Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.[Cl-:10].[Li+].N1C(C)=CC=CC=1C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C=O)C.O>[Cl:10][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: [Cl-]
Reactant: Nc1cccc(CO)c1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A solution of (3-amino-phenyl)-methanol (388 mg, 3.15 mmoles), lithium chloride (270 mg, 6.3 mmoles) and 2,6-lutidine (0.821 mL, 6.93 mmoles) in DMF (10 mL) was cooled at 0° C. under nitrogen atmosphere. Methanesulphonylchloride (0.536 mL, 6.93 mmoles) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water (30 mL) was then added, and the mixture was extracted with AcOEt (3×40 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 10/0 to 8/2) to yield 330 mg of the title compound.
Reaction SMILES: [C:1]([N:5]([OH:10])[CH2:6][C:7]([OH:9])=[O:8])([CH3:4])(C)C.C(=N/O)/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1.BrCC(O[C:25]([CH3:28])([CH3:27])[CH3:26])=O.[Na]>CC(O)C.O>[C:25]([CH:6]([C:7]([OH:9])=[O:8])[N+:5]([O-:10])=[CH:1][C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O/N=C\c1ccccc1
Reactant: CC(C)(C)N(O)CC(=O)O
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(C(=O)O)[N+]([O-])=Cc1ccccc1
Reaction time: 2 h

Procedure:
t-Butyl N-Hydroxyglycine. Z-Benzaldoxime (5.64 g, 46.61 mmol) and t-butyl bromoacetate (7.58 mL, 10 g, 51.27 mmol) were added successively to a solution of sodium (1.07 g, 0.047 g-atom) in 2-propanol (120 mL). The suspension was stirred for 2 h and then poured into water (100 mL). Extraction with dichloromethane, followed by drying over anhydrous magnesium sulfate and concentration gave a residue which was chromatographed on silica gel. Elution with 60% ethyl acetate-hexanes gave t-butyl N-benzylideneglycine N-oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:5][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[C:7]([F:9])[CH:6]=1)#[N:12]
Reactant: Nc1cc(F)cc(F)c1
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: N#CN=C(N)Nc1cc(F)cc(F)c1

Procedure:
3,5-Difluoroaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: COC[N:4]1[C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:32].Cl>C1COCC1.O>[CH3:32][C:5]1[NH:4][C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc3ccc4nc(C)n(COC)c(=O)c4c3c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoate in THF:1N HCl: concentrated HCl (15:10:1, 26 ml) was stirred at 60° C. overnight. The resulting suspension was diluted with water, concentrated in vacuo to remove the THF, and chilled in an ice bath. The solid was filtered, washed with water, and dried in vacuo at 100° C. The resulting ester was dissolved in 1N NaOH (10 ml) and ethanol (~3 ml) and stirred at 60° C. for 4 hours. The solution was acidified with concentrated HCl to pH 1.5 and the resulting precipitate filtered and dried in vacuo at 110° C. to give 4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoic acid (0.195 g). 1H NMR (DMSO-d6, 300 MHz) δ: 2.59 (s, 3H, CH3), 5.46 (s, 2H, CH2O ), 7.17 (d, J=9 Hz, 2H, Ar), 7.80 (overlapping d, J=9 Hz, 2H, Ar), 7.91 (d, J=9 Hz, 2H, Ar), 8.16 (d, J=8 Hz, 1H, Ar), 9.85 (s, 1H, Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:17])([O-])=O.[H][H]>CN(C)C=O.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:17]
Reactant: [H][H]
Reactant: O=C(O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1cccc2c(=O)c(C(=O)O)c[nH]c12
Yield: 74.2 %

Procedure:
A solution of 15.0 g (64 mmol) of 1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid [J. Amer. Chem. Soc. 68, 1264 (1946)] in 300 ml of dimethylformamide is hydrogenated using 1 g of Raney nickel catalyst at 51 psi and 23° C. until the required amount of hydrogen uptake is obtained. The catalyst is filtered off and the filtrate is concentrated to 50 ml and ethanol is added. The solid is collected by filtration and washed with ethanol and ether to give 9.7 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCc2ccc(Cl)cc2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 _mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 4-chlorobenzyl chloride (130 mg, 0.81 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (74 mg, yield 38%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Cl[CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].CN(C=O)C.O>CCOC(C)=O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][C:11]#[C:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCCl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccnc(SCC#CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A mixture of thiocytosine (0.5 g.), N-(4-chlorobut-2-ynyl)phthalimide (1.03 g.), DMF (5 ml.) and 1,5-diazabicyclo[5,4,0 undec-5-ene (0.67 g.) was stirred for 2 hours. The solution was treated with water (20 ml.) and EtOAc (10 ml.) and the insoluble solid collected to give 4-amino-2-(4-phthalimidobut-2- ynylthio)pyrimidine (1.2 g.) m.p. 197°-202° (decomp.).