Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:21]3([OH:31])[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.Cl>[OH:31][C:21]1([C:11]2[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]1
Reactant: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C3(O)CCC(=O)CC3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a solution of 8-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 30) (14.6 g, 34.7 mmol) in tetrahydrofuran (69.4 mL), 6 M hydrochloric acid (138.9 mL) was added, and the obtained solution was stirred at room temperature for 15 hours. The reaction solution was cooled in ice, and 50% aqueous sodium hydroxide solution was added dropwise thereto at 0° C. until it became basic. Thereafter, the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization (n-hexane/ethyl acetate, 70° C.) to obtain the title compound (10.5 g, 27.9 mmol, 80%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.[C:27](OC(=N)N(C(C)C)C(C)C)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:23][C:22]([C:5]1[N:4]2[C:25](=[O:26])[CH:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:16][C:17]1[NH:18][N:19]=[N:20][N:21]=1)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])=[O:24])([CH3:30])([CH3:29])[CH3:28]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 21.1 g. (0.05 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml. of dry methylene chloride is added in one portion a solution of 30.0 g. (0.15 mol.) of O-t-butyldiisopropylpseudourea in 50 ml. of methylene chloride. The mixture is stirred at ambient temperature for 24 hours. The precipitate is removed by filtration and the filtrate evaporated to a residue which is taken up in 200 ml. of benzene and filtered again. The filtrate is extracted with three 100 ml. portions of cold 1N hydrochloric acid. The acidic aqueous extracts are layered with ethyl acetate and the pH adjusted to 7.5 with solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml. portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to give 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.CN(C)[C:30]([C:36](OCC)=O)=[CH:31][CH:32]=[N+](C)C.CC[O-].[Na+].CSCC(C1C=CC2C(=CC=CC=2)C=1)=O>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:36][CH:30]=[CH:31][CH:32]=2)[CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: CSCC(=O)c1ccc2ccccc2c1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc2ccccc2c1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10.6 g), a 2M ethanolic solution of sodium ethylate (18.5 cc) and 2-[2-(methylthio)acetyl]naphthalene (8 g) in ethanol (50 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-5-methylthio-6-(2-naphthyl)-6-oxo-2,4-hexadienoate (5 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]([F:22])[F:21])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:23]O>CO.[OH-].[Li+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]([F:22])[F:21])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:23]2)[CH:7]=1
Reactant: OO
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2OC(F)F)C1=O
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (8.89 g, 0.023 mol) in methanol (380 ml) at 35° C. is added 50% aqueous hydrogen peroxide (2.30 ml, 0.034 mol), immediately followed by 2M aqueous lithium hydroxide (2.30 ml, 0.0046 mmol). After stirring at this temperature for 1 hour the reaction mixture is allowed to cool, then quenched with 10% sodium metabisulfite solution (negative KI-starch indicator test). The reaction mixture is extracted with diethyl ether (×3), then the organic phase is further washed with saturated aqueous sodium bicarbonate (×2) then brine. All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 2-(5-bromo-2-difluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (7.22 g) a yellow gum.
