Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O1CCOCC1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-Asparagine (10.0 g, 75.7 mmol) was placed in a 500 mL round bottom flask equipped with a magnetic stir bar and an addition funnel. 1N Sodium hydroxide (170 mL, 166.5 mmol) was added along with 50 mL dioxane. p-Toluenesulfonyl chloride (15.88 g, 83.27 mmol) dissolved in dioxane (50 mL) was added to the reaction mixture with vigorous stirring. The reaction mixture was then stirred for 2 h at room temperature, cooled to 0° C., and acidified to pH 2-3 with hydrochloric acid (conc.). The desired product 14-2 formed as a white crystalline solid (20.3 g, 94%) that was collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].B(F)(F)F.[CH3:16][CH2:17]OCC>C(O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(F)c1

Procedure:
A solution of 15.0 g of 4-amino-3-fluorobenzoic acid 150 ml of anhydrous ethyl alcohol and 5 ml of boron trifluoride etherate is heated to reflux for 20 hours. Most of the solvent is then removed and 200 ml of water added and the mixture extracted with chloroform. The chloroform extract is washed with an aqueous solution of sodium bicarbonate dried over sodium sulfate and the solvent evaporated to yield an off-white solid which upon recrystallization from ethanolhexane yields ethyl 4-amino-3-fluorobenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:22]2([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:35])[C:15]([O:17]C(C)(C)C)=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>ClCl.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:22]2([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]2=[O:35])[C:15]([OH:17])=[O:16])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)NCC(C(=O)OC(C)(C)C)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C(=O)O)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
A cold (0° C.) solution of tert-butyl α-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (374 mg, 0.669 mmol) in CH2 Cl2 (2 mL) is treated with TFA (2 mL). The solution is maintained at 0° C. for 40 min and then allowed to warm to room temperature under N2. After 1.5 hours, the solution is diluted with CH2Cl2 and stripped (5×). The residual foam is diluted with H2O (5 mL) and extracted into CH2Cl2 (3×20 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 301 mg (90%) of the title compound as a white, amorphous solid:
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([CH3:24])([CH3:23])[CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.CO[C:45]([C:51]1[CH:56]=[CH:55][C:54](C)=[CH:53][CH:52]=1)=[C:46]([C:49]#[N:50])[C:47]#[N:48]>C(#N)C.C(O)C>[CH2:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:10]([N:9]1[C:49]([NH2:50])=[C:46]([C:47]#[N:48])[C:45]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[N:8]1)([CH3:24])[CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)NNC(=O)OC(C)(C)C
Reactant: COC(=C(C#N)C#N)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCO
Product: CC(C)(CNC(=O)OCc1ccccc1)n1nc(-c2ccccc2)c(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 1B (310 mg, 0.92 mmol) was dissolved in 1 mL of dry acetonitrile. Tosic acid (875 mg, 4.6 mmol) was dissolved in 3 mL of dry acetonitrile. Molecular sieves were added to both solutions and stood for 30 minutes. The solution of tosic acid was then added the other mixture and the reaction was stirred at room temperature for 3 hours. After that time the reaction was filtered and the solid washed with acetonitrile and CH2Cl2). The filtrate was concentrated to afford a thick colourless oil. It was dissolved in 2 mL of ethanol. Triethylamine (640 μL, 1.48 mmol) and 2-(Methoxy-p-tolyl-methylene)-malononitrile (182 mg, 0.92 mmol) were successively added. The reaction was then heated at 60° C. for 3 hours. After cooling down, the reaction was concentrated. Water and EtOAc were then added and the aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The oily residue obtained was purified by flash chromatography on SiO2 using 100% CH2Cl2 then CH2Cl2/MeOH 99:1. A colourless oil that solidifies slowly overnight was obtained (m=270 mg, 73%). NMR (ppm, CDCl3): δ 1.58 (s, 6H), 2.36 (s, 3H), 3.77 (d, J=6.63 Hz, 2H), 4.40 (br s, 2H), 5.08 (s, 2H), 5.59 (br t, J=5.94 Hz, 1H), 7.20 (d, J=8.55 Hz, 2H), 7.31 (m, 5H), 7.74 (d, J=8.13 Hz, 2H). 13C NMR (ppm, CDCl3): δ 21.35, 24.18, 50.56, 63.17, 66.99, 76.34, 115.22, 126.09, 128.15, 128.22, 128.33, 128.55, 129.42, 136.34, 139.11, 149.13, 151.57, 156.96. LCMS (+esi): 404.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH:1]1([CH2:7][C@@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
