Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C)C=O.C(Cl)(Cl)Cl.C(O)(=O)C.C(O)C.O>[N:32]1([CH2:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([OH:7])=[O:6])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)c1cccc(C)c1
Reactant: C1CCNCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cccc(CN2CCCCC2)c1
Reaction time: 24 h
Yield: 37.1 %

Procedure:
Methyl 3-methylbenzoate (45.0 g), N-bromosuccinimide (53.4 g) and a catalitic amount of azobisisobutyronitrile were refluxed in carbon tetrachloride (500 ml) with stirring for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), thereby yielding an oil. The oil was dissolved in dimethylformamide (1.5 l) and the mixture, with piperidine (63.2 g) and potassium carbonate (205 g) added thereto, was stirred all day and night at room temperature. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), thereby yielding an oil. Potassium hydroxide (78.0 g), water (325 ml), and ethanol (325 ml) were added to the oil and the mixture was refluxed with stirring for 2 hours. After being neutralized with acetic acid, the reaction mixture, with chloroform added thereto, was filtered. The filtrate was concentrated under a vacuum. The resulting solid was washed with ethanol, thereby yielding 24.4 g of the aimed compound. The resulting solid was washed with ethanol, thereby yielding 24.4 g of the aimed compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([F:14])([F:13])[C:8](OCC)=[O:9].[BH4-].[Na+]>CO>[F:14][C:7]([F:13])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)C(F)(F)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC(F)(F)c1ccccn1
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a 0° C. stirred solution of 3.97 g (19.7 mmol) of ethyl 2-pyridyldifluoroacetate (prepared according to T. Taguchi, et al., Tetrahedron Lett. 1986, 27, 6103) in 40 mL of methanol was added 757 mg (20 mmol) of sodium borohydride in several portions. After stirring for 0.5 h, the cold bath was removed, and stirring continued another 0.5 h. The reaction was quenched with 2M HCl, and the solvents removed under reduced pressure. The residue was partitioned between ether and 10% Na2CO3, the aqueous layer extracted with several portions of ether and the combined organic layers washed with brine, dried over MgSO4 and the solvents removed to give 2.97 g of a yellow oil that was chromatographed on 65 g of fine SiO2 using 99:1 to 97:3 CH2—Cl2-CH3OH to give the title compound as an almost colorless solid:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)C(=O)[N:14]1CC1SC=CC=1.C(N)C1C=CC=CC=1>>[CH2:13]([N:14]1[CH:4]([OH:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]1=[O:11])[C:21]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Solvent: NCc1ccccc1
Product: O=C1c2ccccc2C(O)N1Cc1ccccc1

Procedure:
Compound 20 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of commercially available phthalic anhydride 1 to compound 12 using benzylamine instead of thiophene-2-methylamine in the first step.
Reaction SMILES: [CH3:1][N:2]([O:32][CH3:33])[C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:20]C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][N:2]([O:32][CH3:33])[C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH2:20]
Reactant: CON(C)C(=O)c1cc(OCCCc2ccccc2)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CON(C)C(=O)c1cc(OCCCc2ccccc2)ccc1N
Temperature: 25 °C

Procedure:
N-Methyl-N-methyloxy-2-benzyloxycarbonylamino-5-(3-phenylpropyloxy)benzamide (1.4 g) was dissolved in a mixture of ethyl acetate (10 ml) and methanol (10 ml). To the solution was added 10% palladium-carbon (0.3 g). The mixture was stirred for 24 houks at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. From the filtrate was distilled off the solvent to leave N-methyl-N-methyloxy-2-amino-5-(3-phenylpropyloxy)benzamide as an orange oily product (1.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:34]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])=[CH2:35].[OH-].[K+].[Na+].[Cl-]>CS(C)=O.O>[CH:31]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH:34]=[CH2:35])=[CH:3][C:4]4=[N:10][CH:9]=3)=[O:12])[N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[N:17]=2)[CH2:33][CH2:32]1
Reactant: C=COCCOCCO
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=COCCOCCOc1ccn2c(C(=O)Nc3cccc4c3c(C3CC3)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.2 mmol; prepared as in Example 65, step C)), 2-(2-(vinyloxy)ethoxy)ethanol (1.2 g, 8.8 mmol) and potassium hydroxide (0.61 g, 11 mmol) was dissolved in DMSO (10 mL). The reaction mixture was heated at 95° C. for 20 hours. The mixture was cooled to ambient temperature, transferred into water (100 mL) and saturated aqueous NaCl (200 mL) and stirred at ambient temperature for 4 hours. The resulting solid was collected by vacuum filtration and dried under vacuum to give the product (0.90 g). MS (ES+APCI) m/z=552.9 (M+H).
Reaction SMILES: [N:1]([CH2:18][CH2:19][OH:20])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[Na+]>C(#N)C.O>[N:1]([CH2:18][CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCN(CCO)CCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCN(CCCCCCCC)CCOS(C)(=O)=O
Temperature: 10 °C
Yield: 74.3 %

