Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[OH-].[Na+].O>CO>[C:17]([O:16][C:14]([NH:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4chlorophenyl)-acrylic acid methyl ester (4.6 g, 14.7 mmol) was dissolved in MeOH (300 ml), 2N NaOH (11 ml, 22 mmol) and water (147 ml) added and stirred at 50° C. for 1 hour. The clear reaction mixture was concentrated to ˜150 ml, acidified to pH 3 and extracted twice with TBME. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the title acid as colorless crystals (3.8 g, 87%).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C1(C)C=CC=CC=1.[CH2:13]([C:18]([N:20]=[C:21]=[O:22])=[O:19])[CH2:14][CH2:15][CH2:16][CH3:17]>C(OCC)C>[CH2:13]([C:18]([NH:20][C:21]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:22])=[O:19])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#CC1CN1
Reactant: CCCCCC(=O)N=C=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCC(=O)NC(=O)N1CC1C#N

Procedure:
In a manner analogous to that described in Example 14, from 0.81 g. 2-cyanoaziridine, dissolved in 8 ml. toluene, and a solution of 1.7 g. n-pentanecarbonyl isocyanate in 17 ml. toluene, there are obtained, without purification with diethyl ether, 1.6 g. 1-(N-n-pentanecarbonyl-carbamoyl)-1-cyanoaziridine; m.p. 143°-144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[ClH:21].[H][H].[Cl-].[Na+]>[Fe].CO>[ClH:21].[ClH:21].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: Nc1ccc(C=Cc2ccc(N)cc2)cc1
Temperature: 25 °C

Procedure:
A portion (40.5 grams, 0.15 mole) of 4,4'-dinitrostilbene from A above, concentrated hydrochloric acid (250 milliliters) and methanol (200 milliliters) are added to a flask and maintained therein as stirred mixture. Over the next three hour period, 325 mesh powdered iron is added to the reaction mixture in one grams aliquots until a total of 22.0 grams (0.40 mole) has been added. With each added aliquot of iron, heating with vigorous hydrogen evolution occurs causing frothing of the reaction mixture. Frothing is moderated as needed by cooling of the flask on a sodium chloride and ice bath between iron additions. After completion of the iron addition, the mixture is heated for 16 hours at reflux then cooled to room temperature (25° C.) and filtered. The dark brown liquid filtrate is concentrated o by rotary evaporation under vacuum at 85° C. to one half original volume then decolorized by the addition of activated charcoal. After filtration, the filtrate is desalted by passing through a column of Sephadex G-50. The eluate is rotary evaporated under vacuum to provide a pale tan colored solid. Recovery of this solid followed by drying in a vacuum oven at 110° C. and 5 mm Hg provides a constant product weight of 29.4 grams. Fourier transform infrared spectrophotometric analysis of a nujol mull of the product on a sodium chloride plate confirms the product structure (disappearance of the absorbances observed for the conjugated nitro group, appearance of --NH3+ stretching absorbances at 3040, 2603 and 2550 cm-1 and appearance of a --NH3+ bending absorbance at 1497 cm-1). Proton nuclear magnetic resonance spectroscopy further confirms the product structure. Differential scanning calorimetry of a portion (3.62 milligrams) of the product under a stream of nitrogen flowing at 35 cubic centimeters per minute and using a heating rate of 10° C. per minute with a range of 200° C. to 450° C. reveals a endotherm at 263° C. (enthalpy =162.85 J/g) followed by second endotherm at 291° C. (enthalpy=337.82 J/g).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.CNC.C1COCC1.[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>O>[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:3]([CH3:4])[CH3:2])=[O:26]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(I)c1
Reaction time: 18 h

Procedure:
EDCl (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:41])([CH3:40])[O:20][CH:19]3[CH3:42])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClS([N:47]=[C:48]=O)(=O)=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([C:48]#[N:47])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:41])([CH3:40])[O:20][CH:19]3[CH3:42])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1OC(C)(C)c2cc(-c3cccn3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Product: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 64.6 %

Procedure:
Using the procedure for Example 18, the title compound (0.8 g, 65%) was prepared from 9H-fluoren-9-ylmethyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1 (4H)-carboxylate (1.2 g, 2.1 mmol) and chlorosulfonyl isocyanate (0.28 mL, 3.1 mmol). A white solid: mp 135-136° C.; 1H-NMR (DMSO-d6) δ 7.90 (t, 2H, J=6.7 Hz), 7.64 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.1 Hz), 7.40 (td, 2H, J=7.2, 2.0 Hz), 7.31-7.34 (m, 3H), 7.29 (d, 1H, J=1.2 Hz), 7.04-7.09 (m, 2H), 6.44 (d, 1H, J=3.57 Hz), 5.30 (q, 1H, J=5.6 Hz), 4.86 (dd, 1H, J=10.7, 5.2 Hz), 4.64 (dd, 1H, J=10.8, 5.2 Hz), 4.33 (t, 1H, J=4.7 Hz). 1.50 (s, 3H), 1.30 (s, 9H), 1.20 (s, 3H), 1.03 (d, 3H, J=5.6 Hz); MS (ESI) m/z 590 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:15])[C:4]=1[F:16].[K+].[Br-].[CH3:19]O>>[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[C:5]([F:15])[C:4]=1[F:16]
Reactant: CO
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reaction time: 23 h
Yield: 70 %

