Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=2)[CH:7]=1.CCN(S(F)(F)[F:20])CC>C(Cl)Cl>[F:20][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]2[C:8]=1[CH3:13]
Reactant: Cc1c(CO)nc2ccc(I)cn12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(CF)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
To a stirred solution of (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (600 mg) in DCM (2 ml) was added DAST (500 mg) at −78° C. The reaction mixture was then allowed slowly to warm up to room temperature, and stirred at the same temperature for 16 h. The reaction mixture was then diluted with DCM (100 ml), washed with saturated NaHCO3 solution (100 ml), and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (280 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[CH:20][CH:19]=2)[N:7]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (1 g, 3.6 mmol), 6-aminoindazole (0.5 g, 3.7 mmol), tetrahydrofuran (10 ml), and diisopropylethylamine (0.65 ml, 3.7 mmol) was stirred for 1 hour. After concentrating under reduced pressure, the residue was treated with water (25 ml) and stirred for 10 minutes. The solid was filtered, treated with hydrochloric acid (1 M, 10 ml), stirred vigorously for 10 minutes, and filtered. The solid was purified by flash chromatography on silica eluting with 5% methanol-dichloromethane to yield the title compound (600 mg, 45% yield). 1H NMR (DMSO-d6) 13.04 (br s, 1H), 10.90-10.97 (m, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.71 (m, 2H), 7.53 (m, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 2.50-2.54 (m, 3H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([Li])CCC.C1(C)C=CC(S(O[CH2:29][CH2:30][F:31])(=O)=O)=CC=1>C1COCC1>[F:31][CH2:30][CH2:29][C:2]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: CC(C)(C)OC(=O)C1SCCCS1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CCF)SCCCS1
Reaction time: 1.33 h
Yield: 108.1 %

Procedure:
A solution of commercially available reagent of tert-butyl [1,3]dithiane-2-carboxylate (2.0 g, 9.69 mmol) in THF (20 mL) was cooled to −78° C., and n-butyl lithium (1.67 M solution in n-hexane, 8.62 mL, 13.6 mmol) was then added over 10 minutes. The mixture was stirred for 80 minutes, and 2-fluoro-ethyl toluene-4-sulfonate (2.95 g, 13.5 mmol, known compound, ref. Tetrahedron (2005), 61 (35), 8410-8418) was then added. The mixture was stirred at −78° C. for 30 minutes, and the cooling bath was then removed. The mixture was stirred while allowing the temperature to gradually return to room temperature, and stirred at room temperature for 20 hours. After confirming the consumption of the starting materials by LCMS, the mixture was quenched with water (100 mL), and then extracted with dichloromethane (100 mL). The aqueous layer was further extracted with dichloromethane (50 mL). The combined dichloromethane layer was washed with a saturated aqueous solution (100 mL) of ammonium chloride and a saturated aqueous solution (100 mL) of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure. The resulting residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain tert-butyl 2-(2-fluoro-ethyl)-[1,3]dithiane-2-carboxylate (2.79 g, quant.).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])[CH:11]=2)[S:6][CH2:5][CH2:4]1.C([Li])CCC.[CH3:40][N:41]([CH3:53])[CH2:42][CH2:43][O:44][C:45]1[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=1>O1CCCC1>[CH3:34][C:3]1([CH3:2])[C:12]2[CH:11]=[C:10](/[C:13](/[CH3:14])=[CH:49]/[C:48]3[CH:51]=[CH:52][C:45]([O:44][CH2:43][CH2:42][N:41]([CH3:40])[CH3:53])=[CH:46][CH:47]=3)[CH:9]=[CH:8][C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCS2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(OCCN(C)C)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
32 g of [1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphonium bromide were suspended in 130 ml of tetrahydrofuran and treated at 0° C. with 37 ml of n-butyllithium (1.6 molar in hexane). After stirring at 0° C. for 45 minutes, a solution of 10 g of 4-(2-dimethylaminoethoxy)benzaldehyde in 60 ml of tetrahydrofuran was added dropwise to the orange reaction mixture. The mixture was stirred at room temperature for an additional 1 hour, poured on to ice/water and extracted with ether. The organic phases were washed with water, dried and evaporated. After filtration of the crude product over neutral Alox (eluting agent ether) and recrystallization from hexane/ether, there were obtained 8.7 g of 2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenoxy]-N,N-dimethylethylamine, melting point 81°-82° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH3:28]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:27]([CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH:17]([F:16])[F:29])=[C:21]([CH3:28])[CH:22]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)ccc1OCC(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (580 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride (430 mg, 1.8 mmol, Amine-66) in a similar manner to Intermediate-2.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:13].[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:2]2[S:3][C:4]3[CH2:9][CH2:8][C:7]4[S:10][CH:11]=[CH:12][C:6]=4[C:5]=3[N:1]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc2c(s1)CCc1sccc1-2
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc2c(s1)CCc1sccc1-2

