Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[NH:9][CH3:10])(C)(C)C>Cl>[C:11]([N:8]([CH2:7][C:6]([OH:28])=[O:5])[NH:9][CH3:10])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: CNN(CC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Product: CNN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.7 %

Procedure:
1 L, two-neck, round-bottomed-flask was fitted with a glass stopper and reflux condenser connected to a calcium tube. (N-Fmoc-N′-methyl-hydrazino)-acetic acid t-butyl ester (20 g, 52 mmol) was added. A solution of HCl (150 mL, 4 M solution in dioxane) was added slowly with vigorous stirring in an ice water bath. The reaction mixture was stirred at RT over 1 day. The solution was concentrated completely under reduced pressure at 40° C. A saturated aq. NaHCO3 solution (100 mL) was added and the aqueous layer was washed with diethyl ether (100 mL). Conc. HCl was added dropwise slowly at 0° C. (pH 2-3). The mixture was extracted and the organic layer was retained (500 mL, MC). The solution was dried with sodium sulfate and evaporated in vacuo. The residue was purified by recrystallization with n-hexane and ethyl acetate to give (N-Fmoc-N′-methyl-hydrazino)-acetic acid (12 g, 72%). 1H-NMR (DMSO-d8) δ 12.38 (5, 1H), 8.56 (b, 1H), 7.89˜7.86 (d, J=9 Hz, 2H), 7.70˜7.67 (d, J=9 Hz, 2H), 7.43˜7.29 (m, 4H), 4.29˜4.27 (d, J=6 Hz, 2H), 4.25˜4.20 (t, J=6 Hz, 1H), 3.47 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[CH3:20][NH:21][CH3:22].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:21]([CH3:22])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A solution of 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.3871 mmol) in 1,2-Dichloroethane (2.0 mL) was charged with 2.0 M of dimethylamine in THF (0.2903 mL, 0.5807 mmol) and sodium triacetoxyborohydride (164.1 mg, 0.7743 mmol). The reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow oil. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/7M NH3 in MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a light yellow solid, 64.7 mg (58% yield). 1H NMR (CDCl3, 400 MHz): δ=1.53 (d, J=11.12 Hz, 4H), 1.91 (d, J=11.12 Hz, 2H), 2.08 (d, J=14.65 Hz, 2H), 2.31 (br. s., 6H), 2.45 (br. s., 1H), 2.48-2.58 (m, 1H), 3.14 (s, 3H), 4.30 (s, 2H), 5.07 (br. s., 2H), 6.57 (d, J=8.34 Hz, 1H), 7.26 (br. s., 1H). MS (ES+): m/z 288.21 [MH+] (TOF, polar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]([OH:8])[CH3:11])[C:5]([F:10])=[N:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Br)cnc1F
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
To a solution of 5-bromo-2-fluoronicotinaldehyde (10 g, 49 mmol) in THF (100 mL) at −78° C. was added dropwise methylmagnesium bromide (3.0 M solution in diethyl ether, 24.5 mL, 73.5 mmol). After the addition, the reaction was warmed to room temperature and stirred for 17 h. The mixture was carefully quenched with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0-10% EtOAc/hexanes) gave 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.8 g, 49.1 mmol, 100% yield) as a yellow oil. LC/MS (ESI+) m/z=220 (M+H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44]([O:46][CH2:47][C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)=[O:45])=[N:36][CH:35]=5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.Cl.[CH3:55][O:56][C:57]([NH:59][C@@H:60]([CH:64]([CH3:66])[CH3:65])C(O)=O)=[O:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:55][O:56][C:57]([NH:59][C@H:60]([CH:64]([CH3:66])[CH3:65])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44]([O:46][CH2:47][C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=6)=[O:45])=[N:36][CH:35]=5)=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:5])=[O:58]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)cc4)cc3)cc2[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CO
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)cc4)cc3)cc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of (S)-benzyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.6 g, 0.85 mmol), concentrated HCl (1.5 mL) and ethanol (10 mL) was heated to 60° C. for one hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off three more times, until the crude material was a yellow powder. A portion of the crude amine (0.3 g, ˜0.42 mmol) was dissolved in dimethylformamide (4.7 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (165 mg, 0.9 mmol), HATU (355 mg, 0.9 mmol) and diisopropylethylamine (0.82 mL, 4.7 mmol). The reaction was stirred at room temperature for one hour, and then diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(4′-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.28 g, ˜74%). LCMS-ESI+: calculated for C45H47N7O5: 765.90; observed [M+1]+: 766.47.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].CI.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH3:32])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:13])([F:12])[F:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1OC)C(C)(C)CCC2(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2E,4E,6Z)-8,8,8-trifluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Intermediate 5, 160 mg, 0.37 mmol), K2CO3 (253 mg, 1.83 mmol), MeI (0.12 mL, 1.83 mmol), and acetone (2 mL), was stirred at ambient temperature for overnight. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% EtOAc-hexane) to produce the title compound and its 2-Z isomer as a 2:1 mixture (167 mg). Further purification by HPLC (2.5% EtOAc-hexane) afforded the title compound as a clear oil (87 mg, 53%).