Procedure:
In 200 ml of acetonitrile was dissolved 28.5 g (0.1 mol) of (C8H17)2NCH2CH2OH and then 11.5 g (0.1 mol) of methanesulfonyl chloride was added dropwise to the solution with stirring at 10° C. Then, after stirring the mixture for 3 hours at temperatures below 20° C., the reaction mixture was neutralized carefully with a solution of 4 g (0.1 mol) of sodium hydroxide in 40 ml of water. After concentrating the reaction mixture under reduced pressure, the residue was dispersed in 1 liter of water and the product was extracted with 500 ml of ether. The organic layer obtained was dried by anhydrous magnesium sulfate and then ether was distilled away to provide 27.0 g of (C8H17)2NCH2CH2OSO2CH3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:18][C:19]1[C:24]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)[CH2:17][CH2:16]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccnc1N1CCN(CC2COc3ccccc3O2)CC1
Temperature: 75 °C
Yield: 60.6 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (2.35 g, 10 mmole), 2,3-dichloropyrazine (1.5 g, 10 mmole) and diisopropylethylamine (1.3 g, 10 mmole) were combined in 100 ml of dimethylformamide and heated at 75° C. under N2 for 24 hours. The solvent was removed in vacuum and the residue was filtered through 75 g of silica gel using choroform as the eluent. The relevant fractions were combined, the solvent evaporated and the residue crystallized from isopropanol with addition of 4N isopropanolic HCl to give 2.1 g of title compound as the hydrochloride, m.p. 217°-218° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:7]=2[N:6]([CH2:18][CH3:19])[CH2:5][CH2:4]1)[CH3:2].O.NN>[Pd].C(O)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:8]2[C:9](=[O:10])[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:18][CH3:19])[C:7]=2[CH:14]=1
Reactant: CCN1CCN(CC)c2cc([N+](=O)[O-])ccc2C1=O
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1CCN(CC)c2cc(N)ccc2C1=O
Temperature: 75 °C
Yield: 102.6 %

Procedure:
To a solution of Diethyl-8-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (25.0 g, 0.095 mol) and 10% palladium on carbon (2.0 g) in ethanol (600 mL) was slowly added hydrazine hydrate (150 mL) and heated to 75° C. for 5 hr. After evaporation, toluene (50 mL) and ethanol (50 mL) were added and distilled leaving 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow solid (22.75 g, 85%). Mp 140-141° C.; LCMS (m/e) 233 (M); 1H-NMR (DMSO, 400 MHz) δ 7.14-7.12 (d, 1H, J=8.85 Hz), 6.10-6.09 (d, 1H, J=6.82 Hz), 5.35 (s, 2H), 3.46-3.41 (q, 2H, 7.07 Hz), 3.19-3.16 (t, 2H, J=5.31 Hz), 3.09-3.03 (q, 2H, J=7.07 Hz), 1.12-1.06 (q, 6H, J=7.07 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:15]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:2][C:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCOc1ccc(C=O)cc1
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCOc1ccc(C=CC(=O)c2ccc(C(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of titanium(IV) chloride (13.88 g) in dichloromethane (100 ml) was added Ethyl 4-acetylbenzoate (11.53 g) and 4-n-pentyloxybenzaldehyde (12.68 g) in dichloromethane (50 ml) was added dropwise at 0° C. To the mixture was added triethylamine (12.44 ml) in dichloromethane (30 ml). The mixture was stirred at 0° C. for 30 minutes and diluted with ethyl acetate. The organic layer was washed with water (four times) and brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried to give 1-(4-n-Pentyloxyphenyl)-3-(4-ethoxycarbonylphenyl)-1-propen-3-one (13.45 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10](COCC3C=CC=CC=3)[CH:9]=[C:8]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>N.CO.[Pd]>[NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSC[C@@H](O)[C@@H](CO)NCc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: N
Agent: NN
Solvent: O
Solvent: CO
Product: CSC[C@@H](O)[C@@H](CO)NCc1c[nH]c2c(N)ncnc12
Reaction time: 1 h
Yield: 74.1 %

