Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.O1C=CC=C1C=CC(O)=O.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48]CC2)CCCCC1>O1CCCC1>[CH3:1][N:42]([C:43]1[CH:48]=[CH:49][CH:50]=[CH:45][N:44]=1)[CH3:36]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)C=Cc1ccco1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 568 mg of 2-furanacrylic acid, 15 ml of dry tetrahydrofuran, 707 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 746 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[S:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(C)s3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(C)s3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(5-methylthiophen-2-yl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[C:7]([C:16]([O:18]CC)=[O:17])[C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:42])[NH:28][S:29]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)(=[O:31])=[O:30])=[CH:23][C:22]=1[C:43]([N:45]1[CH2:54][CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1>[CH2:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:42])[NH:28][S:29]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)(=[O:30])=[O:31])=[CH:23][C:22]=1[C:43]([N:45]1[CH2:54][CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
A 25 mL round bottom flask was charged with ethyl 5-butyl-4-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1-phenyl-1H-pyrazole-3-carboxylate (Example 223, 52 mg, 0.070 mmol). THF (2.0 mL) and then 1N aq. NaOH solution (0.140 mL, 0.140 mmol) were added. The reaction mixture was stirred at room temperature overnight. After concentration in vacuo to remove the THF, the reaction mixture was made acidic (pH 3-4) with conc. HCl. The product was extracted with EtOAc and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product (50 mg, 100%) as a yellow oil. A portion (approx. 10 mg) was purified by preparative HPLC to give the title compound (4 mg). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.63 (s, 1H), 8.11-8.05 (m, 3H), 8.01-7.98 (m, 1H), 7.94 (d, J=4 Hz, 1H), 7.90 (d, J=4 Hz, 1H), 7.61-7.55 (m, 2H), 7.52-7.35 (m, 6H), 7.19-7.04 (m, 3.5H), 6.86-6.82 (m, 0.5H), 4.90-4.80 (m, 0.5H), 4.51-4.36 (m, 1.5H), 3.65-3.43 (m, 2H), 2.88-2.49 (m, 4H), 1.12-0.89 (m, 4H), 0.61-0.56 (m, 3H); MS (ESI+) m/z 713.3 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[N:12]([CH3:26])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:27]>C(O)C.[Pd]>[ClH:27].[CH3:26][N:12]1[C:13]2[C:18](=[C:17]3[CH2:22][CH2:23][CH2:24][O:25][C:16]3=[CH:15][CH:14]=2)[C:19]2[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]1=2
Reactant: Cn1c2c(c3c4c(ccc31)OCC=C4)CCN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cn1c2c(c3c4c(ccc31)OCCC4)CCNCC2
Yield: 87.1 %

Procedure:
A solution containing 10-benzyl-7-methyl-7,8,9,10,11,12-hexahydro-3H-azepino[4,5-b]pyrano[3,2-e]indole (0.18 g., 0.51 mmol, Example 1) in ethanol (20.0 mL) was hydrogenated in the presence of palladium-on-carbon (0.07 g.) and 2 N hydrochloric acid (0.51 mL, 0.51 mmol) at 50 psi for 48 hours. After filtration through a pad of celite, the filtrate was concentrated in vacuo. The residue was recrystalized from EtOAc/MeOH to yield the title compound (0.13 g, 84%) as a light yellow solid. M.p.>217° C. (dec.); IR (KBr) 2946, 2877, 2844, 2809, 1609, 1585, 1551, 1467, 1447, 1280, 1267, 1255, 1238, 1109, 787 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 7.07, 6.52, 4.04-4.01, 3.57, 3.31-3.28, 3.19-3.12, 3.07-3.03, 1.96-1.92; 13C NMR (DMSO-d6) δ 148.5, 136.8, 131.2, 125.2, 112.3, 112.1, 110.9, 108.8, 65.4, 46.3, 44.2, 29.7, 23.1, 22.6, 22.4; MS (ESI+) m/z 257 (M++H); HRMS cacld for C16H20N2O+H: 257.1654, found: 257.1646; Anal. Calcd. for C16H20N2O.HCl.H2O: C, 61.83; H, 7.46; N, 9.01. Found: C, 62.07; H, 7.41; N, 9.01.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(O[CH3:25])(=O)=O.[OH-].[Na+]>C(C(C)=O)C.O>[CH3:25][O:20][CH3:9].