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:53][CH:54]1[C:75](=[O:76])[N:56]2[C:57]([C:63]([O:65][CH2:66][C:67]3[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=3)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]12.Cl>ClCCl.N1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:53][C@@H:54]2[C:75](=[O:76])[N:56]3[C:57]([C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=4)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]23)=[O:29])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)C(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1cccnc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(C)(C)C)c4cccnc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
After 1.0 g (1.6 mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-[[(tert-butoxycarbonyl)(3-pyridyl)methoxy]imino]acetic acid and 0.37 g (1.77 mmol) of phosphorus pentachloride were added to 25 ml of dichloromethane, the mixture was stirred at 5° C. for 30 minutes. The resulting solution was dropwise added to a solution containing 0.65 g (1.6 mmol) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride and 1.3 ml of pyridine in 30 ml of dichloromethane. After stirring for an hour below -20° C., the solution was cooled to -40° C. After adding 50 ml of 1N hydrochloric acid, the temperature was reverted to room temperature. The dichloromethane layer was taken out, washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography. The column was eluted with dichloromethane-methanol (10:1) to give 0.90 g (57.7%) of p-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(tert-butoxycarbonyl)(3-pyridyl)methoxy]imino]acetamido]-3-chloromethyl-3-cephem-4-carboxylate.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C.Cl.C[O:32][C:33](=O)[C:34]([CH3:37])([CH3:36])[NH2:35]>C(OCC)(=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.ClCCl>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:33](=[O:32])[C:34]([CH3:37])([CH3:36])[NH:35][C:5]2=[O:11])=[CH:16][N:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)N
Reactant: Nc1cnc(Cl)nc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphosgene (1.38 g, 4.65 mmol) in ethyl acetate (20 ml) at 0° C. a solution of 2-chloro-5-aminopyrimidine (1 g, 7.75 mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added (20 minutes) and the reaction mixture was stirred for 15 minutes at the same temperature. Maintaining the reaction mixture at 0° C., vacuum was applied (10 minutes) for removing the excess of phosgene. A solution of DMAP (0.945 g, 7.75 mmol) in ethyl acetate/dichloromethane 1:1 (8 ml) was added and the reaction mixture was stirred for 5 minutes at the same temperature. 2,2-Dimethylglycine methyl ester hydrochloride (2.37 g, 15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0° C. and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with aqueous buffer (pH3) while the pH was allowed to reach ˜5-6 and two phases were separated. The organic layer was washed with aqueous buffer (pH3) (2×20 ml) and then brine (20 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as orange foam.
Reaction SMILES: C([CH:3]([C:20]([OH:22])=[O:21])[N:4]([C:10](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH3:9])([CH3:8])=[S:7])C.[CH3:23]COCC>Br.C(O)(=O)C>[CH2:10]([N:4]([CH2:5][P:6]([CH3:9])([CH3:8])=[S:7])[CH2:3][C:20]([OH:22])=[O:21])[CH3:23]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(C)(C)=S)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(C)(C)=S
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(dimethylthiophosphinylmethyl)glycine (2 g., 0.005 mole) was dissolved in 36% hydrogen bromide (8 ml) in glacial acetic acid at 0° C. and the resulting mixture was stirred for one hour. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(dimethylthiophosphinylmethyl)glycine (0.7 g., 0.002 mole) as an amber oil, ND22 =1.4832.
