Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C(N(CC)CC)C.[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>C(O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:2]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:3]1)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN1N=C(C)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To an ethanol (250 mL) solution of ethyl hydrazinoacetate monohydrochloride (19.4 g, 125 mmol) was added triethylamine (19.2 mL, 138 mmol), and the mixture was stirred at room temperature for 10 minutes, and then ethyl acetoacetate (16.6 mL, 131 mmol) was added, and the mixture was heated to reflux for four hours. After returning the mixture to room temperature, the solvent was distilled off under reduced pressure. N-heptane (100 mL) was added to the residue to yield a solid, and the obtained solid was filtered and washed with n-heptane to obtain primary crystals of the title compound (17.1 g, 93.0 mmol). Furthermore, the solvent in the filtrate was distilled off under reduced pressure, and to the residue, n-heptane/acetone mixture (1:1) was added to yield a solid, and the obtained solid was filtered. Thus, secondary crystals of the title compound (0.44 g, 2.39 mmol) were obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31]>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(C2CCOCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCOCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.498 mmol), and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (98 mg, 0.647 mmol). The product was collected as a solid, 0.170 g (78%). LCMS E-S (M+H)=436.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.14 (m, 4H), 1.79 (dd, J=12.63, 2.27 Hz, 2H), 2.05-2.18 (m, 5H), 2.19-2.27 (m, 4H), 2.36 (s, 3H), 3.53 (t, J=11.12 Hz, 2H), 3.98 (dd, J=11.49, 3.41 Hz, 2H), 4.33 (d, J=4.80 Hz, 2H), 4.87 (m, J=11.53, 11.53, 4.11, 3.92 Hz, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.59 (t, J=4.93 Hz, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:6][C:5]=1[C:11]([F:13])([F:12])[F:14]
Reactant: COC(=O)c1ccc(O)cc1C(F)(F)F
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CC2)cc1C(F)(F)F
Yield: 102.6 %

Procedure:
4-hydroxy-2-trifluoromethyl-benzoic acid methyl ester (1.1 g, 4.8 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.5 eq) and K2CO3 (1.04 g, 2.0 eq) were added and the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (0.42 mL, 4.3 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried. The title product (1.21 g, yield 92%) was recovered and used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC>CCOCC>[N:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[B:18]([OH:23])[OH:19])=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(Br)c(-c2ccncc2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1ccc(C(F)(F)F)cc1-c1ccncc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A 250-mL round bottom flask was charged with 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (0.242 g, 0.801 mmol), Ether (6.16 ml), and triisopropyl borate (0.223 ml, 0.961 mmol). The flask was cooled to −78° C. for 10 minutes, after which butyllithium (2.5M in hexanes) (0.385 ml, 0.961 mmol) was added dropwise. After 30 minutes the dry-ice bath was removed, and 2N aq NaOH (10 mL), and the resulting biphasic mixture was stirred vigorously. After 1 h, the mixture was diluted with water, and the layers separated. The ether was then extracted with water (×2) and the water layers were combined, and washed with ether. The ether layers were back-extracted once more, and all aqueous layers combined and neutralized to ˜pH=7 with 1N aq HCl to give a clear solution. The aqueous was extracted with DCM (×3) and the combined organics were dried over sodium sulfate, filtered and concentrated. The dried residue was taken up in DCM, and concentrated to give (2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)boronic acid (0.136 g, 0.509 mmol, 63.6% yield) as an off-white solid. [M+H]+=268.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH:32]1([CH2:38]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: OCC1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCCC3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), cyclohexylmethanol (77.6 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 538.1 (M+H); Rt: 2.24 min.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].Cl.[CH3:33][NH:34][CH3:35].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:34]([CH3:35])[CH3:33])=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN(C)C)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Yield: 18.1 %

Procedure:
In a similar manner to Step 2 of Example 6, a crude product of 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.713 g) was dissolved in acetonitrile (20 mL), and the solution was treated with dimethylamine hydrochloride (2.75 g, 33.8 mmol), triethylamine (4.70 mL, 33.8 mmol), acetic acid (1.90 mL, 33.8 mmol) and sodium triacetoxyborohydride (1.10 g, 5.07 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=4/1) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.138 g, yield 19%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](NCCCC)[N:7]=2)[CH2:3]1.C(OC(=O)NC1CN(C2C=CN=C([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])N=2)C1)(C)(C)C.Cl.CO>C(O)=O>[NH2:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:38][CH2:37][CH2:36][CH2:35][NH2:34])[N:7]=2)[CH2:5]1
