Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[CH2:5][CH2:6][C:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([NH2:10])=[O:9])([CH3:3])[CH3:2].[H][H].CCCCCC>C(O)C.C(Cl)Cl.[Ru](=O)=O>[CH:11]1([C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:26]([CH3:28])[CH3:27])([CH2:17][CH2:18][N:19]([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[C:8]([NH2:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1)C(C)C
Reactant: [H][H]
Agent: O=[Ru]=O
Solvent: CCO
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)C1CCCCC1)C(C)C
Temperature: 125 °C
Reaction time: 24 h

Procedure:
10 Parts of α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetamide is dissolved in 130 parts by volume of ethanol and the solution placed in pressure shaker with 1 part of ruthenium dioxide. Hydrogen is introduced at 1000 psi and the reaction mixture heated at about 125° C. and shaken for about 24 hours. Then, the reaction mixture is cooled to room temperature and filtered. The filtrate is stripped of solvent to give an oil. This oil is dissolved in methylene chloride, then hexane added to the solution, methylene chloride evaporated, and the hexane mixture cooled to give α-(cyclohexyl)-α,α-bis[2-(diisopropylamino)ethyl]acetamide, as a crystal solid melting at about 114°-115° C. This compound has the following structural formula ##STR49##
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][S:11][CH3:12])[CH:7]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][S:11][CH3:12])[CH:7]=1
Reactant: C[O-]
Reactant: CSC[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N[C@@H](CSC)C(=O)O)c1

Procedure:
27 g of N-(5-fluoro-2-nitrophenyl)-S-methyl-L-cysteine (0.1 mol) from Example 1 are dissolved in 150 ml of absolute methanol in a four-necked flask, and 14.4 g of 95% sodium methoxide (0.25 mmol) are added in portions, within the space of 20 minutes and under argon, to this solution while stirring well and while cooling by means of an ice bath. The mixture is then heated to reflux for 2 hours while stirring. TLC monitoring then indicates that the reaction is complete.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[CH:20]=3)=[N:15]2)=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[CH3:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Reaction time: 8 h

Procedure:
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (100 mg; 0.25 mmol) and 5 ml of EtOH were put to reaction flask and sodium borohydride (19 mg; 0.5 mmol) was added slowly as EtOH suspension. The reaction was stirred overnight to completion. 0.5 ml of water and 1 ml of 0.5M HCl were added dropwise. The solution was evaporated to dryness, 20 ml of DCM was added and washed with 10 ml of 1 M NaHCO3 and 10 ml of water followed with drying over Na2SO4. After filtration and evaporation 76 mg (76%) of pure title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 1.38 (d, 3H), 4.22-4.48 (m, 3H), 4.74-4.84 (m, 1H), 4.41 (d, 1H), 6.40 (s, 1H), 6.94 (d, 1H), 7.81 (d, 1H), 7.92-8.05 (m, 2H), 8.09 (d, 1H), 8.20 (d, 1H), 13.04 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:16][CH2:17][CH2:18][N:10]1[C:11]([C:13](=[O:15])[CH3:14])=[CH:12][C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])=[N:9]1
Reactant: CC(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCBr
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 150d (5.4 g, 1.0 eq., 26.6 mmol), 1,2-dibromoethane (20.0 g, 4.0 eq., 106.4 mmol), K2CO3 (7.34 g, 2.0 eq., 53.2 mmol), and acetonitrile (100 mL). The reaction mixture was reflux for 5 hrs. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 150e (7.5 g, 91%) as a colorless oil. MS-ESI: [M+H]+ 309.9
Reaction SMILES: C(O)C(O)C[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12]([OH:32])(=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[OH:24]>>[C:12]([OH:32])(=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[OH:24].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[C:12]([OH:32])(=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[OH:24].[C:12]([OH:32])(=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[OH:24].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9]
Reactant: OCC(O)COCC(O)CO
Agent: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Product: OCC(O)CO

Procedure:
From table 7a it appears that for esters of diglycerol and ricinoleic acid optimum wearing reduction is provided with a molar ratio diglycerol mono-ricinoleate/diglycerol di-ricinoleate of about 1.15.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NC[C@@H](O)[CH2:37][OH:38].CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH2:37][OH:38])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: NC[C@@H](O)CO
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 40 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (R)-(+)-3-amino-1, 2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (374.5 mg, 40%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.04 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0649 (M+H C22H21BrF2N3O5 requires 524.0627).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:15][CH:14]=1
Reactant: O=C1NCc2ccccc21
Reactant: Cc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(CN2Cc3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-methyl-benzene (0.222 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 4.24 (s, 2H), 4.76 (s, 2H), 7.15-7.54 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:20])[NH:10][C:11](=[O:19])[NH:12][C:13]=1OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[OH-].[Na+]>CO.[Pd]>[CH2:1]([C:8]1[C:9](=[O:20])[NH:10][C:11](=[O:19])[NH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Oc1[nH]c(=O)[nH]c(=O)c1Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1[nH]cc(Cc2ccccc2)c(=O)[nH]1
Yield: 79.8 %

