Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1ccc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cn1ccc(-c2ccc(/C=C/C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CS(C)=O>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([N:9]2[C:10]([CH2:12][CH3:13])=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CCc1cc(-c2ccccc2)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cc(-c2ccccc2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
To a solution of 3-phenyl-5-ethylpyrazole (1.0 g, 5.8 mmol) in DMSO (5 mL) was added potassium t-butoxide (0.72 g, 6.4 mmol) followed by 4-fluoronitrobenzene (0.65 mL, 6.4 mmol). The mixture was heated at 90° C. for 1 hour, cooled to rt, and quenched with water (50 mL). The precipitate was collected by filtration, redissolved in ethyl acetate (50 mL), treated with active carbon (3 g), and filtered through diatomaceous earth. The mixture was concentrated to 5 mL, and hexane (25 mL) was added. The 1-(4′-nitrophenyl)-3-phenyl-5-ethylpyrazole was collected by filtration (1.70 g, 92%): mp 112-113° C. NMR 8.39 (2H, d), 7.79 (2H, d), 7.90 (2H, m), 7.45 (2H, m), 7.38 (1H, m), 6.66 (1H, s), 2.86 (2H, q), 1.38 (3H, t).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[C:9]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[C:9](=[O:27])[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:13]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(CC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
To a solution of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid tert-butyl ester (157 mg, 0.37 mmol) from Example 36 in 4 mL of methylene chloride was added 2 mL of trifluoroacetic acid. The solution was stirred at room temperature for 5 hours, then concentrated in vacuo. The resultant oil was partitioned between methylene chloride and brine. The aqueous layer was washed with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a gummy solid. Diethyl ether was added, and the resultant precipitate was collected. Hexane was added to the filtrate, and once again the resultant precipitate was collected. The solids were combined and dried in vacuo at 80° C. to give 71 mg (52%) of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid that was >97% pure by HPLC; mp 297°-300° C. dec.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)[C:12]#[N:13].[CH3:28][O-].[Na+].CI.[Cl-].[NH4+]>CO.COCCOC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)([CH3:28])[C:12]#[N:13]
Reactant: N#CC(Sc1nc2ccccc2s1)c1cccc(C(=O)c2ccccc2)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: CI
Product: CC(C#N)(Sc1nc2ccccc2s1)c1cccc(C(=O)c2ccccc2)c1
Yield: 70 %

Procedure:
Methanol (3 ml) and 2 ml of DME were added to 802 mg of alpha-(2-benzothiazolylthio)(m-benzoylphenyl)-acetonitrile, and the mixture was stirred in an argon atmosphere under ice cooling. Then, 0.78 ml of a 2.7 M methanol solution of sodium methoxide was added, and then 0.19 ml of methyl iodide was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and after adding an aqueous solution of ammonium chloride (1 g/20 ml), extracted with 40 ml of methylene chloride three times. The extract was washed with 50 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; benzene and methylene chloride) to afford 580 mg (yield 70%) of alpha-(2-benzothiazolylthio)-alpha-(m-benzoylphenyl)propionitrile as an oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([CH3:33])[C:21]=1[CH3:34]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Br)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2csnc2-c2ccc(Br)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-bromophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.60 (abq, J=10.5, 4.5 Hz, 4H), 6.98 (d, J=7.5 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 5.05 (s, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.62 (t, J=7.0 Hz, 2H), 2.25 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:16].CC(C)([O-])C.[K+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C1COCC1>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][C:9]=2/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[C:5]([CH3:16])=[CH:6]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Cc1c[nH]c2c(C=CC(=O)O)cc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)O)cc(F)cc12
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 3-(5-fluoro-3-methylindol-7-yl)acrylic acid, prepared as in Example 3 (20 g, 92 mmol) in 200 mL THF was added potassium t-butoxide (24.4 g, 206 mmol) in portions over approximately 10 min, while keeping the internal temperature below 18° C. with an ice-water bath. 2,4-Dichlorobenzyl chloride (21.7 g, 110 mmol) was added over a period of 5 min, after which the cooling bath was removed. The reaction mixture was stirred for 24 h, then quenched with 200 mL water, followed by dilution with 200 mL MTBE and 200 mL heptanes. After stirring for 10 min, the layers were separated, and the aqueous layer was filtered through a celite pad. The pad was rinsed with 50 mL water, and the aqueous filtrate was acidified to pH of 1-2 with 2 M HCl. The suspension was diluted with 200 mL MTBE and 100 mL heptanes, stirred for 5 min, then the solids were collected on a fritted glass funnel and rinsed with heptanes. The solids were dried under reduced pressure overnight at 58° C. to afford 24.4 g (70% yield) of the title compound: 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 5.55 (s, 2H), 6.21 (d, 1H, J=8.4 Hz), 6.24 (d, 1H, J=15.6 Hz), 7.22 (dd, 1H, J=10.4, 2.4 Hz), 7.28 (dd, 1H, J=8.6, 2.0 Hz), 7.34 (s, 1H), 7.43 (dd, 1H, J=8.6, 2.4 Hz), 7.66 (d, 1H, J=15.6 Hz), 7.67 (d, 1H, J=2.4 Hz), 12.29 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.C([C:21](CC)(CC)[CH:22](P(O)(O)=O)[C:23]([O-:25])=[O:24])C.[CH2:34]1CCN2C(=NCCC2)C[CH2:35]1>C(#N)C.O>[CH2:34]([O:25][C:23](=[O:24])[C:22]([CH3:21])=[CH:9][C:8]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1)[CH3:35]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(-c2ncc(C=O)n2C2CC2)cc1
