Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@@H:14]([NH:19][C:20](=[O:43])[O:21][C@H:22]([CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[N:30]=[CH:29]1)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].O[C@H]([C@@H](NC(=O)O[C@H](CN1C=C(C2C=CC(C(F)(F)F)=CC=2)N=C1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][C:2]([C@@H:14]([NH:19][C:20](=[O:43])[O:21][C@H:22]([CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[N:30]=[CH:29]1)[C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])(=[O:6])=[O:7]
Reactant: CCCC[C@H](NC(=O)O[C@H](Cn1cnc(-c2ccc(C(F)(F)F)cc2)c1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1cnc(-c2ccc(C(F)(F)F)cc2)c1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCC[C@H](NC(=O)O[C@H](Cn1cnc(-c2ccc(C(F)(F)F)cc2)c1)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
To a solution of 0.20 g (0.28 mmol) of (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate and (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate in 3 mL chloroform was added 0.15 g (0.35 mmol) Dess-Martin periodinane. The reaction mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate and a saturated aqueous sodium thiosulfate solution. The layers were mixed vigorously, and then a saturated aqueous sodium bicarbonate solution was added. The layers were separated, and the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with a methanol:chloroform solution (1:9) to yield 83.2 mg (48%) of (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ES-LCMS m/z 624 (M+H) retention time=3.51 min. HRMS C29H36F3N5O5S m/z 624.2468 (M+H)Cal; 624.2463 (M+H)Obs.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:9]=[N:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][CH2:31][CH2:32][OH:33].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[OH:33][CH2:32][CH2:31][NH:30][C:26]([C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([CH:7]([C:8]3[CH:9]=[N:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:29][C:21]2=[N:22][CH:23]=1)=[O:28]
Reactant: NCCO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)NCCO)cnc3[nH]2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.6 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (80 mg, 0.19 mmol) and 2-amino-ethanol (14 uL, 0.23 mmol) in dichloromethane (1 mL), N,N-dimethylformamide (1 mL) and N-methylmorpholine (60 uL, 0.58 mmol) was added 1-hydroxybenzotriazole hydrate (54 mg, 0.39 mmol), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) in one portion. The mixture was then stirred at 25° C. for 14 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1 N sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid(2-hydroxy-ethyl)-amide (30 mg, 34%) as a white solid: LC/MS m/e calcd for C23H28N4O4S [M+H]+ 456.57, observed 457.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (m, 2H), 1.47 (m, 2H), 1.55-1.84 (m, 5H, H), 2.08 (m, 1H), 2.24 (m, 1H), 3.20 (s, 3H), 3.60 (m, 2H), 3.80 (m, 2H), 4.26 (m, 1H), 6.37 (s, 1H), 7.61 (br, 1 H), 7.85 (br, 1H), 7.97 (m, 1H), 8.29 (m, 1H), 8.59 (br. s., 1H), 8.63 (s, 1H), 11.01 (br, 0.2H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].[Cl-].[NH4+]>O1CCCC1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:20]
Reactant: O=C(c1ccccc1)C(CCOC1CCCCO1)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)C(CCOC1CCCCO1)c1ccccc1

Procedure:
First a Grignard complex is prepared under dry conditions by allowing 3.6 g of magnesium turnings in 25 ml of dry tetrahydrofuran to react with 23.6 g of bromobenzene in 50 ml of dry tetrahydrofuran. Then the evaporation residue obtained in step (a) in 75 ml of dry tetrahydrofuran is added. The reaction mixture is refluxed for 2 h. The cooled mixture is poured into a saturated solution of ammonium chloride. After shaking, the organic layer is separated. The extraction is repeated with ether. Then the organic layers are combined and dried over sodium sulfate. Finally the solvent is evaporated.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]4[CH:23]=[N:22][NH:21][C:18]4=[N:19][CH:20]=3)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:24]N1C(=O)CCC1=O>ClC(Cl)C.ClCCl>[I:24][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:11]3[CH:10]=[C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:16]=2)[NH:21][N:22]=1
