Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][CH2:8][C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][CH2:8][C:7]2=[O:18])[CH2:29][CH2:30]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1CNc2ccccc2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1CNc2ccccc2C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Yield: 97 %

Procedure:
To a solution of 70 mg of the compound of Example 14 dissolved in 10 ml of dioxane was added 0.105 ml (3 equivalents) of 1-(2-pyridyl)piperazine and the mixture heated under reflux for 8 hours. The reaction treatment and purification were conducted as in Example 17, to obtain 86.2 mg of the desired compound (yield 97%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]([OH:21])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.[Cl-].[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][NH3+:61])=[C:56]([C:62]([NH:64][CH3:65])=[O:63])[CH:55]=1.[OH-].[Na+]>O>[O:22]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:61][CH2:60][C:57]2[CH:58]=[CH:59][C:54]([F:53])=[CH:55][C:56]=2[C:62]([NH:64][CH3:65])=[O:63])=[O:20])[C:15]([OH:21])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: O=C(O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reactant: CNC(=O)c1cc(F)ccc1C[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reaction time: 0.5 h

Procedure:
A solution of 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carboxylic acid (1.00 g, 3.09 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.77 g, 4.02 mmol), and 1-hydroxy-7-azabenzotriazole (0.55 g, 4.02 mmol) in degassed dry DMP (20 mL) was aged for 30 minutes to preform the activated ester. Triethylamine (0.47 mL, 3.40 mmol) and {4-fluoro-2-[(methylamino)carbonyl]phenyl}-methanaminium chloride (0.74 g, 3.40 mmol) were added and the reaction stirred for 30 minutes. The reaction was poured into water, the pH was adjusted to 10 using 1N NaOH, and resulting solution was extracted several times with CHCl3. The combined organic extracts were dried over Na2SO4′, filtered, and concentrated to dryness in vacuo. The residue was partitioned between basic water (pH=10 using 1N NaOH) and ether. The layers were separated and the aqueous layer was extracted twice more with ether. The aqueous layer was then acidified to pH=4 using 1N HCl and extracted several times with CHCl3. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to a brown oil. Methanol was added to the flask and the flask was sonicated for 5 minutes. Solids crashed out of the solution upon sonication and were collected by vacuum filtration to afford the title compound as a whitish solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[NH:1][C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1[nH]c2ccccc2c1-c1ccccc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1[nH]c2ccccc2c1-c1ccccc1

Procedure:
The compound is obtained according to Example 34 by reacting 2-amino-3-phenylindole (m.p. 220°-223° C) with phenylisocyanate. M.p. 210°-212° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: OCCCBr
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCCO)CC2)cc2ccccc12
Yield: 25.1 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 3-bromo-1-propanol (315 mg), 3-[1-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (136 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[CH3:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1nc2ccccc2s1
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 68.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methyl-pyridine (110 mg, 0.64 mmol) and 2-but-3-ynyl-benzo[d]thiazole (120 mg, 0.64 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 122 mg (0.44 mmol, 68%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN
Reactant: ClCCOc1cccnc1
Solvent: CO
Product: CNCCOc1cccnc1
Temperature: 100 °C
Yield: 12 %