Procedure:
A solution of 5-benzyl-6-methanesulphonyloxy-2,4-(1H,3H)-pyrimidinedione (3 g) and Et3N (2.1 ml) in MeOH was hydrogenated in the presence of Pd/C 5% (0.3 g) for 3 hr at 35° C. NaOH 5% (2.5 eq) was added and the catalyst filtered off. The solution was acidified to pH 2 with HCl 10%. The precipitated white solid was then collected by filtration, washed with water, ether and dried under vacuum to yield the desired 5-benzyl-2,4-(1H,3H)-pyrimidinedione: 1.635 g, 79.8% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30]([O:32]CC)=[O:31])=[N:25]1)=[O:14].O.[OH-].[Li+]>C1COCC1.O>[OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[N:25]1)=[O:14]
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)nn1-c1ccc([N+](=O)[O-])cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of (S)-ethyl 1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxylate (18.0 g, 38.8 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide monohydrate (5.0 g, 116.8 mmol) followed by stirring at RT for 6 h. The reaction mixture was concentrated invacuo, diluted with water (80 mL) and extracted with diethyl ether (100 mL). The aq. layer was cooled to 0° C., acidified up to pH ˜4 using 3N HCl and extracted with EtOAc (200 mL×2) twice. The combined organic layers were washed with water (200 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a white colored solid 14 g (82%). Rf=0.25 (70% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 12.90-12.50 (brs, 1H), 8.64-8.30 (m, 2H), 8.06-7.72 (m, 1H), 7.24-6.82 (m, 4H), 6.80-6.42 (m, 1H), 5.20-3.80 (m, 6H), 3.40-2.40 (m, 2H), 2.40-2.10 (m, 3H); ES-MS: m/z 437.2 (M+H).
Reaction SMILES: [Na].[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[CH:14][N:15]=2)[CH:12]=1)(OCC)=O.[CH:16]1([N:21]2[C:25]([NH2:26])=[C:24]([C:27]([NH2:29])=[O:28])[C:23]([CH2:30][CH3:31])=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([N:21]2[C:25]3=[N:26][C:2]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([CH:13]=[CH:14][N:15]=5)[CH:12]=4)=[N:29][C:27](=[O:28])[C:24]3=[C:23]([CH2:30][CH3:31])[NH:22]2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1ccc2nccn2c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4nccn4c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 60 h
Yield: 61.1 %