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.CN1CC[O:15][B:14]([C:18]2[CH:19]=[C:20]([S:24]([O-:26])=[O:25])[CH:21]=[N:22][CH:23]=2)[O:13]CC1.[Li+].[OH-].[NH4+]>C(Cl)Cl>[S:24]([C:20]1[CH:21]=[N:22][CH:23]=[C:18]([B:14]([OH:15])[OH:13])[CH:19]=1)(=[O:26])(=[O:25])[NH2:2]
Reactant: CN1CCOB(c2cncc(S(=O)[O-])c2)OCC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cncc(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Step 3) N-Chlorosuccinimide (0.937 g, 7.01 mmol) was added to a suspension of the above prepared lithium 5-(6-methyl-[1,3,6,2]dioxazaborocan-2-yl)-pyridine-3-sulfinate (2 g, 7.24 mmol) in CH2Cl2 (14 mL) and the mixture was stirred for 2 h at rt. A solution of 25% ammonium hydroxide (1.00 mL, 13.4 mmol) was added and the mixture was stirred again for 2 h at rt, then completely evaporated to give the title compound as an off-white solid (1.28 g, 88%) (according to Bioorg. Med. Chem. 2005, 13, 2305-2312). MS (ISP) 201.4 [(M−H)−].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)C1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C1CCCCC1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-cyclohexylacetate hydrochloride (prepared from cyclohexylglycine (Advanced Chemtech) using General Procedure H), the title compound was prepared as a solid (mp=146-150° C.). The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1.[NH2:22][OH:23].CS(C)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17](=[N:22][OH:23])[NH2:18])=[CH:15][CH:14]=2)[N:12]=1
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C(N)=NO)cc2)cs1
Reaction time: 16 h
Yield: 64 %

Procedure:
4-[2-(4,4-Dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.10 mg, 0.33 mmol), prepared in Example 6, was dissolved in tetrahydrofuran (2 mL). A 1M solution of hydroxylamine in dimethyl sulfoxide (1.5 mL, 1.5 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with ethyl acetate and washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (1% methanol/methylene chloride) afforded the title compound (70 mg, 64%) as a white solid. HRMS: calcd for C15H16N4O3S+H+, 333.10159; found (ESI-FT/MS, [M+H]1+), 333.102; Analytical HPLC: purity 100% at 210-370 nm, 6.9 min; 100% at 292 nm, 6.9 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 mm.
Reaction SMILES: [NH2:1][C:2]1([C:15]([F:19])([F:18])[CH2:16][OH:17])[C:11]2([CH2:13][CH2:12]2)[CH2:10][O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:14])=[CH:6][CH:7]=2.[C:20]([N:28]=[C:29]=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Br:14][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][CH2:10][C:11]1([CH2:13][CH2:12]1)[C:2]2([NH:1][C:29]([NH:28][C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[S:30])[C:15]([F:19])([F:18])[CH2:16][OH:17]
Reactant: NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
Under ice cooling, to a solution of 2-(4-amino-6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-yl)-2,2-difluoroethanol (2.24 g, 6.46 mmol) in acetone (45 mL) was added benzoyl isothiocyanate (1.16 g, 7.10 mmol), and the mixture was stirred for 2 hours at room temperature and stirred for 13 hours at 40° C. After concentration, the residue was purified by silica gel chromatography (EtOAc/hexane=1:99-30:70) followed by purification using silica gel chromatography (NH-silicagel, EtOH/CHCl3=0:100-10:90) to give N-{[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]carbamothioyl}benzamide (684 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:20][C:19](=[O:21])[O:18][C@H:17](/[C:22](/[CH3:47])=[CH:23]/[CH:24](O)[CH:25](O)[C@@H](C)C[C@@H]2[C@@H]([C@H](C)[C@@H](O[Si](C(C)(C)C)(C)C)CC)O2)[C@@H:16]([CH3:48])[CH:15]=[CH:14][C@@H:13]2[O:49][CH:50]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:51][C@:12]2([CH3:58])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C>[Si:1]([O:8][C@H:9]1[CH2:20][C:19](=[O:21])[O:18][C@H:17](/[C:22](/[CH3:47])=[CH:23]/[CH:24]=[CH2:25])[C@@H:16]([CH3:48])[CH:15]=[CH:14][C@@H:13]2[O:49][CH:50]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:51][C@:12]2([CH3:58])[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)C(O)C(O)/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)OC(c3ccccc3)O[C@H]2C=C[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)OC(c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)C(O)C(O)/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)OC(c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)OC(c3ccccc3)O[C@H]2C=C[C@@H]1C
Reaction time: 1.5 h

Procedure:
(3aS,4E,6S,7S,11R,13aR)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1E,5S)-6-[(2R,3R)-3-((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)oxiran-2-yl]-3,4-dihydroxy-1,5-dimethylhex-1-en-1-yl}-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f]oxacyclododecin-9-one (1.46 g, 1.73 mmol) was dissolved in THF (30 ml) and water (7.5 ml), followed by addition of sodium metaperiodate (1.11 g, 5.19 mmol) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate and washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto, commercial name Silica Gel 60N, 40-100 μm; heptane:ethyl acetate=10:1→8:1→5:1) to obtain the title compound Q20 (0.485 g) as a colorless oil and to obtain the title compound P18b (0.803 g) as a colorless oil. The title compound P18b was determined to be a mixture of α benzylidene acetal and β benzylidene acetal in a ratio of 1:3.2 by 1H-NMR.