A solution of methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.5 g, 4.2 mmol) in MeOH (4 mL) was added to a solution of NaOH (221 mg, 5.5 mmol) in MeOH/H2O (4 mL/0.25 mL) at −30° C. After 10 minutes was added hydroxylamine-HCl (0.59 g, 8.5 mmol) and NaOH (0.339 g, 8.5 mmol) in MeOH (5 mL) and H2O (5 mL). Stirring was continued at −30° C. for 30 minutes. The reaction solution was poured into 6M HCl (6 mL) at 80° C. and heated for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Crude 1.7 g. Purification using reversed phase chromatography, which gave 0.3 g, yield 22%. Chiral separation using Chiralcel OJ, mobile phase heptane/ethanol 80/20 at 40° C. gave of (2R,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.11 g). 1H NMR (600 MHz, cdcl3) δ 0.91 (d, 2H), 1.06-1.39 (m, 5H), 1.68 (dt, 7H), 1.85 (s, 2H), 1.94 (s, 1H), 2.99 (t, 2H), 3.68 (s, 3H), 4.11 (d, 1H), 4.50 (d, 1H), 5.60 (s, 1H). [α]20D +3.2 (MeCN, c=1).
Reaction SMILES: C=O.[Br:3][C:4]1[C:5]([CH3:18])=[C:6]([CH3:17])[C:7]2[O:11][C:10]([CH2:13]N)([CH3:12])[CH2:9][C:8]=2[C:15]=1[CH3:16].[C:19](O)(=O)C.[C:23]([BH3-])#[N:24].[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[Br:3][C:4]1[C:5]([CH3:18])=[C:6]([CH3:17])[C:7]2[O:11][C:10]([CH2:13][N:24]([CH3:23])[CH3:19])([CH3:12])[CH2:9][C:8]=2[C:15]=1[CH3:16]
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN)O2
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN(C)C)O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
37% formalin aqueous solution (0.5 mL) was added to a solution of methanol (6 mL) containing 1-(5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (250 mg, 0.880 mmol) synthesized in Reference Example 129, acetic acid (140 mg, 2.33 mmol) and sodium cyanoborohydride (98 mg, 1.56 mol) under ice-cooling condition. The mixture was warmed to room temperature and stirred for 15 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution to separate an organic layer. The organic layer was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by basic silica gel chromatography (hexane-ethyl acetate 97:3-88:12) to give 220 mg of the title compound (yield: 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(O)C>[N:21]1[CH:22]=[CH:23][C:18]([C:10](=[N:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(c1ccccc1)c1ccncc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=C(c1ccccc1)c1ccncc1
Yield: 11.9 %

Procedure:
To 6.61 gm (0.05 mole) of t-butylcarbazate dissolved in 100 ml of warm water is added 9.16 gm (0.05 mole) of 4-benzoylpyridine in 30 ml of ethanol. The mixture is refluxed 7 hr. Cooling several weeks yields 1.77 gm (12%) of the title compound having a melting point of 134.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][C:28]1([CH3:52])[C:32](=[O:33])[N:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)[C:30](=[O:46])[N:29]1[CH2:47][CH2:48][CH2:49][CH2:50]O>C(Cl)Cl>[CH3:27][C:28]1([CH3:52])[C:32](=[O:33])[N:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)[C:30](=[O:46])[N:29]1[CH2:47][CH2:48][CH2:49][CH2:50][I:25]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCI
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
787 mg of triphenyl phosphine, 204 mg of imidazole, 762 mg of iodine and 5 ml of methylene chloride are introduced, the suspension is agitated for 45 minutes at ambient temperature, then over about 3 minutes, 1.1 g of 4-(4,4-dimethyl-2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile obtained in Example 1 of EP 0,580,459 in 7 ml of methylene chloride is added. Rinsing is carried out with 1 ml of methylene chloride followed by agitation for 4 hours at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[N+]1([O-])CCOCC1.C(Cl)Cl.C(#N)C>C(OCC)C.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1

