Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1>CO.[OH-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(CCOC)CCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN1CCCc2ccc(Cn3cc(C(=O)O)cn3)cc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Ethyl 1-((1-(2-methoxyethyl)-1,2,3,4-tetrahydroquinolin-7-yl)methyl)-1H-pyrazole-4-carboxylate (484 mg, 0.874 mmol) was dissolved in a mixture of MeOH (5 ml) and 1N NaOH (5.00 ml). The reaction mixture was stirred for 2 hr at 20° C. and the MeOH was removed by evaporation under reduced pressure. The aqeuous phase was washed with AcOEt, then acidified with HCl and extracted with AcOEt. The organic layer was concentrated under reduced pressure to afford the title compound. HPLC (Method H) Rt=2.74 min
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].O>CN(C=O)C.CC#N.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccccc1Nc1ccc(CCCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.8 %

Procedure:
To a solution of 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid (Example 158) (3.0 g, 7.97 mmol) in DMF (40 mL) was added 10% Pd—C (300 mg) at room temperature under argon atmosphere. Hydrogen gas (1 atm) was introduced into the flask and the mixture was stirred for 14 hours at room temperature. The reaction mixture was filtered through a Celite pad to remove Pd—C and concentrated in vacuo. The residue was diluted with MeOH (ca. 50 mL) and concentrated in vacuo. This operation was repeated 3 times to remove any trace of DMF. The residue was diluted with McOH again, and insoluble stuff was removed by filtration. Removing the solvent of the filtrate in vacuo afforded an oil, which was diluted with CH3CN (50 mL) and added dropwise water (100 mL) slowly. The precipitate formed was filtered and dried at 60° C. in vacuo, affording the title compound as a white solid (2.34 g, 85% yield). mp 110-112° C. MS (Fab): 347 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2ccco2)cc(Br)c1OC
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(Br)c1OC

Procedure:
1-(5-(3-Bromo-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(3-bromo-4,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.037 g, 10% yield). MS: m/z 513.1 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[C:18]2[C:19](=[O:37])[N:20]3[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:21]3[C:22](=[O:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:38][CH3:39]>C(Cl)Cl.O>[CH3:11][O:12][C:13]1[C:18]2[C:19](=[O:37])[N:20]3[CH2:35][C:34](=[O:36])[CH2:33][C@H:21]3[C:22](=[O:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:38][CH3:39]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc2c(c1OC)C(=O)N1CC(=O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Anhydrous DMSO (3.28 g, 41.94 mmol) in dry DCM (20 mL) was added dropwise over 5 minutes to a stirred solution of oxalyl chloride (10.48 mL of a 2 N solution in DCM, 20.97 mmol) under a nitrogen atmosphere at −50° C. After stirring for 5 minutess, a solution 7 (5.90 g, 13.98 mmol), in dry DCM (45 mL) was added dropwise over 45 minutes to the reaction mixture, which was then stirred for a further 45 minutes at −50° C. TEA (9.89 g; 97.87 mmol) was added dropwise to the mixture over 15 minutes followed by stirring for a further 15 minutes. The reaction mixture was left to warm to room temperature, diluted with H2O (150 mL) and DCM (100 mL). The organic phase was washed with 1 N HCl (2×100 mL), water (2×100 mL), brine (2×100 mL) and dried over MgS evaporation afforded the crude product (8), which was purified by flash column chromatography using 50:50 petroleum ether (40-60°):EtOAc as eluent. Evaporation of the pure fractions in vacuo afforded the product (4.33 g, 10.3 mmol, 74%). 1HNMR (270 MHz, CDCl3) δ 7.30 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.60 (d, 1H, J=9.89 Hz, SEM amino acetal CH2), 4.69 (d, 1H, J=9.89 Hz, SEM amino acetal CH2), 4.62 (dd, 1H, J=9.89, 3.12 Hz, 11a), 4.26-4.19 (m, 1H, 3), 3.95 (s, 3HOHe), 3.94 (s, 3H, OMe), 3.81-3.49(m, 4H, SEM 1=CH2+1+3), 2.82-2.71 (m, 1H, 1), 0.95 (t, 2H, J=2.01 Hz, SEM 2=CH2), −0.04 (s, 9H, SEM CH3); 13C NMR (67.8 MHz, CDCl3) δ206.8, 168.8, 165.9, 152.4, 147.5, 134.0, 120.4, 111.1, 105.6, 78.2, 67.2, 56.2, 54.8, 52.3, 37.3, 18.3, −1.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(N)CN>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:2]1([NH:1][CH2:9][Si:10]([O:11][CH2:12][CH3:13])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[Si](CCl)(OCC)OCC
