Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:30]([CH3:31])[CH3:29])=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 63.7 %

Procedure:
Following the procedure of Example 7, 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 63.7%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Br)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)[OH:18]>O>[Br:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:5][C:6](=[O:18])[C:7]=1[CH2:8][CH3:9]
Reactant: CCc1c(Br)nc(-c2ccccc2)nc1Br
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCc1c(Br)nc(-c2ccccc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To 8.29 g (26.1 mmol) of crude 4,6-dibromo-5-ethyl-2-phenylpyrimidine was added a mixture of 4 mL of water and 15 mL of concentrated sulfuric acid. The mixture was stirred for 18 h and poured onto 200 g of crushed ice. After the ice had melted the precipitate was collected by filtration and dried under vacuum to afford 7.21 g (99%) of crude 6-bromo-5-ethyl-2-phenyl-4(3H)-pyrimidinone. 1H-NMR (d6 -DMSO)δ1.10(3H,t), 2.55(2H,q), 7.55(3H, m), 8.10(2H,m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[CH:9]=[CH2:10].CCCCCC>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][CH:9]=[CH2:8])=[O:6]
Reactant: O=C(O)CCCCl
Reactant: C=CCO
Solvent: O
Solvent: CCCCCC
Product: C=CCOC(=O)CCCCl
Temperature: 25 °C
Yield: 79 %

Procedure:
To a mixture of 4-chlorobutyric acid (48 ml; 0.48 mole), allyl alcohol (200 ml) and hexane (1.2 l) p-toluenesulfonic acid (16.0 g; 0.08 mole) was added. The obtained mixture was heated for 5 hours at reflux temperature in such a way that water was simultaneously removed with Dean-Stark apparatus (Vogel's Textbook of Practical Organic Chemistry, Fourth Ed., Longman, London, 1978, p. 411). The mixture was then cooled to room temperature and shaken with 7% aqueous sodium hydrogencarbonate solution (2×500 ml). The obtained solution was dried with magnesium sulfate and after the filtration of the drying agent hexane was evaporated. The crude residue was distilled under reduced pressure 10 mbar at the temperature of 95° C. and the title compound (61.2 g; 79%) was obtained in the form of a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][N:19]([CH3:39])[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]([CH3:39])[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:14][CH2:15]2)[CH2:3][CH2:2]1
Reactant: c1ccc(N2CCNCC2)c(C2CC2)c1
Reactant: CN(CCCl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCN1CCN(c2ccccc2C2CC2)CC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 96 °C
Yield: 18.7 %

