Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10](C2CCC(CC(OCC)=O)CC2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC#N)C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C([CH:90]2[CH2:95][CH2:94][CH:93]([CH2:96][C:97]([O:99][CH2:100][CH3:101])=[O:98])[CH2:92][CH2:91]2)C=1>>[CH3:1][Si:2]([CH3:38])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:95]2[CH2:90][CH2:91][CH2:92][CH:93]([CH2:96][C:97]([O:99][CH2:100][CH3:101])=[O:98])[CH2:94]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2ccnn12
Product: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(Oc2ccccc2OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1Oc1cccc(C(=O)O)c1C(=O)O
Yield: 76.6 %

Procedure:
A mixture of 3-(2-methoxy-phenoxy)-phthalic acid dimethyl ester (0.75 g, 2.4 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 2 h. The mixture was cooled and the solvent was removed under vacuum. The residue was dissolved in water (100 mL) and washed with CH2Cl2 (2×100 mL), acidified (HCl), and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.53 g of 3-(2-methoxy-phenoxy)-phthalic acid, in 78% yield; 1H NMR (DMSO-d6) δ 3.76 (s, 3H), 6.82 (dd, J=8.4 Hz, J=0.9 Hz, 1H), 6.95-6.98 (m, 2H), 7.16-7.23 (m, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O.C(Cl)Cl>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[O:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:19][CH2:18]3)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: O=C(O)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Reactant: CC(=O)c1cccc(N)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CCC(COCc2ccccc2)O3)c1O
Temperature: 75 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A suspension of 2-(benzyloxymethyl)-6-chromanecarboxylic acid (0.700 g, 2.35 mmol) in oxalyl chloride (5.98 ml) was heated at 75° C. for 35 minutes. The oxalyl chloride excess was evaporated off in a nitrogen stream and the resulting residue was dissolved in the minimum amount of dry methylene chloride. This solution was added at 0° C. and under inert atmosphere to a solution of 3-amino-2-hydroxyacetophenone (0.550 g, 2.37 mmol), pyridine (7 ml) and dry methylene chloride (40 ml). The resulting mixture was left under stirring at room temperature for 18 h, then diluted with methylene chloride (40 ml), washed successively with 1M HCl and a sodium chloride saturated solution, dried and the solvent was evaporated off under reduced pressure. A crude was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform mixtures of increasing polarity. At a 40% chloroform proportion, 0.732 g of the title compound were eluted (72% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:24])[CH:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(Cc2c(Cl)cccc2Cl)CC1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCCCCC
Solvent: CCO
Product: C[C@@H]1CN(Cc2c(Cl)cccc2Cl)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 4-[(3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5a (2.04 g, 3.49 mmol) was optically resolved repeatedly by HPLC (CHIRALPAK IA (3 cm diameter×25 cm), elution solvent: hexane/ethanol=94/6, flow rate: 22 ml/min.) to give the title compound (a chiral form corresponding to the peak with a shorter retention time) (859 mg, 42.1%) and the optical isomer (a chiral form corresponding to the peak with a longer retention time) (817 mg, 40%), respectively.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[K+].Cl>CS(C)=O.O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cccc(Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.8 %

