Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:31])[C:16](N2C(=O)C3C=CC=CC=3OC2(C)C)=[O:17])[NH:13][C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[OH:34].O.OO.[OH-].[Na+]>O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:31])[C:16]([OH:17])=[O:34])[NH:13][C:12]1=[O:32])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CO
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC1(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O

Procedure:
To a solution of 3-[(R)-2-[(3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl]-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one (7.0 g, 15 mmol) in a solvent mixture of methanol/water (2:1, 45 ml), a 30% aqueous solution of hydrogen peroxide (3.5 g, 30 mmol) was added at room temperature. Then a 28% aqueous solution of sodium hydroxide (2.4 g, 17 mmol) was added dropwise into it and the obtained mixture was stirred until the starting material disappeared in HPLC. After the completion of the reaction, 45 ml of cold water was added to the reaction mixture. After washing with 15 ml of methylene chloride, 35% hydrochloric acid was added to thereby adjust the pH value of the mixture to 3. The crystals thus precipitated were collected by filtration, washed with water and dried. Thus 4.3 g of (R)-2-[(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionic acid was obtained.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)#[N:2].[CH2:24]([O:26]CC)C.Cl.[OH-].[Na+]>CO>[CH3:24][O:26][C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)=[NH:2]
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=N)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions, 6.3 g. (0.02 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline is dissolved in 150 ml. of ethyl ether and 1.8 ml. (0.044 mole) of reagent grade methanol is added. The solution is cooled to 0° C. and anhydrous hydrogen chloride is added until the solution is acid to Congo red paper. The resulting mixture is stored at 0° C. for 2 hours, then allowed to warm to room temperature (25° C) overnight. The reaction mixture is made alkaline with 2N sodium hydroxide, the ether layer separated, washed with 2 × 50 ml. of water, dried over anhydrous magnesium sulfate and evaporated to dryness to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9](=[O:11])[CH3:10])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-aminophenyl)-N-methylacetamide (1.78 g, 10.8 mmol) and pyridine (2.63 ml, 32.5 mmol) in tetrahydrofuran (60 ml) was added 2,2,2-trichloroethyl chloroformate (2.23 ml, 16.2 mmol) with ice-cooling, the mixture was stirred for 2 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue was added hexane and the desired product (3.17 g, 86.4%) as a solid was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[NH:10][C:9]1=S.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>O=P(Cl)(Cl)Cl>[Cl:22][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=1
Reactant: O=c1c2cc(F)ccc2[nH]c(=S)n1-c1ccccc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(Cl)n1-c1ccccc1Cl

Procedure:
A suspension of 306 mg (1.0 mmol) of 3-(2-chloro-phenyl)-6-fluoro-2-thioxo-2,3-dihydro-1H-quinazolin-4-one in 2.0 mL of POCl3 was treated with 350 mg of PCl5 and the mixture was refluxed for 2.5 hours. The solvent was evaporated and the residues were taken up in ethyl acetate, washed with water and brine, and then the solvent was evaporated to give 2-chloro-3-(2-chloro-phenyl)-6-fluoro-3H-quinazolin-4-one as a solid. This material was dissolved in 15 mL of absolute ethanol and 238 mg (2.20 mmol) of 2-aminomethylpyridine and the mixture was refluxed overnight. The reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed twice with water. The organic layer was dried with brine and with MgSO4 and evaporated to give a gum which was crystallized from ether to give 190 mg (50%) of the desired product, m.p. 156-158° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Se](=O)(O)[OH:13].O1CCOCC1>O>[CH:8]([C:9]([CH:10]=[O:13])=[O:11])=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[Se](O)O
Reactant: CC(=O)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)C=Cc1ccccc1

