Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=O)[N:6]=1>P(Cl)(Cl)(Cl)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]#[N:10])[N:6]=1
Reactant: NC(=O)Cc1csc(N)n1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1csc(N)n1
Temperature: 90 °C

Procedure:
A mixture of the product from step (i) (9.5 g) and phosphorous oxychloride (30 ml) was heated at 90° C. for 2 hours. The mixture was evaporated under reduced pressure and poured onto a mixture of ice water and ethyl acetate. The aqueous phase was adjusted to pH 9 with sodium bicarbonate and extracted repeatedly with ethyl acetate. The combined extract was dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with ethyl acetate. Yield 6.1 g. 1H NMR: δ (DMSO) 7.08(br s,2H), 6.40(s,1H), 3.77(s,2H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:28]([O:31][C:32](Cl)=[O:33])([CH3:30])[CH3:29]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[O:33])[C:6]1=[O:14])[CH3:18]
Reactant: CC(C)OC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)OC(C)C)[C@H]1c1ccco1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
(3R, 4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.51 g, 1.91 mmol) in 25 mL of dichloromethane was stirred with diisopropylethyl amine (0.78 mL, 4.4 mmol) and i-propylchloroformate (4.0 mL, 1.0M in toluene, 4.0 mmol) in addition to a catalytic amount of DMAP. The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 5:1 hexane/ethyl acetate) to give 649 mg of the title product (Y: 96%); IR(KBr) 1822, 1812, 1716, 1374, 1314, 1186, 1018, 1004, 746 cm−1 ; 1H-NMR (CDCl3, 300 MHz) δ 7.39 (m, 1H), 6.35 (m, 2H), 5.08 (ABq, J=15.6, 5.6 Hz, 2H), 4.96 (d, J=10.0 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H)), 0.83 (t, J=7.8, 9H), 0.50 (m, 6H); 13C-NMR (CDCl3, 75.5 Hz) δ 165.5, 148.6, 147.8, 142.9, 110.5, 109.9, 77.6, 71.1, 55.9, 21.7, 21.6, 6.3, 4.4; DCIMS M+H calcd for C17H28NO5Si: 354, Found: 354.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:10][CH2:11]O.P(Br)(Br)[Br:14]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:10][CH2:11][Br:14]
Reactant: Cc1cccc(C)c1SCCO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1SCCBr

Procedure:
18.2 g of 2-(2,6-dimethyl phenylthio) 1-hydroxy ethane and 50 ml chloroform are added in a flask and when the mixture is perfectly clear, it is cooled to 0°. To the solution 14.3 g of phosphorous tribromide are added while keeping the temperature to about 0°. After completion of the addition, the inner temperature is let to revert at ambiant temperature then heated to reflux for one hour.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])C.[CH3:21][NH2:22]>C(O)CO>[CH3:21][NH:22][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Reactant: CN
Solvent: OCCO
Product: CNC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.81 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is suspended in 15 ml of ethylene glycol and, while cooling with ice, methylamine is introduced until saturation point is reached. The mixture is then stirred at room temperature for 16 hours, stirred into 100 ml of ice water and the product is filtered off, dried and recrystallized from ethanol-chloroform. 1.42 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid N-methylamide of melting point 281°-285° C. is obtained.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([OH:25])=O)[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([NH:4][CH:5]([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:8])=[O:9])[C:23]([NH:33][O:32][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)=[O:25])(=[O:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of the title compound of Example 11c (930 mg, 2.45 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (287 mg, 2.45 mmol) in anhydrous DMF (40 mL), cooled to zero degrees C., were added EDC (493 mg, 2.57 mmol) and HOBT (393 mg, 2.57 mmol). After stirring at zero degrees C. for 1 hour and at room temperature for 3 hours, the solution was partitioned between EtOAc and H2O. The resulting organic phase was washed with 1M KHSO4 (2×50 mL), saturated NaHCO3 (2×50 mL) and brine (1×50 mL), and dried over Na2SO4. Purification by chromatography (1:1 EtOAc/hexane) yielded the title compound as a colorless oil (400 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 82 %

Procedure:
(1R*,2S*,4R*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (916 mg) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (8 ml), and a 1N aqueous solution (3.3 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (3.3 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (712 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[C:15]([CH3:16])=[C:14]([CH3:17])[NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(#N)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:16][C:15]1[C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])=[CH:3][CH:4]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:13][C:14]=1[CH3:17]
Reactant: Cc1[nH]c2ncnc(Oc3ccc(N)cc3)c2c1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2c1C
Reaction time: 1 h