Reaction SMILES: O[CH:2]([CH2:5][CH2:6][C:7]([F:23])([F:22])[CH:8]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[CH:9]=[CH2:10])[CH:3]=[CH2:4].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:24]1(=[O:34])[N:28]([CH:2]([CH2:5][CH2:6][C:7]([F:23])([F:22])[CH:8]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH:9]=[CH2:10])[CH:3]=[CH2:4])[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: C=CC(O)CCC(F)(F)C(C=C)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(CCC(F)(F)C(C=C)N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Reaction time: 20 h

Procedure:
A mixture of 3-hydroxy-6,6-difluoro-7-phthalimido-1,8-nonadiene (148 mg, 0.46 mmoles), phthalimide (73.5 mg, 0.5 mmoles), triphenylphosphine (131.5 mg, 0.5 mmoles) and diethyl azodicarboxylate (73 l, 0.6 mmoles) in tetrahydrofuran (5 ml) is kept under nitrogen at 25° C. for 20 hours. After concentration under reduced pressure, the title compound is obtained after purification by chromatography on silica (dichloromethane, RF: 0.43): 95 mg (46%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1.O=O>C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: O=O
Solvent: CCOC(C)=O
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
5% Ru/Al2O3 (101 mg, 0.5 mmol) was added to a solution of 2-bromo-7-hydroxymethylimidazo[5,1-b] thiazole (23 mg, 0.1 mmol) in ethyl acetate (2 ml). The air in the system was replaced with oxygen, and the mixture was stirred at 80° C. for 18 hr. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (19 mg, 82%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11](O)=O)=[CH:9][N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=1[NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH:14]1([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[NH:29][C:21]4[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=4[N:19]=3)=[CH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: Nc1ncnc2c1c(C(=O)O)cn2C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Nc1ncnc2c1c(-c1nc3ccc([N+](=O)[O-])cc3[nH]1)cn2C1CCCC1
Reaction time: 6 h
Yield: 28.8 %

Procedure:
4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (ID, 12.0 g, 488 mmol), 1,2-diamino-4-nitrobenzene (11.2 g, 73.1 mmol), and HATU (26.0 g, 73.1 mmol) were combined and stirred in 242 mL of anhydrous NMP under N2 at 50° C. After 6 hrs, reaction was monitored by LCMS confirming the loss of the starting material and the formation of a new component. The reaction mixture was decant into ten 50 mL centrifuge tubes and concentrated overnight in the GeneVac. Dark brown oil was taken up in EtOAc (1.6 L) and extracted using 1.2 L H2O. The organic layer was washed with H2O (3×900 mL) and then concentrated. The residue (dark brown gum) was triturate in ˜900 mL CH2Cl2, 10.02 g of a reddish black solid was collected after filtration and vacuum drying. 1H NMR suggested it contained the coupling product plus 20-30% impurity. The solid was again taken up in 1.5 L EtOAc, washed with H2O (5×900 mL). The organic layer was concentrated and residue triturated in ˜900 mL CH2Cl2, filtered and dried to furnish 7.65 g of a yellow solid. 1H NMR and LCMS suggested the coupling product plus minor impurities (88% pure by LCMS at 210 nm, M/Z 381.5, retention time 2.3 min. with analytical HPLC method 1).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:18])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2].C(O)(=[O:21])C.OO>O>[CH2:1]([O:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:18])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:21])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1CCSc2c(C)cc(C(=O)O)c(C)c21
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: CCOC1CCS(=O)c2c(C)cc(C(=O)O)c(C)c21

Procedure:
A 50-ml egg-plant type flask was charged with 2.9 g (0.011 mol) of 4-ethoxy-5,8-dimethylthiochroman-6-carboxylic acid, 10 ml of acetic acid and 1.3 g (0.011 mol) of a 30% hydrogen peroxide aqueous solution, and the mixture was allowed to react at room temperature for 12 hours. Then, the reaction mixture was poured into 100 ml of water. The precipitated oil was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.5 g of 4-ethoxy-5,8-dimethylthiochroman-6-carboxylic acid-1-oxide (Compound 31) shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:18][C:19]1[N:20]([CH2:40][CH3:41])[C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[N:24]=[C:23]([C:37]#[N:38])[C:22]=2[N:39]=1>CN(C=O)C>[CH2:40]([N:20]1[C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[N:24]=[C:23]([C:37]#[N:38])[C:22]=2[N:39]=[C:19]1[CH2:18][NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:41]
Reactant: CCn1c(CCl)nc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Reactant: Nc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(CNc2ccncc2)nc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Temperature: 80 °C
Yield: 48.2 %

Procedure:
4-Aminopyridine (26 mg, 0.27 mmol) was added to a solution of diisopropylethylamine (0.24 mL, 1.37 mmol) and 2-chloromethyl-1-ethyl-6-(3-trifluoromethy-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.100 g, 0.27 mmol) in DMF (3 mL). The mixture was heated at 80° C. for 2 hours, than filtered. The precipitate was washed with water, then isopropyl ether, dried to afford the title compound (55 mg, 47%) as a solid (mp=340° C.). 1H NMR (DMSO-d6) δ: 8.84 (s, 1H); 8.6-8.5 (m, 2H); 8.31 (d, J=8 Hz, 2H); 7.9-7.7 (m, 2H); 6.97 (d, J=8 Hz, 2H); 5.98 (s, 2H); 4.51 (q, J=7 Hz, 2H); 1.45 (t, J=7 Hz, 3H). MS m/z: 423 (M+1).
