Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].[CH2:26](OS(OCC)(=O)=O)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][CH2:2][S:3]([N:6]([C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[CH2:26][CH3:27])(=[O:5])=[O:4]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the title compound of Example 1, Step H (0.414 g, 1 mmol), diethylsulfate (0.17 g, 1.1 mmol), and potassium carbonate (0.27 g) in acetone (10 mL) was stirred at room temperature for 4 h. After completion of the reaction, the potassium carbonate was filtered off and the solvent was removed on a rotary evaporator. The title compound of Step A, a compound of this invention, was isolated by flash chromatography (0.41 g, 92%) as a white solid melting at 198-200° C. 1H NMR (CDCl3) δ 7.46 (d, 1H), 7.42 (d, 1H), 5.52 (m, 1H), 4.62 (dd, 1H), 4.59 (s, 2H), 4.02 (dd, 1H), 3.80 (m, 4H), 3.60 (dd, 1H), 2.64 (m, 1H), 2.01 (m, 1H), 1.20 (t, 6).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:26][C:7]2=[CH:8][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:6]=32)[C:4]1=[O:27].[F:28][C:29]([F:34])([F:33])[C:30](O)=[O:31].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=[C:7]3[CH2:26][CH:3]([NH:2][C:30](=[O:31])[C:29]([F:34])([F:33])[F:28])[C:4](=[O:27])[C:5]=1[C:6]=23
Reactant: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(N)C(=O)c13
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(NC(=O)C(F)(F)F)C(=O)c13
Yield: 73.5 %

Procedure:
To a suspension of 4-amino-3,4-dihydro-6-methoxy-1-p-toluenesulfonylbenz[cd]indol-5(1H)-one hydrochloride (1.45 g, 3.50 mmol) in dichloromethane (30 ml) were added, while stirring under ice-cooling, anhydrous trifluoroacetic acid (0.61 ml, 4.27 mmol) and triethylamine (1.18 ml, 16.1 mmol). The mixture was stirred for 30 minutes as it was. After completion of the reaction, the reaction mixture was subjected to distillation under reduced pressure. The residue was shaken together with ethyl acetate (40 ml)-1N HCl (30 ml) to allow two layers to be formed. The organic layer was washed with an aqueous saline solution and dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to afford the title compound (1.2 g, 73%, m.p.189°-190° C.)
Reaction SMILES: [Si](O[CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][O:29]S(C)(=O)=O)[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(C(C)(C)C)(C)C.O.[F-].C([N+](CC)(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:17][C:14]1([CH3:18])[N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:12]([CH2:11][C@H:10]2[CH2:26][CH2:27][CH2:28][O:29][CH2:9]2)[CH2:16][O:15]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Yield: 54 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(methylsulfonyloxy)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (37.7 g, 74.2 mmol) in THF (1000 mL) was added tetraethylammonium fluoride hydrate (41 g, 185.5 mmol) in portions. The reaction mixture was stirred under reflux overnight. The mixture was diluted with EtOAc (1000 mL), washed with water (300 mL) and brine (500 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (12.0 g, 54%).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C=O.C(O)(=O)C>CO>[CH3:1][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:26]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1cnc(C2CCNCC2)nc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(C2CCN(C)CC2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
Sodium triacetoxyborohydride (532 mg, 2.51 mmol) was added to methyl 2-(piperidin-4-yl)pyrimidine-5-carboxylate (222 mg, 1.00 mmol), formaldehyde (37% aqueous solution, 1.50 ml, 20.07 mmol) and acetic acid (0.115 ml, 2.01 mmol) in methanol (4.994 ml) at 25° C. The resulting solution was stirred at ambient temperature for 3 days. The reaction mixture was diluted with methanol (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate (223 mg, 94%) as a cream waxy solid. This was used directly with no further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25](Cl)=[O:26].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:25](=[O:26])[CH2:24][C:23]([CH3:29])([CH3:28])[CH3:22])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)CC(C)(C)C
Yield: 94.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), 3,3-dimethylbutanoyl chloride (1.07 g) and pyridine (627 mg) were added, and the mixture was refluxed for 2 hours. Water was added to the reaction mixture, separated, the organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 2.53 g of the titled compound (Yield: 90.1%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:20](=[O:35])[N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[S:14][CH:15]=1)C)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:20]([N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:35])[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]1=2
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)NC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
((1R)-2-(Benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenyl-ethyl)carbamoyl)ethyl)-methylcarbamic acid tert-butylester (0.89 g; 1.70 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 45 min at room temperature. Water (5 mL) was added. Methylene chloride (5 mL), an aqueous solution of sodium hydrogen carbonate (saturated) and sodium hydrogen carbonate (solid) was added until pH 8. The aqueous phase was extracted with methylene chloride (3×10 mL). The combined organic phases were dried (magnesium sulfate) and evaporated in vacuo to afford 0.66 g of (2R)-3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9]Br.O.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1F
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90%). The NMR (CDCl3) was consistent with the assigned structure. The gc of this material showed that it contained only a trace of the 2,6-isomer. This material was used directly in the following step without additional purification. ##STR31##
Reaction SMILES: C([Ge:3](CC)(C=C)C=C)C.[C:10]([C:12]1([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)#[CH:11].[C:23]1([CH3:29])[CH:28]=[CH:27]C=[CH:25][CH:24]=1>>[CH2:24]([C:23]([CH2:28][CH3:27])=[CH:29][GeH2:3][C:11]#[C:10][C:12]1([O:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:25]
Reactant: C=C[Ge](C=C)(CC)CC
Reactant: Cc1ccccc1
Reactant: C#CC1(O[Si](C)(C)C)CCCCC1
Product: CCC(=C[GeH2]C#CC1(O[Si](C)(C)C)CCCCC1)CC
Yield: 55 %

