Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([I:11])=[CH:8][C:6]=2[N:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)([I:11])[CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Yield: 53 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 129 mg of 3-acetamidophenylboronic acid (250 mg) and 23 mg of bis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1M Na2CO3 aqueous solution and 1.5 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 15 min. Upon completion, the reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 20˜100% EtOAc/hexane to yield N-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)acetamide (530 mg, 53%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 42.8 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (85 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT overnight. After the same work-up described in example 3 the residue was triturated with isopropyl ether to produce a solid that was recovered and dried to give pure title compound (85 mg, 0.214 mmol, yield 42.8%) as yellow crystals, m.p.=152°.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][N:23]([CH3:36])[C:24]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31]C)=[O:30])=[O:25])=[CH:4][CH:3]=1.O[Li].O.Cl>CO.O>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][N:23]([CH3:36])[C:24]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([OH:31])=[O:30])=[O:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2cccc(-c3cc(CN(C)C(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 80 °C
Yield: 113.6 %

Procedure:
To a solution of methyl 3-{[({6-fluoro-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)(methyl)amino]carbonyl}benzoate (0.20 g, 0.409 mmol) in MeOH/H2O (1.2/0.6 mL) was added LiOH.H2O (0.086 g, 2.05 mmol). The mixture was heated in a microwave at 80° C. for 30 min following which it was acidified with HCl, concentrated and the concentrate purified using a Gilson HPLC to afford the title compound 0.221 g (quantitative). LC-MS m/z 476 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[CH:18]1([N:21]2[C:30]3[C:25](=[C:26](F)[CH:27]=[C:28]([F:31])[CH:29]=3)[C:24](=[O:33])[C:23]([OH:34])=[C:22]2[CH3:35])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([N:21]2[C:30]3[C:25](=[C:26]([NH:12][C:11]4[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:10]=4[F:9])[CH:27]=[C:28]([F:31])[CH:29]=3)[C:24](=[O:33])[C:23]([OH:34])=[C:22]2[CH3:35])[CH2:20][CH2:19]1
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1c(O)c(=O)c2c(F)cc(F)cc2n1C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(O)c(=O)c2c(Nc3ccc(I)cc3F)cc(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.3 %

Procedure:
LDA (2N solution in heptane/tetrahydrofuran/ethylbenzene, 6 mL, and 12 mmol) was added dropwise to a stirred solution of 2-fluoro-4-iodoaniline (2.085 g, 8.8 mmol) in THF (14 mL) at −78° C. After 10 minutes, a solution of example 6c (0.9 g, 3.57 mmol) in THF (30 mL) was then added at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 13 h. The solution was cooled to 0° C., quenched with 1N HCl (100 mL), extracted with EtOAc and dried (MgSO4). Purification by silica gel chromatography (10% MeOH/DCM) gave 340 mg (20%) of the title compound as light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.72 (s, 1H), 8.41 (s, 1H), 7.73 (dd, 1H, J=10.4, 1.6 Hz), 7.55 (dd, 1H. J=8.4, 1.6 Hz), 7.49 (t, 1H, J=8.4 Hz), 7.03 (dd, 1H, J=10.4, 1.6 Hz), 6.62 (dd, 1H, J=10.4, 1.6 Hz), 3.32-3.42 (m, 1H), 2.54-2.53 (m, 3H), 1.35-1.42 (m, 2H), 0.84-0.89 (m, 2H). MS (ES) [m+H] calc'd for C19H15F2IN2O2, 469; found 469.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A 100 mL round-bottom flask, was charged with 4-bromo-2-phenoxybenzaldehyde (1.00 g, 3.61 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.674 g, 3.62 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.30 g, 10.8 mmol, 3.01 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with H2O (10 mL). The resulting mixture was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92) to provide 1.20 g (74% yield) of tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 447 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([CH:12]([CH2:16][CH3:17])[C:13](=[S:15])[NH2:14])[CH3:11]>C(O)C>[CH3:11][CH2:10][CH:12]([C:13]1[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)[CH2:16][CH3:17]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCC(CC)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(C(CC)CC)n1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (2.5 mL) was added dropwise to a solution of 2-ethylbutanethioamide (example 71, step b) (3.8 g) in ethanol (100 mL) and the resulting mixture heated at reflux overnight. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 20:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 2.8 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:46][CH:47]([CH3:49])[CH3:48])[C:22]([NH:24][N:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:26][C@H:27]([N:29]1C(=O)C2=CC=CC=C2C1=O)[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/C1C=CC=CC=1)=[O:10].[OH2:50].NN>CO>[NH2:29][C@@H:27]([C:26]([N:25]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:50])[CH3:28]
Reactant: CC(C)C[C@@H](C(=O)NN(C[C@@H](C)N1C(=O)c2ccccc2C1=O)c1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: O
Agent: NN
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(C(=O)[C@@H](C)N)c1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reaction time: 5.5 h