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 10 ml of methyl ethyl ketone, 5 ml of the 10% NaOH aqueous solution was added over a period of one hour. The reaction temperature was maintained at 15° - 20°C. The resulting mixture was stirred for 1 hour. 10 ml of water was added to the reaction mixture and methyl ethyl ketone was distilled off. The crystals which formed during the distillation were filtered from the cooled reaction mixture, washed with water and dried to obtain 1.037 g of the 100% purity methyl ether of estrone in a 98.6% yield.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24](=[CH2:27])[CH2:25][NH2:26].CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:26][CH2:25][C:24]([CH3:27])=[CH2:23])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: C=C(C)CN
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: C=C(C)CNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 80 °C
Yield: 58.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 45.5 mg, 0.107 mmol) and 2-methylallylamine (Matrix Scientific, Columbia, S.C.; 0.039 mL, 0.430 mmol) in DMSO (0.8 mL), heating at 80° C. for 30 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (22.0 mg, 0.063 mmol, 59% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br. s.), 7.87 (1H, dd, J=7.6, 1.2 Hz), 7.59 (1H, t, J=5.6 Hz), 7.56 (1H, m, J=8.0, 1.2 Hz), 7.31 (1H, t, J=7.8 Hz), 7.10 (1H, d, J=2.2 Hz), 6.93 (1H, s), 4.86 (1H, s), 4.83 (1H, s), 4.05 (2H, d, J=5.7 Hz), 3.42 (2H, td, J=6.8, 2.3 Hz), 2.86 (2H, t, J=6.8 Hz), 2.57 (3H, s), 1.85 (3H, s). m/z (ESI, +ve) 348.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:18][Mg]Br.C(OCC)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([OH:11])[CH3:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc2occc2c1
Temperature: 25 °C

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanone (1.0 g, 4.5 mmol) in 20 mL THF under nitrogen at 0° C. was added methylmagnesium bromide 3.0M in diethyl ether (2.2 mL, 6.7 mmol) dropwise via syringe. The reaction was allowed to warm to ambient temperature slowly. The reaction was quenched with sat'd aq. NH4Cl and DCM. The aqueous layer was extracted 2×DCM, and the combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo to give 1-(benzofuran-5-yl)-1-phenylethanol as an oil, which was used without further purification. MS (ESI) m/z: Calculated: 238.1; Observed: 238.8 (M++1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH2:41][CH:42]([CH3:44])[CH3:43])([O:17][C:18]1[CH:40]=[CH:39][C:21]2[C:22]3[N:26]([CH2:27][CH2:28][O:29][C:20]=2[CH:19]=1)[CH:25]=[C:24]([C:30]1[N:31]([CH:36]([CH3:38])[CH3:37])[N:32]=[C:33]([CH3:35])[N:34]=1)[N:23]=3)[C:12](OCC)=[O:13])C.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH2:41]([C:11]([O:17][C:18]1[CH:40]=[CH:39][C:21]2[C:22]3[N:26]([CH2:27][CH2:28][O:29][C:20]=2[CH:19]=1)[CH:25]=[C:24]([C:30]1[N:31]([CH:36]([CH3:38])[CH3:37])[N:32]=[C:33]([CH3:35])[N:34]=1)[N:23]=3)([CH2:12][OH:13])[CH2:10][OH:9])[CH:42]([CH3:44])[CH3:43]
Reactant: CCOC(=O)C(CC(C)C)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC(C)C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
To an ice-cooled suspension of LiAlH4 (41.3 mg, 1.09 mmol) in THF (3 mL) was added a solution of 2-isobutyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]malonic acid diethyl ester (195 mg, 0.362 mmol) in THF (2 mL). The reaction mixture was stirred at RT for 1.5 h. To the reaction mixture was added EtOAc (1 mL) and stirring was continued for 10 min. An aqueous solution of Rochelle salt's and EtOAc were then added and stirring continued for a further 1 h. The mixture was filtered through a Celite® pad and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 4-14% MeOH in DCM) affording the title compound as a colourless gum (88.6 mg, 54%). LCMS (Method B): RT 2.87 min [M+H]+ 456.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]2=1.B(Br)(Br)Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]2=1
