg, 51%).
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]1)[C:10](=[O:23])[NH:9][C:8]2=[O:24].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:9]2[C:8](=[O:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH:2]([F:1])[F:25])[CH:6]=3)[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]3)[C:10]2=[O:23])=[CH:29][CH:30]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=CN1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CN1CCC(n2c(=O)n(Cc3ccc(Cl)cc3)c(=O)c3cc(OCC(F)F)ccc32)CC1
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A mixture of 0.15 g of 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 3.7, 0.096 g of 1-(bromomethyl)-4-chlorobenzene and 0.3 g of Cs2CO3 in 3 ml of DMF is stirred at AT for 1 h 00. AcOEt is added and washing is carried out with water and then with a saturated NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with AcOEt, to give 0.116 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[S:12])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[O-].[K+].C(OCC)(=O)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[S:12])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
To 57 mg of ethyl 5-chloro-3-phenylthioindole -2-carboxylate from Preparation 5 in 1.7 mL of dry tetrahydrofuran, under argon, was added 48 mg of solid potassium trimethylsilanolate. The resultant mixture was stirred at room temperature for 20 h. Ethyl acetate and 1N HCl were then added. The organic layer was washed with brine (2x) and dried over MgSO4. Filtration and concentration gave a yellow gum which was triturated with ether hexane to give the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].I[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:7]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])[N:23]=2)[N:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3ccccc3)ccc2n1)C1CC1
Yield: 54.6 %

Procedure:
Using phenol (69 mg, 0.73 mmol), N,N-dimethylformamide (25.0 mL), potassium tert-butoxide (1.16 g, 10.3 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (200 mg, 0.61 mmol) and potassium carbonate (42 mg, 0.31 mmol), and in the same manner as in Example 216, the title compound (98 mg, 54%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH3:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(C)NC(=O)OC(C)(C)C)cc1

Procedure:
Through a mixture of 3-[4-(1-tert-butoxycarbonylamino-ethyl)-phenyl]-acrylic acid ethyl ester (0.22 g, 0.69 mmol) and palladium hydroxide on carbon (100 mg) in ethanol (10 mL) was bubbled hydrogen through a balloon for 17 h. The mixture was filtered through celite and concentrated to afford an off-white solid. M+1=322.
Reaction SMILES: Br[C:2]1[N:27]=[C:5]2[CH2:6][CH:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]3[S:20][CH:21]=[C:22]([CH:24]([F:26])[F:25])[N:23]=3)=[O:12])[CH2:8][CH2:9][N:4]2[N:3]=1.[CH3:28][O:29][CH2:30][C@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>C(OCC)(=O)C>[F:25][CH:24]([F:26])[C:22]1[N:23]=[C:19]([C:14]2[CH:15]=[N:16][N:17]([CH3:18])[C:13]=2[C:11]([NH:10][CH:7]2[CH2:8][CH2:9][N:4]3[N:3]=[C:2]([N:32]4[CH2:33][CH2:34][CH2:35][C@@H:31]4[CH2:30][O:29][CH3:28])[N:27]=[C:5]3[CH2:6]2)=[O:12])[S:20][CH:21]=1
Reactant: COC[C@H]1CCCN1
Reactant: Cn1ncc(-c2nc(C(F)F)cs2)c1C(=O)NC1CCn2nc(Br)nc2C1
Solvent: CCOC(C)=O
Product: COC[C@H]1CCCN1c1nc2n(n1)CCC(NC(=O)c1c(-c3nc(C(F)F)cs3)cnn1C)C2
Temperature: 150 °C