Reactant: O=C(c1cccc(-c2cnc3[nH]ncc3c2)c1)N1CCOCC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccc(-c2cnc3[nH]nc(I)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Morpholin-4-yl-[3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-methanone (2.30 g, 80% pure, ˜6 mmol) and of N-iodosuccinimide (2.50 g, 11.1 mmol) were dissolved in dichloroethane (180 mL). The mixture was stirred under reflux conditions for 5 h, then cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated aqueous solution of sodium thiosulfate (1×) and then with a saturated aqueous solution of sodium bromide(2×), dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with ether (80 mL) and dried to afford [3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-morpholin-4-yl-methanone as a beige powder (2.881 g, 88% yield over two steps). 1H-NMR (500 MHz, d6-DMSO) δ14.19 (s, 1H), 8.92 (d, 1H), 8.14 (d, 1H), 7.91 (m, 1H), 7.83 (m, 1H), 7.59 (ddd, 1H), 7.44 (dt, 1H), 3.75-3.35 (m, 8H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.[ClH:26]>C1COCC1.O>[ClH:26].[C:3]([CH:5]([C:14]1[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: Cc1cc(C(F)(F)F)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C#N)c1nc(C)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1,1,1-trifluoro-2,4-pentanedione (5.00 g; 32.4 mmol) and S-methylisothiourea hemisulfate (4.06 g; 29.2 mmol) in pyridine (3.75 mL) and water (62 mL) was heated at reflux for 1 day. The mixture was cooled to room temperature, extracted with chloroform, and the chloroform extract washed with water to give 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine as an off-white solid (4.60 g, 22.1 mmol). This was dissolved in MeOH (60 mL), and a solution of OXONE® (27.1 g, 44.2 mmol) in water (100 mL) was added over 10 min. The mixture was stirred at room temperature for 4 hr and then extracted with EA. The EA was washed with water, dried, and concentrated to give 4-methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (4.8 g) as a white solid. Sodium hydride (0.16 g of a 60% dispersion in mineral oil; 4.0 mmol) was added to a stirred solution of ethyl cyanoacetate (0.21 mL; 2.0 mmol) in THF (8 mL), and the resulting suspension stirred at room temperature for 15 min. 4-Methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (0.48 g; 2.0 mmol) was then added, and the mixture stirred overnight. Water was added, followed by 1M hydrochloric acid to adjust to pH 3-4. The solid that formed solid was filtered, washed with water, and dried under high vacuum to give ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (0.43 g) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[O:31]=[C:30]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: C1CCNC1
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: O=C(COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)N1CCCC1
Yield: 81.4 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (180 mg, 0.41 mmol) was reacted with pyrrolidine (0.205 ml, 2.45 mmol) to give the title compound as a light brown solid (160 mg, 82%), except that the reaction was run at 45° C. for 18 hours in the presence of 3 Å molecular sieve. NMR Spectrum 1.83 (m, 2H), 1.95 (m, 2H), 3.45 (t, 2H), 3.50 (t, 2H), 5.09 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.18 (d, 1H), 7.29 (m, 1H), 7.37 (d, 1H), 7.77-7.69 (m, 3H), 7.91 (m, 1H), 8.15 (s, 1H), 8.53 (s, 2H), 8.57 (s, 1H), 11.16 (br s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: Cl[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[C:6](C2C=CC=CC=2)[CH:5]=1)=O.[NH2:19][C:20]1[CH:25]=[C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:23]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[CH:22][C:21]=1[NH2:48]>C1C(Cl)=CC=C(Cl)C=1>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2[NH:48][C:21]3[CH:22]=[C:23]([NH:37][S:38]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[C:24]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])=[CH:25][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)([O:10][C:4]1[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(Cl)c1ccc(C(=O)[O-])c(-c2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(N)c(N)cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: Clc1ccc(Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccc(C(=O)Oc5ccccc5)cc4)[nH]c3cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 76.6 %