Procedure:
A solution of 0.22 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-2′-phenyl-2′-(2(R)-phthalimidopropyl)valerohydrazide in 4 ml of methanol was treated with 0.04 g of hydrazine hydrate. The mixture was stirred for 5.5 hours and then the solvent was evaporated. The residue was suspended in 2 ml of dichloromethane and stirred at 4° C. overnight. The suspended solid was filtered off, the filtrate was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (20:1) for the elution. There was obtained 0.189 of (E)-2′-(D-alanyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-2′-phenylvalerohydrazide in the form of a colorless foam.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CC(C)=O.O>[O:18]1[CH2:19][CH2:20][N:15]([C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([CH:7]=2)[CH:2]=[O:1])[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
4-(3-(1,3-Dioxolan-2-yl)-4-nitrophenyl)morpholine (15.9 g, 56.7 mmol) was dissolved in a mixture of acetone and water (100 mL/100 mL). Then p-toluenesulfonic acid (2.0 g) was added and the mixture was heated to reflux for 4 hours. Ethyl acetate was added and the organic phase was washed with saturated sodium bicarbonate and brine, and then dried over anhydrous sodium sulfate, evaporated to afford the crude product 5-morpholino-2-nitrobenzaldehyde, which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH2:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH3:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: C=C(c1ccc([N+](=O)[O-])cc1)c1ccnc2cc(OC)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(C(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 3 h

Procedure:
A mixture of 7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline (0.146 g, 0.477 mmol) and Palladium on carbon, 10% (0.152 g, 1.43 mmol) in EtOAc (10 mL) and MeOH (1 mL) at RT was exposed to an atmosphere of Hydrogen (balloon). After 3 hrs, the mixture was filtered through celite and concentrated in vacuo to afford 4-(1-(7-methoxyquinolin-4-yl)ethyl)benzenamine as a white foam. MH+=279.1.
Reaction SMILES: [OH:1][C@@:2]1([CH3:20])[C:7](=[N:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]2[CH2:17][C@@H:3]1[C:4]2([CH3:19])[CH3:18].C[Mg]Br.C(OCC)C.N12CCCN=C1CCCCC2.[C:40]([O:45][CH2:46][CH3:47])(=[O:44])/[CH:41]=[CH:42]/[CH3:43]>O1CCCC1>[OH:1][C@@:2]1([CH3:20])[C:7](=[N:8][C@H:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH:42]([CH3:43])[CH2:41][C:40]([O:45][CH2:46][CH3:47])=[O:44])[CH2:6][C@H:5]2[CH2:17][C@@H:3]1[C:4]2([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CN=C1C[C@H]2C[C@H](C2(C)C)[C@@]1(C)O
Reactant: C/C=C/C(=O)OCC
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(C)[C@H](N=C1C[C@H]2C[C@H](C2(C)C)[C@@]1(C)O)C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
A solution of 1,1-dimethylethyl N-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylidene]glycinate (11.05 g, 39.3 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −30° C. and treated with a 3M solution of methylmagnesium bromide in diethyl ether (17.1 ml, 51.1 mmol). 1,8-Diazabicyclo[5.4.0]undec-7-ene (7.78 g, 51.1 mmol) was then added and the mixture was stirred for an additional 20 minutes at −30° C. The mixture was then treated with ethyl crotonate and stirring continued for 1 hr. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (35 ml) and then extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over sodium sulphate, filtered and evaporated to give a yellow oil. This material was purified by automated flash silica-gel column chromatography (using a Biotage SP4), eluting with a gradient of 0-20% (over 5 column volumes) then 20-35% (over 14 column volumes) ethyl acetate in hexane, to give 1-(1,1-dimethylethyl) 5-ethyl N-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylidene]-3-methylglutamate (4.2 g) which was used in the next step.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:34][C:35]([O:37]C(C)C)=[O:36])[CH2:6][C@@H:5]1[CH3:41])(=[O:3])[CH3:2].F[C:43](F)(F)[C:44](O)=O.[Cl:49][CH2:50]Cl>>[ClH:49].[CH3:50][CH:43]([N:34]([C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:18]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:41])[CH2:6]1)[C:35](=[O:36])[OH:37])[CH3:44]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(CCN4CCNCC4)c3)cc2[C@H](N(C(=O)O)C(C)C)C[C@@H]1C
Product: Cl

Procedure:
1,1-Dimethylethyl 4-(2-{4-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)-1-piperazinecarboxylate (for a preparation see Intermediate 38) (65 mg, 0.114 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred under nitrogen. The product was concentrated, dissolved in MeOH (1.5 mL), mixed with 1.25M HCl (157 μL) and blown down to dryness to give a white solid (41 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCCBr)cc1
Yield: 91.5 %

