Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])C.[OH-].[Na+]>C1COCC1.CO>[Cl:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]2)=[C:12]([C:10]([NH:9][C:5]([CH3:8])([CH2:6][CH3:7])[C:4]([OH:34])=[O:3])=[O:11])[CH:21]=1
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)C)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 94.3 %

Procedure:
A solution of 36 mg of 2-{[4-chloro-1-(1-isopropyl-piperidin-4-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester in 3 mL THF and 1 ml MeOH was treated with 3 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature for 40 hours. The organic solvent was removed in vacuo. The residue was taken up in 6 ml of water, treated with 2 M hydrochloric acid to adjust the pH to 6˜7, then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 32 mg of 2-{[4-Chloro-1-(1-isopropyl-piperidin-4-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of EXAMPLE 11A (100 mg, 0.3 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (50 mg, 0.4 mmol). The mixture was stirred at ambient temperature for 5 h and partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide the title compound. Yield: 100 mg (82%). MS (DCI/NH3) m/z 430 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([Cl:10])=[C:8](Cl)[S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(Cl)c(Cl)c1NC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1scc(Cl)c1NC(C)=O

Procedure:
was obtained by catalytically hydrogenating a mixture of 25 g of methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate in 300 ml of methanol, 9.5 g of triethylamine and with 10 g of palladium on carbon and room temperature and 760 mmHg column (standard pressure conditions). After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the solvent was distilled off on a Rotavapor and the product was crystallized under water.
Reaction SMILES: I[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(O)c1ccncc1I
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1cnccc1C(=O)O
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a suspension of 1.05 g (4.21 mmol) 3-iodo-isonicotinic acid in 15 ml dimethoxyethane were added successively 0.243 g tetrakis(triphenylphosphine)palladium(0), 4.2 ml 2 M sodium carbonate solution in water and 0.69 g (5.05 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 18 h. After cooling to room temperature the phases were separated and the organic phase was washed twice with water (pH=9). The combined aqueous layers were than adjusted to pH=3 and extracted with five portions ethyl acetate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.68 g (75%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
This example illustrates the direct coupling of benzamide and nitrobenzene to give 4'-nitrobenzanilide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+].[ClH:49].CCOCC>CS(C)=O.C(Cl)Cl.[Cu]I>[ClH:49].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][N:28]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:7]=4[N:8]3[CH3:11])=[CH:4][CH:3]=2)[C:27](=[O:31])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A stirred solution of 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (250 mg, 0.895 mmol) in DMSO (4 mL) under nitrogen was treated sequentially with 4-(benzyloxy)pyridin-2(1H)-one (180 mg, 0.895 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol), CuI (196 mg, 1.04 mmol) and K2CO3 (142 mg, 1.04 mmol). The mixture was placed under vacuum for 30 minutes and then flushed with nitrogen. After stirring overnight at 130° C., the mixture was allowed to cool to room temperature, diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) provided the free-base. This was dissolved in methylene chloride (2 mL) and treated with 2 N HCl in Et2O (1 equivalent) and the mixture was concentrated to provide the title compound (131 mg, 33%) as a yellow solid: mp 270-274° C.; 1H NMR (500 MHz, CD3OD) δ 7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H), 7.43-7.35 (m, 3H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 6.40 (dd, J=7.5, 2.6 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.81-4.80 (m, 1H), 4.58 (d, J=15.3 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.49 (m, 1H), 3.21-3.16 (m, 5H); ESI MS m/z 400 [M+H]+; HPLC (Method B)>98.9% (AUC), tR=13.0 min.