Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[Si:30]([O:14][C:5]1[C:4]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:3]([CH2:1][CH3:2])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CCc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (8.61 g) and imidazole (3.5 g) in dimethyl formamide (40 ml) was treated with t-butyldimethylsilyl chloride (4.50 g) and stirred at 25° C. for 14 hours. The reaction mixture was then poured into ice water and extracted with ether. Drying over magnesium sulfate and evaporation gave methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:34]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:31]([C:44](=O)[CH3:45])[CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].Cl.[OH:53][NH2:54]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:30]=[C:31](/[C:44](=[N:54]/[OH:53])/[CH3:45])[CH:32]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)=O)c2)C(=O)OC(C)(C)C)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(/C(C)=N/O)c2)C(=O)OC(C)(C)C)c1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3-methoxybenzyl((2R,3S)-3-(3-acetyl-5-(benzamido)benzamido)-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (10 mg, 0.0147 mmol) and hydroxyamine hydrochloride (2.0 mg, 0.0294 mmol) in ethanol (0.1 mL) was heated at 80° C. for 2 h. The reaction mixture was purified by reverse phase prep HPLC to give the title compound: HPLC retention time: 2.16 min (method A). MS (ESI) (M+H)+ 697.90
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].C(=O)=O.[N:11]#[C:12][NH2:13]>>[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:12](=[NH:11])[NH2:13])[CH3:2])[OH:6]
Reactant: N#CN
Reactant: CNCC(=O)[O-]
Agent: O=C=O
Agent: [Na+]
Product: CN(CC(=O)O)C(=N)N
Product: O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
1315 g of a 40% strength aqueous sodium sarcosinate solution (pH 14) were introduced into a 2 1 three-necked flask having a mechanical stirrer, heating bath, reflux condenser and gas inlet tube and the mixture was adjusted to pH 9 by introduction of carbon dioxide gas. After heating the solution to 75° C., 338 g of a 50% strength aqueous cyanamide solution were added in the course of 4 hours. The temperature was kept constant at 75° C. during the entire addition period. The pH remained between 9 and 10 without introduction of further CO2 gas. After the addition of cyanamide, the reaction solution was stirred for 2 hours and then cooled to 35° C. The precipitated creatine was filtered off, washed with water and dried. 480 g of creatine monohydrate having a crystal yield of 75% were obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:18].[Ca+2]>O1CCOCC1.O>[OH:18][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(CO)cc1
Yield: 87.8 %

Procedure:
To a suspension of 2 (6.0 g, 22 mmol) in a mixture of 1,4 dioxane (60 ml) and water (60 ml) was added calcium carbonate (10.8 g, 110 mmol). The mixture was heated to reflux for 18 h, concentrated in vacuo and the residue portioned between DCM and water. The organic layer was collected, dried over MgSO4, concentrated in vacuo then recrystalised from diethyl ether to furnish 3 (4.1 g, 89%) as a white solid; M.P. 59-61° C. (Lit 61-64° C.); δH (CDCl3) 3.14 (s, 1H, CH2OH), 4.75 (s, 2H, CH2OH), 7.41-7.49 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.54-7.58 (m, 1H, 4′-H), 7.72-7.76 (m, 4H, 2-, 2′-, 6-, 6′-H) ppm; δC (CDCl3) 64.4 (CH2OH), 126.4 (3′-, 5′-C), 128.3 (3-, 5-C), 130.0, 130.4 (2-, 2′-, 6-, 6′-C), 132.5 (4′-C), 136.4, 137.5 (1-, 1′-C), 140.0 (4-C), 196.9 (Ar2C═O) ppm; νmax (thin film) 3406, 3058, 2921, 1655, 1279 cm−1; m/z (ES) 211 ([M−H]− 100%), 183 (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.CC([O-])=O.[Na+]>CC(O)=O.C(Cl)Cl>[Br:29][C:10]1[S:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:21])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1-c1ncsc1-c1ccc(Cl)cc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-c1nc(Br)sc1-c1ccc(Cl)cc1C
Yield: 93 %

Procedure:
