Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Sn](C)(C)C)[CH:36]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)(Cl)Cl.[F-].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>CN1CCCC1=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]>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([CH2:8][C@H:9]([OH:17])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Reactant: O[C@H](Cc1ccccc1)Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(C[C@H](O)Cc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a solution/suspension of 1-(3-bromophenyl)-3-phenyl-2(R)-propanol (291 mg, 1.00 mmol), 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (427 mg, 1.00 mmol, 1.00 equiv.), Pd2(dba)3.CHCl3 (15.5 mg, 15 μmol, 15 mequiv.) and CsF (304 mg, 2.00 mmol, 2.00 equiv.) in N-methylpyrrolidone (1.0 mL) contained in a dried 100 mL round-bottom flask was added P(t-Bu)3 (10 wt % in hexane, 106 μL) by syringe at room temperature under N2. The mixture was stirred for 3 h at 80° C., after which time TLC analysis indicated that the starting material had disappeared. After cooling, the reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether/aqueous NH3 1:10:0.1-1:1:0.1 to give the product (381 mg, 80%) as a yellowish oil. 1H NMR (CDCl3, 300 MHz) δ 8.47 (s, 1H), 4.34 (s, 1H), 7.47-7.26 (m, 10H), 4.56 (m, 1H), 4.41 (m, 1H), 4.21 (dd, 1H, J=10.0, 3.0 Hz), 4.18-4.11 (m, 2H), 3.93 (t, 2H, J=6.6 Hz), 3.01-2.78 (m, 4H), 2.42-2.20 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: COC1C=C(SC)C2CCN(C)CCC=2C=1.Cl.C[O:19][C:20]1[CH:21]=[C:22]([S:32]([CH3:35])(=[O:34])=[O:33])[C:23]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25][C:24]=2[CH:31]=1.[BrH:36]>>[BrH:36].[OH:19][C:20]1[CH:21]=[C:22]([S:32]([CH3:35])(=[O:34])=[O:33])[C:23]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25][C:24]=2[CH:31]=1
Reactant: COc1cc2c(c(S(C)(=O)=O)c1)CCN(C)CC2
Agent: Br
Agent: COc1cc2c(c(SC)c1)CCN(C)CC2
Agent: Cl
Product: CN1CCc2cc(O)cc(S(C)(=O)=O)c2CC1

Procedure:
Following the procedure of Example 4, Method B, 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 8-methoxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride which is treated with hydrobromic acid to give 8-hydroxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][CH:8]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23][NH2:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.CCOCC>[Cl:2][C:3]1[CH:4]=[C:5]([C:15]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)=[O:17])[C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(Cl)cnc1-c1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCCl
Product: COc1ccc(CNC(=O)c2cc(Cl)cnc2-c2cccnc2)cc1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.500 g, 2.01 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added potassium hydroxide (0.200 g, 3.61 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-chloro-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+C11H7ClN2O2=234.9. To a solution of the bis HCl salt form of 5-chloro-2,3′-bipyridine-3-carboxylic acid (0.613 g, 2.00 mmol) and 3,4-dimethoxybenzylamine (0.367 g, 2.2 mmol) in dimethylformamide (10 mL) was added EDC (0.764 g, 4.00 mmol), HOBt (0.612 g, 4.00 mmol) and triethylamine (0.6 mL, 10 mmol) and the system was stirred in an oil bath at 100° C. for 3 h. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was then tritirated with ether to afford 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide as a bone powder. ESI+ MS [MH]+ C20H18ClN3O3=234.9. To a solution of 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide (0.600 g, 1.56 mmol) in dioxane (5.2 mL) was added 3,5-dichlorophenyl boronic acid (1.50 g, 7.82 mmol), N,N-dicylohexylmethylamine (0.368 mL, 1.72 mmol), and bis(tri-t-butylphosphine)palladium (0.023 g, 0.047 mmol) and the system was stirred at 110° C. for 20 minutes in the microwave. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The reaction mixture was filtered and purified via normal phase chromatography (0→6% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) followed by free basing with saturated sodium carbonate afforded the title compound (2-1) as a white powder. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.95 (s, 1H), 8.66-8.68 (m, 1H), 8.15 (s, 1H), 7.98-8.00 (m, 1H), 7.53-7.54 (m, 2H), 7.46-7.47 (m, 1H), 7.28-7.30 (m, 1H), 6.77 (d, J=5 Hz, 1H), 6.39-6.66 (m, 2H), 5.69 (br s, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H). HRMS [M+H] C26H21Cl2N3O3 calc'd 494.1033, found 494.1023.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=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.[Cu]I>[CH3:9][Si:10]([C:13]#[C:14][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: Nc1ncccc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[Si](C)(C)C#Cc1cccnc1N
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.3 %

Procedure:
To a solution of 2-amino-3-bromopyridine (5.72 g, 33.1 mmol) in N-methylpyrrolidinone (120 mL) were added trimethylsilyl acetylene (9.36 mL, 66.2 mmol), tetrakis(triphenylphosphine)palladium (0) (1.91 g, 1.66 mmol), copper (I) iodide (630 mg, 3.31 mmol) and N,N-diisopropylethylamine (11.5 mL, 66.2 mmol) at room temperature, which was stirred under nitrogen atmosphere for 6 hours at 70° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (5.94 g, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]2[CH2:16][N:17](CCC3C=CC=CC=3)[CH2:18][CH2:19][CH2:20][C@@H:14]2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)OC(Cl)C>ClCCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]2[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C@@H:14]2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]2CCCN(CCc3ccccc3)C[C@H]21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CC[C@H]2CCCNC[C@H]21
Temperature: 23 °C

Procedure:
To a solution of (3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester (1.0 g, 2.64 mmol) in 1,2-dichloroethane (20 mL) was added 1-chloroethyl carbonochloridate (0.286 mL, 2.64 mmol, 1.0 eq) at 0° C. The reaction was stirred with warming to 23° C. over 1 hr, then refluxed for 3 hr. The solvent was removed in vacuo then 20 mL methanol added and the reaction mixture heated to 50° C. for 1 hr. The reaction was concentrated and purified using chromatography (1:2 Ethyl Acetate/Heptane to 100% Ethyl Acetate followed by 12:1 CH2Cl2/Methanol) giving (3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:29])[CH3:28]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:29][CH2:27][CH3:28])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCNCC1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.7 g, 1.8 mmol), ethanamine (1 ml, 70% in water) and ACN (3 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on flash column chromatography and on SCX-3 column (TEA/MeOH). Yield: 0.4 g, 72%. The amine was converted to the hydrochloric acid salt and was crystallized from MeOH/Et2O. M.p. 261° C. MS m/z (rel. intensity, 70 eV) 271 (M+, 19), 226 (4), 207 (9), 79 (6), 58 (bp).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([Cl:9])[C:7]=1[Cl:8].Cl.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)=[CH:28][N:29]=1>>[NH2:1][C:2]1[C:3]([C:13]([NH:38][CH2:37][CH:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:27]3[S:26][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[N:29][CH:28]=3)[CH2:32][CH2:33]2)=[O:15])=[N:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCOc1nc(C(=O)O)c(N)c(Cl)c1Cl
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: Cl
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(N)c(Cl)c1Cl

Procedure:
According to the same procedure described in Example 16, using the compound prepared in Example 431 instead of 4-chloro-3-methoxybenzoic acid and the compound prepared in Example 214 instead of the compound prepared in Example 9, the title compound having the following physical data was obtained.
