Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][N:23]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C1=NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added 4-nitrobenzohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 165 mg of the title compound (85%) as a orange solid in 95.3% purity by HPLC (Rt: 4.80, 5.53, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:10])(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:12][CH2:13][Cl:14]>CN(C)C=O>[Cl:14][CH2:13][CH2:12][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][S:3]1(=[O:10])=[O:9]
Reactant: ClCCBr
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCCN1CCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (823 mg, 60% in oil, 0.0206 mol) in N,N-dimethylformamide (20 mL) was added a solution of tetrahydro-2H-1,2-thiazine 1,1-dioxide (2.53 g, 0.0187 mol) in N,N-dimethylformamide (30 mL). The resulting mixture was stirred at room temperature 1 hour. 1-Bromo-2-chloroethane was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, then chromatographed on silica gel (30 to 70%, ethyl acetate in hexanes). The resulting residue was triturated with ether and the solids were filtered off. The filtrate was concentrated to give 2-(2-chloroethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide, which was partially contaminated with starting material, and was taken on to the next step. 1H NMR (400 MHz, CDCl3) δ 3.60 (t, J=6.6 Hz, 2 H), 3.47-3.42 (m, 4 H), 3.01 (t, J=6.0 Hz, 2 H), 2.18 (m, 2 H), 1.66 (m, 2 H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:22][CH3:23])=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:31][C:32]#[N:33])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:22][CH3:23])=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: COc1ccc2c3c(O)cccc3n(Cc3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(OCC#N)cccc3n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a mixture of 9-benzyl-7-methoxy-9H-carbazol-4-ol (0.86 g, 2.8 mmol) in DMF (30 mL) is added potassium carbonate (1.17 g, 8.5 mmol) and bromoacetonitrile (0.56 mL, 8.0 mmol). The mixture is stirred at room temperature for 18 h. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (100 mL) silica gel using CH2Cl2 as eluent gave 0.9 g (94%) of the title compound; 1H NMR (CDCl3) δ3.86, 5.04, 5.46, 6.73, 6.82, 6.87, 7.05, 7.14, 7.28, 8.15; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 76.00; H, 5.32; N, 8.43.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]=[O:12])[C:5]=2[CH:4]=[CH:3]1.[Mg].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>O1CCCC1>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: COc1ccccc1Br
Reactant: Cn1ccc2c(C=O)cccc21
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cccc2c1ccn2C

Procedure:
Using the procedure of Step B of Example 1, 36.8 g of the product of Step A and 104 ml of a solution of 2-bromo anisole magnesium compound in tetrahydrofuran titrating 1.94N were reacted. Extraction was carried out with ethyl acetate and the extracts were washed with salt water and brought to dryness. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 46.5 g of the expected product melting at 95° C.
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+]>O1CCCC1.CCOCC>[ClH:18].[N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][NH2:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1N1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1ccccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A solution of 17.18 g (0.078 mole) of 2(1-indolinyl)benzonitrile of Example 1a in 150 ml dry tetrahydrofuran (THF) was added dropwise to a rapidly stirred ice cold solution of BH3 in THF (236 ml of 1M solution; 0.236 mole) under nitrogen. At the end of the addition the resultant solution was permitted to warm to room temperature and stir for 3 hours and then heated at reflux for 50 minutes. The product was then cooled to 0° C., treated dropwise with 6N HCl (100 ml), and permitted to stand overnight (about 16 hours) at room temperature. The reaction mixture was cooled to 0° C. and made basic using solid NaOH. The resulting aqueous layer was extracted with ether (200 ml) and the combined organic portions were washed twice with brine (200 ml portions), dried over K2CO3, and concentrated to afford 21.1 g of crude free base. The free amine was dissolved in dry ether (300 ml), cooled to 0° C., and treated with gaseous HCl. The resulting salt was filtered, washed with dry ether (300 ml), and dried under vacuum at 40° C. thus affording 19.25 g (94.4%) of crude salt, m.p. 226°-228° C. Recrystallization of 15.59 g of the crude salt from methanol-ether afforded 10.49 g (67.3% recovery) of 2-(1-indolinyl) benzenemethanamine hydrochloride, m.p. 231°-232° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:14]#[C:15]Br>>[CH3:13][CH:5]([C@H:2]1[CH2:3][O:4][C:15]([NH2:14])=[N:1]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CBr
Reactant: CC(Cc1ccccc1)[C@H](N)CO
Product: CC(Cc1ccccc1)[C@H]1COC(N)=N1

Procedure:
In analogy to example 1b (S)-2-amino-3-methyl-4-phenyl-butan-1-ol was reacted with cyanogen bromide to give (S)-4-(1-methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine. Off-white amorphous solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:17]([O:21][CH2:22][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2:24])([CH3:20])([CH3:19])[CH3:18].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:8]([NH:24][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COC(C)(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.2 %