A solution of 4,5-Bis(4-chloro-2-methylphenyl)thiazole (170 mg, 0.51 mmol), NBS (100 mg, 0.56 mmol) and NaOAc (82 mg, 1.0 mmol) in AcOH (5 mL) and DCM (3 mL) was stirred overnight at rt, and then quenched with water (25 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography to afford 196 mg of product.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:52])[OH:51])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[OH:43])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1CCCCC1.C(O)(=O)C>CS(C)=O>[NH2:1][C@H:2]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:51])[OH:52])=[O:46])[CH2:40][CH2:41][C:42](=[O:43])[OH:44])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: C1CCNCC1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
Fmoc-L-Trp-D-Leu-Gly-L-Arg-L-Glu-L-Asp-OH (50 mg), was dissolved in 0.5 ml of dimethylsulfoxide and 0.5 ml of piperidine was added to the solution. After reacting for an hour, the reaction mixture was neutralized with acetic acid under cooling.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28](=[NH:31])[NH:29]O)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].Cl.[O:45]1CCOCC1>>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:29][C:32](=[O:33])[O:45][N:31]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1
Reactant: C1COCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(C(=N)NO)ccc32)CC1
Agent: Cl
Product: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCNCC2)no1
Temperature: 110 °C
Reaction time: 4 h
Yield: 14.4 %

Procedure:
To a solution of 4-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 1b (0.13 g; 0.31 mmol) in dioxane (5 mL) was added 1,1′-carbonyldiimidazole (75 mg; 0.46 mmol), and the mixture was stirred at 110° C. for 4 hr. The mixture was allowed to cool to rt, and treated with 4N HCl in dioxane (5 mL). The mixture was stirred at rt for 16 hr and evaporated. The residue was suspended in methanol, and the solid was removed via filtration. The filtrate was purified via reverse phase HPLC (eluent gradient: 20 to 40% CH3CN in water containing 0.1% TFA) to yield 8.8 mg (14.4%) of 3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one, 2b as a TFA salt. MS m/z (MH+) 351.1.
Reaction SMILES: [NH2:1][CH:2]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:3]([O:5][CH2:6][C@@H:7]([C:15]([OH:17])=[O:16])[NH:8]C(=O)C(F)(F)F)=[O:4].ClCC(O)=O.[N:29]([O-])=O.[Na+]>O>[N+:1](=[C:2]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:3]([O:5][CH2:6][C@@H:7]([C:15]([OH:17])=[O:16])[NH2:8])=[O:4])=[N-:29]
Reactant: O=N[O-]
Reactant: NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O)C(O)C(F)(F)F
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=C(C(=O)OC[C@H](N)C(=O)O)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a solution of O-(2-amino-3-hydroxy-4,4,4-trifluoro-1-oxobutyl)-N-trifluoroacetyl-L-serine (685 mg) and chloroacetic acid (0.04 ml) in water (7 ml) was added sodium nitrite (227 mg) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and then Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (140 mg) was added. The mixture was stirred for 6 hours at room temperature and chromatographed on carbon (60 ml) eluting successively with water and a 9:1 mixture of water and acetone to give a crude product, which was chromatographed on preparative thin layer chromatography eluting with a 65:35:4 mixture of chloroform, methanol and water, and lyophilized to give O-(2-diazo-3-hydroxy-4,4,4-trifluoro-1-oxobutyl)-L-serine (113 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:28]#[N:29])[C:14](=[O:27])[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CO>CN(C=O)C>[O:27]=[C:14]1[C:13]([C:28]#[N:29])=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:10]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[NH:15]1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccnc(Nc3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
To 5-(2-methylsulfonylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (160 mg, 0.35 mmol) in DMF, under argon, was added a prepared mixture of aniline (129 μL, 1.30 mmole) and potassium bis(trimethylsilyl)amide (0.5M in toluene) (2.6 mL, 1.30 mmole) under argon. The reaction was stirred for 15 minutes and then quenched into ethyl acetate and water. The pH was adjusted to 5.4 with aqueous potassium hydrogen sulfate solution and the ethyl acetate layer removed and concentrated to give a solid. Trituration of the solid from methanol (4 mL) gave 80 mg of a solid.