Reaction SMILES: C(O)=O.C1N=CN([C:9]([N:11]2C=N[CH:13]=[CH:12]2)=[O:10])C=1.[N+](C[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[C-].CCN(CC)CC>C1COCC1.O>[CH2:22]([O:21][C:19]([C:12]1[N:11]=[CH:9][O:10][CH:13]=1)=[O:20])[CH3:23]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cocn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a sol. of formic acid (8.62 mL, 228 mmol) in dry THF (200 mL) was added portionwise CDI (37.05 g, 228 mmol), whereas a gas evolution occurred. The mixture was stirred for 30 min, and a sol. of ethyl isocyanoacetate (25 mL, 228 mmol) in Et3N (60.5 mL, 434 mmol) was added to the reaction mixture. The mixture was stirred at rt for 1 h, then under reflux overnight. The reaction mixture was allowed to cool to rt. Water was added, and the mixture was extracted with Et2O (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated. Purification of the residue by FC (EtOAc/heptane; 1:5 →1:3→1:1) yielded the title compound (27.2 g, 84%). LC-MS: tR=0.58, ES+: 142.07.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][NH:5]1)#[N:2].C(CC1C2N=C(C3C=CC(NC(NCC)=O)=CC=3)N=C(N3CCOC[C@@H]3C)C=2CCN1C(OC(C)(C)C)=O)#N.Cl>O1CCOCC1>[C:1]([CH2:3][C@@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][NH:5]1)#[N:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN[C@H]3CC#N)cc1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3CC#N)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN[C@@H]3CC#N)cc1
Reaction time: 2.5 h

Procedure:
and 1-(4-((S)-8-(cyanomethyl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (xq2): Tert-butyl 8-(cyanomethyl)-2-(4-(3-ethylureido)phenyl)-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.599 g, 0.00112 mol) and 4.0 M of Hydrogen chloride in 1,4-Dioxane (8.5 mL) were combined and shaken for 2.5 hours then concentrated, diluted with sat NaHCO3, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, purified by HPLC, and the diastereomers were separated by SFC. R Diastereomer (xq1): 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.21 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.16 (t, J=5.6, 1H), 4.21-4.05 (m, 2H), 3.89 (d, J=11.0, 1H), 3.75 (d, J=9.1, 1H), 3.60 (dd, J=20.1, 9.2, 2H), 3.54-3.38 (m, 2H), 3.19-3.02 (m, 5H), 2.83-2.63 (m, 2H), 2.55-2.39 (m, 2H), 1.17 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+436.2 (M+H)+; S Diastereomer (xq2) 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.21 (d, J=8.7, 2H), 7.47 (d, J=8.7, 2H), 6.15 (t, J=5.5, 1H), 4.09 (d, J=5.9, 2H), 3.87 (d, J=10.4, 1H), 3.74-3.57 (m, 4H), 3.38 (t, J=10.6, 1H), 3.16-2.98 (m, 5H), 2.78 (d, J=8.1, 1H), 2.69 (d, J=14.5, 1H), 2.57-2.39 (m, 2H), 1.32 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+436.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[S:7](=[O:26])(=[O:25])[C:8]2[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=2[C:10]=1[S:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:4].CO.[Li+].[OH-]>C1COCC1.O.Cl>[O:32]1[C:31]2[CH:35]=[CH:36][C:28]([CH2:27][N:6]3[C:5]([C:3]([OH:4])=[O:2])=[C:10]([S:11][C:12]4[CH:20]=[CH:19][C:15]5[O:16][CH2:17][O:18][C:14]=5[CH:13]=4)[C:9]4[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=4[S:7]3(=[O:26])=[O:25])=[CH:29][C:30]=2[O:34][CH2:33]1
Reactant: COC(=O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To 2-benzo[1,3]dioxol-5-ylmethyl-4-(benzo[1,3]dioxol-5-ylsulfanyl)-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (0.467 g, 0.89 mmol) in THF:methanol:water (5 mL:2 mL:2 mL) was added LiOH(0.46 g, 19 mmol). Stirred at room temperature for 5 hours, diluted with water (80 mL) and 50% HCl (10 mL) then extracted with chloroform (3×80 mL). Dried with magnesium sulfate and removed solvent to afford the title compound as a foam (0.4 g, 88%);
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16](O)=O.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:32][N:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[N:35][C:34]1=[NH2+:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:40][C:36]1[CH:37]=[C:38]([CH3:39])[N:33]2[N:32]=[C:16]([CH:14]3[CH2:15][CH:13]3[C:3]3[N:2]([CH3:1])[CH:6]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]=3)[N:41]=[C:34]2[N:35]=1
