Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH2:29][CH3:30])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([N:28]1[C:24]([C@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:18]2[O:17][C:13]2[CH:12]=[C:11]([F:31])[C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:15]([F:16])[CH:14]=2)=[CH:25][CH:26]=[N:27]1)[CH3:30]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 41.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.080 g, 0.13 mmol) prepared in Example 59a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (25 mg, 42%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:8]1[N:16]2[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH2:1]([C:8]1[N:16]2[C:11]([CH:12]=[N:13][C:14]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:32][CH:31]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)c1ncc2ccc(Cc3ccccc3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(Cc5ccccc5)n4n3)cc2)CC1
Yield: 42 %

Procedure:
Into a microwave vial, 7-Benzyl-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.120 g, 0.442 mmol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.186 g, 0.973 mmol), N,N-Diisopropylethylamine (0.169 mL, 0.973 mmol), and 1-Methoxy-2-propanol (0.50 mL, 5.1 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid (74 mg, 42%). LCMS (E/I+) 399.3 (M+H). NMR 1H (DMSO-d6)-9.74 (bs, 1H), 9.21 (s, 1H), 8.83 (s, 1H), 7.64 (d, 2H, J=8.09 Hz), 7.27-7.34 (m, 4H), 7.20 (bs, 1H), 6.96 (d, 2H, J=8.09 Hz), 6.78 (d, 1H, J=4.85 Hz), 6.60 (d, 1H, J=4.85 Hz), 4.27 (s, 2H), 3.74 (d, 2H, J=12.94 Hz), 3.52 (d, 2H, J=12.14 Hz), 3.09-3.24 (m, 2H), 2.77-2.97 (m, 5H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[C:12]2[N:13]=[C:14](Cl)[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+]>CO.O>[CH2:1]([S:8][C:9]1[N:18]=[C:12]2[N:13]=[C:14]([O:20][CH3:19])[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccn2nc(SCc3ccccc3)nc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccn2nc(SCc3ccccc3)nc2n1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A mixture of 6.0 g (22 mmol) of 2-benzylthio-5-chloro-1,2,4-triazolo[1,5-a]pyrimidine in 25 ml of methanol was treated with 5.0 g (23.8 mmol) of a 25% solution of sodium methoxide in methanol. After stirring for 1.5 hours the reaction mixture was diluted with 100 ml of water and neutralized with 3N HCL (aq). The solid which separated was collected by filtration, washed with water and dried to afford 5.0 g (84%) of the desired product as a white solid, m.p. 126°-128° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: I[Si](C)(C)C.C(OC([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][C:25]([NH:27][C:28]3[N:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41](=[O:44])[NH:42][CH3:43])[C:31]([Cl:45])=[CH:30][N:29]=3)=[CH:26][C:20]=2[NH:19][C:18](=[O:46])[CH2:17]1)=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:45][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([NH:42][CH3:43])=[O:44])=[N:33][C:28]([NH:27][C:25]2[CH:24]=[CH:23][C:21]3[CH2:22][NH:16][CH2:17][C:18](=[O:46])[NH:19][C:20]=3[CH:26]=2)=[N:29][CH:30]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C(=O)OCc2ccccc2)C3)ncc1Cl
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CNC3)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
At 0° C., iodotrimethylsilane (12.3 mg, 0.06 mmol) was added slowly to a solution of 8-[5-chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (25 mg, 0.04 mmol) in methylene chloride (5 mL). The mixture solution was warmed to room temperature and stirred for 1 hour. The mixture was quenched with a few drops of methanol, stirred for 10 minutes and concentrated. The residue was treated with 1N HCl (0.5 mL), and then made basic (pH 10) with potassium carbonate. The mixture was extracted with methylene chloride and chloroform, and then dried over sodium sulfate. Chromatography of the crude solid with preparative TLC using methylene chloride and methanol (25:1) gave 6.3 mg of 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (33%): 1H NMR (300 MHz, CDCl3) δ 8.45 (d, 1H), 8.05 (s, 1H), 7.6 (q, 2H), 7.43 (t, 2H), 7.3 (dd, 1H), 7.13 (d, 2H), 4.0 (s, 2H), 3.43 (s, 2H), 2.92 (s, 3H); MS (m/e): 438.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:31]=[CH:32][C:7]=1[CH2:6]2)=O.