Procedure:
The product from Example 6.8 (0.106 g, 0.254 mmol) was dissolved in 7M NH3-MeOH solution (10 ml), Pd black (106 mg) was added followed by hydrazine hydrate (1.5 ml). The mixture was stirred for 1 h then filtered and the solvent evaporated. The residue was chromatographed on silica gel (CH2Cl2-7M NH3 in MeOH, 85:15) to give (2R,3S)-2-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-4-(methylthio)butane-1,3-diol (0.056 g, 74%) as a colourless solid. [α]D20 −8.4 (c, 0.695, MeOH). 1H NMR (CD3OD) 8.16 (s, 1H), 7.47 (s, 1H), 4.11 (d, j=13.6 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.84-3.74 (m, 2H), 3.64 (dd, J=11.5, 5.0 Hz, 1H), 2.81 (q, J=5.1 Hz, 1H), 2.72 (dd, J=13.6, 4.7 Hz, 1H), 2.55 (dd, J=13.6, 7.6 Hz, 1H), 2.06 (s, 3H). 13C NMR (CD3OD, referenced to the centre line of CD3OD at 49.0 ppm) δ 152.0, 150.8, 146.5, 129.1, 115.5, 114.9, 71.2, 62.5, 61.8, 42.2, 39.3, 16.0. +ESMS Found 298.1333 (M+H)+ C12H20N5O2S requires 298.1338.
Reaction SMILES: [NH2:1][NH2:2].[F:3][S:4]([F:11])=[C:5](Cl)[C:6]([F:9])([F:8])[F:7].O>CO.CCOCC>[F:3][S:4]([F:11])=[C:5]([NH:1][NH:2][C:5](=[S:4]([F:11])[F:3])[C:6]([F:9])([F:8])[F:7])[C:6]([F:9])([F:8])[F:7]
Reactant: NN
Reactant: FS(F)=C(Cl)C(F)(F)F
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: FS(F)=C(NNC(=S(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 0.25 h