Solvent: NCCN
Solvent: Nc1ccccc1
Product: CCO[Si](CNc1ccccc1)(OCC)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
In a 500 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer, 65.7 g of dry aniline (pKb 9.4) were heated to 120° C. and 60 g of chloromethyltriethoxysilane were added in the course of 180 min with stirring and stirring was effected for a further 60 min. Thereafter, the temperature was reduced to 105° C. and 42.4 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min, cooling to 70° C. being effected during this procedure and the heavier ethylenediamine hydrochloride phase then being separated off. The upper phase was subjected to fractional distillation without a distillation column. 18.3 g of aniline having a purity of 84.8%, 14.4 g of aniline having a purity of 97.8% (45% recovery) and 47.8 g (yield 62.9%) of N-phenylaminomethyltriethoxysilane were obtained, the purity of which was determined as 88.9%. The chloride value of the product was 88 ppm.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[C:19]([C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=3)[CH:30]=[C:29]2[C:38](OCC)=[O:39])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1>[C:19]([C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=3)[CH:30]=[C:29]2[C:38](=[O:39])[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(C)(C)C)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (36.5 mL, 1.0 M in THF, 36.5 mmol) was added tert-butyl acetate (4.92 mL, 36.5 mmol), dropwise. After 30 min, a solution of the title compound of Example 14 Step A (4.50 g, 12.2 mmol) in THF (12 mL) was added, and the mixture was held at −78° C. for 30 min, then was placed in a 0° C. bath. After 1.5 h, the reaction mixture was poured into sat. aq. NH4Cl and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20%, then 20 to 100% EtOAc in hexanes) afforded the title compound: LCMS B, tr=3.11 min, m/z 462.2 [M+Na]+; 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J=2.0 Hz, 1H), 7.31-7.24 (m, 5H), 6.97 (d, J=8.5 Hz, 2H), 5.80 (s, 2H), 3.85 (s, 2H), 1.39 (s, 9H), 1.25 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([NH:13]C(OCC=C)=O)=[C:10]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)CC(=O)CC(=O)C1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([NH2:13])=[C:10]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)Nc1sc(C(=O)OC(C)(C)C)cc1OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OC(C)(C)C)c(N)s1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of tert-butyl-2-allyloxycarbonylamino-3-tertbutoxy-5-thiophenecarboxylate (1.64 g, 4.62 mmol) in anhydrous THF (50 ml) was treated with PPh3 (240 mg, 0.923 mmol), dimedone (1.3 g, 9.23 mmol) and Pd(PPh3)4 (300 mg, 0.277 mmol). After 30 minutes, the solvent was evaporated, and the residue purified by flash silica-gel chromatography, eluting with petroleum ether: ether (80:20), to give the title compound (975 mg, 98%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Cl[CH2:28][C@H:29]([OH:32])[CH2:30][OH:31]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Reactant: OC[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1OC[C@H](O)CO
Reaction time: 144 h
Yield: 16.5 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (200 mg, 0.569 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), (R)-3-chloro-1,2-propanediol (252 mg, 2.28 mmol) is added. The mixture is stirred at 60° C. for 24 h before another portion of (R)-3-chloro-1,2-propanediol (252 mg, 2.28 mmol) is added. Stirring is continued at 60° C. for 6 days. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA to give 3-{2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-(R)-propane-1,2-diol (40 mg) as a pale yellow oil; LC-MS: tR=0.84 min; [M+1]+=426.16; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 4.20-4.14 (m, 1H), 3.95-3.85 (m, 4H), 2.80-2.74 (m, 4H), 2.70 (s, 3H), 2.42 (s, 3H), 2.24-2.16 (m, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6 H).