Procedure:
As in reaction conditions of Example I, to 3.99 mL of toluene, the 0.04 g of carbonylchlorhydridebis(tricyclohexylphosphine)ruthenium(II) is added and the reaction was carried out between 1.02 g of diethyldivinylgermane and 0.54 g 1-ethynyl-1-(trimethylsiloxy)cyclohexane. Conversion of the terminal alkyne and raw product yield was 65%. In order to remove the catalyst from the system, the solvent and any residual unreacted reactants were evaporated from the post-reaction mixture and the whole material was transferred onto a chromatographic column filled with silica gel modified with a triethylamine, wherafter product was separated, using hexane as eluent. The product, 1-[{diethylvinylgermyl}ethynyl]-1-(trimethylsiloxy)cyclohexane, was obtained at a yield of 55%, in the form of an oily liquid with a light straw color. The product structure was confirmed by 1H, 13C NMR and GCMS analyses.
Reaction SMILES: C(OC([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Br)c23)C1
Product: Cl

Procedure:
Intermediate 24b is used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].CCN(C(C)C)C(C)C>CCO>[OH:13][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:29]1[CH2:30][CH2:31][C:24]2([C:23](=[O:32])[N:22]([C:17]3[CH2:18][O:19][C:20](=[O:21])[C:16]=3[CH3:15])[CH2:26][CH2:25]2)[CH2:27][CH2:28]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A) (200 mg, 1.05 mmol) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (300 mg, 1.05 mmol) in 10 mL of EtOH was added DIPEA (271 mg, 2.10 mmol). The resulting mixture was stirred at 80° C. overnight, and then cooled to room temperature; the solvent was removed under vacuum. The residue was purified by flash chromatography (ethyl acetate: MeOH=20:1) to afford title compound. MS-ESI (m/z): 441 (M+1)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][C:21]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:23]=4)[CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[C:27]1([C:21]2[CH:20]=[C:19]3[C:24]([CH:25]=[CH:26][C:17]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N+:1]5([CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:9][CH:10]=4)=[O:16])=[CH:18]3)=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)c1ccc2ccc(-c3ccccc3)cc2c1
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)c3ccc4ccc(-c5ccccc5)cc4c3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In DMF (3ml) was dissolved N-[4-(piperidinomethyl)-phenyl]-7-phenylnaphthalene-2-carboxamide (300mg), and to the mixture was added methyl iodide (133 μl). The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-[4-(7-phenylnaphthalene-2-carboxamido)-benzyl]-1-methylpiperidinium iodide (Compound 59) (374mg) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([N:23]([CH3:24])[CH3:22])=[O:21])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: CN(C)C(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g, 0.0166 mole), 1,1'-carbonylidiimidazole (3.21 g, 0.0198 mo;le) and dry tetrahydrofuran (100 ml) was stirred at room temperature for one hour with nitrogen bubbling through it and then refluxed for one hour under a nitrogen atmosphere. The solution which had formed was cooled and a solution of dimethylamine in tetrahydrofuran (21.4 ml of 2.3M solution, 0.05 mole) was added. The reaction mixture was stirred at room temperature under nitrogen overnight. The solvent was removed under reduced pressure and the resulting oil was partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the suspended solid was removed by filtration. The aqueous layer was extracted once more with ethyl acetate (100 ml) and the combined organic layer was washed once with a 5% potassium hydroxide solution (100 ml). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 6.3 g of crude product. Attempts to crystallize the pure free base failed (due to imidazole contamination and trapping of solvents by the solid). The impure product, after triturations in water to remove imidazole, was dissolved in hot isopropyl alcohol, filtered while hot and acidified with hydrogen chloride in isopropyl alcohol. Isopropyl ether was added to precipitate the solid. Filtration and drying under high vacuum gave 1.84 g of the title compound, mp. 203°-205° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]2[CH:12]=1.[NH2:13][C:14]([NH2:16])=[S:15].C(OCC)(=O)C>C(O)C>[ClH:1].[CH3:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:12]=[C:3]([CH2:2][S:15][C:14](=[NH:13])[NH2:16])[N:4]=[C:5]2[CH:10]=1
Reactant: NC(N)=S
Reactant: Cc1ccn2cc(CCl)nc2c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccn2cc(CSC(=N)N)nc2c1
Product: Cl
Yield: 100 %