Procedure:
The title compound was prepared from 4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-amine (106 mg, synthesized according to METHOD I from 4-keto-4,5,6,7-tetrahydrothianaphthene) and 3-chloro-2-methylbenzenesulfonyl chloride (114mg) as described in the synthetic METHOD A to give a white powder (36 mg) with a purity >90%: MS-ES (neg) m/z 395.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[BH4-].[Li+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ncc(Br)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-3-fluoropyridine-2-carbonyl chloride (0.50 g, 2.1 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0° C. and treated with lithium borohydride (1.0 mL, 2 M tetrahydrofuran solution, 2.1 mmol, 1 equiv). After stirring for 30 minutes at 0° C., the mixture was treated with methanol (2 mL) and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14](OC)=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:21][NH2:22]>CO>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:21][NH2:22])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1
Reactant: NN
Solvent: CO
Product: CC1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Temperature: 65 °C
Yield: 64.6 %

Procedure:
Methyl 3-((4-methylpiperidin-1-yl)sulfonyl)benzoate (100 mg, 0.336 mmol) was added to the hydrazine (21.55 mg, 0.673 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield 3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.217 mmol, 64.4% yield). 1H NMR (CD3OD, 400 MHz): δ 8.16 (m, 1H), 8.05 (m, 1H), 7.91 (m, 1H), 7.70 (t, 1H, J=7.6 Hz), 3.74 (m, 2H), 2.28 (m, 2H), 1.69 (m, 2H), 1.32-1.16 (m, 3H), 0.90 (d, 3H, J=6.0 Hz). ESI-MS: 298.1[M+H]+
Reaction SMILES: C([O:5]CCO)CCC.[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>>[C:9]([OH:14])(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:5])=[O:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCOCCO
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 130 °C

Procedure:
A reaction flask equipped with a stirrer, thermometer, and nitrogen inlet tube was charged with 93.6 grams of 2-butoxyethanol and 21 grams of phthalic anhydride. The mixture was heated under nitrogen for 30 minutes at 130° C. The butoxyethyl monoester of phthalic acid produced was a light yellow liquid which crystallized upon standing at room temperature for about one week.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][NH:21][C:22](=[O:38])[C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH:13]=1)[C:6]([O:8]CC)=[O:7])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][NH:21][C:22](=[O:38])[C:23]2[CH:24]=[CH:25][C:26]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:27][CH:28]=2)[CH:13]=1)[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1)OC(C)C
Reactant: Brc1ccccn1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccn2)cc1

Procedure:
Using ethyl 2-isopropoxy-3-[4-methoxy-3-([4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoyl]aminomethyl)phenyl]propanoate and 2-bromopyridine, 2-isopropoxy-3-[4-methoxy-3-[([4-(2-pyridyl)benzoyl]amino)methyl]phenyl)propanoic acid was obtained in the same method as in Example 285).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cccc(N)c1C
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(Nc2nc(Cl)nc(Cl)n2)c1C
Temperature: 5 °C