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[C@H:15]1[CH2:19][C@@:18]2([CH2:24][CH2:23][CH2:22][NH:21][C@H:20]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O.O>[ClH:1].[CH2:37]([N:21]1[CH2:22][CH2:23][CH2:24][C@:18]2([O:17][CH2:16][C@@H:15]([C:5]3[CH:6]=[C:7]([O:10][C:11]([F:14])([F:12])[F:13])[CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[CH2:19]2)[C@@H:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(OC(F)(F)F)cc1[C@@H]1CO[C@]2(CCCN[C@H]2c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(F)(F)F)cc1[C@@H]1CO[C@]2(CCCN(Cc3ccccc3)[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R,5R,6S)-3-(2-Methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4,5]decane hydrochloride (Example 165, 100 mg, 0.2 mmol) and potassium carbonate (38 mg) were dissolved in dimethyl formamide (0.5 mL). Benzyl bromide (0.3 mL) was added and the mixture was stirred at room temperature overnight, then at 60° C. for 3 h. The mixture was cooled, diluted with water (10 mL) and extracted into ether (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL) and ethereal hydrogen chloride (1 M, 1 mL) was added. The solid was collected and dried in vacuo to give the title compound as a crystalline solid (19 mg). 1H NMR (360 MHz, d6 -DMSO) δ 1.75 (3H, m), 2.01 (2H, m), 2.22 (2H, m), 2.96 (1H, m) 3.63 (3H, s), 3.67 (1H, m), 3.92 (1H, m), 4.01 (1H, m), 4.41 (1H, d, J 9.74 Hz), 6.92 (1H, d, J 8.9 Hz), 7.05 (1H, s), 7.13 (1H, d, J 8.65 Hz), 7.31 (2H, d, J 6.53 Hz), 7.42 (3H, m), 7.60 (4H, m), and 7.91 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.[H-].[Na+].[Cl:20][C:21]1[C:26]2[N:27]=C(S(C)(=O)=O)[N:29]=[CH:30][C:25]=2[CH:24]=[CH:23][N:22]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:20][C:21]1[C:26]2[N:27]=[C:16]([NH:15][C:4]3[CH:5]=[CH:6][C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)=[CH:8][C:3]=3[O:2][CH3:1])[N:29]=[CH:30][C:25]=2[CH:24]=[CH:23][N:22]=1
Reactant: CS(=O)(=O)c1ncc2ccnc(Cl)c2n1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A solution of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 24 mg, 0.104 mmol) in THF (1 mL) was treated with sodium hydride (7 mg, 0.175 mmol) at 0° C. After stirring for 20 minutes at room temperature the mixture was cooled to 0° C. and 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 33 mg, 0.135 mmol) was added. The reaction was allowed to reach room temperature and stirred for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH (0.5 mL) were added and the resulting mixture stirred for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 80% EtOAc in cyclohexane to give the title compound (30 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=O)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[K+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[N:19][OH:20])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Yield: 83.1 %

Procedure:
A mixture of 4-chloro 2',4'-dichlorobenzophenone (8 g.), hydroxylamine hydrochloride (2.9 g.), powdered potassium hydroxide (7.7 g.), ethanol (10 ml.) and water (2 ml.) was heated under reflux for 15 minutes. The mixture was poured into water (300 ml.) containing concentrated hydrochloric acid (30 ml.), and the precipitated oil was left to crystallise. The mixture was then filtered, and the solid residue (7.0 g., 83% yield) of 4-chloro-2',4'-dichlorobenzophenone oxime (m.p. 98°-100° C.) was used in the above process without further purification. A sample recrystallised from petrol also had m.p. 98°-100° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:25](=[O:26])[CH2:24][C:23]([CH3:22])=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a solution of 10.0 g of 1-benzyl-4-hydroxypiperidine and a catalytic amount of triethylamine in 10 ml of THF was added dropwise 4.62 g of diketene over 15 minutes. After the addition, the reaction was effected at room temperature for 1.5 hours and then at 50°-60° C. for 4.5 hours. The reaction mixture was concentrated, and then distilled under reduced pressure to obtain 7.20 g of acetoacetic acid-N-benzyl-4-piperidinyl ester (yield: 50.0%), b.p. 146° C./0.13 mmHg.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:9][C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)Oc1cccc([N+](=O)[O-])c1O2
