Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:34][CH2:35][CH2:36][NH2:37]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:37][CH2:36][CH2:35][F:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)NCCF
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (2.16 g, 11.4 mmol)) was dissolved in dichloromethane (80 ml) and cooled to 0° C. in an ice bath. [3-(Dimethylamino)propyl]ethylcarbodiimide hydrochloride (2.84 g, 14.8 mmol), hydroxybenzatriazole (1.54 g, 11.4 mmol) and triethylamine (7.9 ml, 57 mmol) were added and the reaction mixture stirred for 15 minutes. 2-fluoroethylamine hydrochloride (1.134 g, 11.4 mmol) was added in a single portion and then left to stir for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The organic phase was dried over magnesium sulphate and evaporated. The crude product was purified by chromatography on silica using 2:3 iso-hexane:ethylacetate as eluant to afford the product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:8][S:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH2:13][CH2:12][C:11]([NH:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=1)=[O:23]
Reactant: COC(=O)c1cscc1NC(=O)CCCOc1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCOc1ccccc1Cl)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid methyl ester (270 mg, 0.763 mmol) was added to a solution of lithium hydroxide monohydrate (71.1 mg, 1.68 mmol) in a mixture of tetrahydrofuran (7.4 mL) and water (7.4 mL) and the reaction mixture was stirred for 3 hours at room temperature. The tetrahydofuran was evaporated and the solution was neutralized by addition of a solution of hydrochloric acid (1N, 0.39 mL). The precipitate was filtered, washed with water and dried in vacuo to yield the title compound as a yellow solid (218 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C.C(O)(C(F)(F)F)=O>[Br:13][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8](=[O:12])[O:9][CH2:10][C:11]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc2c1COC(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.695 g, 4.3 mmol) in acetic acid (5 mL), Br2 (0.805 g=5 mmol) solution in TFA (5 mL)+acetic acid (5 mL) was added at 10° C. Reaction mixture was stirred for 2 hours and poured over ice water. Yellow precipitate was filtered and dried at 120° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:27].Cl>O1CCCC1>[C:11]1([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCCOCCOCCc1ccccc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=CCCOCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminum hydride (3.3 ml, 1.5M in toluene) was added dropwise to a cooled (0°) stirred solution of 3-[2-[2-phenylethoxy]ethoxy]propanenitrile (1.0 g) from step a) in tetrahydrofuran. After 30 min the mixture was warmed to room temperature and stirred for a further 2 hours. Water and 10% aqueous hydrochloric acid were added cautiously and the reaction stirred for a further 5 min. The reaction was extracted several times with ether and the combined ethereal extracts were washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and evaporated under reduced pressure to yield the subtitled compound as a yellow oil. The material was used in the next step without purification.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH:19]=2)[NH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([N:21]3[C:22](=[O:31])[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]3=[O:30])[CH:19]=2)[N:14]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cnc2[nH]cc(Br)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1cnc2c(c1)c(Br)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
PhSO2Cl (24 mg, 0.136 mmol) was added dropwise over a period of 3 min. to a stirred solution of 42 (31 mg, 0.090 mmol) and pyridine (11.4 mg, 0.144 mmol) in CH2Cl2. The mixture was stirred at r.t. overnight. Additional portion of PhSO2Cl (24 mg, 0.136 mmol) was added, followed by DMAP (3 mg, 0.025 mmol). After additional stirring for 1.5 h, the mixture was partitioned between saturated aqueous NaHCO3:CH2Cl2. The aqueous layer was extracted with CH2Cl2. The combined organic solutions were washed with brine, dried (MgSO4) and concentrated. Purification by PTLC using AcOEt:hexane=1:1 (v/v) as eluent afforded 43 as orange powder (15 mg, 35%). 1H NMR (400 MHz; CDCl3) δ 7.55 (tt, J=6.6, 1.6 Hz, 2H), 7.62 (tt, J=5.3, 2.0 Hz, 1H), 7.84 (dd, J=5.4, 3.0 Hz, 2H), 7.88 (s, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.98 (dd, J=5.4, 3.0 Hz, 2H), 8.23 (dd, J=4.0, 1.3 Hz, 2H), 8.55 (d, J=1.9 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].Cl.Cl.[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:26][CH3:27])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C>C(O)CC.Cl.Cl.C(N(CC1CCCCN1)CC)C.C(#N)C>[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:26][CH3:27])[CH3:24]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A suspension of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (276 g, 0.959 mol), and 2-[(diethylamino)methyl]piperidine dihydrochloride (244.95 g, 100.7 mol), of sodium carbonate (223.9 g, 2.112 mol) and acetonitrile (1.92 liters) are stirred for 6 hours at a reaction temperature of 70° C. After this time, the 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one has 95-97% reacted (TLC). The mixture is left to stand overnight at ambient temperature, then suction filtered. The contents of the filter are washed three times, each time with acetonitrile (60 ml). The dark colored filtrates are discarded. The remaining solid is stirred for a further 2 hours with water (1.5 liters), suction filtered again and washed with another water (300 ml) and finally dried at 40° C. in a circulating air drier. The crude product thus obtained (390 g) is transferred into a 10 liter flask, taken up in 1-propanol (5.14 liters) and, after the addition of 2-[(diethylamino)methyl]piperidine dihydrochloride (13.5 g, 0.0555 mol) and anhydrous sodium carbonate (11.8 g, 0.1113 mol), refluxed for 16 hours. After the addition of activated charcoal (39 g) the mixture is heated to boiling for a further 30 minutes and the boiling hot mixture is then forced through a SEITZ filter. Clarification is repeated twice more in the same way using activated charcoal (20 g). The filtrate is left to stand for 12 hours at ambient temperature, the precipitated crystals are suction filtered and washed twice, each time with 1-propanol (50 ml). The product is again stirred with cold 1-propanol (0.5 liters), suction filtered and again washed twice, each time with 1-propanol (50 ml). It is then dried in a circulating air drier at 40° C. and almost colorless crystals (263 g) are obtained, mp. 226°-227° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C=O)C>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:3]([N:2]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[CH:34][C:24]=3[NH:23][C:20](=[O:22])[CH3:21])[C:27]2=[O:28])[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH3:19]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(O)CC)ccc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC(O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 77.2 %