Procedure:
A solution of cyanuryl chloride (18 g) in hot acetone (70 ml) is poured under stirring into water (40 ml). To the so obtained suspension is added, while keeping the temperature to 5° C., 2,3-xylidine (24 ml). Stirring is maintained for 1 hour at 5° C.; then the reaction mixture is filtered, the precipitate is washed with water to neutrality; it is dissolved in ethyl acetate; the solution is dried over Na2SO4. By concentration 16.8 g of the desired compound are obtained. M.p. 186°-188° C. (ethyl acetate/hexane).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]1[CH2:13][CH2:12][C:11](=O)[CH2:10]1.O>C(O)(=O)C>[S:9]1[C:10]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH:7][C:11]=2[CH2:12][CH2:13]1
Reactant: O=C1CCSC1
Reactant: NNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2c3c([nH]c2c1)CCS3
Temperature: 80 °C
Yield: 48.4 %

Procedure:
To a solution of phenylhydrazine (5.0 g, 46 mmole) in acetic acid (50 ml) was added dihydro-thiophen-3-one (4.72 g, 46 mmole) at room temperature. Following an exothermic reaction, the temperature was maintained at 80° C. for 2 h. The reaction mixture was poured into water (300 ml) and the precipitate was filtered. Purification on a short column of aluminum oxide (activity II, 6% water) using t-butylmethylether as the eluting solvent gave pure 3,4-dihydro-2H-thieno[3,2-b]indole as a yellow solid (3.9 g, 48% yield), m.p. 152-155° C. (lit. m.p. 153° C., WO01/12603) Step 2
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:1][CH2:2][C:3]2([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC1(CO)COC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
To a chilled (0° C.) solution of 4-(hydroxymethyl)-4-methyloxazolidin-2-one (629 mg, 4.8 mmol) in anhydrous pyridine (4 ml) was added in portions tosyl chloride (1.05 g, 5.5 mmol). The solution was allowed to warm to ambient temperature and stirred under nitrogen for 48 hours. Water (12 mL) was added dropwise to the reaction mixture, and the resulting suspension was stirred at ambient temperature for 5 hours. The solids were isolated, and dried under vacuum to afford (4-methyl-2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate 1.17 g (86%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:25])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17](Cl)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:25])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 80 °C
Yield: 32.1 %