Procedure:
Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid 4-amino-2,3-difluoro-5-nitrobenzoic acid (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5–184° C.; 1H-NMR (400 MHz; DMSO) δ 8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) δ −128.85 to −128.92 (m), −153.29 (d); MS (APCl−) 231 (M−1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm−1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[C:41]([NH:40][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:42])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C=NCc1ccccc1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NCc3cccc4ccccc34)ccc21
Solvent: ClCCl
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N(Cc3cccc4ccccc34)C(=O)NCc3ccccc3)ccc21
Temperature: 50 °C
Reaction time: 6 h

Procedure:
1.37 g (3.3 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-1-methyl-5-naphth-1-ylmethylamino-benzimidazole obtained from Example 1, step d was dissolved in 20 mL of dichloromethane at ambient temperature [and] 0.40 g (3.0 mmol) of benzyl isocyanate are added dropwise to the solution. The mixture was then stirred for 6 h at 50° C. and left to stand overnight. The solution was evaporated down in vacuo using the rotary evaporator and purified by column chromatography on silica gel.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:26])[C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:25])[C:16](=[O:17])[N:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14](=[O:23])[N:13]2[CH3:24])=[CH:8][CH:7]=1)C.[NH3:27].C(OCC)C>C(O)(C)C>[ClH:1].[NH2:27][C:5](=[NH:26])[C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:25])[C:16](=[O:17])[N:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14](=[O:23])[N:13]2[CH3:24])=[CH:8][CH:7]=1
Reactant: N
Reactant: CCOC(=N)c1ccc([C@@]2(C)C(=O)N(CC(=O)OC)C(=O)N2C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)CN1C(=O)N(C)[C@@](C)(c2ccc(C(=N)N)cc2)C1=O
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
2.26 g of methyl (S)-(4-(4-(ethoxy-imino-methyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate hydrochloride (6.4 mmol) were suspended in 25 ml of isopropanol and treated with 7.2 ml of a 2N solution of ammonia in isopropanol. The reaction mixture was stirred at 50° C. for 2.5 hours. The mixture was cooled and then treated with 200 ml of diethyl ether. The precipitate was filtered off with suction and dried in a high vacuum.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1>[C:15]([S:18]([N:20]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1)=[O:19])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(=NS(=O)C(C)(C)C)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A mixture of tert-butyl 3-oxocyclobutylcarbamate (2.2 g, 11.9 mmol), 2-methylpropane-2-sulfinamide (1.6 g, 13.1 mmol), Ti(OEt)4 (5.5 g, 24 mmol) in 20 mL of THF was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and then quenched with saturated NH4Cl solution. The formed solid was removed by filtration. The filtrate was evaporated to dryness and the crude residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1)) to give tert-butyl 3-(tert-butylsulfinylimino)cyclobutylcarbamate as clear oil (2.0 g, 58%). MS: (M+H)+=289.1; 1H NMR (300 MHz, CDCl3): δ 5.08 (m, 1H), 4.29 (s, 1H), 3.42-3.00 (m, 4H), 1.43 (s, 9H), 1.22 (s, 9H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH:25][N:24]=1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[N:28]=[C:27]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:9]=3)[N:4]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Reactant: CN(C)C(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Temperature: 100 °C
Yield: 103.3 %

Procedure:
To a solution of 3-iodo-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxamide (3 g, 7.53 mmol) and 2-chloro-4-(tributylstannyl)pyrimidine (3.6 g, 8.04 mmol) in DMF (35 mL) under argon atmosphere was added CuI (1.7 g, 9.02 mmol) and Pd(PPh3)4 (868.5 mg, 0.75 mmol) and argon gas was bubbled for 15 min. The reaction was heated at 100° C. for 1 h. The reaction was quenched with water to give off white precipitate. The suspension filtered, washed with water and dried. The crude was purified by neutral alumina column chromatography (eluting with 100% EtOAc) to give 3-(2-chloropyrimidin-4-yl)-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxamide (3.0 g, 58%) as an off white solid. MS (ESI, pos. ion) m/z: 386.2 (M+1).
Reaction SMILES: C[Si]([NH:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][N:7]=1)(C)C.C[Si]([C:17]#[CH:18])(C)C.C(OCC)C.[NH4+].[Cl-]>N1CCCCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]#[CH:18])=[CH:8][N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: C[Si](C)(C)Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: C#Cc1ccc(N)nc1
Reaction time: 8 h
Yield: 6 %