Reactant: CCC(CC)(CC)C(C(=O)[O-])P(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)=Cc1cnc(-c2ccc(OC)cc2)n1C1CC1
Temperature: 78 °C

Procedure:
3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde (475 mg, 1.96 mmol), triethyl-2-phosphonopropionate (0.63 ml, 2.94 mmol) and DBU (0.44 ml, 2.94 mmol) were dissolved in acetonitrile (5 ml). After stirring at 78° C. o.n. the reaction mixture was cooled to r.t., diluted with water (50 ml) and extracted with DCM. The combined organic phase was dried (Na2SO4), filtered and concentrated, to yield 3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-acrylic acid ethyl ester, which was dissolved in ethanol and hydrogenated at atmospheric pressure over 10% Pd/C (0.5 g) for 24 h. The reaction mixture was filtered through a celite pad and concentrated. After purification on silica gel (EA/DCM=1/1) the isolated product was dissolved in Et2O (10 ml) and treated with HCl (1N in Et2O, 4 ml). The resulting mixture was concentrated and the isolated residue was triturated with Et2O to isolate the title compound solid (466 mg). 1H-NMR: 7.90 (d, 2H), 7.10 (m, 3H), 4.16 (m, 2H), 3.90 (s, 3H), 3.47 (m, 1H), 3.24 (m, 1H), 2.85 (m, 2H), 1.37 (d, 3H), 1.27 (m, 5H), 0.75 (m, 2H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([O:10][C:11]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])[CH3:9].[Br:34][C:35]1[C:40]([CH2:41]Br)=[C:39]([O:43][CH3:44])[C:38]([O:45][CH3:46])=[C:37]([O:47][CH3:48])[C:36]=1[O:49][CH3:50]>O>[Br:34][C:35]1[C:40]([CH2:41][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:29]=2)[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[C:39]([O:43][CH3:44])[C:38]([O:45][CH3:46])=[C:37]([O:47][CH3:48])[C:36]=1[O:49][CH3:50]
Reactant: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)C(=O)OCC
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% oily, 1.02 g, 25.6 mmols) was added to a DMF (80 ml) solution of ethyl 2-ethoxycarbonyl-6-(4-methoxycarbonylphenoxy)hexanoate (8.55 g, 23.3 mmols), with cooling with ice, then allowed to warm to room temperature, and stirred for 30 minutes. Next, a DMF (10 ml) solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (9.47 g, 25.6 mmols) was dropwise added thereto at room temperature, and stirred for 6 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 5:1) to obtain the entitled compound (15.0 g) as an oil.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.C(I)C.Cl>C1COCC1>[CH2:1]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: O=C(O)C1CCC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium diisopropylamide (800 ml; 2.0 M THF solution) in THF (800 ml) was added dropwise over a period of 50 minutes under cooling with ice, a solution of cyclobutanecarboxylic acid (80 g) in THF (100 ml) and the mixture was stirred at room temperature for two hours. To the mixture ethyl iodide (64.0 ml) was added dropwise and the mixture was stirred at room temperature overnight. To the reaction solution was added 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give 1-ethylcyclobutanecarboxylic acid (142 g).
Reaction SMILES: S(=O)(=O)(O)O.C[C:7]1[C:15]([OH:16])=[C:14]([I:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[OH:16][C:15]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[I:17])[C:9]([O:11][CH3:18])=[O:10]
Reactant: Cc1c(C(=O)O)ccc(I)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(O)c1
Yield: 70 %

Procedure:
59 ml (1.10 mol, 2.4 eq) of sulfuric acid are added to a solution of 121 g (0.458 mol, 1 eq) of methyl 3-hydroxy-4-iodobenzoic acid in 700 ml of methanol. The reaction mixture is refluxed for 6 days. The methanol is evaporated off and the reaction medium is then poured into water and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is concentrated and the solid obtained is filtered off and dried. 88.56 g of methyl 3-hydroxy-4-iodobenzoate are obtained in the form of white crystals. Yield=70%
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15](Cl)=[O:16].Cl>CN(C=O)C.C(Cl)Cl.O>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:16]
Reactant: Nc1ccnc(Cl)c1F
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Cl)c2F)c(Cl)c1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
2-Chloro-3-fluoropyridin-4-ylamine (146 mg, 10 mmol) was added to a suspension of sodium hydride (60% dispersed in mineral oil, 80 mg, 2.0 mmol) in DMF (5 mL). The mixture was stirred for 30 minutes then 2,6-dichloro-4-cyano-benzoyl chloride (250 mg, 1.1 mmol) was added and stirring continued for 18 hours. Water (10 mL) and DCM (20 mL) were added to the reaction, and the resultant mixture was acidified with 1M HCl. The organic phase was separated, washed with brine (10 mL), dried over MgSO4, and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM. The crude product was triturated with diethyl ether to give the desired compound as a white solid (230 mg, 67% yield). 1H NMR (400 MHz, CDCl3): δ 8.46 (t, J=5.3 Hz, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.88 (br s, 1H), 7.72 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4042 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.091 g, 0.0023 mol) in DMF (2 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.28 mL, 0.0023 mol) is added. Additional DMF (1 mL) is added and the mixture is stirred for 4 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 80/20) to give 0.5519 g (92%) of the title compound; mp 207-207.75° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1628, 1511, 1467, 1448, 1360, 1226, 1218, 1145, 1096, 878, 849, 840, 804, 764, 649 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.86, 5.27, 6.99, 7.16, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found (av): C, 69.08; H, 4.50; N, 4.26.