Procedure:
A stirred mixture of 5-amino-5-(3-ethoxy-4-methoxyphenyl)pentan-3-ol hydrochloride (1.15 g, 3.97 mmol), 3-acetamidophthalic anhydride (0.82 g, 3.97 mmol) and triethylamine (0.4 g, 3.97 mmol) in DMF (20 mL) was heated at 80-90° C. for 6 hours. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (80 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 77%); 1H NMR (CDCl3) δ 9.52 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.09-7.07 (m, 2H), 6.83-6.80 (m, 1H), 5.61-5.55 (J=3.9, 11.9 Hz, 1H), 4.11 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 1H), 1.78 (b, 1H), 1.62-1.52 (m, 2H), 1.45 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ 170.39, 169.23, 168.11, 148.94, 148.14, 137.32, 135.83, 131.81, 131.19, 124.72, 120.30, 117.94, 115.31, 112.87, 111.09, 70.01, 64.36, 55.86, 51.29, 37.92, 30.46, 24.92, 14.73, 9.90.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)=O.C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Cc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: ClCCl
Solvent: O=CO
Product: CC(=Nc1ccccc1C)c1cccc(C(C)=Nc2ccccc2C)n1
Reaction time: 40 h
Yield: 45.9 %

Procedure:
One g of 2,6-diacetylpyridine and 3.0 ml of o-toluidine were added to an Erlenmeyer flask with 20 ml of methylene chloride. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 40 hours. The solvent was then removed in vacuo, and the flask was placed in the freezer at −30° C. The resulting viscous oil was washed with cold methanol, and a yellow solid formed and was isolated by filtration and identified by 1H NMR as the desired product (959 mg, 45.9%). 1H NMR (CDCl3): δ 8.38 (d, 2, Hpyr), 7.86 (t, 1, Hpyr), 7.20 (m, 4, Haryl) 7.00 (t, 2, Haryl) 6.67 (d, 2, Haryl), 2.32 (s, 6, N═CC—CH3), 2.10 (s, 6, CH3 aryl).
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[F:16][C:17]([F:28])([F:27])[CH2:18][I+]C1C=CC(F)=CC=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C(Cl)Cl>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[CH3:29][N+:30]1[CH:34]=[CH:33][N:32]([CH2:18][C:17]([F:16])([F:27])[F:28])[CH:31]=1
Reactant: Fc1ccc([I+]CC(F)(F)F)cc1
Reactant: Cn1ccnc1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(CC(F)(F)F)c1