Procedure:
To a solution containing 8.7 g (33.6mmole) of p-chlorocarbonylphenylbenzoate dissolved in 50 ml of dichlorobenzene was added 5 g (11.2 mmole) of 1,2-diamino-4,5-bis(p-toluenesulfonamido)benzene. The resulting mixture was heated to reflux under nitrogen (frothing), and was maintained at that temperature for 2 hours. The solution was then distilled to half of the original volume, and heptane was added to precipitate the yellow product. The crude product was filtered, washed with several portions of hexane, and air-dried. The material thus obtained was reprecipitated three times from THF solution using hexane. Recrystallization from methanol afforded 5.6 g (77%) of 2-[p-carbophenoxyphenyl]-5,6-bis(p-toluenesulfonamido)-benzimidazole as an amorphous yellow powder.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[N:27][C:28](F)=[N:29][CH:30]=1>>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:29][CH:30]=1
Reactant: Fc1ncc(Br)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(Br)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 5-bromo-2-fluoro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=2.32 min; Mass spectrum (ESI+): m/z=468/470 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][NH2:28])[CH:20]=1)[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][NH:28][C:5](=[O:7])/[CH:4]=[CH:3]/[C:2]([F:1])([F:9])[CH3:8])[CH:20]=1)[CH3:17]
Reactant: CC(F)(F)/C=C/C(=O)O
Reactant: CCOc1ccnc(NCCN)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccnc(NCCNC(=O)/C=C/C(C)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(4-ethoxy-2-pyridyl)ethane-1,2-diamine (27 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) dissolved in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 18.7 mg of a residue that was purified again by preparative HPLC (gradient of water containing 0.1% trifluoroacetic acid and 10% to 100% acetonitrile). The product obtained was converted to the free base by dissolving in DCM, washing with 1N NaOH solution, water and evaporation to dryness under reduced pressure to yield 13.2 mg of a solid (0.044 mmol, 29%).
Reaction SMILES: OS(O)(=O)=O.Cl[CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:29][CH2:30][CH2:31][N:32]([CH2:45][CH3:46])[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([C:24](=[O:28])[CH2:25][CH2:26]Cl)=[CH:18][CH:17]=3)=[O:10]>C(Cl)Cl.C(OCC)(=O)C>[O:28]=[C:24]1[C:19]2[CH:18]=[CH:17][C:16]3[N:15]([CH2:29][CH2:30][CH2:31][N:32]([CH2:45][CH3:46])[S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[N+:42]([O-:44])=[O:43])(=[O:34])=[O:35])[C:14]4[CH:13]=[CH:12][C:11]5[C:9](=[O:10])[CH2:8][CH2:7][C:23]=5[C:22]=4[C:21]=3[C:20]=2[CH2:26][CH2:25]1
Reactant: CCN(CCCn1c2ccc(C(=O)CCCl)cc2c2cc(C(=O)CCCl)ccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CCCn1c2ccc3c(c2c2c4c(ccc21)C(=O)CC4)CCC3=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
H2SO4 (110 mL) was heated to 40° C. Compound 61 (7.6 g, 12.3 mmol) was added in portions. The reaction mixture was heated to 100° C., kept at this temperature for 2 h (TLC monitoring, CH2Cl2/ethyl acetate 4:1), and poured into ice. The formed gray precipitate was filtered off. Then CHCl3/MeOH 4:1 (500 mL) was poured into the filter. The solid on the filter dissolved, and the formed solution was transferred into a separation funnel. An aqueous solution of Na2CO3 was added. The organic layer was separated, dried with Na7SO4, and evaporated. Acetonitrile was added to the residue. A beige precipitate was filtered off, washed with acetonitrile, with ether, and dried to give 1.56 g (23%) of a beige crystalline product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6]O.[Cl:22]C(N(C)C)=C(C)C>C(Cl)Cl>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][Cl:22]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: C[Si](C)(C)CCOCOc1ccc(CO)cc1C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOc1ccc(CCl)cc1C(F)(F)F

Procedure:
Compound 93-4 (28.5 g) was dissolved in methylene chloride (450 ml), 1-chloro-N,N,2-trimethyl-1-propenylamine (12.9 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was diluted with methylene chloride (200 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-90:10) to give the object product (14.5 g) as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:22]=[CH:21][C:10]2[N:11]([C:16](=[O:20])[CH:17]=NO)[CH:12]([CH3:15])[CH2:13][O:14][C:9]=2[C:8]=1[F:23]>O>[F:23][C:8]1[C:7]([F:6])=[CH:22][C:21]2=[C:10]3[C:9]=1[O:14][CH2:13][CH:12]([CH3:15])[N:11]3[C:16](=[O:20])[C:17]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC1COc2c(ccc(F)c2F)N1C(=O)C=NO
Solvent: O
Product: CC1COc2c(F)c(F)cc3c2N1C(=O)C3=O
Temperature: 80 °C

Procedure:
A solution of 45 mL of 98% sulfuric acid in 18 mL of water is heated to 50° C. to 60° C. and treated portionwise over 30 minutes with 10.5 g (41 mmol) of (7,8-difluoro-3-methyl-2,3-dihydro-1,4-benzoxazin-4-yl)oxoacetaldehyde oxime (Example 29). After the addition is complete, the reaction is heated to 80° C. for 15 minutes and poured onto 200 mL of ice and water. The mixture is stirred until the ice melts and the solid is removed by filtration, washed with water and the wet filter cake is dissolved in dichloromethane. The organic solution is washed with water (2×200 mL), dried (MgSO4), filtered and concentrated in vacuo affording 7.1 g of the title compound, mp 169–171° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:38])([F:37])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:33])([CH2:30][CH:31]=[CH2:32])[C:27](O)=[O:28])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40].CCN(CC)CC>ClCCl>[F:37][C:8]([F:38])([F:7])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([CH3:33])([CH2:30][CH:31]=[CH2:32])[C:27]([N:41]([CH2:42][CH3:43])[CH2:39][CH3:40])=[O:28])=[CH:24][CH:25]=2)=[CH:13][CH:14]=1
Reactant: C=CCC(C)(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(C)(C(=O)N(CC)CC)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 50 °C
Yield: 71.9 %

Procedure:
Oxalyl chloride (57.7 mg, 0.45 mmol) was added dropwise to 49.5 (100 mg, 0.23 mmol) in anhydrous dichloromethane (4 mL). The resulting mixture was refluxed in a sealed tube at 50° C. overnight. The dichloromethane was removed under a stream of N2. Anhydrous ether (2 mL) was added dropwise, followed by diethyl amine (50 mg, 0.69 mmol) and Et3N (70 mg, 0.69 mmol). The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified via flash chromatography (25% ethyl acetate in hexanes). 82 mg of 49.6 was obtained. MS ESI m/e: 496 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.72 (4H, s); 7.69 (1H, s); 7.6-7.5 (3H, m); 7.14 (2H, d, J=8.5 Hz); 7.05 (2H, d, J=8.5 Hz); 5.7-5.6 (1H, m); 5.15 (2H, s); 5.03-5 (2H, m); 3.5-3.2 (2H, m); 3.0-2.9 (2H, m); 2.74-2.64 (2H, m); 1.62 (3H, s); 1.13 (3H, s); 0.72 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[I-].[K+].[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:30][CH2:27][CH:28]=[CH2:29])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: C=CCN
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(SC)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 31, 8-(methylthio)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-(methylthio)-1-[(allylamino)-methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[S:45][C:44]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=2[CH3:55])=[N:43][C:42]=1[CH3:56].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[S:45][C:44]([C:46]5[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=5[CH3:55])=[N:43][C:42]=4[CH3:56])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C)c(Br)s1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(-c2sc(-c3ccc(C(=O)O)cc3C)nc2C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Yield: 93.1 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 mmol), 4-(5-bromo-4-methylthiazol-2-yl)-3-methylbenzoic acid (INTERMEDIATE 42, 1.190 g, 3.81 mmol), potassium phosphate (2.2 g, 10.39 mmol) in THF (5 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.346 mmol). It was degassed, and refilled with nitrogen. The reaction mixture was heated to reflux for 2 hours to see complete conversion by LCMS. It was distributed between 100 mL of water and 300 mL of ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude was purified on a silica gel column, eluting with 30% ethyl acetate in hexanes to give the title compound as white solid (2.2 g, 93% yield). LCMS (M+H)+: 683.0