Procedure:
9.0 g (44.4 mmol) of 1-(2-cyclopropylphenyl)piperazine, 200 ml of dimethylformamide, 15 g (44.4 mmol) of 2-chloro-N-methyl-N-(triphenylmethyl)-ethanamine and 9 g of potassium carbonate are introduced into a 500-ml round bottom flask fitted with a condenser and placed under nitrogen and the mixture is heated to 96° C. for 6 h three times. The solvent is evaporated off, the residue is taken up with water and dichloromethane, the organic phase is separated off, is washed with water and is dried over sodium sulphate and the solvent is stripped off. 4.17 g of 2-[4-(2-cyclopropylphenyl)piperazin- 1-yl]-N-methyl-N-(triphenylmethyl)ethanamine are obtained in the form of oil, which is dissolved in 200 ml of methanol, gaseous hydrochloric acid is bubbled through it for 10 min, the mixture is concentrated, is allowed to stand for 2 days and the precipitate is separated off by filtration. 2.94 g of compound are obtained.
Reaction SMILES: [N:1]1([C:11]2[C:12]([CH2:17][NH:18][CH2:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:28]=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[N:30]1[CH2:39][CH2:40][CH2:41][CH:42]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:1]1([C:11]2[C:12]([CH2:17][N:18]([CH2:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=3)[CH2:42][CH2:41][CH2:40][CH2:39][N:30]3[C:31](=[O:38])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:29]3=[O:28])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(CNCc2ncccc2N2CCCc3ccccc32)c(C)c1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2C(=O)c3ccccc3C2=O)Cc2ncccc2N2CCCc3ccccc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of [3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine in CH2Cl2 and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.36 g, 6.28 mmol) with NaBH(OAc)3 gave 2-{4-[[3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-isoindole-1,3-dione as a yellow fluffy solid. 1H NMR (CDCl3) δ 1.35-1.50 (m, 4H), 1.95-1.80 (m, 2H), 2.03 (s, 3H), 2.22 (s, 3H), 2.50-2.65 (m, 2H), 2.65-2.95 (m, 2H), 3.27-3.40 (m, 2H), 3.45-3.55 (m, 2H), 3.65-3.80 (m, 4H), 5.99 (d, 1H, J=7.7 Hz), 6.59 (t, 1H, J=7.7 Hz), 6.81 (t, 1H, J=1.3, 7.7 Hz), 6.95 (d, 1H, J=7.7 Hz), 7.07 (s, 1H), 7.21 (dd, 1H, J=4.6, 7.9 Hz), 7.50 (dd, 1H, J=1.0, 7.9 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.9 (s, 1H), 8.53 (dd, 1H, J=1.0, 4.6 Hz). Deprotection with H2NNH2.H2O following General Procedure E gave N1-[3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-N1-(3,5-dimethyl-pyridin-2-ylmethyl)-butane-1,4-diamine as a free base.
Reaction SMILES: C(OC(=O)[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[C:8]([O:10]C(C)(C)C)=O)(C)(C)C.[CH:24]1[CH:29]=[C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([CH:34]=O)[C:27]2=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>[Br:21][C:18]1[CH:17]=[C:16]2[C:15]([CH2:7][C:8](=[O:10])[N:22]2[CH2:34][C:33]2[C:27]3[C:28](=[CH:29][CH:24]=[CH:25][CH:26]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C1Cc2ccc(Br)cc2N1Cc1cccc2ccccc12
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
2-(2-Amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (7.73 g, 20.0 mmol) and 1-napthylaldehyde (3.0 ml, 22.0 mmol) were dissolved in 80 ml of acetic acid (AcOH) under an atmosphere of dry N2. To this solution was added 95% sodium triacetoxyborohydride (NaHB(OAc)3) (5.8 g, 26 mmol) and the solution was stirred for 45 minutes. The reaction mixture was concentrated under vacuum and then stirred in 100 ml of a 1:1 solution of DCM/water. To this mixture was slowly added NaHCO3 until the pH˜8. The DCM layer was then washed with saturated aqueous NaHCO3 and dried over MgSO4, filtered and concentrated under vacuum to give a foam which was subsequently dissolved in a solution of 80 ml of TFA and 10 ml of triethylsilane under an atmosphere of dry N2. The mixture was stirred overnight after which time the precipitate was collected, washed with hexanes and dried under vacuum to give 6.43 g of the titled compound as a white solid in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].[NH2:27][CH2:28][CH:29]([OH:36])[CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:27][CH2:28][CH:29]([OH:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:13])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(Cl)cccc1Cl
Reactant: NCC(O)CN1CCCC1
Product: Nc1ncc(-c2ccc(C(=O)NCC(O)CN3CCCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide was prepared from 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and 1-amino-3-pyrrolidin-1-yl-propan-2-ol following procedure 4.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 4.0 g, 16.4 mmol), and 4-bromofluorobenzene (3.45 g, 19.7 mmol) in THF (80 mL)) were added Palladium catalyst Pd(PPh3)4 (0.57 g, 0.49 mmol) and the freshly prepared sodium hydroxide solution (2.0 g, 49.3 mmol in 25 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.75 g (80%) of the product 4-(4-fluoro-phenyl)1H-indole as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:46]=[C:47]([CH2:52][C:53](O)=[O:54])[CH:48]=[C:49]([F:51])[CH:50]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:44][C:45]1[CH:46]=[C:47]([CH2:52][C:53]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:54])[CH:48]=[C:49]([F:51])[CH:50]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cc(F)cc(F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-difluorophenylacetic acid (0.4 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was reslurried in hot acetone (15 mL) to afford 2-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.5 g, 56%) as a white solid: mp, 238-240° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.63 min. (97%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.60 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.89-7.14 (m, 3H), 7.65-7.84 (m, 3H), 8.70 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.91, 41.41, 48.83, 101.62 (101.95, 102.30), 112.18 (112.28, 112.41, 112.51), 121.95, 127.16, 131.52, 133.29, 134.68, 138.91, 140.24 (140.37, 140.50), 160.39 (160.57, 163.64, 163.82), 166.88, 167.41, 169.53, 169.77, 172.72; Anal. Calcd. for C22H17N3O5F2: C, 59.87; H, 3.88; N, 9.52; F, 8.61. Found: C, 59.66; H, 3.83; N, 9.77; F, 8.47.
Reaction SMILES: O1C=CCCC1.[Na].O.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11]C=1.[C:20](=[O:23])(O)[O-:21].[Na+]>C(Cl)Cl>[O:21]1[C:20](=[O:23])[CH:19]=[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]12
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: O=C1C=C2C=CC=C2O1

