Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][CH:20]=[CH2:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCC1=C(C)[C@H](O)CC1=O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C=CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Yield: 96.9 %

Procedure:
Into a mixed solution of 5.5 g of fuming nitric acid and 22 g of acetic anhydride, kept at a temperature of -5° to 10° C., was added dropwise 4 g of (R)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one ([α]D25 : -14.9° (C=1.19, in chloroform), (R)-isomer/(S)-isomer=99.2/0.8). Thereafter, with the same operations as in Example 1, 5.02 g of crude (R)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one was obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@:7]23[CH2:15][O:14][C@@H:13]([CH3:16])[CH2:12][C@H:11]2[CH2:10][O:9][NH:8]3)[S:5][CH:6]=1.[BH4-].[Na+]>C(#N)C.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[NH2:8][C@@:7]1([C:4]2[S:5][CH:6]=[C:2]([Br:1])[N:3]=2)[CH2:15][O:14][C@@H:13]([CH3:16])[CH2:12][C@H:11]1[CH2:10][OH:9]
Reactant: C[C@H]1C[C@H]2CON[C@@]2(c2nc(Br)cs2)CO1
Agent: [Mo]
Agent: [BH4-]
Agent: [C-]#[O+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1C[C@@H](CO)[C@](N)(c2nc(Br)cs2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Molybdenum hexacarbonyl (98%, 6.67 g, 24.8 mmol) was added to a solution of C3 (15.12 g, 49.54 mmol) in a mixture of acetonitrile (390 mL) and water (20 mL), and the reaction mixture was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was chilled in an ice bath, treated portion-wise with sodium borohydride (7.50 g, 198 mmol), and allowed to stir at 0° C. for 1 hour. The mixture was then filtered through a pad of diatomaceous earth, and the pad was washed three times with dichloromethane; the organic portion of the combined filtrate and washes was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Methanol was added to the residue, then removed via concentration under reduced pressure. This methanol treatment was repeated, and the resulting residue was dissolved in dichloromethane, washed twice with 1 M aqueous sodium hydroxide solution, washed once with saturated aqueous sodium chloride solution and concentrated in vacuo, affording the product as a brown solid. Yield: 14.48 g, 47.13 mmol, 95%. LCMS m/z 307.0, 309.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 3.79 (d, half of AB quartet, J=11.5 Hz, 1H), 3.64-3.75 (m, 3H), 3.54 (dd, half of ABX pattern, J=11.5, 4.1 Hz, 1H), 2.46-2.54 (m, 1H), 1.82-1.94 (m, 1H), 1.67-1.74 (m, 1H), 1.32 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:6])[CH3:5])[CH3:2].[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15](Cl)[N:14]=[C:13]2[OH:19]>>[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:6])[CH3:5])[N:14]=[C:13]2[OH:19]
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Reactant: CCNC(C)C
Product: CCN(c1nc(O)c2cccc(Br)c2n1)C(C)C
Temperature: 170 °C
Yield: 97.1 %

Procedure:
A slurry of N-ethylisopropylamine (1.40 mL, 11.56 mmol) and 8-bromo-2-chloroquinazolin-4-ol (407c; 0.10 g, 0.385 mmol) was sealed in a microwave tube and heated to 170° C. for 30 min. The reaction was judged complete and clean. The reaction was partitioned between satd aq ammonium chloride and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(ethyl(isopropyl)amino)quinazolin-4-ol (0.116 g, 0.374 mmol, 97% yield) as a brown semi-solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (2H, m), 6.96 (1H, t, J=7.7 Hz), 4.81 (1H, dt, J=13.4, 6.7 Hz), 3.51 (2H, q, J=7.0 Hz), 1.13-1.24 (9H, m). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N+:3]=1[O-].[CH3:16][C:17]([O:19]C(C)=O)=[O:18]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]([O:19][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1)(=[O:18])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC(F)(F)F)cc[n+]([O-])c1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1nccc(OCC(F)(F)F)c1C
Temperature: 92.5 °C
Yield: 94 %