Procedure:
The 2-chloro-1-(3-pyridyloxy)ethane (2.17 g, 13.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH was adjusted to 1 with 10% HCl solution and impurities were extracted with chloroform (2×50 mL). The pH of the aqueous phase was raised to 6 with 10% NaOH solution and other impurities were extracted with ether (3×25 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.253 g (12.0%) of an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][S:11](=[O:12])[C:6]=2[N:5]2[CH:13]=[N:14][CH:15]=[C:4]2[CH2:3]1.[I:16]I.C(=O)([O-])O.[Na+]>CN(C)C=O>[I:16][C:15]1[N:14]=[CH:13][N:5]2[C:6]3[S:11](=[O:12])[CH:10]=[CH:9][C:7]=3[CH2:8][N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: II
Reactant: CN1CC2=C(n3cncc3C1)S(=O)C=C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC2=C(n3cnc(I)c3C1)S(=O)C=C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22 g of 5,6-dihydro-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one was dissolved in 330 ml of dimethylformamide and treated with 50.6 g of iodine. The mixture was stirred at room temperature for 24 hours and then at 30° for 18 hours. It was then poured into 9 l of saturated aqueous sodium hydrogen carbonate solution. This solution was extracted four times with trichloromethane. The trichloromethane solutions were washed in succession with aqueous sodium thiosulphate solution and with aqueous sodium chloride solution, then dried over sodium sulphate and evaporated in a vacuum. The residue was chromatographed through 2.5 kg of silica gel. An impurity was first eluted with trichloromethane. The main product was then eluted with trichloromethane/ethanol mixtures 199:1 and 99:1. These eluates are evaporated in a vacuum and the residue was crystallized several times from ethyl acetate/diisopropyl ether and then from ethyl acetate. There was obtained 5,6-dihydro-7-iodo-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][ 1,4]diazepine-one of melting point 175°-177°.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][C@@H:12]1[C@@H:20]([O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C@H:19]([CH3:27])[O:18][C:17](=[O:28])[C@@H:16]([NH:29][C:30](=[O:40])[C:31]2[C:36]([OH:37])=[C:35]([O:38][CH3:39])[CH:34]=[CH:33][N:32]=2)[CH2:15][O:14][C:13]1=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[C:50]([O:55][CH2:56]Cl)(=[O:54])[CH:51]([CH3:53])[CH3:52]>CC(C)=O>[C:1]([O:9][CH2:10][CH2:11][C@@H:12]1[C@@H:20]([O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C@H:19]([CH3:27])[O:18][C:17](=[O:28])[C@@H:16]([NH:29][C:30](=[O:40])[C:31]2[C:36]([O:37][CH2:56][O:55][C:50](=[O:54])[CH:51]([CH3:53])[CH3:52])=[C:35]([O:38][CH3:39])[CH:34]=[CH:33][N:32]=2)[CH2:15][O:14][C:13]1=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)OCCl
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CCOC(=O)c3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CCOC(=O)c3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCOC(=O)C(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of 2-((3S,7R,8R,9S)-3-(3-hydroxy-4-methoxypicolinamido)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)ethyl benzoate (50 mg, 0.087 mmol), Na2CO3 (15 mg, 0.14 mmol) and NaI (3.09 mg, 0.021 mmol) in acetone (0.6 mL) was added chloromethyl isobutyrate (15.4 mg, 0.114 mmol) slowly at room temperature (about 22° C.). The resulting reaction mixture was warmed to 50° C. and stirred at 50° C. overnight. The solvent was evaporated and the crude residue was purified via flash chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (35 mg, 76%) as an off-white solid: mp 48-50° C.; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=7.9 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 8.04-7.87 (m, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 6.95 (d, J=5.4 Hz, 1H), 5.85-5.62 (m, 2H), 5.41 (s, 1H), 5.26-5.06 (m, 2H), 4.94 (dd, J=9.8, 6.3 Hz, 1H), 4.42-4.19 (m, 2H), 3.92 (d, J=14.3 Hz, 3H), 3.65 (s, 1H), 2.76 (t, J=9.5 Hz, 1H), 2.62 (dt, J=10.8, 5.5 Hz, 1H), 2.58-2.47 (m, 1H), 2.30 (s, 1H), 1.82 (s, 1H), 1.29 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.9 Hz, 6H), 1.13 (d, J=7.0 Hz, 6H); ESIMS m/z 673 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].NC1C([C:31](NC)=[O:32])=C(OC)C(Br)=CC=1.NC1C=CC(Br)=CC=1C(N(CC)CC)=O>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:9])=[O:5])=[C:11]([O:32][CH3:31])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CNC(=O)c1c(N)ccc(Br)c1OC
Agent: CCN(CC)C(=O)c1cc(Br)ccc1N
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1OC

Procedure:
Prepared analogously to Compound 3C substituting 6-amino-3-bromo-2-methoxy-N-methylbenzamide (Compound 30D) for 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D). MS (ESI): m/z=305.23 [M+H]+. HPLC: tR=2.48 min (ZQ3: polar—5 min).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:21])([F:22])[F:9])[CH:12]=2)[C:18]([OH:20])=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (35.32 mL of a 0.31M stock solution, 10.9 mmol) cooled to −78° C. was treated with (3-trifluoromethyl-phenyl)-acetic acid (1.02 g, 5.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.4 mL, 3:1). The resulting solution was stirred at −78° C. for 3 h. Iodomethylcyclopentane (1.16 g, 5.52 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (3×100 mL) and diethyl ether (1×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (2×100 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded 3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (1.16 g, 80.5%) as an off-white solid: mp 64-65° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+Na+) 309.1079, found 309.1084.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:33])=[C:24]3[C:25](=[O:32])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=4.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:33][C:23]1[CH:22]=[CH:21][C:20]2[NH:16][N:17]=[C:18]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25](=[O:32])[C:24]=1[C:19]=23)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nc2c3c(c(N)ccc31)C(=O)c1ccccc1-2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-5-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The reside is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH2:10]2)C)C=CC=CC=1.CC(O)=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C@H:16]12[NH:9][CH2:10][C@H:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2
Reactant: [H][H]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Yield: 75 %

Procedure:
To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an ThalesNano H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the ThalesNano H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.18-4.00 (m, 1H), 3.85-3.57 (m, 3H), 3.44-3.34 (m, 1H), 3.28 (dt, J=13.1, 6.5 Hz, 1H), 3.24-3.13 (m, 1H), 2.82-2.72 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: O=S(=O)(Cl)CCCCl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O