Reaction SMILES: [O:1]=[C:2]1[CH:16](C(OCC)=O)[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.C(O)C.Cl.C(OCC)C>O>[C:2]1(=[O:1])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CC=CCCCCCCC=CCCC1=O
Agent: CCOC(=O)C1C/C=C/CCCCCC/C=C/CCC1=O
Agent: Cl
Agent: O=C1CC/C=C/CCCCCC/C=C/CC1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=C1CCC=CCCCCCCC=CCC1

Procedure:
The crude ethyl 15-oxocyclopentadeca-3E,11E-dienecarboxylate (prepared as described above) was treated with ethanol (10 ml) and 3N aqueous hydrochloric acid (20 ml) and heated to reflux for 20 hours. The solution was cooled and diethyl ether and water were added. The layers were separated and the organic fraction was dried with magnesium sulfate, filtered and evaporated to provide a brown oil which was purified by column chromatography (10% diethyl ether/hexane) to afford cyclopentadeca-4E,12E-dien-1-one (0.50 g, 17% yield from diethyl hexadeca-4E,12E-diene-1,16-dioate). C15H24O (220.36 g/mole). 1HNMR (500 MHz, CDCl3): 1.15 (m, 4H), 1.34 (m, 4H). 1.97 (m, 4H), 2.24 (m, 4H), 2.45 (m, 4H), 5.30 (m, 2H), 5.39 (m, 2H) ppm. 13CNMR (125 MHz, CDCl3): 26.7, 27.4, 28.4, 31.2, 42.8, 129.2, 131.3, 210.4 ppm. IR (νmax(cm−1)): 2990, 2950, 2910, 2850, 1720, 1440, 1400, 1360, 1080, 980, 720. MS (m/z): 220(M+), 177, 163, 149, 135, 121, 109, 95, 81, 67, 55, 41.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=[O:5])=[O:4].[Cl:28]N1C(=O)CCC1=O.O>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[S:3]([O:6][C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[C:15]([Cl:28])[C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=[O:5])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Temperature: 50 °C
Yield: 47.8 %

Procedure:
To a solution (10 mL) of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (500 mg) obtained in Step C of Example 35 in DMF was added N-chlorosuccinimide (215 mg) at room temperature. The reaction mixture was heated at 50° C. for 21 hr, and the mixture was allowed to be cooled to room temperature. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (259 mg).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11]>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1I
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1I
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 4-Iodo-3-methyl-benzoic acid (5.2 g, 20 mmol) in THF (30 mL) is added 2.0 M borane-dimethyl sulfide complex in THF (40.0 mL, 80 mmol) dropwise. The mixture is stirred overnight. The reaction mixture is quenched carefully at 0° C. with methanol (20 mL) and the mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (80 mL) and water (60 mL). The organic phase is washed with brine (60 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography (gradient EtOAc/Hexane) to afford the title compound as white solid (4.7 g, 95%). 1HNMR (CDCl3) (ppm): 2.4 (3H, s), 4.55 (2H, s), 6.8-7.75 (3H, m).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8]C(O)=CC=1.[CH3:21]I.[H-].[Na+].C(Cl)(Cl)Cl.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>CC(O)=O.CO>[C:14]([N:1]([CH3:21])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:30]=[CH:29][C:33]([O:32][CH3:31])=[CH:8][CH:9]=1)([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CI
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of BOCTyr-OH (0.562 g, 2 mmol) in dry THF at 0° C. CH3I (2.8 g, 20 mmol) and NaH (0.24 g, 10 mmol) were added with vigorous stirring. The reaction mixture was stirred at r.t. for 24 hrs., then chilled, and NaH was destroyed by added EtOAc with water. The clear solution was evaporated to dryness and the residue was taken up in 10 ml of water. The aqueous solution was extracted with ether (2×10 ml), acidified with citric acid and extracted with EtOAc. The organic layer was washed with 5% hypo solution and water, dried over Na2SO4 and evaporated to dryness. The product was obtained as an oil: yield 0.56 g (91%); FABMS m/z 310 (M+H): 10. 0.5:0.5 Rf 51 (CHCl3 : MeOH: AcOH); Anal. Calcd. for C16H24NO4 : Mr 310.1663 (M+H); Found: Mr 310.1654 (M+H) (HRFABMS).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C([O-])(=O)C.[Na+]>CN(C)P(=O)(N(C)C)N(C)C.[Pd]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:12]=[CH:11][C:10]#[N:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: C=CC#N