Procedure:
40 ml of 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-oxide (0.078 mole) in methylene chloride were dropwise added to a solution of 28.7 ml acetanhydride and 0.182 g 4-dimethylaminopyridine, then methylene chloride was distilled off and the residue was heated to a temperature of from 90 to 95° C. for 4-5 hours. At the end of the reaction, 3.6 ml of water were added and acetic acid was removed by vacuum distillation to obtain an oil product. The yield was 94-96%, determined by HPLC.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.C[Al](C)C.C[Al](C)C.C1N2CC[N:38]([CH2:39]C2)[CH2:37]1.CNC>O1CCCC1.[Cl-].[Na+].O>[CH2:21]([N:18]1[CH2:17][CH2:16][N:15]([C:14]2[C:8]3[O:7][C:6]([C:4]([N:38]([CH3:39])[CH3:37])=[O:3])=[CH:10][C:9]=3[CH:11]=[CH:12][CH:13]=2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1
Reactant: C1CN2CCN1CC2
Agent: CNC
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1
Temperature: 120 °C
Yield: 87.7 %

Procedure:
7-(4-Benzyl-piperazin-1-yl)-benzofuran-2-carboxylic acid ethyl ester (1.0 g, 2.74 mmol) and DABAL-Me3 (0.56 g, 2.20 mmol) were mixed in tetrahydrofuran (5 mL). Dimethylamine (2M in THF) (2.2 mL, 4.39 mmol) was added and the mixture was heated by microwave irradiation to 120° C. for 15 min. Brine was added and the mixture was extracted with dichloromethane, dried over Na2SO4, filtered and the solvent removed by rotary evaporation. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-2%) giving 7-(4-benzylpiperazin-1-yl)-N,N-dimethylbenzofuran-2-carboxamide (0.70 g, 1.93 mmol) in 70% yield.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]([O:15][CH2:16][CH:17]=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COCCOC>[Cu].[Zn].C(OCC)C>[CH2:8]([O:15][CH2:16][CH:17]1[CH2:18][C:3](=[O:4])[C:2]1([Cl:7])[Cl:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCOCc1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: O=C1CC(COCc2ccccc2)C1(Cl)Cl

Procedure:
Trichloroacetyl chloride (108 ml, 0.96 mol) was added slowly to a stirred suspension of freshly activated zinc-copper couple (56 g), allyl benzyl ether (50 ml, 0.32 mol), dry 1,2-dimethoxyethane (95 ml) and dry diethyl ether (550 ml) in a 2 L three-neck flask under argon. The reactants were heated under gentle reflux for 3d. The products were then filtered and the residue was washed with ether. The combined filtrate and washings were concentrated under reduced pressure. Light petroleum ether was added and the mixture was stirred vigorously. The supernatant was decanted and more light petroleum ether was added. After vigorous stirring the supernatant was again decanted and mixed with the original supernatant. The resulting solution was washed with saturated NaHCO3 twice and brine once. The organic phase was dried over MgSO4 and the solvent was evaporated to give a light yellow oil which was used directly in the next step. 1H NMR (CDCl3, 300 MHz): δ 3.10-3.25 (m, 2H), 3.36-3.57 (m, 1H), 3.65-3.75 (m, 1H), 3.83-3.88 (m, 1H), 4.57 (s, 2H), 7.27-7.40 (m, 5H).
Reaction SMILES: N1CCC(CO)CC1.C([O:11][C:12](=[O:45])[C@:13]([NH:37]C(OC(C)(C)C)=O)([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]1)[CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:22]C(C)(C)C(C)(C)[O:19]1)C.[ClH:46]>O>[ClH:46].[ClH:46].[NH2:37][C:13]([CH2:27][CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([CH2:35][OH:36])[CH2:33][CH2:34]1)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:22])[OH:19])[C:12]([OH:45])=[O:11]
Reactant: CCOC(=O)[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCC(CO)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: OCC1CCNCC1
Solvent: O
Product: NC(CCCCB(O)O)(CCN1CCC(CO)CC1)C(=O)O
Temperature: 25 °C
Yield: 53 %