Reaction SMILES: N1CC[O:4]CC1.C[CH:8]1[CH2:25][C:24]2[C:10](=[CH:11][C:12]3[N+:17]([O-:18])=NC(CCC=O)=[N:14][C:13]=3[CH:23]=2)[CH2:9]1.[BH3-]C#N.[Na+].[CH3:30][C:31]([OH:33])=O>CCO>[N+:17]([C:12]1[CH:11]=[C:10]2[C:24]([CH2:25][CH2:8][CH2:9]2)=[CH:23][C:13]=1[NH:14][C:31](=[O:33])[CH3:30])([O-:18])=[O:4]
Reactant: CC(=O)O
Reactant: CC1Cc2cc3nc(CCC=O)n[n+]([O-])c3cc2C1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Reaction time: 0.5 h

Procedure:
Morpholine (0.64 mL, 7.3 mmol) was added to a solution of aldehyde 101 (0.47 g, 1.8 mmol) in EtOH (20 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (0.35 g, 5.5 mmol) was added and the mixture stirred at 0° C. for 30 min, then HOAc (0.5 mL) was added and the mixture stirred at 20° C. for 30 min. The solvent was evaporated and the residue partitioned between DCM and water, the organic phase was dried, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give (i) starting material 101 (83 mg, 17%) and (ii) alcohol 103 (134 mg, 28%) as a white solid: mp (MeOH/EtOAc) 70-71° C.; 1H NMR δ 8.21 (s, 1H, H-9), 7.71 (s, 1H, H-5), 3.78 (t, J=6.1 Hz, 2H, CH2O), 3.20-3.28 (m, 2H, CH2), 3.15 (t, J=7.2 Hz, 2H, CH2), 2.64-2.78 (m, 3H, H-7, CH2), 2.35 (br s, 1H, OH), 2.12-2.19 (m, 2H, CH2), 1.19 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 165.7, 154.6, 148.7, 147.3, 132.3, 122.6, 114.4, 62.1, 41.2, 40.9, 35.0, 30.6, 24.7, 20.2. Anal. calcd for C14H17N3O2.¼H2O: C, 63.7; H, 6.7; N, 15.9. Found: C, 63.7; H, 6.6; N, 15.9%; and (iii) 1-oxide 102 (331 mg, 55%) as a yellow gum: 1H NMR δ 8.22 (s, 1H, H-9), 7.70 (s, 1H, H-5), 3.60 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.21-3.28 (m, 2H, CH2), 3.05 (br t, J=7.4 Hz, 2H, CH2), 2.65-2.77 (m, 3H, H-7, CH2), 2.47-2.54 (m, 6H, 3×CH2N), 2.11 (p, J=7.3 Hz, 2H, CH2), 1.19 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 165.7, 154.4, 148.5, 147.5, 132.3, 122.7, 114.4, 66.7 (2), 55.1, 53.5 (2), 41.2, 40.9, 35.2, 35.0, 24.7, 20.2; MS (FAB+) m/z 392 (MH+, 100%), 311 (20); HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1978, found 329.1978.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](/[CH:24]=[CH:25]/[C:26]4[CH:36]=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[OH-].[Na+]>[C:1]12([C:11]3[CH:12]=[C:13](/[CH:24]=[CH:25]/[C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:35][CH:36]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc(OCOCCOC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COCCOCOc1ccc(/C=C/c2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
2.0 g (4.0 mmol) of ethyl 4-[(E)-2-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)ethenyl]-benzoate and methanolic sodium hydroxide solution (1.6 g of sodium hydroxide in 50 ml of methanol) were introduced into a round-bottomed flask. The mixture was refluxed for four hours and evaporated to dryness, and the residue was taken up in water and acidified to pH 1. The aqueous phase was extracted with ethyl acetate and the organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from the minimum amount of ethyl ether, filtered and dried. 1.4 g (74%) of the expected acid, with a melting point of 207–208° C., was collected.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2(OCC[O:7]2)[CH2:5][N:4]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3]1=[O:19].Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:20][C:2]1([CH3:1])[C:6](=[O:7])[CH2:5][N:4]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3]1=[O:19]
Reactant: C[C@H](c1ccccc1)N1CC2(OCCO2)C(C)(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)=O
Product: C[C@H](c1ccccc1)N1CC(=O)C(C)(C)C1=O
Yield: 77.4 %

Procedure:
A mixture of 18.23 g of 9,9-dimethyl-8-oxo-7-[1-(R)-phenylethyl]-7-aza-1,4-dioxaspiro[4.4]nonane, 70 ml of 1N hydrochloric acid and 20 g of p-toluenesulfonic acid in 250 ml of acetone was heated under reflux for 20 hrs. During the reaction, 20 g of p-toluenesulfonic acid was further added. Solvent was removed under reduced pressure and the residue was extracted with chloroform. The extract was washed with a saturated sodium bicarbonate aqueous solution and dried. Solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (300 g of silica gel in a column) while eluting with a mixture of n-hexane and ethyl acetate (4:1, v/v) to yield 11.85 g of the titled compound. 1H-NM(CDCl3) δ ppm;1.20, 1.26 (each 3H, s), 1.60 (2H, ABq, J=16 Hz), 5.80 (1H, q, J=7.2 Hz), 7.32 (5H, s)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][NH:11][CH3:12])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8]
Reactant: CN(Cc1nn(C)c(C#N)c1Br)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1nn(C)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.9 %

Procedure:
To a 0° C. solution of compound 47 (1.0 g, 3.0 mmol) in DCM (15 mL) was added 4 N HCl in dioxane (3.8 mL, 15 mmol). Allowed to stir at room temperature for 3 hours, then concentrated under vacuum to give compound 109 (810 mg, quantitative) as a white solid.