Procedure:
4-(4-Aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine was dissolved in toluene (16 mg) (0.8 ml) and acetonitrile (0.5 ml) under reflux, and then 4-fluorophenyl isocyanate (7.9 μM) was added. The mixture was stirred for 1 hour and returned to room temperature, and then the reaction system was concentrated, diethyl ether was added to the residue, and the resulting crystals were filtered out. The crystals were washed with diethyl ether to obtain the title compound (5 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47].CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:40][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])=[O:39])=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:28])([F:29])[F:30])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)OCC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a stirring suspension of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (207 mg, 0.345 mmol) and 2-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)ethanone (100 mg, 0.345 mmol) in acetonitrile (4 mL) at 0° C. was added DIEA (70.0 μl, 0.379 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for 16 h. The reaction mixture was poured onto citric acid (50 mL, 0.1 N aqueous solution) and extracted with EA (3×20 mL). The combined organic extracts were washed successively with NaHCO3 (20 mL), brine (20 mL) then dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 254 mg (91%) of 2-(4′-methyl-[1,1′-biphenyl]-4-yl)-2-oxoethyl 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoate INT-38 as a white foam. LCMS-ESI (m/z) calculated for C46H43F3N2O8: 808; found 831 [M+Na]+, tR=3.10 min (Method 10).
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([N:16]([CH:27]([CH3:31])[C:28](=O)[CH3:29])[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8].C[O-].[Na+]>CO>[CH3:6][C:7]([N:16]1[CH:27]([CH3:31])[C:28]([CH3:29])=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:17]1=[O:26])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8]
Reactant: CC(=O)C(C)N(C(=O)Cc1ccccc1F)C(C)(C)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cccc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.0 g of N-[1-methyl-1-(3-chlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-(2-fluorophenyl)acetamide and 1.5 g of a 28% methanol solution of sodium methoxide, followed by stirring at room temperature for 5 minutes. After the solvent was distilled off, water was added, followed by extraction with ethyl acetate. After dried over anhydrous sodium sulfate, the solution was concentrated and then subjected to column chromatography to obtain 0.9 g of the desired 1-[1-methyl-1-(3-chlorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:22]2[C:21](=[O:31])[CH2:20][N:19](CC3C=CC=CC=3)[CH2:18][C:17]=2[NH:16][C:15]=1[CH3:39])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl.[H][H]>[Pd].O>[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:22]2[C:21](=[O:31])[CH2:20][NH:19][CH2:18][C:17]=2[NH:16][C:15]=1[CH3:39])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1=C(C(=O)OCCOc2ccccc2)C(c2ccccc2C)C2=C(CN(Cc3ccccc3)CC2=O)N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)OCCOc2ccccc2)C(c2ccccc2C)C2=C(CNCC2=O)N1

Procedure:
The hydrochloride from above (21.5 g), 500 ml of methanol, 5 ml of concentrated hydrochloric acid, 15 ml of water and 0.6 g of 10% palladium on carbon were shaken with hydrogen (50 psig initial pressure) for 20 hours. The catalyst was separated and the solution was evaporated to dryness in vacuo. The residue was slurried with diethyl ether and filtered. The solid was triturated with refluxing ethanol, filtered and dried to obtain 12 g of the title compound as the hydrochloride, m.p. 238°-240° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:23][C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:24]([Cl:23])=[O:26])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cl)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 1M solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.84 g, 2.88 mmol) in anhydrous THF was added dropwise triphosgene (1.28 g, 4.32 mmol) and triethylamine (0.92 mL, 6.62 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure to give the desired product, 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carbonyl chloride as an orange solid was used immediately in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([N:8]([C@@H:9]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:21]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:22])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](Cc1ccc2ccccc2c1)N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of N-benzyl-N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-alanine (2.9 g), glycine methyl ester hydrochloride (0.9 g) and 1-hydroxybenzotriazole hydrate (1.06 g) in dichloromethane (50 ml) was added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.43 ml) at ice-bath temperature. The resulting mixture was stirred at room temperature for 2 days and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with dilute hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation of the solvent gave (2S)-2-[N-benzyl-N-(tert-butoxycarbonyl)amino]-N-methoxycarbonylmethyl-3-(2-naphthyl)propanamide.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[C:15]([O-])(O)=O.[Na+].[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)O)o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)o1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a 200 mL round-bottomed flask with condenser was added 5-methyl-2-furancarboxylic acid (2.5 g, 19.82 mmol) in Methanol (100 mL). H2SO4 (10.5 mL, 197 mmol) was added slowly at room temperature. The reaction mixture was heated to 50° C. overnight. The reaction mixture was cooled to 0° C. and a saturated solution of NaHCO3 was added to neutral pH followed by 5N NaOH to pH 10. CHCl3 was added and the organic phase was separated, dried with Na2SO4 and concentrated affording the title compound (2.3 g, 16.3 mmol, 82%): LC-MS (ES) m/z=141 (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([NH:29][C:8]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1)N[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
A solution of pyridin-3-yl-carbamic acid phenyl ester (1.6 g) in dry THF (20 ml) is treated with (R)-1-benzyl-pyrrolidin-3-ylamine (1.9 g, 1.05 eq) and then heated using microwave radiation at 110° C. for 1000 s. The solvent is removed in vacuo and purification of the crude product by chromatography on silica eluting with DCM followed by EtOAc and EtOH affords the title compound as an oil. (MH+ 297).
Reaction SMILES: CC(O[C:5]([CH3:7])=[O:6])=O.[F:8][C:9]([F:25])([F:24])[C:10]([N:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)=[O:11]>C(O)(=O)C.O>[F:25][C:9]([F:8])([F:24])[C:10]([N:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[C:20]([NH:23][C:5](=[O:6])[CH3:7])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2.75 mL acetanhydride was added to 5 g 3-trifluoracetyl-7-amino-1,2,4,5-tetrahydro-benzo[D]azepine in concentrated acetic acid. The mixture was stirred 17 h at RT, diluted with water and stirred for another 1 h at RT. The precipitate was filtered, washed with water and dried to give 5.35 g of the desired product. Rf: 0.46 (DCM/MeOH=19/1), (M+H)+=301
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:22][C:18]1[CH:17]=[C:16](/[CH:15]=[CH:14]/[C:11]2[CH:10]=[CH:9][C:8]([N:6]3[C:5](=[O:23])[CH2:4][CH:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]3)=[CH:13][CH:12]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Cl
Reactant: NC1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A suspension of 61 mg (0.18 mmol) of (RS)-(E)-4-amino-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-pyrrolidin-2-one hydrochloride in 2.5 ml of dichloromethane is treated with 45 mg (0.44 mmol) of triethylamine. The mixture is cooled to 0° C. and, thereafter, 20 mg (0.26 mmol) of acetylchloride are added. After 1 hour at 0° C., the mixture is left to warm to RT and is diluted with dichloromethane. After washing with water, the organic layer is dried over magnesium sulfate and evaporated. The crude product is crystallised from ether to yield 49 mg (78% of theory) of (RS)-(E)-N-(1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidin-3-yl)-acetamide as a light brown solid; MS: m/e=339 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:20])[N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:32]([O:34][C:35]([CH3:37])=[CH2:36])=[O:33].Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:32](=[O:33])[O:34][C:35]([CH3:37])=[CH2:36])[N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 348 %