Procedure:
Triethylamine (9.5 ml, 68.0 mmol) and benzaldehyde (6.37 ml, 63.0 mmol) were added to a methanol (300 ml) solution of methyl O-tert-butyl-L-serinate hydrochloride (12.0 g, 57.0 mmol) and the resulting mixture was stirred at room temperature for 6 hours. Sodium borohydride (3.23 g, 86.0 mmol) was gradually added under ice cooling and then the resulting mixture was stirred at room temperature for 2 hours. An aqueous solution of saturated ammonium chloride (100 ml) was added to the reaction mixture. After concentration under reduced pressure, the residue was diluted with ethyl acetate and the precipitated insoluble matter was removed by filtration. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.3 g, 100%) as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12](Br)[CH2:13][Br:14])(=O)C.[O-]CC.[Na+].C(Cl)(Cl)Cl>C(O)C>[Br:14][CH2:13][CH:12]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11]1
Reactant: CC(=O)Oc1ccccc1CC(Br)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: BrCC1Cc2ccccc2O1
Temperature: 0 °C
Yield: 65.7 %

Procedure:
340 mg (1.0 mmol) of compound 001B, which had been prepared in Step B, was dissolved in 3 ml of ethanol, followed by cooling to 0° C. To the resultant solution was dropwise added 1.2 ml (1.2 mmol) of a 1N solution of sodium ethoxide in ethanol and then, the resultant mixture was stirred at 0° C. for 2 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a 10% aqueous citric acid solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001C, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of hexane-ethyl acetate (30:1), to thereby obtain 140 mg of compound 001C as a transparent oily substance (yield: 66%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]([CH3:14])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]2[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]([CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c2c1CCCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)c2c1CCCC=C2
Temperature: 25 °C

Procedure:
A solution of 4-bromo-1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (6.213 g, 24.35 mmol) and p-toluenesulfonic acid monohydrate (0.46 g, 2.44 mmol) in toluene (100 ml) was heated under reflux in a reaction vessel equipped with a Dean-Stark trap under dehydrating conditions for 0.5 hr. After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane) to give the objective substance.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:9]([CH2:12][C:13](O)=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[F:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:9]([CH2:12][C:13]([NH:2][CH3:1])=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C(O)CC1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CNC(=O)CC1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Yield: 47.6 %

Procedure:
Methanamine (2 M solution in THF, 259 μL, 0.52 mmol) was added to a stirred suspension of {7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 15, 40 mg, 0.10 mmol) and TEA (43 μL, 0.31 mmol) in EtOAc (2 mL) at rt. A thick white precipitate was formed. Addition of T3P (50 wt. % in EtOAc, 123 μL, 0.21 mmol) to the mixture resulted in a clear, pale yellow reaction solution. The mixture was stirred at rt over night. EtOAc (10 mL) was added and the mixture was washed with sat. aq. NaHCO3 (5 mL), HCl (1 M, 5 mL) and brine (5 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (using 5% MeOH in DCM as eluent), dissolved in ACN/water (approx. 5 mL, 1:4) and freeze-dried to give the title compound (19 mg, 46%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]1[C:19]([CH2:20][O:21][Si](C(C)(C)C)(C)C)=[C:18]([Cl:29])[CH:17]=[CH:16][N:15]=1.[C:31](O)(=[O:33])[CH3:32]>>[C:31]([O:21][CH2:20][C:19]1[C:14]([C:13]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[N:15][CH:16]=[CH:17][C:18]=1[Cl:29])(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(NC(=O)c2nccc(Cl)c2CO[Si](C)(C)C(C)(C)C)c(N)c1
Product: CC(=O)OCc1c(Cl)ccnc1-c1nc2ccc(C(C)(C)C)cc2[nH]1
Yield: 44 %

Procedure:
A solution of 160g (10 g, 22 mmol) in acetic acid (100 mL) was stirred at 120° C. for 5 h. See FIG. 5. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=3:1) to afford (2-(6-(tert-butyl)-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methyl acetate 160h (3.5 g, 44%) as a yellow solid. MS-ESI: [M+H]+ 358.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:15]([O:17]CC)=[O:16])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:15]([OH:17])=[O:16])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
39 mg (0.09 mmol) of ethyl 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 28 mg (purity 92%, 70% of theory)
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(O[C@@H:21]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=O)C>O>[C:24]([O:23][C@@H:22]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:38][C@@H:21]1[O:16][C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[CH3:6])(=[O:26])[CH3:25]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc([N+](=O)[O-])cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
SnCl4 (0.6 ml) is added slowly to a solution of 2-methyl-4-nitrophenol (ref.: J. S. ANDERSON and K. C. BROWN, Synthetic Commun., 13, 233-236, 1983) and 1,2,3,4,6-penta-O-acetyl-β-D-galactose (1 g, 2.56 mmol), kept at room temperature. The reaction mixture is then stirred under nitrogen for 12 hours at 60° C. After hydrolysis in iced water, extraction with CH2Cl2, followed by washing with a saturated solution of sodium bicarbonate and then water, gives 42, which is then purified by chromatography on silica gel (yield=45%).
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([OH:18])[CH:9]=[CH:10][C:11]=2[O:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:20]1([N:26]2[C:30]([SH:31])=[N:29][N:28]=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([N:26]2[C:30]([S:31][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([OH:18])[CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:29][N:28]=[N:27]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOc1ccc(O)c2c1C(=O)N(CCl)S2(=O)=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(O)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 88 %