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1.O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[C:8]3[CH:9]=[C:10]4[C@:5]([CH2:3][OH:2])([CH2:6][C:7]=3[CH:32]=[N:31]2)[CH2:14][N:13]([S:15]([C:18]2[CH:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:12][CH2:11]4)=[CH:34][CH:35]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-ylpyridine-3-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-4a-carboxylic acid methyl ester (17 g) in dichloromethane (300 mL) under nitrogen at −78° C. was treated with a 1.0 M solution of diisobutylaluminium hydride in toluene (123 mL). After 1 hour at −78° C., the solution was diluted with water and the phases separated. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford the title compound as a white solid (16.7 g). 1H NMR (CDCl3): δ 8.56-8.53 (d, 1H, J=2.4 Hz), 7.81-7.77 (dd, 1H, J=9.0, 2.4 Hz), 7.44-7.38 (m, 3H), 7.19-7.12 (m, 3H), 6.65-6.60 (d, 1H, J=9.0 Hz), 6.31-6.28 (d, 1H, J=2.5 Hz), 4.08-4.03 (dd, 1H, J=12, 2.4 Hz), 3.99-3.92 (m, 1H), 3.84-3.79 (m, 4H), 3.69-3.64 (m, 4H), 3.37-3.30 (m, 1H), 3.14-3.08 (d, 1H, J=16 Hz), 2.82-2.70 (m, 1H), 2.58-2.48 (m, 1H), 2.42-3.34 (m, 1H), 2.28-2.16 (m, 3H).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]([F:49])([CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([OH:48])[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH2:24]O>ClCCl>[F:22][C:23]([F:49])([CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([OH:48])[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH2:24][O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](CC(F)(F)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](CC(F)(F)COS(=O)(=O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
The mixture of pyridine (124 μl) and trifluoromethanesulfonic anhydride (206 μl) in dichloromethane (5 ml) was stirred at -20° C. under argon atmosphere for 5 min. To this solution the alcohol (7) (400 mg, 1.02 mmol) in dichloromethane (10 ml) was added and the mixture was stirred at room temperature for 40 min. The usual work-up (dichloromethane for extraction) gave the triflate (8) (612 mg), which was used in the next step without further purification. 1H-NMR δ: 0.73 (3H, s, 18-H3), 1.00 (3H, s, 19-H3), 1.15 (3H, d, J=6 Hz, 21-H3), 3.56 (2H, m, THP), 3.85 (1H, m, 3-H), 4.50 (2H, t, J=12 Hz, 24-H2), 4.70 (1H, m, THP), 5.37 (1H, m, 6-H). 19F-NMR δ: +12.2 (3F), +41.3 (2F).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(C)(C)C.C(B(CC)CC)C.Br[C:24]1[C:25]([O:34][CH3:35])=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[CH:29]=[O:30].[OH-].[Na+].OO>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([O:34][CH3:35])[C:24]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:31][C:28]=1[CH:29]=[O:30]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: Cn1ccc2ccccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCB(CC)CC
Agent: OO
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
Ex-15A: 1-Methylindole (5.0 g, 38.1 mmol) was dissolved in tetrahydrofuran (190 mL) and nitrogen was bubbled into the solution for 15 min. The solution was then cooled to 0° C. and tert-butyllithium (1.6 M solution in pentane, 23.5 mL, 40.0 mmol) was added dropwise and the mixture was stirred for 30 min at 0° C. and then warmed to room temperature and stirred for an additional 1 h. Triethylborane (1.0 M solution in THF, 45.7 mL, 45.7 mmol) was added, and the reaction mixture was stirred for 1 h at room temperature. To the crude indolylborate, generated in situ, was added 5-bromo-2,4-dimethoxybenzaldehyde (9.3 g, 38.1 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.48 g, 0.95 mmol). The solution was immediately heated to 60° C. and aged for 30 min. Upon completion, as determined by HPLC, the reaction was treated with 10% aqueous sodium hydroxide (190 mL) and 30% hydrogen peroxide (38 mL) with ice-cooling for 20 min. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic extracts were washed with brine (2×75 mL), dried over sodium sulfate and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:3 to 3:1) gave 7.69 g (77%) of 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde as a yellow solid, mp 153–153° C. 1H-NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 7.87 (s, 1H), 7.37 (d, 1H, J=7.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.20–7.28 (m, 1H), 7.12 (t, 1H, J=6.8 Hz), 6.55 (s, 1H), 6.48 (s, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.55 (s, 3H). Anal. Calcd. for C18H17NO3: C, 73.20; H, 5.80; N, 4.74; Found: C, 72.98; H, 5.89; N, 4.73.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[N:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:27]([OH:28])[C:26]4[C:21](=[N:22][CH:23]=[CH:24][N:25]=4)[C:20]3=[O:29])=[N:16]2)=[CH:11][CH:10]=1>C(#N)C.C(Cl)Cl>[CH2:1]([NH:5][C:6]([O:28][CH:27]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[C:20](=[O:29])[N:19]1[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[N:18][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: ClCCl