Reactant: Cc1cc(C)n(N)c(=[NH2+])n1
Reactant: Cn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)n2nc(C3CC3c3nc(-c4ccccc4)cn3C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (70 mg, 0.289 mmol) in DMF (2.0 mL) was added 1-amino-4,6-dimethylpyrimidin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (98 mg, 0.289 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (93 mg, 0.289 mmol) and triethylamine (0.040 mL, 0.289 mmol) at rt. After 2 h stirring at rt, the reaction mixture was stirred at 70° C. for 12 h. The crude product was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (20% to 100% over 12 min gradient; flow: 40 mL/min) Collected the pure fractions and removed solvent. Obtained 5,7-dimethyl-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine as a white solid in 47% yield. Prepared hydrochloride salt by adding 1.0 M HCl and MeOH and removing solvent. 1H NMR (500 MHz, METHANOL-d4) δ 6.28 (s, 1H), 6.18-6.14 (m, 2H), 5.97 (s, 1H), 5.92-5.88 (m, 2H), 5.87-5.84 (m, 1H), 2.39 (s, 3H), 1.72-1.69 (m, 1H), 1.62-1.57 (m, 1H), 1.29-1.27 (m, 3H), 1.17 (s, 3H), 0.70 (dt, J=9.2, 6.1 Hz, 1H), 0.62-0.59 (m, 1H); MS (ESI) 345 (M+H); Rf=1.84 (Condition A).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([S:29]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:30])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(F)c(Cl)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.4 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3-chloro-4-fluorobenzene-1-sulfonyl chloride (25 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (4 mg, 14%) as a white solid. MS (ESI+) for C18H18ClFN2O3S m/z 397 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)[CH:18]=[C:17]([C:31]([O:33]C)=O)[C:13]=4[NH:14][C:15]=3[CH:16]=2)[CH2:5][C@@H:4]([CH3:35])[O:3]1.[NH3:36]>CO>[CH3:35][C@H:4]1[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=5)[CH:18]=[C:17]([C:31]([NH2:36])=[O:33])[C:13]=4[NH:14][C:15]=3[CH:16]=2)[CH2:7][C@@H:2]([CH3:1])[O:3]1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3C[C@@H](C)O[C@@H](C)C3)ccc12
Reactant: N
Solvent: CO
Product: C[C@@H]1CN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
A suspension of methyl 7-((2S,6R)-2,6-dimethylmorpholino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (16 mg, 0.033 mmol) in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated at 80° C. for 48 hr. Removal of the solvent followed by preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=75:25 to A:B=25:75 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-((2S,6R)-2,6-dimethylmorpholino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (12.9 mg, 0.026 mmol, 79% yield) as an orange solid. MS (ESI) m/z 469.28 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.47 (1H, s), 8.39 (1H, t, J=4.27 Hz), 8.23 (1H, d, J=8.55 Hz), 8.20 (1H, s), 7.72(2H, d, J=4.27 Hz), 7.07-7.11 (1H, m), 7.01-7.08 (1H, m), 3.80-3.91 (2H, m), 3.70-3.76 (2H, m), 2.43-2.53 (2H, m), 1.29 (6H, d, J=6.41 Hz).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:4](OCC)=O)=[O:2].C[O-].[Na+].[N+:20]([NH:23][C:24]([NH2:26])=[NH:25])([O-:22])=[O:21]>CO>[N+:20]([NH:23][C:24]1[NH:26][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:25]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)C(C=O)Cc1ccc(C)nc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Yield: 27.3 %

Procedure:
A solution of ethyl 2-formyl-3-(6-methyl-3-pyridyl)propionate (1.55 g) in methanol (20 ml) was added to a solution of sodium methoxide (from 0.161 g sodium) in methanol (20 ml). Dried nitroguanidine (0.729 g) was added over 5 minutes and the mixture was stirred and boiled under reflux overnight and evaporated to dryness. The residue was dissolved in water (50 ml) and the solution was extracted with chloroform (2×25 ml, discarded) and acidified to pH 5 with acetic acid. The solid which precipitated out was filtered off and recrystallised from methanol-acetic acid to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.5 g) m.p. 215°-216° (decomp.).