Procedure:
A solution containing 100 parts of 4-phenyl-3-buten-2-one, 106 parts of selenous acid, 160 parts of dioxane and 20 parts of water is heated to the reflux temperature. After the initial vigorous reaction has subsided, the mixture is heated at that temperature for an additional 30 minutes. The supernatant is then decanted from the metallic selenium and is concentrated under reduced pressure. Distillation of the residue under reduced pressure affords, as a yellow oil, styrylglyoxal, boiling at about 120° at 2.5 mm. pressure.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C(OCC)(=O)C>[Cl:1][C:2]([C:3]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=[CH:17][CH:18]=[CH:19]1)=[O:4])([Cl:7])[Cl:6]
Reactant: Clc1ccc(-c2ccc[nH]2)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C(Cl)(Cl)Cl)C1(c2ccc(Cl)cc2)C=CC=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A solution of trichloroacetyl chloride (11.26 g, 0.0619 mol) in ether is treated with a solution of 2-(p-chlorophenyl)pyrrole (10.0 g, 0.0503 mol) in ether, stirred for four hours at room temperature, treated with saturated potassium carbonate solution and diluted with ethyl acetate. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow solid. The solid is recrystallized from 2-propanol to give the title product as a yellow solid (12.63 g, mp 166°-168° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c1
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 28.9 %

Procedure:
Using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.19 mmol) obtained in step 5 and propionic acid (0.071 mL, 0.95 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.032 g, 40%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:29])=[CH:27][CH:26]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 70.1 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), (4-hydroxy-phenyl)-carbamic acid tert-butyl ester (14.7 g, 68 mmol) and K2CO3 (18.9 g, 136 mmol) in DMF (300 mL) was heated at 110° C. for 1 hour under N2, cooled to room temperature, and then poured into ice-H2O (1200 mL) under stirring. The aqueous mixture was extracted with AcOEt (600 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give pale brown crystal, which was purified by washing with i-Pr2O and dried at 40° C. overnight under reduced pressure to give the title compound as pale yellow crystal (18.5 g, 70%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[N+:28]([C:31]1[CH:32]=[C:33]([C:37](=[O:41])[C:38]#[C:39][CH3:40])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=1)=[O:41]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC#CC(=O)c1cccc([N+](=O)[O-])c1
Product: C/C(=C/C(=O)c1cccc([N+](=O)[O-])c1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 120 mg (0.25 mmol) of Intermediate 45 and 48 mg (0.25 mmol) of Intermediate 42 to yield 67 mg of Example 25: TLC (DCM/MeOH (4:1): Rf=0.52; 1H NMR (DMSO-d6, 400 MHz) δ11.52 (d, 1H, J=9.1), 8.52 (s, 1H), 8.24 (d, 1H, J=8.2), 8.21 (d, 2H, J=7.7), 7.87 (d, 2H, J=7.7), 7.66 (t, 1H, J=7.9), 7.45 (m, 3H), 7.10 (d, 2H, J=8.2), 6.79 (d, 2H, J=8.3), 5.74 (s, 1H), 4.13 (t, 2H, J=6.6), 4.07 (br s, 1H), 3.15 (m, 1H), 2.87 (t, 2H, J=6.4), 2.75 (m, 1H), 2.31 (s, 3H), 1.68 (s, 3H).; low resolution MS (ES+)m/e 556.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](N)=[C:7](N)[CH:6]=1)C.[B:14]1(B2OC(C)(C)C(C)(C)O2)[O:18]C(C)(C)C(C)(C)[O:15]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([B:14]([OH:18])[OH:15])=[CH:7][CH:6]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(B(O)O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 228.9 %

Procedure:
Referring to Scheme 11-1, to a solution of the bromide 1 (2.0 g, 4.2 mmol, prepared according to published conditions) in dioxane (60 mL) was added bis(pinacolato)diboron (4.32 g, 17 mmol), Pd(PPh3)4 (0.49 g, 0.42 mmol) and potassium acetate (2.06 g, 21 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 5 h, and then diluted with ethyl acetate (150 mL). The organic phase was washed with H2O (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was further purified by silica gel column chromatography (haxanes/ethyl acetate=1/4 to 0/1 (v/v)) to give 2 (1.73 g, 79% yield). LC-MS (ESI): m/z 523.3 (M+H)+.
Reaction SMILES: [C:1]([C:8]1[C:9]([NH:19][CH3:20])=[C:10]([C:14](=O)[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:22][OH:23]>>[C:1]([C:8]1[C:9]([NH:19][CH3:20])=[C:10]([C:14](=[N:22][OH:23])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NO
Reactant: CNc1c(C(=O)OC(C)(C)C)cccc1C(=O)C(=O)O
Agent: Cl
Product: CNc1c(C(=O)OC(C)(C)C)cccc1C(=NO)C(=O)O