Procedure:
6-Chloropyridine-2-carboxylic acid (1.00 g, 6.347 mmol), 2,2,2-trifluoroethan-1-ol (0.683 mL, 9.520 mmol) and potassium hydroxide (1.424 g, 25.387 mmol) were dissolved in DMSO (25 mL) and heated at 100 C for 18 h. The reaction mixture was re-treated with potassium hydroxide (0.356 g, 6.347 mmol) and heated at 100 C for 18 h. The reaction mixture was then re-treated with 2,2,2-trifluoroethan-1-ol (1.367 mL, 19.040 mmol) and potassium hydroxide (0.356 g, 6.347 mmol) and heated at 110 C for 18 h. The reaction mixture was then further re-treated with potassium hydroxide (0.356 g, 6.347 mmol) and 2,2,2-trifluoroethan-1-ol (0.683 mL, 9.520 mmol) and the mixture was stirred at room temperature for 72 h. Water (10 mL) was added and acidified to pH 1 with 1M hydrochloric acid. The aqueous was extracted with EtOAc (3×15 mL) and the organic layer was washed with brine (15 mL). This was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown gum. The crude material was purified by FCC (DCM: MeOH, 90:10) to afford the title compound as a yellow solid (1.26 g, 90%). Method B HPLC-MS: MH+ requires m/z=222 Found: m/z=222, Rt=1.71 min (79%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:43])[C:31]4[C:36]([C:37]=3[C:38]3[S:42][CH:41]=[N:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][Si](C(C)(C)C)(C)C)[CH:12]=3)[C:3]=12>Cl.CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:43])[C:31]4[C:36]([C:37]=3[C:38]3[S:42][CH:41]=[N:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one single enantiomer (intermediate R.3, second eluted enantiomer under the conditions described above, 0.089 g, 0.14 mmol) was dissolved in a solution of 1M HCl in EtOH (0.5 ml) and the mixture was stirred at RT overnight. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford title compound as a pale blue solid (0.048 g, 0.096 mmol, 74%). This compound proved to be the second eluted enantiomer under Chiral HPLC conditions of Method A7: Rt=20.1 min, ee=98.4%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:30])([CH3:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2([C:17]3[CH:18]=[C:19]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:21][CH:22]=3)SCCCS2)[CH:8]=[CH:9][CH:10]=1.CC(C)=[O:33]>CN(C=O)C.[Cu]=O.[Cu](Cl)Cl>[OH:1][CH2:2][C:3]([CH3:30])([CH3:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:18]=2)=[O:33])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(CO)Cc1cccc(C2(c3cccc(CC(C)(C)CO)c3)SCCCS2)c1
Reactant: CC(C)=O
Agent: Cl[Cu]Cl
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CC(C)(CO)Cc1cccc(C(=O)c2cccc(CC(C)(C)CO)c2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A suspension of copper(II) oxide (0.96 g, 12.1 mmol) and anhydrous copper(II) chloride (3.2 g, 23.8 mmol) in acetone (80 mL) was heated to reflux. A solution of 230 (4.44 g, 10.0 mmol) in acetone (20 mL) and DMF (1.2 mL) was added dropwise over 5 min. After 90 min at reflux temperature, the reaction mixture was cooled to room temperature and filtered. The insoluble material was washed with CH2Cl2 (3×20 mL). The combined organic solutions were washed with aqueous 2 N Na2CO3 solution (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; hexanes/acetone=80/20) to give 232 (2.5 g, 71%) as an oil. 1H NMR (CDCl3): δ 7.68-7.30 (m, 8H), 3.31 (s, 4H), 3.03 (s br., 2H), 2.65 (s, 4H), 0.88 (s, 12H). 13C NMR (CDCl3=77.00 ppm): δ 197.42, 139.06, 136.96, 134.60, 131.88, 127.78, 127.55, 70.39, 44.07, 36.30, 23.80. HRMS (LSIMS, nba): Calcd for C23H31O3 (MH+): 355.2273, found: 355.2263. HPLC: 94.5% pure.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:15]O>>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Br