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:4]2[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 129.8 %

Procedure:
5-Nitrothiophene-2-carbonitrile (2.0 g, 13 mmol), 4-fluorophenol (2.9 g, 26 mmol) and potassium carbonate (5.4 g, 39 mmol) were suspended in dimethylsulfoxide (30 mL), and the mixture was stirred for 30 minutes at 60° C. Water and ethyl acetate were added to the reaction mixture, which was then separated, the organic layer was washed with water twice, then, NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (3.7 g, containing 4-fluorophenol) was obtained as a brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][N:25]([C:33](=[O:34])[CH2:32][C:30]#[N:31])[CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: N#CCC(=O)O
Reactant: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CCC2(CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a solution of 5-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine hydrochloride (270 mg, 0.6159 mmol) in a mixture of DCM and DMF (6 mL/2 mL) were added TEA (253.2 mg, 2.502 mmol), cyanoacetic acid (52.1 mg, 0.733 mmol), HOAT (124.8 mg, 0.9169 mmol) and EDCI (177.5 mg, 0.9259 mmol). The reaction mixture was stirred at rt for 1.5 h then quenched with water (30 mL), and extracted with DCM/MeOH (10/1, 80 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1). The crude product was recrystallized from MeOH (10 mL) to give the title compound as a white solid (106.6 mg, 36.91%).
Reaction SMILES: [C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2-benzoyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (2.78 g, 69.6 mmole). After 10 min, 4-benzyloxybenzyl chloride (14.85 g, 63.8 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (150 mL) and extracted with EtOAc (2×150 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (26.61 g, 97%) as a white solid: MS (ES) m/e 473 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:6]([C:17]([OH:19])=O)=[CH:5][N:4]=1)#[N:2].[N:20]1([CH2:26][CH:27]([NH2:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.Cl.O.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[N:20]1([CH2:26][CH:27]([NH:34][C:17]([C:6]2[C:7]([NH:9][CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:19])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: N#Cc1ncc(C(=O)O)c(NCC2CCCCC2)n1
Reactant: NC(CN1CCOCC1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(C(=O)NC(CN2CCOCC2)c2ccccc2)c(NCC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-cyano-4-(cyclohexylmethylamino)-pyrimidine-5-carboxylic acid (0.33 mmol, step 1.4) in DMF (2.0 mL) are added 2-morpholin-4-yl-1-phenylethylamine (69 mg, step 1.3), EDCl—H2O (0.50 mmol) and HOAt (0.50 mmol) at room temperature. After stirring at room temperature for 24 h, the reaction mixture is diluted with AcOEt. The mixture is washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; 1H NMR (DMSO) δ 0.6-1.08 (m, 2H), 1.20-1.35 (m, 3H), 1.65-1.78 (m, 6H), 2.48-2.53 (m, 2H), 2.60-2.62 (m, 2H), 2.87-2.93 (m, 2H), 3.31-3.35 (m, 1H), 3.36-3.44 (M, 1H), 3.60-3.68 (m, 4H), 5.29-5.35 (m, 1H), 7.34-7.36 (m, 1H), 7.43-7.47 (m, 2H), 7.50-7.52 (m, 2H), 8.86 (s, 1H), 9.00-9.04 (m, 1H), 9.21 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][NH:25]2)=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCOCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:27]=[C:26]4[C:22]([CH:23]=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cc[nH]c4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol) and 6-hydroxyindole (0.21 g, 1.5 mmol, Aldrich) in 1,4-dioxane (10 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). The mixture was heated at reflux for 8 h, and after cooling to room temperature, the reaction mixture was concentrated in vacuum. EtOAc (30 mL) was added, and the organic layer was washed with brine (10 mL), water (15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After the product was purified by silica gel chromatography (5:1 hexanes/EtOAc), the residue was dissolved in acetone (3 mL). Water (4 mL) was then added dropwise to afford a white precipitate, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 206–209° C. MS (ESI, pos. ion) m/z: 356 (M+1); Anal. Calcd for C19H12F3N3O.(H2O)0.2: C, 63.58; H, 3.48; N, 11.71. Found: C, 63.82; H, 3.37; N, 11.61