Reactant: COc1ccc2oc3c4ccccc4c(=O)[nH]c3c2c1
Agent: BrB(Br)Br
Solvent: O
Product: O=c1[nH]c2c3cc(O)ccc3oc2c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-Methoxy-6H-11-oxa-6-aza-benzo[a]fluoren-5-one (22a) (5.0 g) was cooled using an ice bath, and boron tribromide (1 M in methylene chloride, 95 mL, 95 mmol, 5 eq.) added in a steady stream under nitrogen. The reaction was heated at reflux under inert atmosphere for two hours, then cooled to room temperature and poured into water (150 mL). The resulting suspension was allowed to stir for 1 h, filtered, and the solids were washed with water (2×200 mL). The solids were then diluted with 5 N sodium hydroxide (600 mL) using heating. The resulting solution was cooled to 0° C. using an ice bath and the solution was acidified to pH 1 using conc. HCl. The resulting precipitate was vacuum filtered, and the solids washed sequentially with water (3×300 mL) and diethyl ether (300 mL) then dried overnight using a vacuum oven at 50° C. to provide Compound 23a as a gray solid. Yield=4.74 g (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[S:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:15])=[O:14]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[S:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: COC(=O)C=Cc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of the product of example 86 (200 mg, 0.608 mmol) in MeOH (10 ml) was added Pd/C (20 mg, 10% Pd on carbon). The mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (PE/EA=3/1) to give the desire product (150 mg, yield 74.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CSc2cccc(OC)c2)cccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 806.2 %

Procedure:
To a solution of 3-methoxythiophenol (0.54 g, 0.48 mmol) and triethylamine (0.43 ml, 0.59 mmol) in dichloromethane (30 ml) was slowly added methyl 2-bromomethyl-6-nitrobenzoate (1.45 g, 5.3 mmol) under ice-cooling, followed by stirring for 3 hours. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give methyl 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoate (1.29 g, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a stirred solution at room temperature of 4-acetylbenzoic acid (395 mg, 2.41 mmol) in anhydrous DMF (15 ml) under nitrogen were added Et3N (369 μl, 2.65 mmol) and BOP reagent (1.171 g, 2.65 mmol), respectively. After 30 min, a solution of t-butyl (2-amino-phenyl)-carbamate (551 mg, 2.65 mmol), Et3N (1.01 ml, 7.22 mmol) in anhydrous DMF (5 ml) was added dropwise. After 19 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4Cl, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane:40/60→50/50) to afford the title compound III (500 mg, 1.41 mmol, 59% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ(ppm): 9.47 (bs, 1H), 8.10–8.00 (m, 4H), 7.91 (d, J=7.9 Hz, 1H), 7.33–7.15 (m, 3H), 6.67 (s, 1H), 2.67 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CO.O.[F:22][C:23]([F:39])([F:38])[C:24]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=1)[CH:35]=O)([OH:29])[C:25]([F:28])([F:27])[F:26].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:28][C:25]([F:26])([F:27])[C:24]([C:30]1[CH:37]=[C:34](/[CH:35]=[C:8]2/[C:9](=[O:12])[C:10]3[C:6]([CH2:7]/2)=[CH:5][C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:33]=[N:32][CH:31]=1)([OH:29])[C:23]([F:39])([F:38])[F:22]
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (0.1 g, 0.40 mmol)), MeOH/H2O (1:1), was added 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)nicotinaldehyde 259 (0.132 g, 0.485 mmol) and NaOH (0.032 g, 0.80 mmol). The reaction was stirred at RT for 6 h. The reaction mass was diluted with chloroform and washed with water (3×25 ml). The organic layer was dried over sodium sulphate and concentrated to get the crude 263, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 263.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH:3]=[N:2]1.[C:9]([O:13][C:14](=[O:31])[NH:15][C@H:16]1[CH2:21][C:20](=O)[CH2:19][S:18][C@@H:17]1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[CH:17]1[C@@H:16]([NH:15][C:14](=[O:31])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:21][C@@H:20]([N:7]2[CH2:8][C:4]3[C:5](=[N:1][NH:2][CH:3]=3)[CH2:6]2)[CH2:19][S:18]1