Procedure:
A mixture of 2-(2-chloro-6-propyl-pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxy-propyl)-amide (31.4 mg), 4-(trifluoromethoxy)phenylboronic acid (19 mg), sodium carbonate (0.4M aqueous solution, 0.5 mL), and acetonitrile (0.5 mL) was degassed with argon for five minutes. Tetrakis(triphenylphosphine) palladium(0) was added and the mixture was heated to 80° C. for 4 hours. The reaction mixture was taken up in ethyl acetate, washed twice with brine, and the volatiles were removed in vacuo. The product was purified on silica gel, using 50% ethyl acetate/hexanes as the mobile phase, to give 13.5 mg of 4-methyl-2-[6-propyl-2-(4-trifluoromethoxyphenyl)pyrimidin-4-ylamino] pentanoic acid (3-ethoxypropyl) amide. ESI-MS (m/z) 497 [M+H]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].[BH4-].[Na+]>C1COCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][OH:15]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dibenzo[b,d]furan-2-carbaldehyde (191 mg, 973 μmol) in THF (10 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (37 mg, 0.978 mmol) and the mixture was stirred for 2 h at RT and quenched by adding 10 mL of a 1 N aq. HCl solution. The reaction mixture was stirred at RT for 20 min and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum to afford dibenzo[b,d]furan-2-ylmethanol CCH 34116 as an off-white solid (192 mg, 100% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:11]2[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=[C:10]2[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:35][N:36]([CH3:38])[CH3:37])=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Product: CN(C)C=CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (50 mg, 0.11 mmol) and N,N-dimethylformamide dimethyl acetal (1 mL) is heated at 80° C. for 14 h. After cooling down to room temperature, excess N,N-dimethylformamide dimethyl acetal is removed under vacuum to provide 5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as yellow solid (56 mg, 100%). HPLC-MS calculated for C28H22ClN5O2 (M+H+): 496.2. Found: 496.2.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([NH:15][C:16]2[C:17]([C:26]([OH:28])=O)=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8]2.FC(F)(F)[C:31](OC(=O)C(F)(F)F)=[O:32]>ClCCl>[CH3:31][O:32][C:4]1[CH:3]=[C:12]2[O:11][C:10]([CH3:13])([CH3:14])[CH:9]=[CH:8][C:7]2=[C:6]2[C:5]=1[C:26](=[O:28])[C:17]1[CH:18]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]3=[CH:25][C:16]=1[NH:15]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(Nc2cc3ccccc3cc2C(=O)O)c2c1OC(C)(C)C=C2
Solvent: ClCCl
Product: COc1cc2c(c3[nH]c4cc5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution containing 1.94 mmol of the compound obtained in Step 1 in 20 ml of anhydrous dichloromethane, maintained at 0° C. under argon, there are added 9.71 mmol of trifluoroacetic anhydride. After reacting for 3 days at ambient temperature, the reaction mixture is concentrated under reduced pressure. The residue is taken up in a mixture of dichloromethane and aqueous NaHCO3 solution. After extraction with dichloromethane, the combined organic phases are treated in conventional manner. Chromatography of the residue over silica gel (dichloromethane) allows the expected product to be isolated, the latter being subsequently recrystallised from ethyl ether.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[CH:17](SC)[CH2:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethane (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMR τ (CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[NH:38][NH2:39]>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[N:38]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:39]1
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c2cc(F)ccc2n1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=482.2 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[C:14]([NH:21][C@H:22]([C:38]([OH:40])=[O:39])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C@H:22]([NH:21][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:38]([O:40][CH2:2][C:3]#[N:4])=[O:39])=[CH:25][CH:26]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)O
Reactant: N#CCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)OCC#N
Reaction time: 18 h
Yield: 93 %

Procedure:
Chloroacetonitrile (1 mL) and DIPEA (20 mg, 34 μL, 0.21 mmol) were added to Boc-p-benzoylphenylalanine (61 mg, 0.19 mmol). The reaction was stirred for 18 h, then concentrated under reduced pressure. SiO2 flash chromatography (40% ethyl acetate in hexanes) afforded 70 mg of a pale yellow oil in 93% yield. Rf 0.5 in 50% ethyl acetate in hexanes. 1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J=7.1, 4.9 Hz, 4H), 7.59 (t, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 5.00 (d, J=7.4 Hz, 1H), 4.83 (d, J=15.7 Hz, 1H), 4.72-4.69 (m, 2H), 3.25 (dd, J=13.7, 5.8 Hz, 1H), 3.16 (dd, J=13.1, 6.5 Hz, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 196.4, 170.6, 155.1, 140.3, 137.6, 136.9, 132.7, 130.8, 130.2, 129.4, 128.5, 113.9; HRMS (ESI) m/z calcd for C23H24N2NaO5 [M+Na]+ 431.158. found 431.158.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2>CC(C)=O>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1
Temperature: 25 °C

Procedure:
A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A, 700 mg, 1.99 mmol), 2-bromoacetyl-4-ethylpyridine* (545 mg, 2.39 mmol), potassium carbonate (1.37 g, 13.9 mmol) and acetone (20 ml) was stirred at room temperature. After stirring for 3 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 ml, 3.98 mmol) was added. The resulting mixture was stirred for an additional 19 h and then concentrated. The residue was diluted with dichloromethane (200 ml) and washed with water (100 ml×2). The organic layer was dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane/dichloromethane (1:4:1) to give the title compound including impurity. The crude product was washed with ethyl acetate to give 297 mg (42%) of the title compound as yellow solids.