Procedure:
A solution of 5-tert-butyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine from Example B3 (1.00 g, 3.8 mmol) in THF (20 mL) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.5 mL, 7.5 mmol). The resultant mixture was stirred at −78° C. for 30 min. Isopropenyl chloroformate (0.45 mL, 0.41 mmol) was added and stirring was continued at −78° C. for 30 min. The reaction mixture was quenched at −78° C. with aq HCl (2 N, 4 mL, 8 mmol), was warmed to RT and partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide prop-1-en-2-yl 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.5 g, 38% yield). MS (ESI) m/z: 351.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[C:3]=1[CH3:17].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[C:3]=1[CH2:17][Br:18]
Reactant: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2nc(Br)cc(Br)c2CBr)c(F)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4,6-dibromo-2-(2,4-difluorophenyl)-3-methylpyridine (5.0 g, 13.77 mmol, 1 eq) in CCl4 (125 mL) was added N-bromosuccinimide (2.95 g, 16.6 mmol 1.2 eq) and benzoyl peroxide (340 mg, 1.37 mmol, 0.1 eq). The mixture was brought to and maintained at reflux until all the starting material was consumed (approx 3.5 h). The reaction mixture was cooled to 0° C. and the succinimide was filtered off. The solvent was removed under reduced pressure and the product was purified by flash column chromatography on silica gel elufing with 2% Et2O in hexanes giving 4,6-dibromo-3-(bromomethyl)-2-(2,4-difluorophenyl)pyridine. Mass spectrum (ESI) 440.1 (M+1); 442.1 (M+3); 444.1 (M+5); 446.1 (M+7). 1H NMR (500 MHz, CDCl3) δCHCl3: 7.84 (1H, s); 7.50 (1H, m); 7.05 (1H, m); 6.96 (1H, m); 4.44 (2H br s).
Reaction SMILES: [N+]([C:4]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[C:5]=1[CH:6]=[CH:7][N:8]1CCCC1)([O-])=O.O.NN>C1C=CC=CC=1.[Ni]>[Cl:19][C:13]1[C:14]([O:17][CH3:18])=[CH:15][CH:16]=[C:4]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: COc1ccc([N+](=O)[O-])c(C=CN2CCCC2)c1Cl
Agent: [Ni]
Agent: NN
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2[nH]ccc2c1Cl
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of 2-nitro-5-methoxy-6-chloro-β-pyrrolidinostyrene (5.28 g, 18.7 mmol) in benzene (100 ml) was stirred under nitrogen at 20° C. Raney nickel (0.50 ml) was added, followed by hydrazine hydrate (1.6 ml). After 30 minutes, more hydrazine hydrate was added (1.6 ml), and the mixture was stirred for a further 11/2 hours. After filtration through celite, the filtrate was evaporated to dryness to leave a dark yellow crystalline residue, which was purified by chromatography (SiO2 ; CHCl3), then recrystallised from benzene/hexane to give 4-chloro-5-methoxyindole (2.85 g) m.p. 112°-3° C.