Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[I:28]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[I:28][C:12]1[S:11][C:10]([O:9][C:8]2[CH:15]=[CH:16][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:14][CH:13]=1
Reactant: II
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(I)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 7A (1.52 g, 6.5 mmole) in tetrahydrofuran (80 mL) at −78° C. was added a solution of 2.5M n-butyl lithium in hexane (2.84 mL, 7.1 mmole) and stirred for 2 hours. Solid iodine (1.80 g, 7.1 mmole) was added and the mixture was allowed to warm up to room temperature for an hour. The reaction mixture was diluted with ethyl acetate and added an aqueous solution of 10% sodium thiosulfate. The ethyl acetate layer was dried over magnesium sulfate, dried over magnesium sulfate and filtered through silica gel to remove polar impurities. The silica gel was washed with ethyl acetate until no UV active spot was apparent on TLC plate. Evaporation of the solvent yielded the title compound as light-yellow oil, 2.30 g (Quantitative). 1H NMR (300 MHz, CDCl3) δ ppm 7.29 (s, 1H) 7.09-7.22 (m, 2H) 6.84-6.96 (m, 2H) 4.42-4.61 (heptet, J=5.88 Hz, 1H) 1.34 (d, J=5.88 Hz, 6H). MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12.[O:16]([CH2:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[O:16]([CH2:23][C:24]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C[C@@]1(C)S[C@@H]2[C@H](N)C(=O)N2C1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C[C@@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
6β-Amino-2α-vinyl-2β-methylpenam-3-carboxylic acid is acylated in acetone-water with phenoxyacetyl chloride in the presence of sodium carbonate to provide the title compound.
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]1[CH:15]=[CH:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[CH:7]=1.[Br:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:22]=1[O:34][CH3:35]>>[Br:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]([C:29]2[O:30][C:31]([C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]3[CH:15]=[CH:14][C:9]4[N:10]([CH3:13])[N:11]=[N:12][C:8]=4[CH:7]=3)=[CH:32][CH:33]=2)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc2c(c1)nnn2C
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc4c(c3)nnn4C)o2)cc(OC)c1Br
Yield: 34 %

Procedure:
N,2-Dimethoxy-N-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetamide was coupled with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the procedure for the synthesis of Example 13. Purification by chromatography provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)ethanone as a light yellow foam (0.153 g, 34% yield). MS: m/z 486.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:22][C:23]#[N:24])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.C([Sn]([N:38]=[N+:39]=[N-:40])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:17]([CH2:22][C:23]2[NH:40][N:39]=[N:38][N:24]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N(CC#N)S(C)(=O)=O)c2nc1OC
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(N(Cc3nnn[nH]3)S(C)(=O)=O)c2nc1OC
Yield: 70.2 %

Procedure:
A mixture of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(cyanomethyl)methanesulphonamide (100 mg, 0.256 mmol) and tributyltin azide (170 mg, 0.512 mmol) (Synthesis, 1976, 329) in toluene (10 ml) was heated at reflux for 18 hours. After cooling the mixture was concentrated under reduced pressure and the residue purified by flash chromatography (gradient elution from dichloromethane to 90:10:1 dichloromethane: methanol:ammonia) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(5-tetrazolylmethyl) methanesulphonamide as an off-white solid (78 mg, 70%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:18])=[O:17])=[C:9]([O:29][CH2:30][O:31][CH3:32])[CH:8]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:59]1[CH:64]=[C:63]([F:65])[C:62]([F:66])=[C:61]([F:67])[CH:60]=1.[PH2](=O)[O-].[K+]>O.C(OCC)(=O)C.O1CCOCC1>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:59]3[CH:64]=[C:63]([F:65])[C:62]([F:66])=[C:61]([F:67])[CH:60]=3)=[CH:8][C:9]=2[O:29][CH2:30][O:31][CH3:32])(=[O:18])=[O:17])[CH:24]=1)#[N:26]
Reactant: COCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Reactant: Fc1cc(Br)cc(F)c1F
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=[PH2][O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COCOc1cc(-c2cc(F)c(F)c(F)c2)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 80 °C
Reaction time: 15 h
Yield: 104.6 %