Procedure:
A mixture of the resultant alcohol from Example 16D (1.0 equivalent), N-methylmorpholine-N-oxide (1.5 equivalents), molecular sieves, and a catalytic amount of TPAP is stirred in a CH2Cl2/acetonitrile mixture until the reaction is judged complete by TLC analysis. The mixture is diluted with ethyl ether and filtered through SiO2. The product is purified by chromatography on silica gel.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([S:9][C:10](=[N:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:11]C(OC(C)(C)C)=O)[CH:7]=[CH2:8].[I:27]I.O>ClCCl>[I:27][CH2:8][CH:7]1[CH2:6][S:9][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11]1
Reactant: II
Reactant: C=CCSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CI)CS1
Yield: 74.6 %

Procedure:
17 g of sodium bicarbonate are added, at a temperature in the region of 20° C., to a suspension of 25.4 g of tert-butyl allylsulphanyl-[(tert-butoxycarbonyl)amino]methylidenecarbamate in 650 cm3 of dichloromethane, followed by addition of a solution of 24.4 g of iodine predissolved in 850 cm3 of dichloromethane. After 72 hours at a temperature in the region of 20° C., 500 cm3 of water and 500 cm3 of saturated sodium bicarbonate solution are added to the reaction medium and the resulting mixture is then extracted with twice 1 dm3 of ethyl acetate. The organic phases are washed with saturated sodium sulphite solution and then with saturated sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is crystallized from ethyl acetate. 20.5 g of tert-butyl N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate are obtained in the form of a yellow solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.41 (s: 9H); 2.97 (dd, J=11.5 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 3H); 4.12 (mt: 1H); 9.89 (unresolved complex: 1H)].
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:16]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CCC3)C(C)(C)C)n1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CNCCC3)C(C)(C)C)n1
Reaction time: 3 h

Procedure:
To Compound 517 (219 mg, 0.43 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.26 mL, 16.36 mmol). After 3 hours of stirring, the solution was concentrated under reduced pressure. The residue was brought to pH 8 with saturated aqueous NaHCO3. The aqueous solution was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a colorless oil which was dissolved in methanol and loaded onto an ion exchange column (Phenomenex®, SCX). The column was washed with methanol to remove impurities, and the title compound was eluted with a solution of 2N ammonia in methanol. After concentration of the methanol solution, Compound 519 was obtained as a pale yellow solid (148 mg, 84% yield). 1H-NMR (400 MHz, (CD3)2SO) δ: 0.99 (s, 9H), 1.72 (m, 2H), 2.34 (s, 3H), 3.00 (m, 2H), 3.29 (s, 1H), 4.14 (t, 2H), 4.27 (m, 2H), 5.15 (d, 1H), 7.53 (m, 5H), 7.85 (d, 1H). LCMS (+ESI) m/z 409.2 [M+H]+.
Reaction SMILES: [C:1](NCC(C1C=CC(N)=C(N)C=1)(C)C)(=O)C.[S:17](=[O:20])(O)[O-:18].COC1C=C(SC)C=CC=1C=O.COC1C=C(SC)C=CC=1C1NC2C=CC=CC=2N=1.Cl.[NH2:53][CH2:54][C:55]([C:58]1[CH:76]=[CH:75][C:61]2[N:62]=[C:63]([C:65]3[CH:70]=[CH:69][C:68]([S:71][CH3:72])=[CH:67][C:66]=3[O:73][CH3:74])[NH:64][C:60]=2[CH:59]=1)([CH3:57])[CH3:56]>C(O)C.CO>[CH3:1][S:17]([NH:53][CH2:54][C:55]([C:58]1[CH:76]=[CH:75][C:61]2[N:62]=[C:63]([C:65]3[CH:70]=[CH:69][C:68]([S:71][CH3:72])=[CH:67][C:66]=3[O:73][CH3:74])[NH:64][C:60]=2[CH:59]=1)([CH3:57])[CH3:56])(=[O:20])=[O:18]
Reactant: CC(=O)NCC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1cc(SC)ccc1-c1nc2ccc(C(C)(C)CN)cc2[nH]1
Reactant: O=S([O-])O
Agent: COc1cc(SC)ccc1-c1nc2ccccc2[nH]1
Agent: COc1cc(SC)ccc1C=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1cc(SC)ccc1-c1nc2ccc(C(C)(C)CNS(C)(=O)=O)cc2[nH]1