Reactant: CCCCNc1nccc(N2CC(N)C2)n1
Reactant: CCCCNc1nccc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: NCCCCc1nccc(N2CC(N)C2)n1
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 98 %

Procedure:
[1-(2-Chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester To a flask containing 2,4-dichloropyrimidine (1.6 g, 10.7 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) in i-PrOH (40 mL) was added azetidin-3-yl-carbamic acid tert-butyl ester monohydrochloride (2.1 g. 12.2 mmol). The reaction mixture was heated to 70° C. for 72 h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by flash chromatography on SiO2 (100% hexane increasing gradient to 60% EtOAc-Hexane) to yield two isomeric products. The minor upper Rf product was obtained as a white solid (326 mg, 11%), and the desired major lower Rf product was also obtained as a white solid (2.1 g, 69%). [1-(2-Butylamino-pyrimidin-4-yl)azetidin-3-yl]-carbamic acid tert-butyl ester. To a solution of [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in i-PrOH (3.0 mL) was added butylamine (600 μL, 6.0 mmol). The reaction mixture was heated to 95° C. in a sealed tube for 36-48 h followed by cooling to room temperature. The reaction mixture was then concentrated and the crude residue purified by flash chromatography on SiO2 using (100% EtOAc increasing the gradient gradually to 5% 2M NH3-MeOH) to yield the desired product (260 mg, 92%). [4-(3-Amino-azetidin-1-yl)-pyrimidin-2-yl]-butyl-amine. To a solution of [1-(2-butylamino-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in formic acid (4 mL) was added 6N HCl (300 μL). The reaction mixture was stirred at room temperature for 15-30 minutes. Then, MeOH (10 mL) was added and stirred for 10 minutes. The contents were then concentrated and the crude residue purified by flash chromatography on SiO2 using an increasing gradient of (0 to 10% NH3/MeOH in CH2Cl2) to yield the desired product (225 mg, 98%) as the free base. MS (ESI): mass calcd. for C11H19N5, 221.3 m/z found, 222.2 [M+H]+. 1H NMR (CD3OD): 7.61 (d, J=7.3, 1H), 5.99 (d, J=7.1, 1H), 4.6-4.7 (m, 2H), 4.28-4.48 (m, 3H), 3.40 (bs, 1H), 1.54-1.62 (m, 2H), 1.31-1.41 (m, 2H), 0.90 (t, J=7.4, 3H). The compounds in Example 85 through Example 94 were prepared using methods analogous to those described for Example 84.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:26]([CH3:27])=[CH:25][C:18]2[N:19]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:29]1[C:40]2[C:41]3[C:36]([C:37](B(O)O)=[CH:38][CH:39]=2)=[N:35][CH:34]=[CH:33][C:32]=3[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=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:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:26]([CH3:27])=[CH:25][C:18]2[N:19]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[S:21][C:17]=2[C:16]=1[C:37]1[C:36]2[C:41]3=[C:32]([CH2:31][CH2:30][O:29][C:40]3=[CH:39][CH:38]=1)[CH:33]=[CH:34][N:35]=2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Reactant: Cc1cc2nc(C3CC3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc2nc(C3CC3)sc2c(-c2ccc3c4c(ccnc24)CCO3)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
To a solution of (S)-2-(7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (18) (23 mg, 0.047 mmol) in DMA (2 ml), was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (25 mg, 0.099 mmol), 2N K2CO3 solution (0.11 ml, 0.22 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). The reaction mixture was reacted at 85° C. for 2 hs. The reaction was cooled down, washed by saturated NaHCO3 solution, extracted by EtOAc. The organic phase was combined, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. Two isomers were separated and went through the chemistry sequence as above. LCMS-ESI+: calc'd for C33H38N2O4S: 559.2 (M+H+). Found: 559.1 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>C(O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][N:30]=[C:17]2[CH2:18][CH2:19][CH:14]([NH:13][C@H:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=3)[CH2:15][CH2:16]2)=[CH:25][CH:24]=1
Reactant: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1CCC(=NNc2ccc(Br)cc2)CC1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
To a solution of 22.3 gm (85.01 mMol) N-((R)-(+)-α-methyl-(4-nitrophenyl)ethyl)-4-aminocyclohexanone in 375 mL ethanol were added 19.0 gm (85.0 mMol) 4-bromophenylhydrazine hydrochloride and 6.73 gm (85.1 mMol) pyridine. The reaction mixture was heated to 80° C. for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic solution was washed sequentially with aqueous potassium carbonate and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 31.66 gm (86%) N-((R)-(+)-α-methyl-(4-nitrophenyl)-ethyl)-4-aminocyclohexanone 4-bromophenylhydrazone as a brown solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:52])[CH2:12][C:11]2[N:10]3[CH2:13][CH2:14][N:15]([C:18]4[N:25]=[CH:24][CH:23]=[C:22]([C:26]5[CH:31]=[C:30]([NH:32][C:33]6[CH:38]=[CH:37][C:36]([N:39]7[CH2:44][CH2:43][N:42]([CH:45]8[CH2:48][O:47][CH2:46]8)[CH2:41][C@@H:40]7[CH3:49])=[CH:35][N:34]=6)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=5)[C:19]=4[CH:20]=[O:21])[C:16](=[O:17])[C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1>>[F:52][C:4]1([F:3])[CH2:12][C:11]2[N:10]3[CH2:13][CH2:14][N:15]([C:18]4[C:19]([CH2:20][OH:21])=[C:22]([C:26]5[CH:31]=[C:30]([NH:32][C:33]6[CH:38]=[CH:37][C:36]([N:39]7[CH2:44][CH2:43][N:42]([CH:45]8[CH2:48][O:47][CH2:46]8)[CH2:41][C@@H:40]7[CH3:49])=[CH:35][N:34]=6)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=5)[CH:23]=[CH:24][N:25]=4)[C:16](=[O:17])[C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(F)(F)CC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(F)(F)CC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 51.8 %