Procedure:
Using methyl 4-amino-2-methoxybenzoate (1.01 g) and 3-chloropropane-1-sulfonyl chloride (0.9 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (839 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([SH:12])=[C:9]([OH:11])[CH:10]=1.CC(C)([O-])C.[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][C:23]=1[N+]([O-])=O>>[F:21][C:22]1[CH:23]=[CH:24][C:25]2[S:12][C:8]3[C:9]([O:11][C:26]=2[CH:27]=1)=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:13])[F:14])=[CH:6][CH:7]=3
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Oc1cc(OCC(F)(F)F)ccc1S
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Fc1ccc2c(c1)Oc1cc(OCC(F)(F)F)ccc1S2

Procedure:
3-Fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin can be prepared according to the teachings provided herein and the knowledge in the art. Briefly, treating 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol with base followed by addition of 1,4-difluoro-2-nitrobenzene can afford 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin. For example, 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol can be combined with potassium tert-butoxide followed by combination with 1,4-difluoro-2-nitrobenzene which upon heating can afford 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin. In an exemplary embodiment, the solvent used to dissolve potassium tert-butoxide and 1,4-difluoro-2-nitrobenzene can be anhydrous N,N-dimethylformamide. For example, 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol dissolved in a THF/MTBE mixture can be added to potassium tert-butoxide in N,N-dimethylformamide; subsequent to their combination, under the conditions disclosed herein, the mixture can then be treated with 1,4-difluoro-2-nitrobenzene dissolved in N,N-dimethylformamide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([O:24][C:25](=[O:27])[CH3:26])[C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH:10]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:29]=[CH:28][C:8]([CH:9]2[CH:18]([OH:19])[C:17]3[C:12](=[C:13]([O:24][C:25](=[O:27])[CH3:26])[C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2coc3c(OC(C)=O)c(OC(C)=O)ccc3c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccc(C2COc3c(ccc(OC(C)=O)c3OC(C)=O)C2O)cc1
Temperature: 25 °C
Reaction time: 55 h

Procedure:
Palladium-on-charcoal (5%, 0.07 g) was added to a suspension of 4′,7,8-triacetoxyisoflavone (0.5 g, 1.3 mmol) in methanol (100 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 55 h. The catalyst was removed by filtration through Celite and the filtrate was evaporated in vacuo to yield 4′,7,8-triacetoxyisoflavan-4-ol in quantitative yield. A nuclear magnetic resonance spectrum revealed the product to be a clean 1:1 mixture of cis- and trans-4′,7,8-triacetoxyisoflavan-4-ol. Mass spectrum: m/z 400 (M, 5%); 358 (12); 298 (12); 256 (24); 196 (20); 162 (70); 154 (100); 120 (80).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].[N:11]([Sn](C)(C)C)=[N+:12]=[N-:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]1[NH:13][N:12]=[N:11][N:5]=1
Reactant: N#Cc1c(F)cccc1I
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Fc1cccc(I)c1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-6-iodobenzonitrile (17.82 g, 72.15 mmol) and azidotrimethyltin (15.00 g, 72.88 mmol) in 150 mL toluene was heated to 125° C. for 72 hours. The solution was cooled to room temperature and partitioned between ethyl acetate and 0.5 N HCl. The organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 5-(2-fluoro-6-iodophenyl)-1H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 291.01 for M+H+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[C:67]([C:68]#[N:69])=[CH:66][CH:65]=[CH:64][C:63]=3[Cl:70])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:70][C:63]1[CH:64]=[CH:65][CH:66]=[C:67]([C:68]#[N:69])[C:62]=1[N:59]1[C:55]2=[N:56][CH:57]=[N:58][C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:43])=[C:54]2[CH:61]=[N:60]1
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.203 mL, 0.20 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AH9) (149 mg, 0.20 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured onto a phase separator. The organic phase was reduced to give a gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (45.0 mg, 44.8%, 58% ee). 1H NMR (400 MHz, CDCl3) d 2.23 (3H, s), 3.77-3.62 (4H, m), 4.20-4.04 (2H, m), 6.01 (1H, m), 7.51-7.46 (1H, m), 7.55 (1H, t), 7.72 (1H, dd), 7.84-7.76 (1H, m), 8.03 (2H, d), 8.46 (1H, d), 8.55 (1H, d), 9.19-8.96 (1H, m) OH not observed. m/z (ES+) (M+H)+=494; HPLC tR=1.82 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:18]1(=[O:30])=[O:29])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[S:18](=[O:29])(=[O:30])[N:19]([CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:20](=[O:22])[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Reactant: Br[Mg]c1ccccn1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C(O)c3ccccn3)cc2OCc2ccccc2)S1(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde (Example 81, step B) (75 mg, 0.17 mmol) in anhydrous THF (4 mL) at −78° C. is added dropwise 2-pyridyl magnesium bromide (0.25M in THF, 1.36 mL, 0.34 mmol). The reaction is stirred at −78° C. for 1 h, then is quenched with saturated NH4Cl. The mixture is extracted with EtOAc and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure and the crude material is purified by column chromatography using a gradient of 0-50% EtOAc/hexane to afford the title compound as a colorless oil: (M−H)−=526.