Procedure:
571.5 mg (1.82 mmol) of [3S-[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one was dissolved in 20 ml of methylene chloride (freshly filtered through aluminum oxide, activity I) under a positive argon pressure. 2.0 ml (21.9 mmol) of dihydropyran (freshly dist. from sodium) was added under stirring followed by a crystal of p-toluenesulfonic acid monohydrate (9.7 mg; 0.05 mmol). The mixture was stirred at room temperature for 30 min, poured into 50 ml of sat. aqueous sodium bicarbonate and extracted three times with 30 ml of methylene chloride. The extracts were washed twice with 50 ml of brine, combined, dried over MgSO4 and concentrated at reduced pressure. The crude product (1.14 g, oil) was chromatographed on a 100 g silica gel column with ether/petroleum ether (1:1) yielding 797 mg (1.65 mmol)91% of [3S-[3α,3aα,4α(1E,3R*),-5β,6aα]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one as a clear oil(mixture of THP-diastereomers). [α]D25 -32.46° in CHCl3, c=0.8780.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.[NH2:23][NH2:24].O>N1C=CC=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:5][N:4]=[N:3][C:2]=2[NH:23][NH2:24])=[CH:9][CH:10]=1
Reactant: NN
Reactant: Clc1ccc(-c2cnnc(Cl)c2-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Yield: 96 %

Procedure:
3-Chloro-4,5-bis(4-chlorophenyl)pyridazine (10.0 g, 30.0 mmol) was dissolved in pyridine (30 mL) and hydrazine mono-hydrate was added (4.5 g, 90.0 mmol). The reaction mixture was refluxed for 3 h and was then added to water (100 mL). The pale colored solid was collected by filtration and rinsed thoroughly with water. The product was dried in a vacuum oven to give the title compound, 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (9.5 g, 96%). MS: M+H=331. 1H NMR (DMSO-d6, 500 MHz): δ 8.59(1H, s), 8.56 (1H, br), 7.40 (2H, d, J=10 Hz), 7.35 (2H, d, J=10.0 Hz), 7.14–7.16 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[Br:14]Br.C(Cl)Cl>C(OCC)C>[Br:14][CH:7]1[C:6](=[O:13])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8]1
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(Br)CO2
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 6-methoxy-4-chromanone (35 g) in ethyl ether (1.6 liters) at 5-101 C. was added dropwise over 30 minutes 10.6 ml of bromine. The mixture was stirred at 5-10° C. for 30 minutes and then allowed to warm to room temperature. After 2 hours tlc (CH2Cl2) indicated formation of less polar products and only a trace of starting material remaining. The reaction mixture was washed with water (1 liter), saturated NaHCO3 (500 ml), and brine (500 ml). dried over MgSO4, and concentrated in vacuo to a yellow solid. The crude product was purified by silica gel flash column chromatography on 2.4 Kg fine silica gel, eluting with a gradient system consisting of 3:1 hexanes/dichloromethane followed by 2:1 hexanes/dichloromethane and finally 30% hexanes/dichloromethane. This afforded title product as a yellow solid in 80% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:42][C:43]1[O:44][C:45](=[O:49])[O:46][C:47]=1[CH3:48].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:48][C:47]1[O:46][C:45](=[O:49])[O:44][C:43]=1[CH2:42][O:37][C:36](=[O:38])[CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1
Reactant: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Reactant: Cc1oc(=O)oc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(=O)oc1COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Yield: 32.3 %