Reaction SMILES: [Na].C([O:5][C@@H:6]1[C@@H:11]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[C@@H:10]([O:25]C(=O)C)[C@@H:9]([CH2:29][O:30]C(=O)C)[O:8][C@H:7]1[S:34][C@@H:35]1[O:48][C@H:47]([CH2:49][O:50]C(=O)C)[C@H:42]([O:43]C(=O)C)[C@H:41]([NH:54][C:55](=[O:66])[C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[C:58]([O:64][CH3:65])[CH:57]=2)[C@H:36]1[O:37]C(=O)C)(=O)C.C[O-].[Na+].C1COCC1>CO>[CH3:63][O:62][C:60]1[CH:61]=[C:56]([CH:57]=[C:58]([O:64][CH3:65])[CH:59]=1)[C:55]([NH:54][C@H:41]1[C@@H:42]([OH:43])[C@@H:47]([CH2:49][OH:50])[O:48][C@@H:35]([S:34][C@@H:7]2[O:8][C@H:9]([CH2:29][OH:30])[C@H:10]([OH:25])[C@H:11]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)[C@H:6]2[OH:5])[C@@H:36]1[OH:37])=[O:66]
Reactant: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H](S[C@@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](NC(=O)c4cc(OC)cc(OC)c4)[C@H]3OC(C)=O)[C@@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](S[C@@H]3O[C@H](CO)[C@H](O)[C@H](NC(=O)c4cc(OC)cc(OC)c4)[C@H]3O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
Sodium (1.5 mg, 0.07 mmol) was dissolved in methanol (1 ml). Bis(2,4,6-tri-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-β-D-galactopyranosyl) sulfane 14 (11 mg, 0.012 mmol) was dissolved in methanol (1 ml) and the sodium methoxide solution was added. The mixture was stirred at room temperature for 3 h. After this time, a precipitate had appeared. THF (3 ml) was added, and the precipitate dissolved. Duolite C436 (H+) was added, and the mixture was stirred for 5 minutes. After this time, the mixture was filtered and concentrated in vacuo. The residue was purified by HPLC (gradient H2O→MeCN) to give bis(3-deoxy-3-(3,5-dimethoxybenzamido)-β-D-galactopyranosyl) sulfane 19 (4.7 mg, 58%). White solid;
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(Cl)=[O:15].Cl.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]([C:32]3[CH:41]=[C:40]4[C:35]([CH2:36][CH2:37][NH:38][CH2:39]4)=[CH:34][CH:33]=3)[N:29]=[C:28]([NH2:42])[N:27]=2)[CH2:22][CH2:21]1>>[NH2:42][C:28]1[N:29]=[C:30]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][N:38]([C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:12][N:11]=4)=[O:15])[CH2:39]3)=[CH:34][CH:33]=2)[CH:31]=[C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)[N:27]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccc(-c5ccccc5)cn3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 5-phenylpyridin-2-amine (Matrix Scientific, Cat. #007056), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=521.2.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH2:12].C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1.[O:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]2[N:33]=[CH:34][C:35]3[CH2:41][CH2:40][NH:39][CH2:38][C:36]=3[N:37]=2)[CH2:27][CH2:26]1>C(Cl)Cl>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][C:18]([N:39]1[CH2:40][CH2:41][C:35]2[CH:34]=[N:33][C:32]([NH:31][CH:28]3[CH2:27][CH2:26][O:25][CH2:30][CH2:29]3)=[N:37][C:36]=2[CH2:38]1)=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Reactant: NCc1cc2ccccc2[nH]1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc2ccccc2[nH]1)N1CCc2cnc(NC3CCOCC3)nc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1H-indol-2-yl)methanamine hydrochloride (50 mg, 0.27 mmol, CASRN 21109-25-1) and DCM (2.5 mL) at RT were added sequentially TEA (50 μL, 0.36 mmol) and CDI (44 mg, 0.27 mmol) and the reaction was stirred at RT for 30 min. This solution was added to a solution of 28 (55 mg, 0.229 mmol) and TEA (95.7 μL, 0.687 mmol) in DCM (5 mL) and the combined solution was stirred overnight. This solution was loaded directly a SiO2 chromatography column and eluted with a gradient hexane/EtOAc (0 to 10% EtOAc) to afford 57 mg (61.1%) of I-114: 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.07 (s, 1H), 7.54 (d, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.12-7.17 (m, 1H), 7.04-7.08 (m, 1H), 6.31-6.32 (m, 1H), 4.99-5.03 (m, 1H), 4.87 (d, 1H, J=7.7 Hz), 4.50 (d, 2H, J=5.9 Hz), 4.34 (s, 2H), 3.94-4.04 (m, 3H), 3.65-3.69 (m, 2H), 3.49-3.56 (m, 2H), 2.66-2.71 (m, 2H), 1.98-2.04 (m, 2H), 1.46-1.57 (m, 2H); MS (APCI-pos) M+1=407.4.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:24])=O.C1C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([Cl:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
o-Phenylbenzoic acid (163 mg) was dissolved in 5 ml of methylene chloride, a catalytically effective amount of N,N-dimethylformamide was added dropwise, and 0.165 ml of oxalyl chloride was added dropwise. After 3 hours of stirring at room temperature, benzene was added and the solvent was evaporated to obtain o-phenylbenzoic acid chloride.