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)Oc1cccc(N)c1O2
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 1000 ml of anisole and 1000 ml of THF were added 81 g (0.295 mole) of 2,6-dinitrodibenzodioxin and 25 g of 10% palladium/carbon and hydrogen gas was passed through the mixture for 8 hours at room temperature with stirring. The 10% palladium/carbon was filtered and rinsed with THF. The filtrate and the rinsings were mixed, concentrated, and dried under reduced pressure to give 61.9 g (0.289 mole) of 2,6-diaminodibenzodioxin in a 98.0% yield. The product showed a purity of 94.2 area % (HPLC, 254 nm).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[CH2:3]1.[BH4-].[Na+].Cl>C(O)C>[OH:11][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[CH2:3][C:2]1([CH3:14])[CH3:1]
Reactant: CC1(C)Cc2ccc(C#N)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2ccc(C#N)cc2C1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Step A. 2,2-dimethyl-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile (17.8 g, 0.096 mol) in ethanol at 0° C. was added NaBH4 (7.27 g, 0.192 mol) as a solid and the resulting mixture was warmed to rt gradually and stirred for ˜16 h. After cooling to 0° C., aq HCl (1N, 300 mL) was added slowly with vigorously stirring. After additional stirring at 0° C. for 30 min and rt for 2 h, the reaction mixture was concentrated to remove ethanol, then extracted with EtOAc (400 mL). The aqueous portion was further extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (80 mL×2), sat. aq. NaHCO3 (80 mL), brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil. HPLC Ret. time: 2.62 min. LCMS MH+ (m/z) 188.33. 1H NMR: (DMSO-d6, 400 MHz): δ 7.65 (s, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 5.49 (d, 1H), 4.59 (d, 1H), 2.70 (m, 2H), 1.13 (s, 3H), 0.83 (s, 3H).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH:15]2[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=1.[OH-].[Na+].CCO>O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CC1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2CC2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of tetrahydrofuran. To the stirred solvent was added ethyl 2-(4-methoxyphenyl)cyclopropanecarboxylate (8 g, 36 mmol). The reaction mixture was cooled to 0° C. and sodium hydroxide (2.1 g, 54 mmol) in water (5 mL) was added drop wise, followed by ethanol (10 mL). The reaction mixture was stirred for 8 h at room temperature. The reaction mixture was concentrated to distill off the solvent; the crude was acidified with 1N hydrochloric acid to make acidic pH and extracted with ethyl acetate (50 mL). The layers were separated; the organic layer was washed with brine solution (20 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as off white solid (6.5 g, yield: 94.2%). 1H NMR (300 MHz, CDCl3): δ 6.96-6.99 (d, 2H), 6.74-6.77 (d, 2H), 3.71 (s, 3H), 2.46-2.53 (m, 1H), 1.72-1.78 (m, 1H), 1.52-1.58 (m, 1H), 1.27-1.32 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([O:14][CH3:15])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:6][CH:7]=1.[F:16][CH:17]([F:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.O.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]>[F:16][CH:17]([F:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:7]=[N:6][C:5]([CH2:8][N:9]([S:10]([CH3:13])(=[O:12])=[O:11])[O:14][CH3:15])=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)=[O:19]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Reactant: CON(Cc1ccc(Br)cn1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CON(Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To a stirred solution of N-(5-Bromo-pyridin-2-ylmethyl)-N-methoxy-methane sulfonamide (0.2 g, 0.678 mmol) in N-Methyl-2-pyrrolidone (8 mL) is added and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)ethyl]-acetamide (0.27 g, 0.678 mmol). Reaction mixture is degassed with nitrogen for 15 minutes then added tris(dibenzylideneacetone)dipalladium(0) (0.06 mg, 0.068 mmol) and Tri-2-furylphosphine (0.03 g, 0.136 mmol) simultaneously. The resulting reaction mixture is stirred at 80° C. for 5 hours. Diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash using 50% ethyl acetate in hexane as an eluent to afford the title compound (0.05 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.16 (s, 3H), 3.49 (s, 3H), 4.30-4.37 (m, 1.5H), 4.41-4.46 (m, 0.5H), 4.46 (s, 2H), 4.54-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (m, 1H), 5.94 (d, J=4.2 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.16 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 8.14-8.16 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.86 (d, J=8.72 Hz, 1H), 8.91 (d, J=2.08 Hz, 1H). LCMS (m/z): [M+H]=461.9.