Procedure:
The N-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (20 mg) obtained in (Example 5.16) <Step 7> and (R)-2-(methoxymethyl)pyrrolidine (0.5 ml) were heated at 150° C. for 4 days. Thereafter, ethyl acetate (50 ml) and a saturated saline (20 ml) were added to the reaction solution, and an organic layer was then extracted. The obtained organic layer was dried over sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by preparative thin-layer chromatography (silica gel: eluent; ethyl acetate), so as to obtain the title compound (2.1 mg) in a yellow amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][SH:6].C([Li])CCC.[O:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]1[C:15]([OH:17])=[O:16].OS(O)(=O)=O>O1CCCC1.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:13][CH:14]([CH:18]([S:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C1OC1c1ccccc1CCCCCCCCc1ccccc1
Reactant: COC(=O)CCS
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of methyl-3-mercaptopropionate (0.8 ml, 7.2 mmole) in tetrahydrofuran (3 ml) was added dropwise at -10° C. to a solution of n-butyllithium (3.2 ml, 2.5M in hexane) in tetrahydrofuran (10 ml) under an inert atmosphere. In a second flask, 2,3-epoxy-3-[2-(8-phenyloctyl)phenyl]propanoic acid (1 gm, 2.84 mmole) was suspended in tetrahydrofuran (4 ml) and stirred at -10° C. under an inert atmosphere while a solution of titanium isopropoxide (2.2 ml, 7.15 mmole) in tetrahydrofuran (6 ml) was added dropwise keeping the internal temperature below 0° C. The resulting solution was again cooled to -10° C. and added via syringe to the above mercaptide solution, and the whole was subsequently stirred for 1 hour at 0° C. The reaction mixture was diluted with water, treated with 10% H2SO4 and extracted 3 times with ethyl acetate. The combined ethyl acetate extracts were washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography of the residue on silica gel using hexane-ethyl acetate-formic acid (65/35/0.5) yield the title compound. Anal.: Calcd for C27H36O5S 0.5 H2O: C, 67.33; H, 7.74. Found: C, 67.33; H, 7.46. 250 MHZ MR (CDCl3) δ1.28-1.68 (12 H,m) 2.50-2.92 (8 H,m) 3.70 (3 H,s) 4.62 (1 H,d) 4.68 (1 H,d) 7.10-7.60 (9 H, m).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:28])=[CH:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C[Si](C)(C)[O-:31].[K+]>O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:28])=[CH:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[C:12]([C:15]([NH2:16])=[O:31])=[N:13][CH:14]=1
Reactant: CC1=CCCc2nc(Nc3cc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)ccc21
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1=CCCc2nc(Nc3cc(N[C@@H]4CCCC[C@@H]4N)cnc3C(N)=O)ccc21
Temperature: 100 °C

Procedure:
A suspension of 5-((1R,2S)-2-aminocyclohexylamino)-3-(5-methyl-7,8-dihydroquinolin-2-ylamino)picolinonitrile (19 mg, 0.051 mmol) and potassium trimethylsilanolate (98 mg, 0.76 mmol) in 1,4-dioxane (1 mL) was heated to 100° C. in an oil bath for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DMSO, filtered, and purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to yield 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5-methyl-7,8-dihydroquinolin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C22H29N6O [M+H]+ 393. found 393.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH3:15])[CH:10]=[C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:31]([N:25]1[CH2:26][C@@H:16]([C:9]2[CH:10]=[C:11]([CH2:13][CH2:14][CH3:15])[CH:12]=[C:2]([Cl:1])[C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCCc1cc(Cl)c(C(=O)OCC)c(/C=C/C(=O)OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(Cc3ccccc3)C[C@H]2C(=O)OC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of (E)-ethyl 2-chloro-6-(3-methoxy-3-oxoprop-1-enyl)-4-propylbenzoate (0.92 g, 2.96 mmol) in 20 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.77 g, 3.25 mmol) and trifluoroacetic acid (0.045 mL, 0.6 mmol). The solution was allowed to stir at 40° C. for 2 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.1 g, 0.4 mmol) and trifluoroacetic acid (2 drops) were added and the reaction was stirred at 40° C. for an additional 30 min and then at ambient temperature for 18 h. The reaction was quenched with sat'd aq NaHCO3 and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, 6:1 hexane/EtOAc) to afford 1.17 g (90%) of the title compound as an oil. LRMS (ES)+: 444.25/446.24 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH:14][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])(=[O:12])=[O:13]
Reactant: CCCCN=C=O
Reactant: CSc1cccc(SC)c1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNC(=O)NS(=O)(=O)c1c(SC)cccc1SC
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A stirred suspension of 5.0 g (0.02 mol) of 2,6-bis(methylthio)benzenesulfonamide, 8.3 g (0.06 mol) potassium carbonate and 3.4 ml (0.03 mol) n-butyl isocyanate was heated at reflux for four hours. After stirring at 25° overnight, the mixture was poured into ice and 30 ml 10% HCl. The resulting precipitate was collected, washed several times with water and air dried to provide 6.5 g of the title compound, m.p. 151°-154°.
Reaction SMILES: C(O[C@@H:5]1[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C[Si]([N:52]=[N+:53]=[N-:54])(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[C:21]([O:20][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:35][C@@H:18]1[O:17][C@@H:16]1[C@@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:42][C@@H:5]([N:52]=[N+:53]=[N-:54])[C@H:6]([O:7][C:8](=[O:10])[CH3:9])[C@H:11]1[O:12][C:13](=[O:15])[CH3:14])(=[O:23])[CH3:22]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of β-lactose octaacetate (203 mg, 0.3 mmol), trimethylsilyl azide (41 mg, 0.35 mmol), and SnCl4 (40 mg, 0.15 mmol) in CH2Cl2 (1.5 ml) was stirred overnight at room temperature. The solution was diluted with CH2Cl2 (20 ml) and washed twice with 1 M potassium fluoride solution (5 ml), water (5 ml) and evaporated affording 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl azide (25) (178 mg 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=O)[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.CN(C=O)C.[Br:20]N1C(=O)CCC1=O>ClCCl>[NH2:12][C:7]1[C:8]([C:9]([O:10][CH3:11])=[O:14])=[C:3]([O:2][CH3:1])[C:4]([Br:20])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)ccc(Br)c1OC