Procedure:
A solution of 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoic acid (450 mg, 0.82 mmol), 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (146 mg, 0.99 mmol) and potassium carbonate (170 mg, 1.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (175 mg, yield 32%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.Cl.C(N=C=N)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].CCOC(C)=O>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][C:11](=[O:13])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: COc1ccc(CCN)cc1OC
Agent: CCN=C=N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CCC(=O)NCCc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 3-(3-methoxy-phenyl)-propionic acid (1.19 g, 6.62 mmol) and 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (1.33 g, 6.95 mmol) in THF (20 mL) is added 2-(3,4-dimethoxy-phenyl)-ethylamine (1.20 g, 6.62 mmol). The mixture is stirred at rt for 14 h. The mixture is poured onto H2O (100 mL) and EtOAc (100 mL). The organic layer is washed successively with saturated sodium hydrogen carbonate solution, 10% citric acid and saturated sodium chloride solution. The resulting organic layer is concentrated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]1[CH2:17][C:16](=[O:18])[O:15][C:13](=[O:14])[CH2:12]1>C1(C)C=CC=CC=1>[CH3:10][CH:11]([CH2:17][C:16](=[O:18])[NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)CC(=O)NCCc1ccccc1

Procedure:
A solution of 2-phenylethylamine (6.3 ml) in dry toluene (50 ml) was added dropwise to a stirred solution of 3-methylglutaric anhydride (6.4 g) in dry toluene (250 ml) at 0° under a nitrogen atmosphere. After complete addition the mixture was heated at reflux temperature for 3 hours. The solution was evaporated and the residual oil triturated with ether (150 ml). The solid was filtered and dried to give the sub-title intermediate (3.3 g), mp 78°-80°.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:75][B:76]([OH:87])[C:77]1[CH:85]=[CH:84][C:80]([C:81](O)=[O:82])=[CH:79][C:78]=1[F:86]>C(Cl)Cl>[C:37]([CH2:36][C:12]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:81]([C:80]3[CH:84]=[CH:85][C:77]([B:76]([OH:87])[OH:75])=[C:78]([F:86])[CH:79]=3)=[O:82])[CH2:5][CH2:6]2)[CH2:13]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccc(B(O)O)c(F)c6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.0 g, 2.0 mmol) in methylene chloride (DCM) (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.2 g, 2.6 mmol), N,N-diisopropylethylamine (1.1 mL, 6.1 mmol), and 4-(dihydroxyboryl)-3-fluorobenzoic acid (0.37 g, 2.0 mmol). The mixture was stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue was purified using HPLC to give 0.54 g (41%) of the corresponding product {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid. LC-MS: 659.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)(=[O:11])=[O:10])=[C:4]([CH3:29])[CH:3]=1.[S].[CH2:31](N)[CH2:32][NH2:33]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[NH:33][CH2:32][CH2:31][N:27]=3)=[CH:22][CH:21]=2)(=[O:10])=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)CNCCNC(=O)CCc2ccc(C#N)cc2)c(C)cc1Cl
Reactant: NCCN
Agent: [S]
Product: Cc1cc(S(=O)(=O)CNCCNC(=O)CCc2ccc(C3=NCCN3)cc2)c(C)cc1Cl

Procedure:
Analogously to 13b), N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]propionamide was prepared from 1.15 g (2.65 mmol) of N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-(4-cyanophenyl)propionamide, 85 mg (2.65 mmol) of sulphur and 4 ml of ethylenediamine.