Procedure:
100 g (406 mmol) of 2-bromo-3-nitrobenzoic acid, 22 g (609 mmol) of conc. HCl and 1 l of methanol are heated under reflux for 24 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is recrystallised from ethanol. Yield: 94.6 g (363 mmol), 89.5% of theory.
Reaction SMILES: CNC.[CH3:4][C:5](=[O:10])[CH2:6][C:7](=[O:9])[CH3:8].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:6]([C:5](=[O:10])[CH3:4])[C:7](=[O:9])[CH3:8])=[CH:15][CH:16]=1
Reactant: Oc1ccc(CCl)cc1
Reactant: CC(=O)CC(C)=O
Agent: CNC
Agent: Cl
Solvent: O
Product: CC(=O)C(Cc1ccc(O)cc1)C(C)=O
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of p-chloromethyl phenol in acetonitrile (Example 12) was reacted with equimolar dimethyl amine and equimolar 2,4-pentanedione by stirring together for 1 hour. The reactive mixture was diluted with water, acidified with hydrochloric acid, extracted with ether, and then the ether extract was dried with sodium sulfate. The residual oil was triturated with benzene to yield 78% of 3(4' hydroxybenzyl)-2,4-pentanedione, M.P. 93°-94.5° C. Infrared and nuclear magnetic resonance spectra confirmed the identity of the product.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:29])[C:7]([CH3:28])([CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:25][OH:26])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C>O.C(O)C>[OH:26][CH2:25][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:28])([CH3:27])[C:6]([OH:29])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(CO)CCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(CO)CCCCC(C)(C)C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a homogeneous solution of potassium hydroxide (1.18 g, 21 mmol) in water (1.12 mL) and ethanol (3.8 mL) was added 7-hydroxymethyl-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (2.9 g, 7.5 mmol) and the reaction mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo, cooled to room temperature, and the residue was extracted with diethyl ether (2×50 mL). The pH of the aqueous layer was adjusted to 1 by addition of hydrochloric acid. The product was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the crude product which was purified by column chromatography on silica (hexanes:ethyl acetate=60:40) to yield 7-hydroxymethyl-2,2,12,12-tetramethyltridecanedioic acid (2.0 g, 81%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.64 (br., 3H), 3.50 (d, 2H, J=4.4 Hz), 1.60-1.20 (m, 17H), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.3, 65.2, 42.1, 40.5, 40.1, 30.6, 27.1, 25.2, 25.0. HRMS (LSIMS, nba): Calcd. for C18H35O5 (MH+): 331.2484. found 331.2484.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[C:25]2[S:32][CH:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>[Cu]Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:24]1[C:25]2[S:32][CH:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: Clc1ncnc2ccsc12
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Product: O=C(CC(=O)Nc1ccc(Oc2ncnc3ccsc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (46 mg, 0.15 mmol), 4-chlorothieno[3,2-d]pyrimidine (17 mg, 0.10 mmol), cesium carbonate (49 mg, 0.15 mmol), and copper(I) chloride (10 mg, 0.10 mmol) were placed in a test tube. The tube was sealed, flushed with nitrogen, charged with 1-methyl-2-pyrrolidinone (0.3 mL) followed by 2,2,6,6-tetramethyl-3,5-heptanedione (4.0 μL, 0.02 mmol). The reaction was stirred at 120° C. for 2 h. The reaction mixture was purified by preparative HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the desired product as a colorless oil. Lyophilization with methanol/water gave the title compound (23 mg, 52%) as a white solid. 1H NMR (CD3OD) δ 8.54 (s, 1H), 8.21 (d, 1H, J=5.5 Hz), 7.69 (dd, 1H, J=12.4, 2.0 Hz), 7.49 (m, 3H), 7.27 (m, 2H), 6.96 (t, 2H, J=8.9 Hz), 3.47 (s, 2H); MS(ESI+) m/z 441.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]>CCO.[Pd]>[NH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: Cc1cc(C)c(NCC(=O)N(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(NCC(=O)N(C)C)c(N)c1
Reaction time: 72 h

Procedure:
To a solution of N2-(2,4-dimethyl-6-nitrophenyl)-N1,N1-dimethylglycinamide from Step A (2.54 g, 10.1 mmol) in EtOH (50 mL) was added 10% Pd/C (500 mg). The reaction mixture was stirred under a hydrogen atmosphere (ca. 1 atm) for 72 h, then filtered through a Celite pad, washing with EtOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=222 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[CH:26]=[C:25]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:34].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][C:21]1[CH:26]=[C:25]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:34])=[O:6]
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Reactant: Nc1cc(Sc2ccccc2)ccc1O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Nc2cc(Sc3ccccc3)ccc2O)c(F)c1