Reaction SMILES: Br.C(O)(=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25](C(OCC3C=CC=CC=3)=O)[CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:10][CH:9]=1.CCOCC>C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][NH:25][CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:12][CH:13]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Agent: Br
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
1.7 ml of 25% hydrogen bromide-acetic acid are added to a solution of 1.07 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 2 ml of benzene under ice-cooling, and the mixture is stirred at room temperature for 2 hours. Then, ether is added to the mixture, and the precipitates are collected by filtration and washed with ether. Water and benzene are added to said precipitates, and the mixture is alkalized with potassium carbonate. The benzene layer is collected, washed with water, dried and then evaporated to remove solvent. Ether is added to the residue, and crystalline precipitates are collected by filtration and recrystallized from a mixture of ethyl acetate and n-hexane. 0.47 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13](Cl)=[O:14].[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C.Cl>ClCCl>[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:14]
Reactant: COc1ccc2ccccc2c1C(=O)Cl
Reactant: COC[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1C(=O)c1c(OC)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-naphthalene-1-carbonyl chloride (0.50 g, 2.27 mmol) in dry dichloromethane (5 mL) at 0° C. under a N2 atmosphere was added 2-(S)-methoxymethylpyrrolidine (0.32 g, 2.75 mmol) and triethylamine (0.47 mL, 3.39 mmol). The mixture was allowed to warm to rt and stirred overnight, after which time it was poured into N HCl (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 10-30% ethyl acetate in hexane. The title compound was obtained as a colorless solid (0.374 g, 55%). 1H NMR (300 MHz, CDCl3) δ 1.90 (m, 6 H), 2.99 (m, 1 H), 3.21 (m, 1 H), 3.48 (m, 3 H), 3.95 (m, 3 H), 4.59 (m, 1 H), 7.29 (m, 1 H), 7.37 (m, 1 H), 7.48 (m, 1 H), 7.76 (m, 3 H); MS (ESI) m/z=300 [M+H].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCO
Solvent: ClCCl
Product: COCCOC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methoxyethanol (295 mg, 3.9 mmol) in DCM (total volume: 0.5 mL) was added to a solution of oxalyl chloride (0.5 mL, 5.8 mmol) in DCM (total volume 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the resulting residue was dissolved in DCM (3.9 mL) to yield a 1.0M solution in DCM.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([O:21][C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25])[CH2:14]C2CCCCC2)=[CH:7][C:6]=1[NH:28][C:29](=[O:45])[CH2:30][CH:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH3:4])([CH3:3])[CH3:2].[ClH:46]>O1CCOCC1>[ClH:46].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@:13]([O:21][C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25])([CH2:2][CH2:1][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH3:14])=[CH:7][C:6]=1[NH:28][C:29](=[O:45])[CH2:30][CH:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CC(=O)O[C@@H](CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1)CC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CC(=O)O[C@](C)(CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1)CCC1CCCCC1

Procedure:
Following a procedure similar to that described in Example 119, but using N,N-dimethylglycine (S)-1-(2-{4-t-butyl-3-[2-(9H-xanthen-9-yl)acetamido]phenyl}ethyl)-2-cyclohexylethyl ester (prepared as described in Example 120) and a 4N solution of hydrogen chloride in dioxane as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: CN(C)C.[CH3:5][O:6][CH2:7][CH:8]1[O:29][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[O:10][CH:9]1[CH2:30][O:31][CH3:32])[N:18]=[CH:17][N:16]=[C:15]3[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=1.[CH3:33][Si:34]([CH3:38])([CH3:37])[C:35]#[CH:36]>[Cu](I)I.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>[CH3:5][O:6][CH2:7][CH:8]1[O:29][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[O:10][CH:9]1[CH2:30][O:31][CH3:32])[N:18]=[CH:17][N:16]=[C:15]3[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:36]#[C:35][Si:34]([CH3:38])([CH3:37])[CH3:33])[CH:23]=1
Reactant: C#C[Si](C)(C)C
Reactant: COCC1Oc2cc3ncnc(Nc4cccc(I)c4)c3cc2OC1COC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)C