Procedure:
A mixture of Example 470A (9.8 g, 50.7 mmol), DMF (50 mL), and dichloromethane (150 mL) was cooled to 0° C., treated portionwise with N-bromosuccinimide (12.6 g, 76 mmol), stirred until all the starting material was consumed, and filtered. The filter cake was washed with dichloromethane combined filtrates were concentrated, treated with anhydrous methanol (450 mL), and heated to reflux for 54 hours. Purification by flash column chromatography on silica gel with 15% ethyl acetate/hexanes provided the desired product. MS (ESI(+)) m/e 260, 262 (M+H)+, 277, 279 (M+NH4)+, 282, 284 (M+Na)+; (ESI(−)) m/e 258, 260 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, 1H), 6.50 (d, 1H), 5.63 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1ccnc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N)n1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (150 mg, 1.158 mmol) and sodium methoxide (188 mg, 3.47 mmol) in methanol (2.9 ml) was heated to 100° C. via a Biotag microwave for 40 min. The crude product mixture was purified by RP-HPLC to give 2-(methyloxy)-4-pyrimidinamine (73 mg, 0.583 mmol, 50% yield). MS (ES+) m/z 126.0 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([NH2:23])[CH2:16][CH2:17][CH2:18][C:19](O)([CH3:21])[CH3:20].Cl>>[NH2:23][CH:15]([CH3:14])[CH2:16][CH2:17][CH2:18][C:19]([C:7]([C:19]([CH3:21])([CH2:18][CH2:17][CH2:16][CH:15]([NH2:23])[CH3:14])[CH3:20])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:21])[CH3:20]
Reactant: CC(N)CCCC(C)(C)O
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: Cl
Product: CC(N)CCCC(C)(C)C(c1ccccc1)(c1ccccc1)C(C)(C)CCCC(C)N

Procedure:
16.8 parts of diphenylmethane were reacted with 36.4 parts of heptaminol hydrochloride according to the procedure of Example 2. Distillation gave 22.4 parts of bis-(6-amino-2-methylhept-2-yl)diphenylmethane b0.4 230°-44° C. Analysis of this fraction showed it to contain 73% of the 4,4'-isomer with the following percentage composition by weight
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4]2([CH2:21][O:22][CH2:23][CH2:24]1)[C:17]1[CH:16]=[C:15]([OH:18])[CH:14]=[C:13]([F:19])[C:12]=1[O:11][C:10]1[C:5]2=[CH:6][C:7]([Br:20])=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH2:36](I)[C:37]([CH3:40])([CH3:39])[CH3:38]>O>[Br:20][C:7]1[CH:6]=[C:5]2[C:10]([O:11][C:12]3[C:13]([F:19])=[CH:14][C:15]([O:18][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=3[C:4]32[CH2:21][O:22][CH2:23][CH2:24][C:2]([NH2:1])=[N:3]3)=[CH:9][CH:8]=1
Reactant: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with (E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-ol (222.7 mg, 0.566 mmol), cesium carbonate (738 mg, 2.265 mmol), and DMF (2832 μL) to give a yellow suspension. The resulting mixture was stirred for 10 min, then neopentyl iodide (225 μL, 1.699 mmol) was added. The vial was capped and heated to 100° C. for 2 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH2:7][S:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:7][S:8]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)CCCC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 27 %

Procedure:
Cs2CO3 (0.51 eq) was added to a solution of 4-(aminosulfonyl)butanoic acid (1 M) in DMF. After 1 h, benzyl bromide (1 eq) was introduced and the reaction left to stir overnight before diluting with DCM and filtering. The filtered liquor was concentrated in vacuo, the residue taken up in DCM and washed with saturated aqueous NaHCO3, water and brine, before being dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with Et2O afforded the title compound as a white solid (27%). (ES+) m/z 280 (M+Na)+
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH:8]([C:10]([O:12]CC)=[O:11])[CH2:7][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]2.[Li+].[OH-]>C1COCC1>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH:8]([C:10]([OH:12])=[O:11])[C:9]2=[N:1][NH:2][CH:3]=[C:4]2[CH2:5]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl ester 4b (250 mg, 0.846 mmol) in THF (5 mL) was cooled to 0° C. and 1 M LiOH (2.12 mL, 2.12 mmol) was added. The mixture stirred at 0° C. for 30 min followed by stirring at rt for 2 h. The THF was removed in vacuo and the remaining aqueous solution diluted with deionized H2O to a total volume of 8 mL. The aqueous mixture was extracted with Et2O (3×) and cooled to 0° C. 2 M HCl was added to obtain pH=3 and the mixture extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over MgSO4 and filtered through a Celite plug capped with a layer of MgSO4. The solution was concentrated to give the title compound 5b as brittle ivory foam crushed to an ivory solid; 136 mg, 60%, MS m/z 266.0 (ESI−, M−1).