Procedure:
To a slurry of 2-fluoro-4-formylbenzoic acid (0.600 g, 3.57 mmol) in 10 mL anhydrous DCM under nitrogen was added 3 drops DMF, followed by oxalyl chloride (0.380 mL, 4.28 mmol). The reaction was allowed to stir under N2. The reaction was allowed to stir for 4 h and concentrated in vacuo to a yellow oil. This material was dissolved in 10 mL THF and was added via pipette to a slurry of 2-amino-4-(phenylthio)phenol hydrochloride (0.906 g, 3.57 mmol) and diisopropylethylamine (1.55 mL, 8.92 mmol) in THF at 0° C. The bright yellow slurry was allowed to stir overnight. The mixture was treated with 1N HCl and DCM, and the organic layer was extracted 1×DCM. The organics were dried, filtered, and concentrated in vacuo. The orange oil was dissolved in 5 mL DCM, and a thick yellow precipitate resulted. This was collected by filtration, rinsing with DCM to give 2-fluoro-4-formyl-N-(2-hydroxy-5-(phenylthio)phenyl)benzamide as a bright yellow solid. MS (ESI) m/z: Calculated: 367.1; Observed: 366.0 (M−−1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[CH:26]=[C:25]2[C:32]#[N:33]>O1CCCC1.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[CH:26]=[C:25]2[C:32]1[NH:33][C:19]2=[N:18][CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=1
Reactant: Cc1cnccn1
Reactant: COc1ccc2c(c1)c(C#N)cn2C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of diisopropylamine (59.9 mL) in tetrahydrofuran (1400 mL), at −15° C. and under nitrogen, was treated with a solution of n-butyllithium in hexanes (131 mL, 1.6M) over 25 minutes, whilst maintaining the temperature below −10° C. After stirring for 30 minutes the mixture was treated with methylpyrazine (26.8 g) over 15 minutes, then stirred for 1 hour and then treated with a solution of 5-methoxy-1-methyl-1H-indole-3-carbonitrile [53g, Reference Example 1(a)] in tetrahydrofuran (600 mL) over 1 hour, keeping the temperature below −10° C. The reaction mixture was allowed to warm to room temperature over 2 hours, then stood overnight, then treated with water (100 mL). The tetrahydrofuran was removed in vacuo and the resultant mixture was partitioned between ethyl acetate (500 mL) and water (20 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organics were washed with water (500 mL) then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1, v/v) to give the title compound (19.4 g) as a grey solid, m.p. 270–272° C. MS: 279 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[N:1][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (150 mL), 189a (3.0 g, 8.8 mmol), and N-bromosuccinimide (1.56 g, 8.8 mmol). The mixture was stirred at room temperature overnight. It was then concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 10:1 petroleum ether/ethyl acetate to afford 189b as a yellow solid (2.85 g, 73.4%). MS: [M+H]+ 343.3. 1H NMR (500 MHz, (CD3)2CO) δ 8.03 (s, 1H), 7.94 (s, 1H), 3.48-3.46 (m, 4H), 3.42-3.40 (m, 4H), 1.33 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][CH2:15][C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([N:14]([CH2:15][C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:43]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:44])([CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(CNC2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)c(CN(C(=O)C2CCCCC2)C2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Reaction time: 2 h

Procedure:
To 3-{[(1-benzyl-3-methylpyrrolidin-3-yl)amino]methyl}-1-methylquinolin-2(1H)-one (1846 mg, 5.11 mmol) in CH2Cl2 (25 ml) was added DIEA (1.338 ml, 7.66 mmol). Cyclohexane carbonyl chloride (0.757 ml, 5.62 mmol) was added and the reaction stirred for 2 hours. The reaction was quenched with MeOH then concentrated in vacuo. The resulting material was twice purified by silica gel chromatography on an Isco Companion (5-35% acetone/hexane for first run, 5-25% acetone/hexane for second run). 2.12 g, 88% over two steps.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>C(O)(C)C.CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]3[N:3]=2)[CH:23]=1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 160 °C
Reaction time: 24 h
Yield: 32.1 %

Procedure:
In a sealed tube, ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 500 mg, 2.22 mmol), (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride salt (513 mg, 2.22 mmol), and diisopropylethylamine (0.774 mL, 4.43 mmol) were combined in isopropanol (2 mL) and heated at 160° C. for 3 days. 2N NaOH (6 mL) and MeOH (5 mL) were added and the reaction mixture stirred at ambient temperature for 24 hours, followed by heating to 40° C. for 3 hours. The reaction was partially concentrated, treated with saturated aqueous NH4Cl (10 mL) and the mixture extracted with EtOAc. The combined organic extracts were filtered, concentrated and the residue purified by reverse phase chromatography eluting with 0-60% acetonitrile/water to yield the title compound as a pink solid (254 mg, 32.2% yield). MS (apci) m/z=357.0 (M+H).