Product: CCCCNC(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 50.7 %

Procedure:
n-Butyl isocyanate (5 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (7.8 g.) in anhydrous acetonitrile (156 cc.) and the mixture is heated at the reflux temperature for 7 hours. The insoluble product is filtered off and washed with anhydrous acetonitrile (2 × 10 cc.). The product obtained is dissolved in methylene chloride (430 cc.) and the resulting solution is washed by successive decantations with 0.1N sodium hydroxide solution (85 cc.) and water (85 cc.). After drying, the organic phase is concentrated to dryness under reduced pressure (20 mm.Hg). Recrystallisation of the residue obtained, from acetonitrile (230 cc.), gives 5-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (5.2 g.) melting at 264° C.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[CH:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[NH:20][C:19]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:18]1.C([O-])(O)=O.[Na+]>C(O)(C)C>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:18]=1
Reactant: Fc1cccc(Cl)c1C1C=C(c2ccc(Cl)cc2)Nc2ncnn21
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CC(C)O
Product: Fc1cccc(Cl)c1-c1cc(-c2ccc(Cl)cc2)nc2ncnn12
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A sample of NBS (299 mg, 1.68 mmol) was added to a solution of 7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (3a) (101 mg, 0.28 mmol) in isopropanol (5 mL). The reaction mixture was refluxed for 36 h, then cooled to room temperature, treated with saturated NaHCO3 solution (20 mL) and extracted with EtOAc (15 mL×3). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The given residue was purified through silica gel column chromatography (EtOAc/Hexanes 30:70) to afford a 42 mg white solid of 4a in 42% yield. m.p. 238-239° C. Rf=0.33 (EtOAc/Hexanes 30:70). MS: MH+=359. 1H NMR (500 MHz, CDCl3): δ 8.48 (s, 1H, CHar), 8.15 (d, J=7.5 Hz, 2H, CHar), 7.57-7.39 (m, 5H, CHar), 7.20-7.19 (m, 1H, CHar). HPLC: 97.9% (Method C, tR=5.47 min).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl>[I-].[Na+].C1COCC1.CN(C=O)C>[C:12]1([CH2:11][N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:7])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCN1
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCCCN1Cc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
To a DMF (20 mL) solution of δ-valerolactam (1.0 g), sodium hydride (404 mg), 1-(chloromethyl)naphthalene (1.78 g) and sodium iodide (151 mg) were added one by one at 0° C., and the reaction solution was allowed to be warmed to 60° C., and was agitated for 6 hours. 2N hydrochloric acid and THF were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane: elution solvent; ethyl acetate=1:2->ethyl acetate), and 2.42 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:43])[NH:7][C:8]2[CH:42]=[CH:41][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:36])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=4)[CH2:16][CH:15]3[C:37]([O:39]C)=[O:38])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([CH2:4][NH:5][C:6](=[O:43])[NH:7][C:8]2[CH:42]=[CH:41][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:36])([C:28]([F:31])([F:30])[F:29])[C:32]([F:34])([F:35])[F:33])=[CH:23][CH:22]=4)[CH2:16][CH:15]3[C:37]([OH:39])=[O:38])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2C(=O)O)cc1
Yield: 83 %

Procedure:
Methyl 1-(4-(3-(cyclopropylmethyl)ureido)benzoyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-2-carboxylate (0.032 mmol, 0.02 g) and sodium hydroxide (0.032 mmol, 1.298 mg) were combined and heated to 80° C. in methanol (1 mL) for 6 hours in a reactivial. The reaction mixture was concentrated under reduced pressure. The resulting residue was passed down an SCX column to afford the title compound (16 mg). MS (ESI) m/z 603.2 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:15]#[N:16])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:2].O[C:19]1C=C[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[C:15]([CH:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[C:19]2[C:1](=[C:2]3[CH:25]=[CH:24][N:23]=[C:22]3[CH:21]=[CH:20]2)[O:3][C:4]1=[O:17])#[N:16]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCOC(=O)C(C#N)=Cc1cccc(OC)c1