Procedure:
A mixture of 10.0 g of 4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluoromethanesulfonate, 5.33 g of bis(pinacolato)diboron, 467 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex, 317 mg of 1,1′-bis-(diphenylphosphino)ferrocenepalladium(II), 5.61 g of potassium acetate, and 113 mL of 1,4-dioxane was stirred under an argon atmosphere at 80° C. for 15 hours. To the reaction mixture were added 4.02 g of 1-bromo-3,4,5-trifluorobenzene, 467 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex, 12.14 g of potassium phosphinate, and 40 mL of 1,4-dioxane. The mixture was stirred under argon atmosphere at 80° C. for 24 hours, and ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate-hexane) to give 10.09 g of 5-cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxymethoxybiphenyl-4-yl)ethyl]benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:19])=[O:18])[C:5]=1[C:6]([O:8]C)=[O:7])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:18])=[O:19])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Yield: 94.8 %

Procedure:
Two reactions were run simultaneously. For each reaction, a solution of Example 385H (0.26 g, 0.68 mmol) and lithium hydroxide hydrate (0.275 g, 6.5 mmol) in dioxane (3 mL) and water (1.5 mL) was heated to 160° C. for 15 minutes. The combined reaction mixture was acidified to pH 2.0 with 1 N HCl and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product, 0.475 g, 94.8% yield. 1H NMR (DMSO-d6) δ 1.10 (t, 3H) 1.22 (t, 3H), 2.54 (q, 2H), 3.80 (q, 2H), 6.80 (d, 1H), 7.20 (d, 1H), 7.30 (t, 1H), 7.40 (dd, 1H), 7.65-7.75 (m, 2H), 9.90 (s, 1H), 13.25 (br s, 1H); MS (ESI(−)) m/e 366 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:31])([F:32])[F:30])=[CH:28][C:3]=3[C:2]([F:1])([F:34])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:19][NH:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([O:19][N:20]([CH3:21])[C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1cccc(N=C=O)c1
Reactant: CNOCc1ccccc1
Solvent: C1CCOC1
Product: CSc1cccc(NC(=O)N(C)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
3-(Methylthio)phenyl isocyanate (2.0 g, 12 mmol) was added dropwise to a solution of N-benzyloxy-N-methylamine (1.55 g, 11.3 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature for 2 hours then concentrated under vacuum. The residue was purified by flash chromatography (silica gel; ethyl acetate:hexanes) to provide 3.26 g of 1-benzyloxy-1-methyl-3-[3(methylthio)phenyl]urea as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(C(O)=O)[CH2:33]C[CH2:31]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:29][CH2:28][CH2:33][CH2:30][CH2:31][CH2:27]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Reactant: O=C(O)C1CCC1
Product: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCCCCC1

Procedure:
Cycloheptane carboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (compound of Formula II where R1=cycloheptyl and Q1=Ph-(3-OBn)) was prepared according to the procedures described for the synthesis of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]amide (compound of Formula III where R1=cyclobutyl and Q1=Ph-(3-OBn)) above except for the substitution of cycloheptane carboxylic acid for cyclobutanecarboxylic acid; MS (ES) 450.2 (M+1), 452.2 (M+3).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@H:5]2[C:6](=[O:25])[N:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C@@H:14]3[CH2:19][C@@:15]3([C:20]([O:22][CH3:23])=[O:21])[NH:16][C:17](=[O:18])[C@@H:4]2[CH2:3]1.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:1][C@@H:2]2[CH2:27][CH2:26][C@H:5]3[C:6](=[O:25])[N:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C@@H:14]4[CH2:19][C@@:15]4([C:20]([O:22][CH3:23])=[O:21])[NH:16][C:17](=[O:18])[C@@H:4]3[CH2:3]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)N2
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)N2
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Solvent: ClCCl
Product: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of compound 43 (0.13 mmol), TEA (0.39 mmol), and DMAP (0.009 mmol) in anhydrous DCM (0.3 mL) was added 4-bromobenzenesulfonyl chloride (0.17 mmol) in DCM (0.15 mL) dropwise. The reaction mixture was stirred at room temperature under nitrogen for 16 hrs. The crude material was washed sequentially with 0.5N HCl and 2.5% NaHCO3. The organics were concentrated to yield compound 44 as a yellow oil in a quantitative yield. MS (ESI, EI+): m/z=598 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[O:9])[CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[O:26][C:27]=1[Br:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:9])[CH2:3][C@@H:2]2[CH3:1])=[O:30])[O:26][C:27]=1[Br:28]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: Cc1cccc(-n2cnc(C(=O)N3CCN[C@@H](C)C3)n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-n2cnc(C(=O)N3CCN(C(=O)c4cc(Br)c(Br)o4)[C@@H](C)C3)n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 86 mg (0.30 mmol) ((S)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]triazol-3-yl)-methanone, 84 mg (0.30 mmol) 4,5-dibromo-2-furoic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.[CH2:23]([N:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][C:28](O)=[O:29])[CH:24]=[CH2:25].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:28](=[O:29])[CH2:27][N:26]([CH2:23][CH:24]=[CH2:25])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: C=CCN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC(=O)N1CCC[C@H]1C(=O)OC)C(=O)OCc1ccccc1
Yield: 238.9 %