Procedure:
Air is passed into a solution of 13 g. of 4-(2-acetamidomethylprop-2-yl)-1,2-diaminobenzene (obtained in Example 1f) and 18 g. of the bisulphite adduct of 2-methoxy-4-methylmercaptobenzaldehyde in 500 ml. methanol for 8 hours at ambient temperature. The reaction mixture is then evaporated and the residue purified by column chromatography (1.5 liters silica gel; trichloromethane:methanol:glacial acetic acid 10:1:0.2 v/v/v). There are obtained 16 g. 5-(2-acetamidomethylpropan-2-yl)-2-yl)-2-(2-methoxy-4-methylmercaptophenyl)-benzimidazole in the form of a brownish viscous mass which is boiled under reflux in 400 ml. ethanol and 100 ml. concentrated hydrochloric acid for 3 days. The reaction mixture is then evaporated and the residue is rendered alkaline with 2N aqueous sodium hydroxide solution and extracted with dichloromethane. The product is purified by column chromatography (silica gel; dichloromethane/methanolic ammonia 10:1 v/v) to give 5.4 g. 5-(2-aminomethylpropan-2-yl)-2-(2-methoxy-4-methylmercaptophenyl)-benzimidazole in the form of a brownish viscous mass, as well as 1 g. of unreacted starting material. 2.7 g. of the product are mesylated analogously to Example 33 to give 3.1 g. of the title compound in the form of a dihydrate; m.p 237°-239° C.
Reaction SMILES: C1(=O)OC(=O)C2=CC=CC=C12.NCCCCCO.O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([NH:30][C:31](=[O:32])[C:26]=12)=[O:29].P(Br)(Br)[Br:37]>C1(C)C=CC=CC=1.O>[Br:37][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([NH:30][C:31](=[O:32])[C:26]=12)=[O:29]
Reactant: O=C1NC(=O)c2c(CCCCCO)cccc21
Reactant: BrP(Br)Br
Agent: NCCCCCO
Agent: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)c2c(CCCCCBr)cccc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Phthalic anhydride (43.0 g, 0.29 mole) and 5-aminopentanol (29.9 g, 0.29 mole) in 250 ml dry toluene (dried over 4A sieves) were heated to reflux in a 120° C. oil bath with stirring for three hours. The system was equipped with a Dean-Stark trap for the azeotropic removal of water (5.3 ml). Upon TLC confirmation of complete formation of the intermediate, 5-hydroxypentylphthalimide (Rf =0.66 (A)), phosphorous tribromide (18.2 ml, 0.19 mole) in 20 ml dry toluene was added dropwise to the hot reaction mixture and the mixture was stirred for 1.5 hours at 100° C. After removal of an orange precipitate by filtration through a pad of Celite, the filtrate was concentrated by rotary evaporation, and the resulting oil was crystallized from absolute ethanol as white plates. Yield: 64.7 g (75.3%). Mp 59.5°-66.0° C. TLC: Rf =0.78 (A). MW calc. 295.10, found 295. Anal. calc. for C13H14NO2Br: C, 52.72; H, 4.76; N, 4.73; Br, 26.98. Found: C, 53.17; H, 4.91; N, 4.62; Br, 27.14. HPLC 100%. 1H NMR (CDCl3) 1.50 (2H, m), 1.72 (2H, m), 1.92 (2H, m), 3.40 (2H, t, 7 Hz), 3.70 (2H, t, 7 Hz), 7.72 (2H, m) and 7.90 (2H, m) for AA'BB"system.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([Cl:3])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)Cl)cc1OC
Reaction time: 2 h