Procedure:
2-Amino-5-bromopyridine (8.65 g, 50.0 mmole) and bis-trimethyl-silylacetamide (36.76 mL, 150.0 mmole) was stirred at 100° C. overnight. The mixture was purified by distillation to give 10.41 g (85%) of the protected amine. 2-Trimethylsilylamino-5-bromopyridine (4.90 g, 20.0 mmole), bis(triphenylphosphine)palladium(II) chloride (0.70 g, 1.00 mmole) and trimethylsilylacetylene (5.65mL, 40.0 mmole) in piperidine (2 mL) was stirred under nitrogen at 80° C. overnight. Diethyl ether and NH4Cl (aq) was added to the mixture and the organic phase was separated, dried over Na2SO4 and evaporated. Tetrabutylammonium chloride (50.0 mL, 100.0 mmole) and THF (250 mL) was added to remove the protection groups and the mixture was stirred overnight. THF was evaporated. The residue was purified by silica gel column chromatography (EtOAc/Hexane, 40:60) to give 2.36 g, (6%) of the titled compound. 1 H NMR (250 MHz, CDCl3) δ 3.05 (s, 1H), 4.65 (br s, 2H), 6.45 (d, 1H), 7.50 (dd, 1H), 8.25 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]2[CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:18]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]2[CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:18])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C1CC1
Reactant: CCOP(=S)([S-])OCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a round-bottom flask, was added a solution of methyl 5-cyano-2-cyclopropyl-4-methylbenzoate (compound 190.3, 220 mg, 0.920 mmol, 1.00 equiv, 90%) in tetrahydrofuran (6 mL). A solution of O,O′-diethyl dithiophosphate (300 mg, 1.61 mmol, 2.00 equiv) in water (1.5 mL) was added to the solution, and the resulting mixture was stirred overnight at 80° C. in an oil bath (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (5:1) as eluent. The collected fractions were combined and concentrated in vacuo to furnish 100 mg (39%) of methyl 5-carbamothioyl-2-cyclopropyl-4-methylbenzoate as a yellow solid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[P:15]([O-:23])([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:16])[CH3:19]
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: CCOP(=O)([O-])OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1C(=O)N(COP(=O)(OCC)OCC)S(=O)(=O)N1C
Yield: 66 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.16 mmol), diethyl phosphate (Formula III: A=B=Et) (0.96 g, 6.63 mmol), tetrabutylammonium bromide (94 mg, 0.29 mmol) and triethylamine (0.63 g, 6.23 mmol) in methylene chloride (20 ml) was allowed to reflux for 24 hours. After adding an additional tetrabutylammonium bromide, the mixture was refluxed for an additional 48 hours, and then cooled. The mixture was purified by silica gel flash chromatography (ethyl acetate/hexane) to afford 0.98 g (66%) of 2-(diethoxyphosphinyloxymethyl)-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: A=B=Et; R1 =H; R2 =propyl; R3 =CH3) as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[C:44]([C:46]#[N:47])[CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[N:45]=[C:44]([C:46]#[N:47])[CH:43]=[CH:42][CH:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(Br)n1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccc(C#N)n5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-2-cyanopyridine (283 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (466 mg, 88%) as a light yellow oily substance.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[N+:34]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].CO>CN1CCCC1=O.[C].[Pd]>[NH2:34][C:20]1[C:21]2[S:25][C:24]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[N:23][C:22]=2[CH:32]=[CH:33][C:19]=1[O:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:37]=[CH:38][CH:39]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3[N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3N)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]-7-nitro-1,3-benzothiazol-6-yl}oxy)phenyl]benzamide (2.5 g, 4.62 mmol) produced in Example 37(iii) in 1-methylpyrrolidin-2-one (20 ml)/methanol (50 mL) was added 10% palladium-carbon (250 mg), and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere (3 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with water (200 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (870 mg, 37%) as a pale-yellow powder.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(OCCC1N(CCC2C=CC=CC=2)C(SC2C=C(F)C=C(F)C=2)=C(C(C)C)N=1)(=O)N.[CH2:40]([O:47][CH2:48][C:49](Cl)=[O:50])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:49](=[O:50])[CH2:48][O:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)COCc1ccccc1
Agent: CC(C)c1nc(CCOC(N)=O)n(CCc2ccccc2)c1Sc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In 50 ml of methylene chloride was added 15.0 g (35.8 mmol) of glycine ethyl ester hydrochloric acid, followed by addition of 9.2 9 (75.3 mmol) of 4-dimethylaminopyridine under ice-cooling. After stirring for 10 minutes, 6.5 ml (39.4 mmol) of benzyloxyacetylchloride was added dropwise under ice-cooling over 30 minutes. The temperature was raised up to room temperature, and the mixture was stirred for 12 hours. To the mixture, 20 ml of methylene chloride was added, and filtered. To the filtrate, 5% hydrochloric acid was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and 9.0 g of N-benzyloxyacetylglycine ethyl ester was obtained (yield 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H]>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N)c1
Yield: 72.5 %

Procedure:
Acetic acid 3-nitro-4-(t-butyl-diphenyl-silanyloxy)-phenyl ester (5.0 g, 11.86 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Excess Raney Ni was added and the mixture placed under an atmospheric of hydrogen overnight. The mixture was filtered through a Celite pad and the solvent removed to give the title compound as a solid (3.5 g, 8.6 mmol).