Reactant: c1n[nH]c2c1CNC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CS[C@@H]1c1cc(F)ccc1F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CSC1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The bis-toluenesulfonic acid salt of 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (48 mg, 0.169 mmol) was dissolved in dry DMA (1.2 mL), tert-butyl[(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-thiopyran-3-yl]carbamate (Intermediate 2) (17.3 mg, 0.05 mmol) and triethylamine (65 μL, 0.469 mmol) were added and the solution was stirred at RT for 10 min. Acetic acid (43 μL, 0.75 mmol) was added and the solution was stirred at room temperature for 5 min and then transferred to a 50 degree oil bath. After 5 min, 1M sodium cyanoborohydride in THF (190 μL, 0.19 mmol) was added. After 30 min, the solution was cooled to room temperature and added to a mixture of ethyl acetate (30 mL) and saturated aqueous NaHCO3 (10 mL). The organic phase was washed with water (2×10 mL), brine (1×5 mL), dried with MgSO4., filtered and evaporated to an oil. Examination of the crude oil by HNMR showed an approximately 4:1 ratio of diastereomeric amines at C-5. The oil was purified by 1×500 micron preparative thin layer chromatography using 15:1 methylene chloride/10% ammonium hydroxide in EtOH as developing solvent. The more polar band was removed, eluted with the developing solvent mixture and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:16].N#N>>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1cc(C2(C)CC2)ccc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: N#N
Product: Cc1cc(C2(C)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Yield: 81.8 %

Procedure:
2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid (2.139 g, 11.243 mmol) and phosphoruspentachloride (2.575 g, 12.37 mmol) were charged into a 50 ml flask under stirring. These both solids dissolved at 100° C. The reaction mixture was stirred 2 hours at 120° C. with an reflux condenser in a N2 atmosphere. After that the resulting phosphorus oxylchloride was distilled off at 140° C. from the reaction mixture. The whole reaction mixture was cooled to room temperature and the reaction mixture still remained as a solution. The desired product was distilled by Kugelrohr distillation (150° C./4 mbar) to give 2-Methyl-4-(1-methyl-cyclopropyl)-benzoyl chloride (1.92 g, 9.2 mmol)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.[C:21](#[N:23])[CH3:22].[CH:24]([CH:27]1[C:38](=[O:39])[C:37]2[C:36]3[O:35][C:34]([CH3:40])=[N:33][C:32]=3[CH:31]=[CH:30][C:29]=2[CH2:28]1)([CH3:26])[CH3:25]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[OH:39][C:38]1([CH2:22][C:21]#[N:23])[C:37]2[C:36]3[O:35][C:34]([CH3:40])=[N:33][C:32]=3[CH:31]=[CH:30][C:29]=2[CH2:28][CH:27]1[CH:24]([CH3:26])[CH3:25]
Reactant: CC#N
Reactant: Cc1nc2ccc3c(c2o1)C(=O)C(C(C)C)C3
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)C(O)(CC#N)C(C(C)C)C3
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (917 mg, 5.68 mmol) in tetrahydrofuran (10 mL) was added 1.6M butyllithium/hexane solution (3.55 mL, 5.68 mmol) at −78° C., and the mixture was stirred for 15 min. Thereto was added a solution of acetonitrile (313 μL, 5.95 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred for 30 min. Then, a solution of 7-isopropyl-2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (650 mg, 2.84 mmol) in tetrahydrofuran (2 mL) was added. After stirring for 30 min, the reaction solution was diluted with saturated aqueous ammonium chloride solution and ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0) to give the title compound (614 mg, yield 80%).