Procedure:
1-(3-Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCI) (0.453 g, 2.36 mmol) was added to a solution of proline methyl ester hydrochloride 30 (0.356 g, 2.15 mmol), acid 55 (0.590 mmol, 2.35 mmol) and triethylamine (0.481 g, 4.73 mmol) in dichloromethane (20 cm3) at 0° C. The resultant solution was stirred for 19 h, washed with 2M aqueous hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and the solvent removed to yield an oil which was purified by chromatography (silica gel, hexanes:ethyl acetate, 2:1, 1:1) to afford protected dipeptide 56 (0.508 g, 66%) as a colourless oil. Dipeptide 56 was shown to be a 76:24 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated by integration of signals at δ 22.0 and 24.5, 24.7, assigned to the Proγ-C atoms of the minor and major conformers respectively). In addition, restricted rotation about the GlyN—CO carbamate bond was also observed resulting in a further 1:1 mixture of conformers: [α]D −54.6 (c 1.17 in CH2Cl2); δH (400 MHz; CDCl3; Me4Si) 1.81-2.14 (4H, m, Proβ-H2, Proγ-H2), 3.29-3.58 (2H, m, Proδ-H2), 3.64, 3.66, 3.69* (3H, s, OCH3), 3.84-4.20 [4H, m, CH2(allyl), Glyα-H2], 4.40-4.48 (1H, m, Proα-H), 5.07-5.17 (4H, m, OCH2Ph, ═CH2), 5.69-5.81 (1H, m, C(H)═CH2) and 7.24-7.30 (m, 5H, Ph); δC (100 MHz; CDCl3) 22.0* (CH2, Proγ-C), 24.62, 24.73 (CH2, Proγ-C), 28.66, 28.73 (CH2, Proβ-C), 31.1,* 31.3* (CH2, Proβ-C), 45.93, 45.98 (CH2, Proδ-C), 46.5* (CH2, Proδ-C), 47.5, 48.0 (CH2, Glyα-C), 50.0, 50.6 [CH2, CH2(allyl)], 50.0,* 50.6* [CH2, CH2(allyl)], 52.0, (CH3, OCH3), 52.31,* 52.5* (CH3, OCH3), 58.4,* 58.5* (CH, Proα-C), 58.8 (CH, Proα-C), 67.2, 67.3 (CH2, OCH2Ph), 117.0, 117.5 (CH2, ═CH2), 127.5, 127.7, 127.8, 128.3, (CH, Ph), 133.2, 133.4 (CH, C(H)═CH2) 136.4, 136.5 (quat., Ph), 155.8, 156.3, (quat., NCO2), 167.1 (quat., Gly-CO), 167.4,* 167.5* (quat., Gly-CO). 172.0,* 172.2* (quat., Pro-CO) and 172.3, 172.4 (quat., Pro-CO); m/z (EI+) 360.1676 (M+. C19H24N2O5 requires 360.1685).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C([BH3-])#N.[Na+].[C:13]1([CH2:19][CH2:20][CH:21]2[C:25]3[CH:26]=[C:27]([CH:30]=O)[CH:28]=[CH:29][C:24]=3[O:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:20]([CH:21]1[C:25]2[CH:26]=[C:27]([CH2:30][NH:6][CH:5]([CH3:7])[C:4]([NH:3][CH3:2])=[O:8])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22]1)[CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc2c(c1)C(CCc1ccccc1)CO2
Reactant: CNC(=O)[C@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(C)NCc1ccc2c(c1)C(CCc1ccccc1)CO2
Reaction time: 12 h
Yield: 76.1 %