Procedure:
(2-Amino-6-borono-2-[2-(4-hyrdoxymethylpiperidin-1-yl)-ethyl]-hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 16, except piperidin-4-ylmethanol is used as the amine in step 6. The final step is as follows: a solution of (R)-2-tert-butoxycarbonylamino-2-[2-(4-hydroxymethyl-piperidin-1-yl)-ethyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (78 mg) in 6 N hydrochloric acid (5 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give the title compound as a colorless foam (20 mg, 53%); 1H NMR (D2O, 300 MHz) δ 3.48 (m, 2H), 3.33 (d, J=6 Hz, 2H), 3.21 (m, 1H), 3.04 (m, 1H), 2.86 (m, 2H), 2.19 (2H, t, J=8.5 Hz), 1.86 (m, 2H), 1.60-1.78 (m, 3H), 1.20-1.36 (m, 5H), 1.09 (m, 1H) and 0.64 (t, J=7.5 Hz, 2H,); MS (+CI): m/z for C12H25BN2O4: expected 272.2. found 273.2 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.C([N:22](CC)CC)C>ClCCl>[NH2:22][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (9.56 mL, 124 mmol) was added dropwise over 10 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate (20.7 g, 103 mmol) and triethylamine (21.5 mL, 154 mmol) in dichloromethane (300 mL) at 0° C. After stirring for 3 hour at 0° C., the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20:80 to 50:50), to give the title compound as an oil.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N+:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][C:28]([C:26]2[N:27]=[C:23]([N:21]3[CH2:22][CH:19]([OH:18])[CH2:20]3)[S:24][CH:25]=2)=[O:29])=[CH:33][CH:34]=1)([O-:40])=[O:39]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CC(O)C2)n1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)azetidine (93 mg, 0.16 mmol) (obtained as described in Reference Example 2(5)) in anhydrous tetrahydrofuran (4.7 ml) were added acetic acid (0.028 ml, 0.49 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (0.48 ml, 0.48 mmol) in an ice bath. The mixture was stirred for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (42.4 mg, yield 81%) as a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:47])([F:48])[F:49])[CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccc([N+](=O)[O-])cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (332 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200–400 mesh, 90/10 hexane s/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as an off-white solid: mp 109–110° C.; EI-HRMS m/e calcd for C21H22F3N3O3S (M+) 453.1334, found 453.1334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12].C[Li].[CH3:26]COCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH3:26])=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]
Reactant: CCOCC
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C=O)ccc2Cl)cc1OC
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(C)O)ccc2Cl)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N-(2-chloro-5-formyl-phenyl)-3,4-dimethoxy-benzenesulfonamide (1.77 g, 5 mmol) in THF (20 mL) at −78° C. was added dropwise a solution of methyl lithium in ether (1.6 M, 8.6 mL, 2.75 eq). The mixture was stirred at −78° C. for 30 min and then allowed to warm to RT. The mixture was partitioned between EA and NH4Cl solution, the aqueous phase was once more extracted with EA and the combined organic layers were dried over MgSO4 and concentrated. The residue was dried under hv to give the desired product (1.8 g, 100%) as a yellowish oil.
Reaction SMILES: [O:1]([CH:8]([P:13](=[O:16])([OH:15])[OH:14])[P:9](=[O:12])([OH:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:18]>O>[O:1]([CH:8]([P:13](=[O:14])([O-:15])[O-:16])[P:9](=[O:10])([OH:11])[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:18].[Na+:18]
Reactant: O=P(O)(O)C(Oc1ccccc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])C(Oc1ccccc1)P(=O)(O)O

