Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=3[O:32][CH2:33][O:34][CH3:35])(O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:4]([Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=3[O:32][CH2:33][O:34][CH3:35])=[CH:17][CH2:16]2)=[CH:13][CH:14]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1ccc(C2=CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: 25 °C

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-[2,4-bis(methoxymethoxy) phenyl]cyclohexanol (125 mg, 0.25 mmol), toluene (10 ml) and p-toluene sulfonic acid monohydrate (3 crystals). The reaction mixture was heated to reflux temperature for 30 min, then cooled to room temperature before adding saturated aqueous sodium bicarbonate (5 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The title compound was isolated without further purification as an oil (118 mg, 98%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (9H, s), 1.84 (1H, m), 2.00 (1H, m), 2.27 (1H, m), 2.44 (2H, m), 2.56 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 5.15 (2×2H, s), 5.79 (1H, m), 6.67 (1H, dd), 6.77 (2H, d), 6.78 (1H, d), 7.07 (2H, d), 7.11 (1H, d).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH3:37])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([OH:15])=[C:7]([C:16]3[NH:21][C:20]4[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=4[S:18](=[O:35])(=[O:34])[N:17]=3)[C:6]2=[O:36])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CC3CC3)C1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 164D (0.100 g, 0.1912 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (4 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the bicarb layer extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification.
Reaction SMILES: CC([C:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[C:25]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)=[C:6]([CH3:10])[C:7]([O-:9])=[O:8])(C)C.C(O)(C(F)(F)F)=O>>[C:25]1(=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:14]2[CH:15]=[CH:16][C:11](/[CH:5]=[C:6](\[CH3:10])/[C:7]([OH:9])=[O:8])=[CH:12][CH:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C(=O)[O-])=C(c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 92.4 %

Procedure:
The general hydrolysis procedure described for 195 was followed. (1,1-dimethylethyl (2E/2Z)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}-2-methyl-2-propenoate (214) (0.200 g, 0.46 mmol) was treated with TFA to afford 0.160 g (92%) of the title compound 215 as a mixture of E and Z (˜65:35) isomers. The pure E isomer was isolated by HPLC to afford the title compound 214 as a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9].[CH3:12][O:13][CH:14]([O:19][CH3:20])[C:15](OC)=[O:16].CCN(C(C)C)C(C)C>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH:9][C:15](=[O:16])[CH:14]([O:19][CH3:20])[O:13][CH3:12]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cc(Br)ccc1F
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)C(=O)NCc1cc(Br)ccc1F
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-2-fluorobenzylamine hydrochloride (15.0 g, 62 mmol), methyl dimethoxyacetate (10.0 g, 75 mmol), and DIPEA (10.3 mL, 62 mmol) in methanol (15 mL) was heated at 60° C. for 16 h in a bomb apparatus. After cooling to RT, the solvent was evaporated and DCM (150 mL) was added. The solution was washed with water (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. It was purified by column chromatography on silica gel using EtOAc/Hexanes (1:1) to give the title compound. 1H NMR (CDCl3, 300 MHz) δ=3.42 (s, 6H), 4.53 (d, J=4.8 Hz, 2H), 4.81 (s, 1H), 6.96 (t, J=6.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.51-7.54 (m, 1H). MS(ES+): m/z=305.73/307.69 [MH+]. HPLC: tR=2.89 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH3:17]
Reactant: Cc1cccc(CO)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of 3-methylbenzyl alcohol (1.08 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.91 g of the product 396. 1H NMR (CDCl3) δ 7.3-7.1 (m, 4H), 4.60 (s, 2H), 4.23 (q, 2H), 4.09 (s, 2H), 2.36 (s, 3H), 1.29 (t, 311); MS: m/z 209 (M++1).