Procedure:
To a solution of N-methyl-alaninamide hydrochloride (0.50 g, 3.61 mmol) in methanol (10 ml), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.36 g, 5.69 mmol) and a solution of 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-carboxaldehyde (0.90 g, 3.61 mmol) in methanol (10 ml) were added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (ethyl acetate/methanol=98/2) affording 0.93 g of title compound (77% yield).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([O:19]C)=O)[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][O:26][NH2:27].C(O)(=O)C>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([NH:27][O:26][CH3:25])=[O:19])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Reactant: CON
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CONC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Temperature: 63 °C
Reaction time: 28 h
Yield: 5.6 %

Procedure:
To methyl 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.6 g, 2 mmol) in methanol (10 ml) and water (1 ml) were added sodium hydroxide (0.56 g, 14 mmol) and O-methylhydroxylamine (0.668 g, 8 mmol). The resulting mixture was stirred for 28 hours at 63° C. Acetic acid (2 mL) was added to precipitate undesired byproduct, 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, which was removed by filtration. The filtrate was concentrated in under reduced pressure; the residue was dissolved in methanol and purified by preparative HPLC to provide the title compound as a white powder (0.035 g, 5.6% yield). 1H NMR (300 MHz, DMSO-d6) d ppm 3.76 (s, 3H) 5.60 (s, 2H) 6.75 (d, J=2.83 Hz, 1H) 7.17-7.24 (m, 2H) 7.32-7.39 (m, J=5.46 Hz, 2H) 7.76 (d, J=3.20 Hz, 1H) 8.47 (s, 1H) 12.08 (s, 1H) 12.89 (s, 1H). LC-MS (APCI, M+H+): 316.1. HPLC: 95% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([NH2:15])=[CH:13][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)[CH:6]=[N:7][CH:8]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:41].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:15][C:14]1[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:10][CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=1)=[C:24]([CH3:41])[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: COc1cncc(-c2ncc(N3CCOCC3)cc2N)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cncc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 5′-methoxy-5-morpholino-2,3′-bipyridin-3-amine (75.1 mg, 0.26 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.11 g, 0.4 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (20.7 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium (0) (11 mg, 0.012 mmol), and sodium tert-butoxide (76.4 mg, 0.8 mmol) in dry toluene (3.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (30-50% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford an impure yellow solid. The light yellow solid was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (1H, d, J=1.5 Hz), 8.69 (1H, dt, J=4.6, 1.3 Hz), 8.39 (1H, d, J=2.9 Hz), 8.11 (1H, d, J=2.4 Hz), 7.96 (2H, m), 7.82 (1H, br. s.), 7.64 (1H, dt, J=9.4, 1.2 Hz), 7.44 (1H, m), 7.06 (2H, m), 6.57 (1H, d, J=2.4 Hz), 3.97 (3H, s), 3.89 (4H, m), 3.29 (4H, m), 2.24 (3H, s). Mass Spectrum (pos.) m/e: 541.2 (M+1).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.C(N(CC)CC)C.S(Cl)([Cl:36])=O>C1(C)C=CC=CC=1>[Cl:36][CH2:25][C:21]1[N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][N:22]=1
Reactant: OCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ClCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of (1-trityl-1H-imidazol-2-yl)-methanol (9.92 g; CAS 102152-03-4) in toluene (160 ml) was cooled under an argon atmosphere to 0° C. and treated with triethylamine (8.1 ml). Then, thionylchloride (2.96 ml) was added dropwise. The reaction mixture was stirred for 1 hour at 0° C., then treated with 500 ml ice-cold H2O. The mixture was extracted with EtOAc. The organic layer was washed with H2O, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (silica gel; eluent: CH2Cl2/methanol 95:5) to give 2-chloromethyl-1-trityl-1H-imidazole (2.73 g) as off-white solid. MS 359.0 ([M+H]+)