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A stock solution consisting of 0.1041 g (1.25×10-4 mol) of diacetato-bis-(tris-o-tolylphosphine)-palladium(II) in 50 ml of hexamethylphosphoric acid triamide is prepared under argon. 1 ml of stock solution, 9.25 g (50 mmols) of 4-bromobenzaldehyde, 3.66 ml (55 mmols) of acrylonitrile and 4.51 g (55 mmols) of anhydrous sodium acetate are added, under argon, to 19 ml of hexamethylphosphoric acid triamide, and the mixture is stirred at 130° C. for 8 hours. The hexamethylphosphoric acid triamide is removed under a high vacuum and the product is distilled. 6.58 g (41.9 mmols) of 4-formylcinnamonitrile are obtained, corresponding to a yield of 84% of theory (conversion figure 16800; Pd content 0.005 mol %).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[C:31]([O:37][CH3:38])[N:30]=1>C(Cl)(Cl)Cl>[Br:28][C:29]1[N:30]=[C:31]([O:37][CH3:38])[C:32]([CH:33]=[CH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:35][CH:36]=1
Reactant: COc1nc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1nc(Br)ccc1C=CC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
(tert-Butoxycarbonylmethylene)triphenylphosphorane (1.74 g) was added to a solution of 6-bromo-2-methoxynicotinaldehyde (500 mg) in chloroform (5 mL) under ice-cooling, followed by stirring for one hour. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give tert-butyl 3-(6-bromo-2-methoxypyridin-3-yl)acrylate as a colorless oil (726 mg, 100%).
Reaction SMILES: CS[C:3]1[CH:4]=[CH:5][C:6]([Br:9])=[N:7][CH:8]=1.Cl[C:11]1C=CC=C(C(OO)=O)C=1.[S:21]([O-:25])([O-])(=O)=[O:22].[Na+].[Na+]>C(Cl)Cl>[CH3:11][S:21]([C:3]1[CH:4]=[CH:5][C:6]([Br:9])=[N:7][CH:8]=1)(=[O:25])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)([O-])[O-]
Reactant: CSc1ccc(Br)nc1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 5-methylthio-2-bromopyridine from step 1 (18.9 g, 0.093 mol) in methylene chloride (600 mL), was added portionwise m-chloroperbenzoic acid (48 g, 0.19 mol) at 0° C. and the mixture was stirred for 2 hours at room temperature. Aqueous saturated sodium sulfate (Na2SO3) (200 mL) was added and stirred for 15 minutes and organic phase was separated and washed with aqueous saturated sodium bicarbonate (NaHCO3) (200 mL), dried over MgSO4, and concentrated in vacuo gave the title compound (20.9g, 96%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([S:23][CH3:24])=[N:15][N:16]3[C:21](I)=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH2:33][O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.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>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([S:23][CH3:24])=[N:15][N:16]3[C:21]([C:28]4[C:29]([O:36][CH3:37])=[CH:30][C:31]([CH2:33][O:34][CH3:35])=[CH:32][C:27]=4[O:26][CH3:25])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CSc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CCOCC4)CC4CC4)c(SC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine (50 mg) dissolved in a mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL) was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (50 mg), tetrakis(triphenylphosphine)palladium(0) (40 mg) and barium hydroxide octahydrate (56 mg), and the reaction mixture was heated and stirred for 3 hours at 80° C. Water and ethyl acetate were added to the obtained reaction mixture, insoluble residue was filtered out with celite, and the filtrate was extracted with ethyl acetate. The organic extracts were combined and washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and then by column chromatography using NH Silica (Fuji Silysia) to afford the title compound (36 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:27]=1.C[O-].[Na+].C([NH2:34])=O>>[Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:34])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:27]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 57 %

Procedure:
10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 66 mg (57% yield) of the title compound.