Procedure:
32.2 g of 2-(3-BOC-methylaminophenyl)-glyoxylic acid are reacted with 13.8 g of hydroxylamine hydrochloride in the manner described in Example 4. Crystallisation from CH2Cl2 /CH3OH/ether/hexane yields 2-(3-BOC-methylaminophenyl)-2-hydroxyiminoacetic acid. M.p. 135° (decomposition). IR: 3620, 3600-2300 (wide), 1688, 1600, 1590 (shoulder) cm-1 (CH2Cl2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-])=O.[OH2:13]>CN(C=O)C>[O:13]1[CH2:6][CH2:5][C@@H:4]([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7]2)[CH2:12]1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: O
Solvent: CN(C)C=O
Product: Nc1cccc2c1ccn2[C@@H]1CCOC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (2.5 g) and (S)-tetrahydrofuran-3-yl methanesulfonate obtained in the above-described Step (1.01 g) were added to a solution of 4-nitro-1H-indole (980 mg) in DMF (10 mL), and the reaction solution was stirred at 100° C. for 24 hours. Water was added to the reaction solution, the reaction solution was extracted with ethyl acetate twice, and then washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate). THF (10 mL) was added to the resultant residue, 10% palladium on carbon (100 mg) was added, and the reaction solution was stirred under hydrogen atmosphere at room temperature for 14 hours. The insolubles were filtrated with celite, and the solvent was evaporated under vacuum. Thereafter, the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 1-((R)-tetrahydrofuran-3-yl)-1H-indol-4-amine as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33].C(OCC)C>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of the compound (30) (3 g, 6.528 mmol) in ethyl acetate (10 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (33 ml) under ice-cooling and the resulting mixture was stirred for 3 h. To the reaction mixture was added diethyl ether and the precipitation which apl)eare(d was filtered off to give 2.77 g of compound (32). This compound was used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N:11]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(N)cc(Cl)c1N
Reactant: BrCCOCCBr
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N2CCOCC2)cc(Cl)c1N
Temperature: 180 °C
Yield: 91 %

Procedure:
2,5-Diamino-3-chloro-benzonitrile (387 mg), bis-(2-bromoethyl)ether (0.35 mL) and N,N-diisopropyl-ethylamine (1.25 mL) were mixed in N,N-dimethylformamide (4 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (20 mL) was added and the crude mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo to furnish 0.50 g (91%) of the title compound as a brown solid. LC-MS (m/z) 238 (MH+); tR=2.31, (UV, ELSD) 85%, 95%. 1H NMR (500 MHz, DMSO-d6): 2.97 (m, 4H), 3.69 (m, 4H), 5.59 (s; 2H), 7.04 (d, 1H), 7.29 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH3:14])[O:11][C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@H:10]1[O:11][C@H:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@@H](C(F)(F)F)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CNC[C@@H](C(F)(F)F)O1
Yield: 67.4 %

Procedure:
N-benzyl-trans-2-trifluoromethyl-6-methylmorpholine [1223452-62-7] (7.5 g, 28.93 mmol) was added to a suspension of Pd/C 10% (1 g) in methanol (150 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere until 1 equivalent of hydrogen was absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was evaporated, yielding 3.3 g (67%) of Intermediate 30 as an oil that was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(=O)([O-])O.[Na+].[C:12]1([CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:23]3[C:24]([NH2:27])=[N:25][O:26][C:22]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1CCCC1>O>[C:12]1([CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:23]3[C:24]([NH:27][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[N:25][O:26][C:22]=3[CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1noc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1noc2cc(OCc3ccccc3)ccc12
Reaction time: 18 h