Procedure:
600 ml of thionyl chloride were added dropwise to a suspension of 549.4 gm of 3,4-dimethoxyphenyl-acetic acid in 600 ml of methylene chloride, while stirring, over a period of 2 hours. After the evolution of gas had ceased (16 hours), the mixture was refluxed for an hour. After the volatile components had been removed, the residue was distilled in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Yield: 94.9 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (0.500 g, 1.96 mmol), 4-acetamidopiperidine (0.335 g, 2.45 mmol), and diisopropylethyl amine (1.0 mL, 5.8 mmol) in CH2Cl2 (5 mL) was stirred for 15 min at rt. The reaction mixture was then washed with 1 N HCl (2×5 mL) followed by brine (10 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (0.672 g, 95%). The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.09-8.05 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.38 (m, 2H), 6.08 (d, J=8.0, 1H), 3.87-3.79 (m, 2H), 2.93-2.85 (m, 2H), 2.00-1.93 (m, 5H), 1.59-1.51 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methylphenylmercapto)-butylchloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Br:28].[OH-].[Na+].O>C(O)C>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[CH2:19][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:17])=[CH:11][N:12]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)c(CSc2ccc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 99 %

Procedure:
As described in Method A, N-(4-fluoro-phenyl)-6-mercapto-nicotinamide IIa (745 mg, 3 mmol, 1 eq.) and 2-bromomethyl-4-methoxyphenyl bromide (0.84 g, 3 mmol, 1 eq.) were suspended in ethanol (36 ml). To the suspension, 1 N sodium hydroxide (5.1 ml, 6 mmol, 2 eq.) was added, and the reaction mixture heated to gentle reflux for 2 hours, then water (200 ml) was added to the reaction mixture while still hot. Upon cooling, a white precipitate formed, and this was filtered, washed with 50% aqueous ethanol, then water and dried in the oven to afford 1.33 g (99% yield, >95% purity by LC-MS) of 6-(2-bromo-5-methoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide, intermediate VII, as an off-white solid. ESI-MS m/z=448.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:17])[CH2:13][S:12](=[O:15])(=[O:14])[CH2:11][C:10]([NH2:16])=[N:9]1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:23]([O-:25])=[O:24])=[CH:4][C:3]=1[C@:8]1([CH3:17])[CH2:13][S:12](=[O:14])(=[O:15])[CH2:11][C:10]([NH2:16])=[N:9]1
Reactant: O=[N+]([O-])O
Reactant: C[C@@]1(c2ccccc2F)CS(=O)(=O)CC(N)=N1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 100 %

Procedure:
To a solution of (R)-5-(2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (497 mg, 1.94 mmol, Eq: 1.00) in conc. sulfuric acid (14.8 g, 8.06 ml, 151 mmol, Eq: 78) was added at 0° C. 100% nitric acid (189 mg, 134 μl, 3.01 mmol, Eq: 1.55) and the mixture was stirred at 0° C. for 1 hour. Poured into sat NaHCO3-sol., extracted with ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left the (R)-5-(2-fluoro-5-nitro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (584 mg, 1.94 mmol, 100% yield) as a light yellow oil. MS (ISP): m/z=302.1 [M+H]+.