Reaction SMILES: C(C1C=C([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[O:12])N(C2C=CC=C(CO[Si](C(C)(C)C)(C)C)C=2)N=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[NH2:10])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2)n(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 166.1 %

Procedure:
To a solution of 1-(3-t-butyl-1-{3-[(t-butyldimethylsilyloxy)methyl]phenyl}-1H-pyrazol-5-yl)-3-(3-chlorophenyl)urea (120 mg, 0.12 mmol) in THF (2 mL) was added TBAF (1.0 M, 0.13 mL, 0.13 mmol). The reaction mixture was stirred at RT for 2.5 h. The solvent was removed under reduced pressure. EtOAc was added into the residue followed by 1N—HCl (5 drops). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to yield 1-(3-t-butyl-1-(3-hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-chlorophenyl)urea as a white powder (34 mg, 71% yield). 1H-NMR (CDCl3): δ 8.11 (s, 1H), 7.34 (t, J=2.0 Hz, 1H), 7.05-7.25 (m, 7H), 6.99 (dt, J=1.3, and 7.8 Hz, 1H), 6.39 (s, 1H), 4.39 (s, 2H), 1.33 (s, 9H); MS (EI) m/z: 399 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:27][CH2:28][CH3:29])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:33])(=O)=O>>[Cl:33][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Product: CCCc1cc2c(Cl)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1

Procedure:
Synthesized as described in Example 22C from 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole and sulfuryl chloride: MS (ES) m/z 441 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([CH2:32][C@H:33]4[CH2:38][CH2:37][C@H:36]([CH3:39])[CH2:35][CH2:34]4)[C:16]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@H:19]4[CH3:31])=[N:17][C:13]=3[CH:12]=[C:11]([C:40]3[NH:44][C:43](=[O:45])[O:42][N:41]=3)[N:10]=2)[CH:6]=[N:7][CH:8]=1>O1CCOCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([CH2:32][C@H:33]4[CH2:34][CH2:35][C@H:36]([CH3:39])[CH2:37][CH2:38]4)[C:16]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]4[CH3:31])=[N:17][C:13]=3[CH:12]=[C:11]([C:40]3[NH:44][C:43](=[O:45])[O:42][N:41]=3)[N:10]=2)[CH:6]=[N:7][CH:8]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl solution in 1,4-Dioxane (4.0 M, 1.0 ml, 4.0 mmol) was added to a stirred solution of (R)-tert-butyl 4-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate (164 mg, 0.263 mmol) in 1,4-dioxane (1 ml) at room temperature, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give 3-(4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-2-((R)-2-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (HCl salt). MS ESI calc'd. for C26H31ClN8O2 [M+H]+ 523. found 523.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(ON1C(=O)N(OC(=O)C)C(=O)N(OC(=O)C)C1=O)(=[O:16])C.C(O)(=O)C.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[C:1]1(=[O:16])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)On1c(=O)n(OC(C)=O)c(=O)n(OC(C)=O)c1=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=CC=C2C1=Cc1ccccc12

Procedure:
A mixture of 1.00 g of fluorene, 0.055 g of 1,3,5-triacetoxy-hexahydro-1,3,5-triazine-2,4,6-trione (3% by mole relative to fluorene), 9.0 g of acetic acid, 0.008 g of cobalt(II) acetate.4 H2O and 0.007 g of manganese (II) acetate .4 H2O was stirred at 120° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 6 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield fluorenon in 93% yield at 99% conversion of fluorene.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:10].C(O)(=O)C>>[BrH:10].[Br:10][CH2:8][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCCC1
Agent: Br
Solvent: CC(=O)O
Product: BrCCCN1CCCC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1.833 g of 3-pyrrolidin-1-ylpropan-1-ol was dissolved in 8.4 ml of 5.1 M hydrogen bromide/acetic acid solution, and stirred overnight at 100° C. The solvent was evaporated away, the resulting residue was suspended in ethyl acetate, and the formed solid was taken out through filtration, washed with ethyl acetate and dried under reduced pressure. The above process was repeated three times to obtain 2.92 g of the entitled compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:3]1[CH:17]([CH3:19])[CH3:18].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:17]([C@H:3]1[C:2](=[O:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([CH3:19])[CH3:18]