Procedure:
8.8 ml (0.092 mol) of ethyl chloroformate and 10.6 g (0.126 mol) of sodium hydrogen carbonate are added to a solution of 10.1 g (0.042 mol) of 6-(phenylmethoxy)-1,2-benzisoxazol-3-amine in 100 ml of a 9:1 mixture of tetrahydrofuran and water. The mixture is stirred for 18 hours and then the solvent is evaporated off and the residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. After crystallization from isopropyl alcohol and recrystallization from n-butanol, 11.5 g of product are obtained.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].[CH3:36][O:37][CH2:38][CH:39]([NH2:42])[CH2:40][CH3:41]>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH:39]([CH2:38][O:37][CH3:36])[CH2:40][CH3:41])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: CCC(N)COC
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Solvent: O=C(O)C(F)(F)F
Product: CCC(COC)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-]
Yield: 81.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (39.6 mg, 0.093 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine (191.0 mg, 1.85 mmol) were treated substantially as described in Part C of Example 19a to produce 30 mg (81%) of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 397.19 [(M+H)+, 100].
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2C)[S:4]1(=[O:6])=[O:5].[Cl:16]C1C=CC=C2C=1C(=O)NS2(=O)=O.C=O>>[OH:1][CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:16])[S:4]1(=[O:6])=[O:5]
Reactant: O=C1NS(=O)(=O)c2cccc(Cl)c21
Reactant: Cc1cccc2c1C(=O)N(CO)S2(=O)=O
Agent: C=O
Product: O=C1c2c(Cl)cccc2S(=O)(=O)N1CO

Procedure:
2-Hydroxymethyl-4-chlorosaccharin was prepared in the same manner as 2-hydroxymethyl-4-methylsaccharin, in Example 1, from 4-chlorosaccharin (1.00 g; 4.60 mmol) and formalin (37%; 3.22 ml; excess). All attempts to crystallize the viscous oily product resulted in decomposition to the starting material, and the product was thus used in the next step without characterization.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:33]1([CH2:38]OS(C(F)(F)F)(=O)=O)[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1.C(OCC)(=O)C>[CH:33]1([CH2:38][C@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]([N:3]2[C@H:2]([CH3:1])[C@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:5][C:4]2=[O:13])=[O:22])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=S(=O)(OCC1CCCC1)C(F)(F)F
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The title A compound, (4R,5S)-4-methyl-5-phenyl-3-phenylacetyl-oxazolidin-2-one (5.00 g, 16.93 mmol) is dissolved in anhydrous THF (50 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (1 M in THF, 16.93 mL, 16.93 mmol) is added dropwise over 10 min. To this is added a solution of the title B compound, trifluoromethanesulfonic acid cyclopentylmethyl ester (3.93 g, 16.93 mmol) in anhydrous THF (15 mL). The reaction is stirred at −78° C. for 10 min, then the cold bath is removed. The reaction is allowed to stir and warm to RT. After one hour, the reaction is concentrated to remove the solvent, resulting in a yellow oil. This is dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The organic solution is dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil. This is recrystallized from hexanes to afford (4R,5S)-3-((R)-3-cyclopentyl-2-phenyl-propionyl)-4-methyl-5-phenyl-oxazolidin-2-one as a white solid: 1H NMR (400 MHz, DMSO-D6) 0.8 (d, J=6.6 Hz, 3 H) 1.1 (d, J=16.2 Hz, 2 H) 1.4 (m, 2 H) 1.5 (d, J=5.8 Hz, 2 H) 1.6 (s, 2 H) 1.8 (d, J=7.1 Hz, 2 H) 2.0 (d, J=13.4 Hz, 1 H) 4.8 (s, 1 H) 5.1 (s, 1 H) 5.7 (d, J=7.1 Hz, 1 H) 7.3 (s, 1 H) 7.4 (m, 9 H); LC/MS 378.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26]1(O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: OC1CCCCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCCCC2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and cyclohexanol in analogy to Example 9c): MS (ISN): 442.3 (M−H)−; MS (ISP): 444.2 (M+H)+, 344.1 ((M-Boc)+H)+ (100%).