Procedure:
Hydrazine (0.67 g, 0.02 mole) in methanol (5 ml) was stirred in a dry ice-acetone bath while pentafluorothioacetyl chloride (1.8 g, 0.0088 mole) in ether (3 ml) was added dropwise. After 15 minutes at 0° C., the mixture was poured into water and the insoluble material (0.35 g, mp 271° C. dec) was removed. An additional 0.7 g, mp 270° C. dec was recovered by concentrating the ether solution. Total yield of N,N'-bis(pentafluorothioacetyl)hydrazine is 1.05 g (66%); 1H NMR (acetone-d6): 4.78 (pentuplet); IR (KBr): 3190 (NH), 1635 (C=O), 895°-825 (SF5).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:28]=2)=[O:24])[CH:20]=[C:19]([Cl:41])[C:18]=1O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH:28]=2)=[O:24])=[CH:20][C:19]=1[Cl:41])(=[O:5])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(O)c(Cl)c2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(OS(=O)(=O)C(F)(F)F)c(Cl)c2)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (3.55 mL, 21.1 mmol) was added to a cooled (−75° C. ) solution of 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]phenyl]methyl]amino]carbonyl]phenol (7.50 g, 17.6 mmol) and triethylamine (9.8 mL, 70.4 mmol) in dry dichloromethane (70 mL). After stirring for 3 h at ˜−70° C., the reaction was quenched with solid ammonium chloride (6 g). The solvent was evaporated and ethyl acetate was added. The solution was washed with 1 N HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered, evaporated and dried under high vacuum to give trifluoromethanesulfonic acid, 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]phenyl]methyl]amino]carbonyl]phenyl ester (9.46 g, 97%) as pale orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[N:17]([O-])=O.[Na+].[OH-].[Na+]>Cl>[F:16][C:3]1[C:2]([NH:1][NH2:17])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: O=N[O-]
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A suspension of 6-amino-7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (13.0 g) in conc. hydrochloric acid (70 g). was cooled to 0° to 5° C., and a saturated solution of sodium nitrite (5.1 g) was dropwise added thereto at 0° to 5° C., followed by stirring for 2 hours. The resultant mixture was cooled to -30° C., and a solution of anhydrous stannous chloride (28.1 g) in conc. hydrochloric acid (30 g) was added thereto at once, followed by stirring at 0° to 5° C. for 3 hours. Celite (50 g) was added to the reaction mixture, which was neutralized with 10 % aqueous sodium hydroxide solution below 10° C. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6 -yl-hydrazine (8.2 g).
Reaction SMILES: CC#N.[O:4]([C:11]1[CH:12]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[CH:20]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[O:34][CH2:33]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>C(OCC)C.CCO>[O:4]([C:11]1[CH:12]=[C:13]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[CH:20]=2)[CH2:33][CH:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)C1CO1
Reactant: c1ccc(Oc2cccc(NCc3cccc(C4CCCO4)c3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Solvent: CCOCC
Solvent: CC#N
Product: OC(CN(Cc1cccc(C2CCCO2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 40 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
To a CH3CN (1 mL) solution of the amine (0.32 g, 0.93 mmol) from EX-608E was added 1.1,1-trifluoro-2,3-epoxypropane (0.24 mL, 2.8 mmol) and Yb(OTf)3 (0.115 g, 0.18 mmol). The cloudy solution was stirred in a sealed flask at 40° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.13 g (30%) of the desired 3-[(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C26H26NO3F3.0.5 EtOH: C, 67.33; H, 6.04; N, 2.94.Found: C, 67.49; H, 6.08; N, 2.91.HRMS calcd. 458.1943 [M+H]+, found: 458.1937. 1H NMR (C6D6) δ0.45 (d, 1H), 1.43 (m, 3H), 1.79 (m, 1H), 1.99 (m, 1H), 3.24 (m, 1H), 3.43 (m, 1H), 3.76 (m, 2H), 4.24 (s, 2H), 4.60 (t, 1H), 6.35 (m, 1H), 6.43 (dd, 1H), 6.54 (dd, 1H), 6.8 (m, 2H), 6.9-7.0 (m, 7H), 7.15 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N([O-])=O.[Na+].[F:16][B-](F)(F)F.[Na+]>Cl>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([F:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(F)cc1
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
4-t-Butylaniline (14.9 g, 100 mmol) was suspended in aqueous hydrochloric acid (50 ml, 6M) at 5° C. Sodium nitrite (7.6 g, 110 mmol in 10 ml water) was added at such a rate that the temperature was kept between 5°-7° C. Following the addition the resulting solution was stirred for 15 min. and sodium tetrafluoroborate (15.4 g, 140 mmol in 30 ml water) was added at 5-8° C. The mixture was stirred for 15 min. 4-t-Butylbenzenediazonium tetrafluoroborate was filtered off, dried with suction and washed with diethyl ether to yield 20.96 g. This diazonium salt was decomposed by heating to 140° C. on an oil-bath. The product was distilled off at reduced pressure. Yield 11.15 g colorless oil.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[O:35]1[CH:36]=[CH:37][C:33]([C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[C:29]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:28]=2)=[O:32])=[CH:34]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.93 min, MH+ 505. NMR: δH [2H6]-DMSO 9.99,(1H, s), 9.32,(1H, t), 9.15,(1H, d), 8.95,(1H, b), 8.38,(1H, s), 8.33,(1H, dd), 7.81,(2H, d), 7.75,(1H, d), 7.68,(1H, d), 7.33–7.30,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 7.01,(1H, s), 4.51,(2H, d), 2.99,(3H, s), 2.32,(3H, s).
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH2:40]>>[CH3:39][NH:40][C:28]([C:25]1([C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:37])[CH3:38])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:26]1)=[O:29]
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN
Product: CNC(=O)C1(c2cc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)ccn2)CC1
Yield: 59 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 59% of theory; LC (method 3): tR=2.57 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])=[CH:13][C:12]([C:23]([OH:25])=[O:24])=[C:11]([OH:26])[CH:10]=1.FC(F)(F)C(O)=O>C(#N)C>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[CH:16][C:15]=1[C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[C:11]([OH:26])=[C:10]([I:8])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O

Procedure:
198 mg (0.88 mmol, 1.1 eq) of NIS was added at room temperature to a solution of 200 mg (0.8 mmol) of diflunisal in 4 ml of acetonitrile and a catalytic quantity of 18 μl (0.24 mmol, 0.3 eq) of trifluoroacetic acid. It was stirred continuously. The solvent was evaporated at low pressure, it was diluted with dichloromethane and the product was then worked up as in example 1.