Procedure:
By the method of part F of Example 45 condensation of 2-chloromethyl-4-ethoxy-7-hydroxysaccharin (1.95 g) and 1-phenyltetrazol-5-thiol sodium salt (1.5 g, reaction time about 8 hours) and purification of part of the product (2.5 g., 88% yield) from ethanol gave 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-hydroxysaccharin, mp 178°-180° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:13][C:14]#[C:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cl-].[Na+].O>[CH2:13]([O:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCBr
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CCOc1ccc(S(C)(=O)=O)cc1
Reaction time: 6 h
Yield: 95 %

Procedure:
2.88 g (15.9 mmol) of 4-methylsulfonylphenol was added to and dissolved in a dimethylsulfoxide solution (30 mL) of 2.12 g (15.9 mmol) of 1-bromo-2-butyne, and then 2.64 g (19.1 mmol) of potassium carbonate was added thereto. After stirred for 6 hours, brine was added thereto and extracted with ethylacetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. 3.39 g (15.11 mmol) of 1-but-2-ynyloxy-4-methanesulfonylbenzene (V-1) was obtained as a roughly-purified product (yield 95%). Its physical properties are shown below.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:25])([CH3:24])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[N:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[NH4+].[Cl-]>CCO.O.[Fe]>[C:3]([SiH2:7][O:8][C:9]([CH3:25])([CH3:24])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[N:20]=[C:19]([NH2:21])[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2ncc([N+](=O)[O-])n2)co1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2ncc(N)n2)co1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-4-nitro-2H-[1,2,3]triazole (103 mg, 0.30 mmol), iron powder (51 mg, 0.91 mmol) and NH4Cl (82 mg, 1.52 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 90 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. The residue was redissolved in CH2Cl2 (20 mL), dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC:rf (19:1 CH2Cl2-MeOH)=0.20. LC-MS-conditions 02: tR=0.96 min; [M+H]+=310.46.
Reaction SMILES: C(O)C.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[OH-].[Na+].ClCCl>C(O)(=O)C>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1ccc(N(c2ccc(F)c(Cl)c2)[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(C(=O)O)cc2)c2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
To an ethanol solution containing 1.7 g of 3(S)-[(3-chloro-4-fluorophenyl)-(4-ethoxycarbonylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 mmol) was added 6 ml of a 5 N sodium hydroxide solution, followed by stirring at room temperature for 15 hours. Dichloromethane and acetic acid were added to the reaction solution to make the reaction solution acidic. After washing with water three times and with an aqueous saturated sodium hydrogencarbonate solution once, the solvent was distilled off under reduced pressure to thereby obtain 1.50 g of white powdery 3(S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=2)=[O:11])=[CH:4][CH:3]=1.[I-].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([Zn+])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:2]2[CH:3]=[CH:4][C:5]([C@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=3)=[O:11])=[CH:6][CH:7]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])CC1
Agent: [I-]
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
The title compound was produced in analogy to example 3, steps 1 and 2. Thus, reaction of (R)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-2-methylpyridazin-3(2H)-one (example 25, step 1) with (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide produced 4-{4-[(R)-3-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester, which after cleavage of the tert-butoxycarbonyl group led to (R)-2-methyl-6-(3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropanoyl)pyridazin-3(2H)-one. This compound was then reacted with methanesulfonyl chloride to afford the title compound. White solid, MS: 494.3 [M+H]+.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([S:23]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([S:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=3[F:44])[N:28]=2)(=[O:25])=[O:24])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:44][C:38]1[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][S:35][C:29]1[N:28]=[C:27]([NH:26][S:23]([N:21]2[CH2:20][CH:19]([OH:18])[CH2:22]2)(=[O:25])=[O:24])[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1
Reactant: COc1cc(NS(=O)(=O)N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CC(O)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 34 using 3-{[tert-butyl(diphenyl)silyl]oxy}-N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}azetidine-1-sulfonamide (the product from step ii) (0.29 g) and 1M solution of tetrabutylammoniumfluoride in THF (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then triturated with MeOH, Et2O followed by iso-hexane to give the title compound as a white solid. Yield: 40 mg
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[CH:24]([C:25]1[N:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[O:23]
Reactant: COC(=O)c1ccc(CO)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.3 %

Procedure:
Dess-Martin periodinane (2.54 g, 5.98 mmol) was added to a solution of methyl 6-(hydroxymethyl)pyridine-3-carboxylate (Intermediate 190, 1.00 g, 5.98 mmol) in DCM (75 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 hrs before being diluted with DCM (50 mL), washed with a 1:1 mixture of saturated aqueous solution of sodium bicarbonate and sodium thiosulfate (3×75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under vacuum to provide the title compound (1.02 g, 105%). Method B HPLC-MS: MH+ requires m/z=166 Found: m/z=166, Rt=1.44 min (62%).