Procedure:
(2,2,2-Trifluoroethyl)(4-fluorophenyl)iodonium bis(trifluoromethanesulfonyl)imide (17.6 g, 30 mmol) and methylene chloride (60 ml) were placed in a reaction vessel to convert the inside of the reaction vessel to a nitrogen atmosphere. While stirring and cooling in an ice bath, 1-methylimidazole (2.46 g, 30 mmol) was added dropwise thereto. After the dropwise addition thereof, the ice bath was removed, and the mixture was allowed to react at room temperature for 3 hours. After the completion of the reaction, the solvent was removed by distillation. The resulting liquid product was washed with hexane (or pentane), water, and then hexane (or pentane). Subsequently, this liquid product was dissolved in a small amount of ethyl acetate, and a large amount of ether was added thereto to separate the liquid product. The liquid product was separated from the solvent and then dried at 110° C. for 6 hours under reduced pressure using a vacuum pump. Thus, pure 1-methyl-3-(2′,2′,2′-trifluoroethyl)imidazolium bis(trifluoromethanesulfonyl)imide (compound 9) was obtained as a liquid substance (yield 11.5 g, 86%). When the product is colored, it may be subjected to decolorization with active carbon. Separately, p-fluoroiodobenzene was obtained from the aforementioned hexane (or pentane) wash in a substantially quantitative manner.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)N(C)C)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) in acetonitrile (10 mL), was added dimethyl carbamyl chloride (0.21 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-1,1-dimethyl-urea as an off-white solid (290 mg, 52% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10190 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 4.66 min (98.7%); mp, 264-268° C.; 1HNMR (DMSO-d6) δ 2.14-2.20 (m, 1H, CH), 2.56-2.86 (m, 12H, N(CH3)2, CHCH2, CH3), 4.31 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.00 (t, J=5 Hz, 1H, CH2NH), 7.54-7.89 (m, 3H, Ar), 11.03 (s, 1H. NH); 13C NMR (DMSO-d6) δ 20.95, 23.38, 30.61, 35.85, 43.20, 56.49, 119.88, 123.54, 126.30, 133.91, 139.98, 145.59, 154.27, 158.09, 160.50, 169.49, 172.62. LCMS MH=372; Anal Calcd For C18H21N5O4+0.5H2O: C, 56.83; H, 5.83; N, 18.41. Found: C, 56.71; H, 5.81; N, 18.18.
Reaction SMILES: [C:1]1([C:7]#[C:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16]>C1COCC1.CCCCCC>[OH:16][CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#Cc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(C(O)C#Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 4.40 mL (40.0 mmol) of phenylpropyne in 30 mL of THF under nitrogen at -75° C. was added a solution of 16 mL (40 mmol) of 2.5M n-butyllithium in hexane over 20 min. The resulting light yellow solution was warmed to 0° C. and stirred for 30 min. This solution was added via syringe to a slurry of 6.25 g (38.0 mmol) of methyl 4-formylbenzoate in 30 mL of THF at -30° C. over 20 min. The resulting light yellow solution was warmed to room temperature and stirred for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted twice with ether, dried (MgSO4) and evaporated. Purification by flash chromato-graphy (5×15 cm column, 1:19 ether/dichloromethane as elutent) gave title compound as a white solid, mp 48°-50° C., 9.36 g, 88% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:39])[CH2:35][C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH:22][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of the amino compound 120 (400 mg, 1.08 mmol) in DMF (10 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (444 mg, 2.25 mmol), EDC (519 mg, 2.70 mmol) was added HOBT (364 mg, 2.70 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 117 (348 mg, 58% yield) as a white solid. 1H NMR (DMSO-d6). δ ppm: 10.58 (s, 1H), 10.06 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.10-7.76 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.88 (dd, J=2.4 and 13.2 Hz, 1H), 7.74 (s, 1H)), 7.51 (t, J=8.8 Hz, 1H), 7.43 (dd, J=1.6 and 8.8 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.21-7.14 (m, 2H), 6.66 (d, J=5.6 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.34 (t, J=7.2 Hz, 3H). MS (m/z): 534.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:28]([Sn:32](I)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: CCCC[Sn](I)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred and cooled (−90° C.) solution of bromide 4 (206 mg, 0.66 mmol) in THF (2.5 mL) was added dropwise 1.5 M solution of tert-butyllithium in pentane (1 mL, 1.51 mmol). After 35 min additional stirring at −90° C., tri-n-butyltin iodide (0.23 mL, 0.79 mmol) was added in one portion. The mixture was stirred at −90° C. for 10 min, −78° C. for 40 min, and then allowed to warm to r.t. The mixture was partitioned between AcOEt-brine. The aqueous layer was extracted with AcOEt (3×) and the combined organic solutions were dried (MgSO4), and concentrated to afford the crude stannane 17, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Reaction time: 21 h
Yield: 74.4 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-chlorophenyl isocyanate (0.29 ml, 2.40 mmol) in THF (2 ml) was added Et3 N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 74%) as a pale brown powder. 1H-NMR (CDCl3) δ 3.57 (s, 2H), 3.70 (s, 3H), 7.02–7.28 (m, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.48 (s, 1H), 8.00–8.11 (m, 2H); MS (ESI) m/z 397 (M+), 399 (M++2), 401 (M++4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][CH:5]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cccc(F)c23)CC1
Yield: 26.3 %

Procedure:
A stirred solution of 4-fluoroindole (400 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (250 mg, 27%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1CBr

Procedure:
Synthesized from 3-methylpicolinonitrile (1.00 g, 8.47 mmol), NBS (1.66 g, 9.31 mmol) and DBPO (103 mg, 0.42 mmol) in CCl4 according to Method A. Yield: 616 mg, 3.12 mmol, 37%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 4.63 (s, 2H), 7.54 (dd, J=7.9, 4.9 Hz, 1H), 7.92 (dd, J=7.9, 1.5 Hz, 1H), 8.64 (dd, J=4.9, 1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=26.8, 115.2, 127.1, 133.2, 138.1, 138.3, 150.5; MS (ESI): m/z=199.79 [M+H]+.