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].Cl.[NH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:34][CH3:35])=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.C(N(CC)CC)C>ClCCl>[CH3:33][S:30]([NH:29][C:27]1[CH:28]=[C:23]([CH2:22][CH2:21][NH:20][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:1])[CH:24]=[CH:25][C:26]=1[O:34][CH3:35])(=[O:32])=[O:31]
Reactant: COc1ccc(CCN)cc1NS(C)(=O)=O
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCCCC(=O)NCCc2ccccc2)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N'-carbonyldiimidazole (3.25 g, 0.02 moles) was added in portions under nitrogen to a suspension of 6-oxo-6-(2-phenylethylamino)hexanoic acid (4.98 g, 0.02 moles) in dry dichloromethane (100 ml). The mixture was stirred for 30 mins, the product from step (b) (5.6 g, 0.02 moles) and triethylamine (2.8 ml, 2.02 g, 0.02 moles) were added, and stirring continued for a further 4 hr. The precipitate was collected and the filtrate washed with dilute hydrochloric acid and aqueous sodium bicarbonate solution and evaporated. The residue and the original precipitate were combined and recrystallised from methanol giving the sub-title compound (6.6 g) as white needles mp 193°-195°.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C@@H:4]([C:6]([NH:8][C@@H:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1)=[O:7])[NH2:5].F[C:33](F)(F)[C:34]1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=C[CH:39]=1.C(=O)C(C)(C)C>CC(C)=O>[CH:34]([NH:5][C@H:4]([C:6]([NH:8][C@@H:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1)=[O:7])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])([CH3:39])[CH3:33]
Reactant: CC(C)(C)C[C@H](N)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Agent: CC(C)(C)C=O
Solvent: CC(C)=O
Product: CC(C)N[C@@H](CC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 4-methyl-N1-(3aR,4S,6aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide from Example 419 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and acetone for pivalaldehyde in the procedure described in Example 281: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26-8.29 (m, 1H), 8.13-8.16 (m, 2H), 7.89-7.91 (m, 2H), 4.21-4.26 (m, 1H), 3.85 (dd, J=9.9, 2.3 Hz, 1H), 3.36 (dd, J=7.5, 4.1 Hz, 1H), 3.15-3.20 (m, 2H), 2.98 (dd, J=9.6, 6.7 Hz, 1H), 2.83 (hept, J=6.2 Hz, 1H), 2.51-2.62 (m, 2H), 1.91-1.97 (m, 1H), 1.79-1.88 (m, 2H), 1.63-1.81 (m, 1H), 1.51-1.59 (m, 1H), 1.47 (dd, J=14.1, 7.5 Hz, 1H), 1.31 (ddt, J=9.6, 12.8, 6.4 Hz, 1H), 1.03 (dd, J=6.2, 2.7 Hz, 6H), 0.98 (s, 9H); MS (ESI+) m/z 504 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24]([NH:1][C:2]1[N:7]=[C:6]([N:8]([CH3:9])[CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)=[O:25])(=[O:22])=[O:21]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(N(C)C)nc(N)n1
Solvent: CC#N
Product: COc1cc(N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 700 ml of acetonitrile containing 25 g of 2-amino-4-dimethylamino-6-methoxypyrimidine at ambient temperature was added, dropwise, 32.5 g of 2-chlorobenzenesulfonylisocyanate. The mixture was warmed to 40° and then allowed to stir for five hours at ambient temperature. The solid product named above was isolated by filtration and washed with a small amount of cold ethyl ether. It melted at 224°-226°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[CH3:23]N(C=O)C>>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[N:15]([CH3:23])[C:16](=[O:21])[C:17]([F:19])([F:18])[F:20]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(C)C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred suspension of NaH (112 mg, 2.80 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. was added 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester (750 mg, 2.55 mmol) portion wise. The resulting mixture was stirred for 1 h, then Mel (175 mL, 2.80 mmol) was added and the progress of the reaction was followed by LCMS. Upon consumption of 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester, the reaction mixture was quenched with aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoic acid methyl ester. MS m/z: 275.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OCC)(=O)C.CO>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C=CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Yield: 88.6 %

Procedure:
1.58 g (6.96 mmol) of N-(3-acetyl-phenyl)-N-methyl-methanesulfonamide were dissolved in 15 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.12 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl methanesulfonamide as a yellowish-white solid were obtained (yield 88.6%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:2]=[CH2:3].[Cu](C#N)[C:27]#[N:28]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5](=[O:25])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:2]=[CH2:3]
Reactant: N#C[Cu]C#N
Reactant: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a solution of the compound prepared in Example 3 (2.00 g) in DMF (40 ml), copper cyanide (520 mg) was added. The mixture was vigorously stirred for 3 hours at 50° C. The reaction mixture was cooled, and diluted with ethyl acetate and water. The solution was filtered, the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.12 g) having the following physical data.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[CH:16]([N:9]1[C:10]2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=[CH:8]1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Yield: 69.8 %

Procedure:
To a stirred solution of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (320 mg, 1.29 mmol) in THF (2 mL) was added LiOH.H2O (160 mg, 3.88 mmol) in water (2 mL) at room temperature and heated at reflux for 2 h. The THF was removed under reduced pressure and the resulting aqueous layer was acidified with 1 N HCl (pH ˜6) and extracted with ethyl acetate (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (210 mg). 1H NMR (400 MHz, DMSO-d6): δ 1.42 (d, 6H), 3.88 (s, 3H), 4.85 (m, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.26 (s, 2H), 7.45 (s, 1H), 12.68 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O.ClCCl>C(O)(=O)C>[C:10]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH3:9])=[CH:4][C:5]=1[OH:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(O)c(C(C)(C)C)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
The starting compound 2-tert-butyl-4-chloro-5-methyl-phenol was prepared by t-butylation in the following manner: 4-chloro-3-methyl-phenol (10.0 g, 70 mmol) was dissolved in glacial acetic acid (30 mL) at ambient temperature. tert-Butanol (10.1 mL, 1.5 equivalents) was added, and subsequently 95% sulfuric acid (3.75 mL, 1 equiv.). The reaction vessel was closed with a drying tube and heated at 50° C. After 1 d, additional amounts of tert-butanol (5 mL) and sulfuric acid (1.8 mL) were added and heating was continued. After 3 d, dichlormethane (150 mL) was added, and the solution was washed three times with saturated aqueous sodium chloride (150 mL). Drying and evaporation of the solution provided 14.9 g of a pale yellow oil. Pure 2-tert-butyl-4-chloro-5-methyl-phenol was obtained by flash chromatography (silica/toluene-heptane 7:3) as a colourless oil, 1H NMR (CDCl3): δ 7.19 (s, 1H), 6.52 (s, 1H), 4.70 (s, 1H), 2.26 (s, 3H), 1.37 (s, 9H); TLC (silica/toluene-heptane 7:3) Rf=0.45.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[C:13]([NH2:14])=[N:12][NH:11][C:10]=3[C:5]2=[C:4]([CH3:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:14][C:13]2[C:9]3[S:8][C:6]4[C:5]([C:10]=3[NH:11][N:12]=2)=[C:4]([CH3:15])[CH:3]=[C:2]([CH3:1])[N:7]=4)=[CH:20][CH:19]=1
Reactant: Cc1cc(C)c2c(n1)sc1c(N)n[nH]c12
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNc2n[nH]c3c2sc2nc(C)cc(C)c23)cc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
The 6,8-dimethyl-1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridin-3-amine (70 mg, 0.32 mmol) was stirred in DCE (3.2 mL). To this solution was added 4-methoxybenzaldehyde (0.12 mL, 0.96 mmol), acetic acid (0.040 mL, 0.64 mmol) and NaBH(AcO)3 (140 mg, 0.64 mmol). The resulting slurry was stirred for 1 hr, LC\MS indicates the reaction is nearly complete. The reaction was stirred another hour, then diluted with DCM (15 mL) and treated with aqueous 1N NaOH (12 mL). The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated under vacuum to give 180 mg of crude residue. The residue was purified by reverse-phase HPLC to give 80 mg of the pure product as a yellow TFA salt. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.30 (d, J=8.6 Hz, 2H), 7.11 (s, 1H), 6.85 (2H, J=8.6 Hz, 2H), 5.74 (s, 1H), 4.32 (s, 2H), 3.70 (s, 3H), 2.62 (s, 3H), 2.50 (s, 3H). LC/MS: RT=0.63 min., m/z=339.0 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:39])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of acryloyl chloride (26 mg, 0.29 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 132, 120 mg, 0.26 mmol) in THF (3 mL), which was cooled in an ice/methanol bath to approx −15° C. The mixture was stirred for 1 h, gradually warming to 0° C. The mixture was then diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL). The resulting aqueous wash solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were then dried (MgSO4) and concentrated in vacuo onto silica. Part-purification was achieved by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 and impure product containing fractions were combined and concentrated in vacuo. Purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 and then eluting with 0-3% CH3OH in CH2Cl2 gave the title compound (19 mg, 14%) as a cream foam; 1H NMR (CDCl3): 1.82-1.97 (4H, m), 2.00-2.06 (2H, m), 2.13-2.24 (1H, s), 2.25-2.39 (1H, m), 2.29 (3H, s), 2.67-2.98 (4H, m), 3.17-3.26 (3H, m), 3.66 (1H, br s), 3.86 (3H, s), 4.18 (2H, t), 5.64-5.71 (1H, m), 6.30-6.47 (2H, m), 6.78 (1H, s), 6.81 (1H, d), 7.44 (1H, s), 8.06 (1H, s), 8.34 (1H, d), 9.24 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 515.15.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>C(O)CCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)cc1Cl
Reactant: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Solvent: CCCCO
Product: COc1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of compound, 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol (3.97 g, 13.7 mmol), 3-chloro-4-methoxyaniline (2.13 g, 13.7 mmol) in 1-butanol (30 mL) was stirred at 120° C. for 12 hours. The mixture was then cooled to temperature in the range of 20-40° C. The solid precipitated was filtered, collected, stirred in isopropanol (10 mL), filtered, and dried to give the desired compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[CH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19](Cl)([Cl:23])[C:20](Cl)=O.P(Cl)(Cl)(Cl)=[O:26]>CCOCC.[Cu].[Zn]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([C:19]([Cl:23])([Cl:18])[CH2:20][C:17]2=[O:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)CC2(Cl)Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 1-benzyloxycarbonyl-4-methylenepiperidine (11.1 g, 49.3 mmol) and zinc-copper couple (95: 5, 7.98 g, 12.2 mmol) in 200 ml of anhydrous ether was added a solution of trichloroacetyl chloride (10.18 ml, 91.2 mmol) and phosphorous oxychloride (8.77 ml, 94.0 mmol) in 50 ml of anhydrous ether. The reaction mixture was refluxed overnight. After cooling to room temperature, the solution was filtered through celite and the filtrate was washed with brine and cold sodium bicarbonate, dried over magnesium sulfate and upon evaporation afforded the title compound as a yellow liquid, 15.3 g (crude).