Procedure:
Sodium metal (0.21 g, 9.2 mmol) was dissolved in ethanol (25 ml) and 6-carboethoxyimidazo[1,2-a]pyridine (1.75 g, 9.2 mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.02 g, 4.6 mmol) were added. The reaction mixture was heated to reflux for 24 hours, cooled to room temperature and stirred for 60 hours. The solvent was removed in vacuo, the residue was dissolved in water (100 ml) and the solution was neutralized by the addition of concentrated HCl. A precipitate was obtained which was collected by filtration through a glass frit. The solid was recrystallized from ethanol and washed with ether to afford 0.98 g (62%) of 1-cyclopentyl-3-ethyl-6-(6-imidazo[1,2-a]pyridinyl)-pyrazolo[3,4-d]pyrimidin-4-one as white crystals, m.p. >300° C. when dried for 18 hours at 120° C. in high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1.C(N(CC)CC)C.[Br:28][CH2:29][C:30](Br)=[O:31]>ClCCl>[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][Br:28])[CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=C(Br)CBr
Reactant: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNc1cc(NC(=O)CBr)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To N-{2-[(6-amino-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (5) (1.20 g) in anhydrous dichloromethane (100 ml) was added triethylamine (1.23 ml), then bromoacetylbromide (768μl) in 2 aliquots. The mixture was left to stir at room temperature for 10 mins then was partitioned between dichloromethane (50 ml) and water (50 ml). The aqueous layer was extracted with dichloromethane (3×50 ml) and the organic layers combined, dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the resulting solid purified via column chromatography on silica gel eluting with a mixture of ethyl acetate and petrol ether (1:1 v/v), then ethyl acetate, then a mixture of ethyl acetate and methanol (95:5 v/v) to furnish the title compound (195 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1)[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[OH-].[Na+]>O1CCCC1>[CH3:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=1)[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1
Reactant: CN(C(=O)c1ccc(C(F)(F)F)cc1)c1ccnn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)cc1)c1ccnn1C
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
Under cooling in an ice bath, lithium aluminum hydride (56 mg) was added to a tetrahydrofuran (3.2 mL) solution of N-methyl-N-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)benzamide (138 mg), and the obtained solution was then heated to reflux at 75° C. for 2.5 hours. Thereafter, a 1 M sodium hydroxide aqueous solution was added to the reaction solution under cooling in an ice bath, and the obtained solution was then stirred at a room temperature for 1.5 hours. Thereafter, the reaction suspension was filtrated with Celite, and the filtrate was then concentrated under a reduced pressure. The residue was diluted with ethyl acetate. The resultant was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=70:30 to 50:50), so as to obtain the title compound (42 mg) in the form of a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][OH:6])[CH2:3][OH:4].FC1C=CC(B(O)O)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:4][CH2:3][C:2]([F:7])([F:1])[CH2:5][OH:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCC(F)(F)CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
A suspension of 2,2-difluoropropane-1,3-diol (Compound 59I, 6.0 g, 53.5 mmol), 4-fluorophenylboronic acid (1.5 g, 10.7 mmol) and K2CO3 (11.0 g, 80.3 mmol) in DMF (50 mL) was treated with benzyl bromide (8.9 mL, 74.9 mmol). The reaction mixture was stirred at RT for 72 h, diluted with ethyl acetate (200 mL) and washed with water (5×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give yellow oil which was purified by column chromatography (SiO2, 20% ethyl acetate/hexanes) to give 5 g (50%) of the desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.34 (m, 5H), 4.70 (s, 2H), 3.89-3.88 (m, 2H), 3.77 (t, J=12.6 Hz, 2H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:54])[C@@H:20]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C:41](=[O:47])[NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)=[O:35])[N:29]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:28]=2)=[O:26])[CH2:21][CH2:22][NH2:23])[CH2:15][CH2:14]1)=[O:12])[CH3:9].N1C=CC=CC=1.CC(OC(C)=O)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:54])[C@@H:20]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C:41](=[O:47])[NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)=[O:35])[N:29]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:28]=2)=[O:26])[CH2:21][CH2:22][NH:23][C:3](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCN)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCNC(C)=O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 302 mg 4-[(S)-4-amino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 5 ml dichloromethane were added 96 μl pyridine, 5 mg DMAP and 48 μl Ac2O at 0° C. After 1 h stirring at this temperature the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). Yield: 27 mg MS (ES+): m/e=695.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:16][Mg+].[Br-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16])=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cn1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cn1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of (R)-2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-2-yl)-meth-(E)-ylideneamide (6.04 g, 20.9 mmol) in 100 mL of CH2Cl2 was cooled to −50° C. MeMgBr (10.4 mL, 31.3 mmol, 3M in Et2O) was added slowly dropwise via syringe pump over 1 h. The reaction mixture was stirred at −50° C. for 30 min and then quenched by the addition of 100 mL of satd aqueous NH4Cl solution. The mixture was partitioned between 200 mL of CH2Cl2 and 150 mL of water. The organic phase was washed with 150 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 50-90% EtOAc in hexanes, to provide 5.38 g (84%) of (R)-2-methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:18](OC)=[O:19])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][OH:19])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cnn(-c3ccc(F)cc3)c2cc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A solution of methyl 1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carboxylate (1.52 g, 5.35 mmol) and THF (36 mL) was cooled to about 0° C. and to it was added DIBAL-H (1 M solution in toluene, 11.2 mL, 11.2 mmol) and stirred for about 2 h. To the reaction mixture was added DIBAL-H (1 M solution in toluene, 6.0 mL, 6.0 mmol) and stirring was continued for 2 h. The reaction was quenched with EtOAc (˜20 mL) and allowed to warm to ambient temperature. To the reaction mixture was added 10% aqueous Rochelle's salt (40 mL) and stirred for about 16 h. The reaction mixture was partially concentrated under reduced pressure and partitioned between EtOAc (60 mL) and water (20 mL). The aqueous layer was back extracted with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM/MeOH 100:0 to 0:10) to afford (1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)methanol (1.14 g, 4.45 mmol, 83%). LC-MS (Table 1, Method g) Rt=2.01 min, m/z 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[Se:7])=[CH:4][CH:3]=1.Cl[CH:12]([CH:15]=O)[CH:13]=[O:14].C(=O)([O-])[O-].[Mg+2]>COCCOC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[Se:7][C:12]([CH:13]=[O:14])=[CH:15][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=CC(Cl)C=O
Reactant: NC(=[Se])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: COCCOC
Product: O=Cc1cnc(-c2ccc(Cl)cc2)[se]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a suspension of 4-chloroselenobenzamide (219 mg, 1 mmol) and 2-chloromalonaldehyde (160 mg, 1.5 mmol) in 1,2-dimethoxyethane (1.5 ml) is added magnesium carbonate (42 mg, 0.5 mmol) and the resulting mixture is stirred at 60° C. under an atmosphere of nitrogen for 3 hours. The crude reaction mixture is then filtered through a plug of silica and washed with ethyl acetate, and filtrate is concentrated to give a brown solid. The crude product is purified by flash chromatography on silica gel to give 2-(4-chlorophenyl)selenazole-5-carbaldehyde (162 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1cccc(F)c1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cccc(F)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 89 %

Procedure:
N-(3-Fluorophenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 3-fluoroaniline. Yield: 89% of theory; m.p. 278°-279° C (decomp.; from xylene).