Procedure:
Compound 72-2 (4.22 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (7.58 g) and N-bromosuccinimide (5.14 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (5.37 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:13]1([CH2:12][O:11][C:4]2[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OCC1CCCC1
Temperature: 100 °C
Yield: 94 %

Procedure:
5-Chloro-3-cyclopentylmethoxy-2-nitro-pyridine (1.3 mmol) is dissolved in DMF (10 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 100° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-Cyclopentylmethoxy-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 94%. HPLC (method C): 2.31 min; LC-MS (method A): 2.48 min, 315.15 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:9](=[O:26])[N:10]1[CH2:13][C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:9]([N:10]1[CH2:11][C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:13]1)=[O:26]
Reactant: CCCCCC1(c2ccc(F)cc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC1(c2ccc(F)cc2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reaction time: 1 h

Procedure:
780 mg (1.56 mmol) of tert-butyl[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-(4-fluoro-phenyl)azetidin-1-yl)ethyl]carbamate are solubilized in 10 ml of dichloromethane. 4 ml of trifluoroacetic acid are introduced. The reaction medium is stirred for 1 hour and then concentrated to dryness. The residue is taken up in a 1N aqueous solution of sodium hydroxide and extracted with dichloromethane and then the resulting product is dried over magnesium sulphate, filtered and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Al+3].[Cl-].[Cl-].[Cl-].Br[CH2:16][C:17](Br)=O.[NH2:20][C:21]([NH2:23])=[S:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16]3[N:20]=[C:21]([NH2:23])[S:22][CH:17]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: O=C(Br)CBr
Reactant: NC(N)=S
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: Nc1nc(-c2c[nH]c3ncc(Cl)cc23)cs1

Procedure:
The title compound was synthesized in 2 steps in a manner similar to that described above using 5-chloro-7-azaindole (0.32 g, 1.17 mmol), AlCl3 (0.47 g, 3.51 mmol), bromoacetylbromide (0.1 mL, 1.46 mmol) and thiourea (0.158 g, 2.08 mmol) (0.21 g, 67.5%, 2 steps) as pale brown solid. Mass Spec.; MS 251 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.97(s, 1H), 8.50(d, 1H), 8.22(d,1H), 7.84(d,1H),7.02(brs,2H), 6.83(s,1H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:19]1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:30]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:40][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[S:7]([C:4]1[C:5]([CH3:19])=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:8])=[O:9])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: Cc1ccccc1S(=O)(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was coupled to L-phenylalanine benzyl ester toluenesulfonic acid salt using the procedure described in Method 3 to give the title compound as an oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[N:16]([CH3:24])[N:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=[O:13])=[CH:7][CH:6]=1)C.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]([C:18]1[CH:19]=[C:15]([NH:14][C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)=[O:13])[N:16]([CH3:24])[N:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a dry flask is added 872 mg (2.5 mmol) of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-benzoic acid ethyl ester in 30 mL dry methylene chloride and cooled to 0° C. Next, 10.12 mL of 1M DIBAL in hexanes (4 eq., 10.12 mmol) is added and the reaction is allowed to reach room temperature. The mixture is then stirred for 1 hour, and 60 mL of ethyl acetate and 100 mL of sodium tartrate saturated aqueous solution are added, and the mixture is stirred for another 30 min. Then the organic layer is separated and washed with water and dried over magnesium sulfate, filtered, and evaporated to a white solid weighing 720 mg (2.4 mmoles, 95%, ES+(m/z) 303 [M+H]).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:3]1[C:2]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: O=C1CCC1
Reactant: Cc1ccc(Br)c(Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(O)CCC2)c(Cl)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A suspension of molecular sieves (4 Å) and 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) in THF (50 mL) was cooled to −15° C. 1.3 M isopropyl magnesium chloride lithium chloride complex solution in THF (19.6 mL, 25.4 mmol) was added within 30 min. Stirring was continued for 1 h at −15° C. Cyclobutanone (1.87 g, 2.00 mL, 26.6 mmol) was slowly added. Stirring was continued for 2 h at −15° C. and for further 2 h at 0° C. Water (2.5 mL) was added, the mixture was concentrated in vacuo, and poured onto sat. aqueous NH4Cl solution. The mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with ice water (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 140 g, heptane/EtOAc 0-40% in 120 min.) to give the title compound (3.33 g, 70%) as white solid, MS (ESI): m/e=198.1 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[H-].[Na+].[C:14](Cl)(=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccc2cnccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)Nc1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6-aminoisoquinoline in DMF cooled to 0° C. was added NaH and the solution was stirred for 30 minutes at 0° C. Then hydrocinnamoyl chloride was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with EtOAc, extracted with NaHCO3(sat), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 10% hexanes/EtOAc) gave N-(isoquilin-6-yl)-3-phenylpropanamide (E2).