Procedure:
A solution of (phenoxymethylene)-bisphosphonic acid (53 g) in water (300 ml) was titrated with 2N sodium hydroxide to pH=5.5. The title compound was precipitated by the addition of acetone (1500 ml). The crystalline salt was filtered and washed with acetone. Drying in vacuo over potassium hydroxide at room temperature gave the title compound in the form of a tetrahydrate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)COc1ccccc1
Solvent: ClCCl
Product: CC(C)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: -45 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a stirring solution of isobutoxybenzene (0.60 g, 4.0 mmol) in dichloromethane (5 mL) at −45° C. was added chlorosulfonic acid (0.6 mL, 9.1 mmol) dropwise, and the reaction mixture was stirred at −45° C. for 1 h. The reaction mixture was then warmed to 0° C. and additional chlorosulfonic acid (0.6 mL, 9.1 mmol) was added dropwise. The reaction mixture was then stirred at 0° C. for 1 h and poured into ice. The aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to give 4-isobutoxybenzene-1-sulfonyl chloride (0.32 g, 1.1 mmol, 28%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:11][S:12]([O:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([CH3:10])([CH3:9])[CH3:1])(=[O:14])=[O:13]
Reactant: CC(C)(C)C#CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg of the resulting alcohol compound was dissolved in 1 ml of ethyl acetate, and 60 μl of methanesulfonyl chloride and 200 μl of triethylamine were added. The mixture was stirred at room temperature for 1 hour, and then the precipitate of triethylamine hydrochloride was removed by filtration. The filtrate was diluted with ethyl acetate, and washed succesively with a saturated aqueous solution of sodium bicarbonate, 1N hydrochloric acid and a saturated aqueous slution of sodium chloride, then worked up in a customary manner to give 150 mg of the captioned compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[OH:19][CH2:20][C:21]([NH2:23])=[O:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:23][C:21](=[O:22])[CH2:20][OH:19])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: NC(=O)CO
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(CO)Nc1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Yield: 26.6 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 2-hydroxyacetamide (0.017 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (16 mg, 27% yield). 1H NMR (DMSO-d6, 500 MHz): δ 8.48 (d, J=7.0 Hz, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.75-7.65 (m, 3H), 5.75 (t, J=7.0 Hz, 1H), 4.16 (d, J=7.0 Hz, 2H). LCMS (Method B): RT=4.73 min, m/z: 354.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(O)(=O)C.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C)c(N)c(C(=O)O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(C)c(N)c(C(=O)O)c3)cc12
Reaction time: 3 h
Yield: 57.8 %

Procedure:
551 mg (1.09 mmol) of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzoic acid was dissolved in 10 mL of glacial acetic acid. 500 μL of 70% perchloric acid was added and the mixture left at ambient temperature for 3 h. The resulting solution was diluted with 100 mL of water and the resulting precipitate filtered off and dried by suction to afford 234 mg (0.63 mmol, 57%) of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzoic acid as an orange-red solid. MS: m/z 375.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH:18]([OH:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccccc3Cl)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccccc3Cl)c21
Reaction time: 1.5 h

Procedure:
To a cooled suspension of 9-(2-chlorobenzylamino)-3,4-dihydroacridin-1(2H)-one (4.0 g) in 75 ml of tetrahydrofuran was added 6.5 ml of 1M solution of lithium aluminum hydride in THF. This was stirred at ice bath temperature for 1.5 hours.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([O:73][CH2:74][CH:75]3[CH2:77][CH2:76]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:78].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:75]1([CH2:74][O:73][C:70]2[N:69]=[CH:68][C:67]([C:57]3[C:56]([CH3:78])=[C:55]([NH:47][C:46]4[C:41]([N:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[N:42][CH:43]=[C:44]([N:48]5[CH2:49][CH2:50][O:51][CH2:52][CH2:53]5)[CH:45]=4)[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=3)=[CH:72][CH:71]=2)[CH2:76][CH2:77]1
Reactant: Cc1c(-c2ccc(OCC3CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(OCC3CC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 2,5-dimorpholinopyridin-3-amine (0.088 g, 0.33 mmol), 4-chloro-2-(6-(cyclopropylmethoxy)pyridin-3-yl)-5,7-difluoro-3-methylquinoline (0.1 g, 0.28 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.067 g, 0.70 mmol) in toluene (2.8 mL) at 100° C. for 1.6 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 2-(6-(cyclopropylmethoxy)-pyridin-3-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (1H, d, J=1.8 Hz), 8.00 (1H, dd, J=8.5, 2.4 Hz), 7.77 (1H, d, J=4.9 Hz), 7.63 (1H, dd, J=10.0, 1.6 Hz), 7.55 (1H, d, J=2.7 Hz), 7.41-7.49 (1H, m), 6.98 (1H, d, J=8.6 Hz), 6.43 (1H, d, J=2.7 Hz), 5.75 (1H, s), 4.18 (2H, d, J=7.2 Hz), 3.57-3.84 (8H, m), 3.15 (2H, br. s.), 2.99 (4H, m), 2.83 (2H, br. s.), 2.09 (3H, s), 1.23-1.34 (1H, m), 0.54-0.62 (2H, m), 0.33-0.41 (2H, m). Mass Spectrum (ESI) m/e=589.3 (M+1).