Product: COc1cccc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1

Procedure:
Alternatively, compounds of Formula III can be prepared as shown in Schemes 3 and 4. Condensation of 3,5-dimethoxybenzaldehyde with ethyl cyanoacetate in the presence of a base such as piperidine produces the 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester. Treatment of the ester with 3-methoxyphenol in the presence of NaH produces the 3-cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene. Similarly, reaction of 3-(3-methoxy-phenyl)-2-cyano-acrylic acid ethyl ester with 4-hydroxyindole produces 3-cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>O.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH3:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Mix 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (3.1 g, 7.01 mmol) with anhydrous MeOH (100 mL) and treat with acetic acid (4.0 mL, 69.8 mmol) and formaldehyde (1.6 mL, 21.30 mmol, as a solution in water). Stir the mixture at room temperature for 30 min and then treat with sodium cyanoborohydride (1.3 g, 19.6 mmol). Stir the mixture at room temperature overnight and concentrate in vacuo. Partition the resulting residue between CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). Remove the organic solution and extract the aqueous phase with additional CH2Cl2 (2×100 mL). Combine the organic solutions and wash with water (50 mL), then dry, filter, and concentrate in vacuo. Purify the crude material by flash chromatography, using 8% MeOH (2M NH3)/CH2Cl2 as eluent, to give 1.6 g (50%) of the title compound as a yellow solid. ES/MS m/z (35Cl) 456 [M+1]+.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C=C(C)C=1)C(O)=O.CC1C=C(C(Cl)=O)C=C(C)C=1.[CH3:27][C:28]1[CH:29]=[C:30]([C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:31]=[C:32]([CH3:34])[CH:33]=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:30]2[CH:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[CH:31]=2)=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: Cc1cc(C)cc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cc1cc(C)cc(C(=O)O)c1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)cc(C)c4)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3,5-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 3,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 3,5-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][CH:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.Cl.CNC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:19][N:21]([CH3:22])[C:16]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:12]([F:15])([F:14])[CH2:11]1)=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(F)(F)C1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid (2.1 g, 7.92 mmol) in N,N-dimethylformamide (100 mL) were added 1,1′-carbonyldiimidazole (CDI, 2.56 g, 15.82 mmol), dimethylamine hydrochloride (1.29 g, 15.82 mmol) and triethylamine (2.4 g, 23.71 mmol). After 16 h, the mixture was diluted with ethyl acetate, then was washed sequentially with cold water (×2) and brine, The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford tert-butyl 5-(dimethylcarbamoyl)-3,3-difluoropiperidine-1-carboxylate (1.4 g, 60% over two steps) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](O)([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=1)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:11]1[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccc3ccccc3c1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Yield: 100 %

Procedure:
3-Hydroxy-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.80 g, 19.3 mmol) and 10 mL TFA are stirred at 23° C. in 80 mL of CH2Cl2 for 2.5 h. The volatiles are removed and the residue partitioned between 100 mL of saturated NaHCO3 and 100 mL EtOAc. The aqueous layer is extracted with 2×50 mL EtOAc, and the combined organics are washed with 3×50 mL H2O, 1×50 mL brine, dried over MgSO4, filtered, and stripped to give 4.50 g (19.1 mmol, a 100% yield) of the title compound as a white solid. MS (ES) m/z (relative intensity): 236 (M++H, 100).