Reactant: CC(C)[C@H]1C(O)CCN1C(=O)OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(C)[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
To a solution (26 mL) of benzyl (2S)-3-hydroxy-2-isopropylpyrrolidine-1-carboxylate (3.22 g) in dehydrating acetonitrile were added molecular sieves 4A powder (2.31 g) and 4-methylmorpholine-N-oxide (2.86 g), and the mixture was cooled to 0° C. tetra-n-Propylammonium perruthenate (0.16 g) was added, and the mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The insoluble material was filtered through Hyflo Super-Cel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound as colorless oil (yield: 2.74 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[N:6][CH:7]=1.ClCCl.[CH2:16](N(CC)CC)[CH3:17].C(OCC)(=O)C>CCO.O>[CH:16]([C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[N:6][CH:7]=1)=[CH2:17]
Reactant: CCN(CC)CC
Reactant: Brc1ccc(-n2cnnn2)nc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1ccc(-n2cnnn2)nc1
Temperature: 90 °C

Procedure:
To a stirring solution of 5-bromo-2-(1H-tetrazol-1-yl)pyridine (1.0 g, 4.42 mmol), in EtOH (70 mL) were added bis[(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.361 g, 0.442 mmol), potassium vinyl trifluoroborate (1.18 g, 8.85 mmol, 2 equiv.), triethylamine (1.23 mL, 8.85 mmol, 2 equiv), and water (0.5 mL). The reaction mixture was heated to reflux (90° C., oil bath). Upon completion as determined by reverse phase HPLC-MS (1-2 h) and TLC (eluent: 10% ethyl acetate in hexanes), the reaction was cooled to room temperature, and then was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The extracts were concentrated and chromatographed over a column of SiO2 (0-20% EtOAc/hexanes as eluent). Evaporation of the solvent yielded the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]12[C:16]3[C:8](=[CH:9][C:10]([NH:17][C:18]4[N:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][N:19]=4)=[CH:11][C:12]=3[CH2:13][CH2:14][CH2:15]1)[CH2:7][CH2:6][CH2:5]2.Br[CH2:30][CH3:31].[Cl-].[NH4+]>CN(C)C=O>[CH2:30]([N:17]([C:10]1[CH:9]=[C:8]2[C:16]3[C:4]([CH3:3])([CH2:5][CH2:6][CH2:7]2)[CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=1)[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)[CH3:31]
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Reactant: CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN(c1cc2c3c(c1)CCCC3(C)CCC2)c1ncc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A suspension of sodium hydride (60%, 0.008 g) in N,N-dimethylformamide (2 ml) was added with ethyl 2-[(5,6,6a,7,8,9-hexahydro-6a-methyl-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.033 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with bromoethane (0.021 ml), and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was suspended in ethanol (5 ml), the suspension was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.025 g, yield: 76%) as colorless needles (melting point: 257-258° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.[OH-].[Na+]>CC#N.O>[N:9]1([C:4]2[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)[N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: Clc1nc(Cl)nc(N2CCCCCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(N3CCCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To the solution of crude 1-(4,6-dichloro-1,3,5-triazin-2-yl)azepane (0.77 mmol) in CH3CN/H2O (1/1, 20 ml) was added cis-4-amino-cyclohexanecarboxylic acid (110 mg, 0.77 mmol, 1 equivalent), followed by 1N NaOH (1.54 ml, 1.54 mmol, 2 equivalents). The reaction mixture was stirred at room temperature 5-6 hrs. The crude product was used in the next step.