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].[B:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=1)([OH:7])[OH:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH4+].[Cl-].Cl>O.CN(C=O)C>[CH2:3]([N:2]([CH3:1])[C:12]([C:11]1[CH:15]=[CH:16][C:8]([B:5]([OH:6])[OH:7])=[CH:9][C:10]=1[F:17])=[O:14])[CH3:4]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: CCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(B(O)O)cc1F
Reaction time: 3 h
Yield: 79.9 %

Procedure:
N-Methylethanamine (1.5 mL, 17.46 mmol) was added to a DMF (10 mL) solution (sonicated to help dissolve) of 4-borono-2-fluorobenzoic acid (1.13 g, 6.14 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.54 g, 6.68 mmol). After 3 h at room temperature, saturated NH4Cl (50 mL) and water (10 mL) were added. The mixture was acidified to pH 3 with concentrated HCl (˜0.5 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4) and concentrated to give a thick brown oil, which was treated with water (7 mL) and allowed to stand overnight. The white needles were removed by filtration. The filtrate was purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 30-50% solvent B gradient) to give the expected product as white glassy solid (1.1036 g, 80% yield). LC retention time: 2.49 min (analytical HPLC Method A).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.[CH2:12]([C:19]1[NH:24][C:23](=[O:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=2)=[CH:21][N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([C:19]1[NH:24][C:23](=[O:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([I:11])[S:10][C:3]=34)=[C:28]([F:33])[CH:27]=2)=[CH:21][N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccnc2cc(I)sc12
Reactant: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a mixture of 7-chloro-2-iodothieno[3,2-b]pyridine (0.030 g, 0.10 mmol; prepared according to the procedure described by Ragan, J. A. Org. Proc. Res. Dev. 2003, 7, 676) and 2-benzyl-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one (0.025 g, 0.084 mmol) in DMF (1 mL) was added Cs2CO3 (0.033 g, 0.10 mmol). The reaction mixture was stirred at 130° C. for 18 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude dark yellow solid. Purification of the crude product was achieved by flash column chromatography (25:1 dichloromethane/methanol) and then by trituration with dichloromethane. The resulting solid was filtered, washed with dichloromethane, collected and dried under vacuum to yield the desired product (0.008 g, 17%) as a pale yellow solid. LRMS (ESI pos) m/e 556 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:19])=[C:6]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[CH3:20]I>CN(C)C=O>[CH3:3][C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)c(O)c(C(=O)C2CCCCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(C)cc1C(=O)C1CCCCC1
Temperature: 25 °C
Yield: 105 %

Procedure:
53 Grams of 60% sodium hydride was gradually added to a solution prepared by dissolving 256.2 g of cyclohexyl 3,5-dimethyl-2-hydroxyphenyl ketone in 1 liter of dimethylformamide with stirring, generating the temperature of the reaction mixture was risen to 70° C. by generating the heat. After continuation of stirring for 30 minutes, the reaction mixture was cooled to room temperature and thereto was added dropwise 233 g of methyl iodide. The reaction mixture was further stirred at the same temperature for 2 hours and then added to 1 liter of ice water and stirred. The organic layer was extracted with 3 liters of ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 285.2 g of cyclohexyl 3,5-dimethyl-2-methoxyphenyl ketone.