Procedure:
A mixture of 2-chloromethyl-7-methylimidazo[1,2-a]pyridine (5.0 g) and thiourea (2.2 g) in ethanol (10 ml) was refluxed for 20 minutes and the mixture was added to a ethyl acetate (100 ml) under stirring. The isolated precipitate was collected by filtration and washed with ethyl acetate to give S-(7-methylimidazo[1,2-a]pyridin-2-ylmethyl)isothiourea hydrochloride (7.11 g).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C:38]([CH3:47])([CH3:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CCOC(/N=N/C(OCC)=O)=O.C([O-])(=O)C(C)C>C1COCC1>[C:42]([O:41][C:39](=[O:40])[C:38]([CH3:47])([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2O)cc1
Agent: CC(C)C(=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.5 %

Procedure:
To a solution of 388A (1.70 g, 7.35 mmol) and PPh3 (5.80 g, 22.1 mmol) in anhydrous THF (35 ml) was added t-butyl 2-hydroxyisobutyrate (3.83 ml, 22.1 mmol) followed by DEAD (3.47 ml, 22.1 mmol), the reaction mixture was stirred at rt for 19 h. More reagents PPh3 (1.16 g, 4.41 mmol), isobutyrate (0.77 ml, 4.41 mmol) and DEAD (0.69 ml, 4.41 mmol) were added, and the mixture was stirred for another 50 h, concentrated and purified by silica gel flash column chromatography to afford 388B (2.62 g, 96%) as a light pink crystalline solid (50%-80% CH2Cl2-hexanes).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4.53 g, 19.8 mmol) and K2CO3 (4.146 g, 30 mmol) in THF (30 mL) was added phenyl chloroformate (4.071 g, 26 mmol). It was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with DCM. Extracts were dried over MgSO4 and concentrated. The crude product was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate as solid (5.12 g, 74%). 1H NMR (300 MHz, CDCl3) 1.34 (s, 9H), 2.43 (s, 3H), 6.5 (s, 1H), 7.0 (s, 1H), 7.15 (d, 2H), 7.36 (m, 7H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[CH:20]=[C:19]([N:21](C(OC(C)(C)C)=O)[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:33][CH3:34])[C:8]=2[C:7]1=[O:35].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:33][CH3:34])[C:8]=2[C:7]1=[O:35]
Reactant: COc1c2n(c3c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c2n(c3c(NS(C)(=O)=O)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O

Procedure:
A cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-4-(N-tert-butoxylcarbonyl-N-methanesulfonyl-amino)-8-methyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (90 mg, 0.15 mmol) and trifluoroacetic acid (2 mL) in anhydrous dichloromethane (3 mL) was stirred for 3 hours. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [Na].[CH2:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][S:3]1(=[O:14])=[O:13].Cl[CH2:16][CH:17]([OH:25])[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[CH2:26]([OH:28])[CH3:27]>>[OH:25][CH:17]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:16][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:2][S:3]1(=[O:13])=[O:14].[CH2:26]([O:28][CH:17]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:16][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:2][S:3]1(=[O:13])=[O:14])[CH3:27]
Reactant: O=C1NS(=O)(=O)Cc2ccccc21
Reactant: OC(CCl)CN1CCOCC1
Reactant: CCO
Agent: [Na]
Product: CCOC(CN1CCOCC1)CN1C(=O)c2ccccc2CS1(=O)=O
Product: O=C1c2ccccc2CS(=O)(=O)N1CC(O)CN1CCOCC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 20 %
Yield: 63 %

Procedure:
In dry ethanol (10 mL) was dissolved metallic sodium (23 mg, 1 mmol.), and to the solution was added 1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide (197 mg, 1 mmol.). The mixture was stirred at 50° C. for 30 min. To the reaction solution was added 1-chloro-3-morpholino-2-propanol (198 mg, 1.1 mmol.). The mixture was then heated for 6 hours under refluxing. The reaction liquid was placed under reduced pressure to distill the solvent off. The resulting residue was treated with 1N hydrochloric acid and ethyl acetate. The aqueous layer was taken out, and made basic by addition of potassium carbonate. The oil precipitated and was extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off. The resulting residue was treated by silica gel column chromatography (chloroform/methanol=40/1) to give 3-(2-hydroxy-3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide (215 mg, yield 63%) as a colorless oil, and 3-(2 -ethoxy3-morpholinopropyl)-1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide (70 mg, yield 20%) as an colorless oil.