Product: COCC1Oc2cc3ncnc(Nc4cccc(C#C[Si](C)(C)C)c4)c3cc2OC1COC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 ml of trimethylamine was mixed with the titled compound of Example 45 (40 mg, 0.075 mmol), 1-trimethylsilylacetylene (15 mg, 0.15 mmol), copper iodide (16 mg, 0.084 mmol) and tetrakis(triphenylphosphine)palladium (26 mg, 0.022 mmol), followed by stirring for 12 hours at a room temperature. Then, the reaction mixture was filtered to obtain a filtrate, which was then concentrated and purified by a column chromatography (mobile phase: hexane:ethylacetate=2:3(v:v)) to prepare the titled compound (33 mg, 97%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>C(#N)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: OB(O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OB(O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixture of (4-(bromomethyl)phenyl)boronic acid (500 mg) and potassium carbonate (643 mg) in acetonitrile (10 mL) was added morpholine (0.304 mL), and the mixture was stirred at room temperature for 60 hr. To the reaction mixture was added water, 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 obtained solid was washed with diisopropyl ether and ethyl acetate to give the title compound (449 mg).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc([C@H]2CCNC[C@@H]2F)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol) in 1.5 mL DCM at rt was added TFA (0.5 mL, 6.5 mmol), and the mixture was stirred for 3 h. The mixture was then concentrated in vacuo to dryness to yield 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate (126 mg, 0.41 mmol), which was used directly in step D.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(=O)CCl
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cn2ccnc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
A solution of 2-amino-3-chloropyrazine (10 g, 77.5 mmol), chloroacetone (30 mL, 387 mmol) in MeOH (25 mL) is refluxed overnight at 88° C. It is then stirred for 1 h at 0° C. and any solid that forms, is filtered off and washed twice with MeOH (5 mL). The mother liq. are evaporated, diluted with EtOAc, and washed with HCl 2N, water and brine. The water and HCl mother liq. are evaporated to give a yellow solid that is neutralized with a saturated solution of K2CO3 in water, extracted with DCM, dried with MgSO4 anh. filtered and concentrated. The crude material is purified by column chromatography using a gradient of (DCM/MeOH: 1/0 to 99/1) to give 8-Chloro-2-methyl-imidazo[1,2-a]pyrazine as an orange solid (1.02 g, 7.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][N:37]=[C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:36]6[CH:35]=[C:34]([CH3:33])[O:38][N:37]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cc(C2(N)CC2)no1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cc(C)on5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methylisoxazol-3-yl)cyclopropanamine (0.074 g, 0.5 mmol, 1.1 eq), HOBT (0.094 g, 0.69 mmol, 1.5 eq), EDC.HCl (0.0.13 g, 0.69 mmol, 1.5 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml). Yield: 0.1 g (39.22%). 1H NMR (400 MHz, CD3OD): δ 1.39-1.48 (m, 4H), 2.36 (s, 3H), 2.380-2.382 (d, 3H, J=0.8 Hz), 2.96 (s, 3H,), 4.05, (s, 3H), 6.05 (d, 1H, J=0.8 Hz), 7.12 (s, 1H), 7.26-7.34 (m, 3H), 7.58-7.59 (d, 1H, J=1.2 Hz), 7.62-7.64 (d, 1H, J=8.8 Hz), 7.81 (s, 1H), 7.96-7.98 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:5]1([CH2:4][O:3][C:1]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([O:26][N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])=[O:25])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:14])=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 0 °C

Procedure:
A 7.17 g portion of carbobenzyloxy glycyl-L-phenylalanine and 2.30 g of N-hydroxysuccinimide were slurried in 100 ml of acetonitrile, cooled in an ice bath, with the addition of 5 ml of dimethylformamide, to obtain solution. A precooled solution of 4.12 g of dicyclohexylcarbodiimide in 50 ml of acetonitrile was added dropwise. The mixture was stirred in the ice bath for 2 hours, then refrigerated overnight, filtered and the filtrate concentrated in vacuo. The residue was taken up in 125 ml of ethyl acetate, washed with precooled 5% aqueous sodium bicarbonate, then twice with water, dried and concentrated in vacuo. The residue was dissolved in 125 ml of 2-propanol and refrigerated overnight. The resulting gum was taken up in tetrahydrofuran and concentrated in vacuo, giving 6.5 g of 1-[[N-[N-[(phenylmethoxy)carbonyl]glycyl]-L-phenylalanyl]oxy]-2,5-pyrrolidinedione.