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(c2ccc(Br)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC(c2ccc(Br)cc2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed methanol (5 L), methyl 3-(4-bromophenyl)cyclobutane-1-carboxylate (2175 g, 8.08 mol, 1.00 equiv), followed by the addition of a solution of sodium hydroxide (1623 g, 40.58 mol, 5.02 equiv, 5 M) in water (5 L). The resulting solution was stirred at 80° C. for 3 h, cooled to 30° C. and concentrated under vacuum. The resulting solution was diluted with 10 L of H2O and 8 L of DCM, and then extracted with 2×2 L of dichloromethane. The pH value of the combined aqueous layers was adjusted to 5-6 with hydrogen chloride (6 mol/L). The resulting solution was extracted with 3×4 L of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with 1.5 L of hexane and 300 mL of EA. The solids were collected by filtration. The filtrate was concentrated under vacuum and combined with the previous solids to afford 1312 g (crude) of 3-(4-bromophenyl)cyclobutane-1-carboxylic acid as a dark red solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.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>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=2)=[C:17]([F:24])[CH:16]=1
Reactant: CC(=O)Nc1cc(Cl)c(C=O)cn1
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2ccc(Cl)cc2F)c(C=O)cn1
Temperature: 85 °C
Yield: 59.6 %

Procedure:
To a stirred solution of N-(4-chloro-5-formylpyridin-2-yl)acetamide (3 g, 15.11 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.63 g, 15.11 mmol), cesium carbonate (9.84 g, 30.2 mmol) in a mixture of water (8 mL) and THF (25 mL) was added tetrakis(triphenylphosphine)palladium (19.19 mg, 0.017 mmol) and the reaction was heated to 85° C. overnight (14 h). The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EtOAc as eluant), yielding N-(4-(4-chloro-2-fluorophenyl)-5-formylpyridin-2-yl)acetamide as an off-white solid (2.8 g, 9.01 mmol, 60% yield). LC/MS (ESI) m/e 291.0 [(M)−, calcd for C14H9ClFN2O2 291.0], LC/MS retention time (method A): tR=1.69 min; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.84 (d, J=Hz, 1H), 8.88 (s, 1H), 8.13 (s, 1H), 7.61 (dd, J=2.00, 10.00 Hz, 1H), 7.46-7.48 (m, 2H), 2.11 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:30])([CH3:29])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10]2)[CH2:7][CH2:6][CH2:5]1.O1CCCC1.CO.Cl>>[CH:4]1([N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:29])([CH3:30])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:10][CH:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12]2)[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C2CCC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C3CCC3)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.58 g, 14 mmol) added to a solution of ethyl 3-(3-(cyclobutyl(((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.91 g, 1.4 mmol) in Tetrahydrofuran (12 ml, 150 mmol) and Methanol (3 ml, 60 mmol). The reaction mixture was stirred overnight at RT, upon which it was acidified with 1 N HCl to pH=6. The volatiles were removed in vacuo and the remaining water removed by azeotropic distillation with ethanol followed by 18 hours on lyophilizer. The resulting off white solid was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1>>[ClH:1].[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:2]2[N:11]=[C:10]([NH:23][CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:26]=1
Reactant: NC1CCCc2ccccc21
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(NC3CCCc4ccccc43)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 1,2,3,4-tetrahydro-1-naphthylamine and 3,5-dimethylpyrazole. Mp. 221° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[NH:21][CH:22]=[CH:23][C:11]=23)[CH2:4]1.N1C=CN=C1.Cl[Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32].O>CN(C)C=O.CCOC(C)=O>[CH:31]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[NH:21][CH:22]=[CH:23][C:11]=23)[CH2:4]1)([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCC[C@@H](CO)C1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCC[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 4-{[cis-3-(hydroxymethyl)cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (125 mg) in N,N-dimethylformamide (1.25 ml) were added imidazole (40 mg) and chloro(triisopropyl)silane (125 μl). The mixture was stirred at ambient temperature for 18 hours. To the mixture were added water and EtOAc. The mixture was extracted with EtOAc and washed with saturated aqueous sodium hydrogencarbonate and brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform:methanol=100:1-95:5 to give ethyl 4-{[cis-3-{[(triisopropylsilyl)oxy]methyl}cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (170 mg) as a brown oil.