Procedure:
Following the procedures as described in Example 130, sodium borohydride reduction of 140a (200 mg) afforded 140 as a yellow solid (104 mg, 51%). LCMS: [M+H]+ 686.3. 1H NMR (500 MHz, DMSO) δ 8.62 (d, J=2.0, 1H), 8.46-8.49 (m, 2H), 7.83 (d, J=3.0, 1H), 7.45 (d, J=2.5, 1H), 7.35-7.38 (m, 2H), 7.25 (d, J=9.5, 1H), 6.64 (s, 1H), 4.95-4.97 (m, 1H), 4.54-4.57 (m, 2H), 4.38-4.48 (m, 4H), 4.15-4.27 (m, 3H), 3.87-3.90 (m, 1H), 3.67 (s, 1H), 3.59 (s, 3H), 3.26-3.39 (m, 3H), 3.08-3.10 (m, 1H), 2.92-2.96 (m, 1H), 2.63-2.67 (m, 2H), 2.52-2.55 (m, 1H), 2.30-2.36 (m, 2H), 2.18-2.24 (m, 3H), 0.93 (d, J=6.0, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:28]([Cu])#[N:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:28]#[N:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 530 (M+H)+.
Reaction SMILES: C(OC([N:11]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]([NH2:19])([CH3:18])[C:12]1=[O:20])=O)C1C=CC=CC=1.[ClH:21].[H][H].O>C(O)C.[Pd]>[ClH:21].[NH2:19][C:13]1([CH3:18])[CH2:14][CH2:15][C:16](=[O:17])[NH:11][C:12]1=[O:20]
Reactant: [H][H]
Reactant: CC1(N)CCC(=O)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(N)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature. To this solution was added 4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydrogen for 3 hours. To the mixture was added water (50 mL) to dissolve the product. This mixture was filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue. The solid was slurried in ethanol (20 mL) for 30 min. The slurry was filtered to afford 1.38 g (93%) of α-amino-α-methylglutarimide hydrochloride as a white solid: 1H NMR (DMSO-d6) δ 11.25 (s, 1H), 8.92 (s, 3H), 2.84-2.51 (m, 2H), 2.35-2.09 (m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 1.03 min (94.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:45]([OH:47])=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:48][CH2:49][CH:50]([CH2:52]O)[OH:51].C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:45]([O:47][CH2:52][CH:50]([OH:51])[CH2:49][OH:48])=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:38])[CH2:25][CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27]2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC2C=Nc3ccccc32)NS(=O)(=O)c2ccccc2)C(=O)OCC(O)CO)cc1
Yield: 79.3 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(N′α-benzenesulfonyl-L-tryptophanyl)-L-lysine (170 mg, 0.25 mmol) dissolved in a solution of DMF (1 mL) was treated with glycerol (100 μL, 1.37 mmol) and EDC (100 mg, 0.5 mnol) and stirred overmght. Them, the solution was poured in 5% citric acid and extracted with EtOAc. The solvent was evaporated and the residue purified by preparative HPLC to give 150 mg (79%) of the final product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:23](N=P(N(C)C)(N(C)C)N(C)C)(C)([CH3:25])[CH3:24].[Br-]>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:23]=[CH2:24])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), ally) bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20 C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][C:12]([CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:37][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Sodium hydride (55% suspension in oil, 0.48 g) was added to a solution of diethyl 2-(3-phenylpropyl)malonate (2.78 g) in a mixture of N,N-dimethylacetamide (10 ml) and toluene (20 ml). The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture 4-benzyloxybenzyl chloride (2.45 g) was added and the mixture was stirred at ambient temperature for 30 minutes and then at 60° C. for 30 minutes. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1 as the eluant to afford the desired compound (3.91 g) as a syrup.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[C:26]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])[CH:20]([NH:33]C(OC(C)(C)C)=O)[C:19]2=[O:41])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C(Cl)Cl>[NH2:33][CH:20]1[C:19](=[O:41])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([CH:25]=[C:26]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)OS(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1)OS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-mesyloxyprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) in acetonitrile (12 cc) is heated to 38° C. A solution of p-toluenesulphonic acid monohydrate (0.63 g) in acetonitrile (10 cc) is added in the course of 20 minutes and the mixture is then kept at 38° C. for 1 hour. It is diluted with methylene chloride (30 cc) and the solution obtained is washed with a saturated solution of sodium bicarbonate (20 cc) and then with distilled water (50 cc), dried over sodium sulphate and concentrated to a volume of 15 cc under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields a solution of the Z form of 7-amino-2-benzhydryloxycarbonyl-3-(2-mesyloxyprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, to which triethylamine (0.7 cc) is added (Solution A).