Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])#[N:2].[CH2:11]([CH2:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:20](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:11]([CH2:18][NH:19][CH:20]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(OCC)OCC
Reactant: NCCc1ccccc1
Reactant: CC(C)COC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)COC(=O)C(C#N)=CNCCc1ccccc1

Procedure:
Isobutyl cyanoacetate (5.8 g), benzylmethylamine (7 ml), triethyl orthoformate (14 ml) and p-toluenesulphonic acid (5 mg) were heated under reflux for 1 hour. The cooled reaction mixture was triturated with petroleum ether (bp 40°-60° C.) and the solid filtered off. Recrystallisation from ethanol gave isobutyl 3-(benzylmethylamino)-2-cyano-2-propenoate, m.p. 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][NH2:12]>CO.C(O)C>[ClH:1].[CH3:11][NH:12][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNc1ccc(C(=O)O)cn1
Product: Cl
Temperature: 140 °C
Yield: 69 %

Procedure:
6-chloronicotinic acid (4.5 g) was dissolved in methanol (50 ml), treated with 33% methylamine in ethanol solution (25 ml) and heated in a sealed bomb at 140° C. for 18 hours. The mixture was cooled and evaporated to dryness. Trituration with 1:1 methanol/diethyl ether gave the title compound (3.7 g, 69%). MS (+ve is an electrospray) m/z 153 (MH+. 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16]>>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:14]2\[C:13](=[O:15])[NH:12][C:11](=[O:16])[S:10]\2)=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
A compounds of Formula 3A can be synthesized according to Scheme 1A, wherein 4-hydroxybenzaldehyde is condensed with thiazolidine-2,4-dione under Knoevenagel conditions to produce (E)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione. This intermediate can then be reduced to the compound of Formula 3A by, for example, hydrogenation.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[O:5].[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:8]1[CH2:15][CH2:16][O:17][C:7]1([CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1(CC(=O)OCC)OCCO1
Yield: 42 %

Procedure:
A solution of diethyl 1,3-acetonedicarboxylate (12 g, 59.3 mmol), ethyleneglycol (9.93 mL, 178 mmol), and p-toluenesulfonic acid monohydrate (564 mg, 2.97 mmol) in benzene (80 mL) was refluxed under heating removing water for 10 h by Dean-Stark trap. The benzene layer was washed with a saturated aqueous sodium bicarbonate solution and brine. The solvent was distilled away and the residue obtained was purified by flash chromatography (10 to 40% EtOAc in heptanes) yielding diethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate (42%). LCMS (m/z): 247.2 (MH+), 0.65 min; 1H NMR (400 MHz, CDCl3) δ ppm 4.17 (q, J=7.04 Hz, 4H) 4.03 (s, 4H) 2.95 (s, 4H) 1.27 (t, J=7.24 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]([CH2:24][C:25]([N:27]([N:29]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)[CH3:28])=[O:26])[CH2:9][C:10]([NH:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH3:16])=[O:11])[CH:7]=1.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]([CH2:24][C:25]([N:27]([N:29]2[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:37]2)[CH3:28])=[O:26])[CH2:9][C:10]([NH:12][CH2:13][CH2:14][NH:15][CH3:16])=[O:11])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N(CC(=O)NCCN(C)C(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNCCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
The compound (294 mg, 0.54 mmol) obtained in step A was dissolved in dichloromethane (5.5 ml), 4N hydrochloric acid-ethyl acetate solution (1.35 ml) was added, and the mixture was stirred at room temperature for 8 hr. The aqueous layer was alkalified by addition of saturated aqueous sodium hydrogen carbonate, and the organic layer was extracted with dichloromethane, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (NH silica gel use, methanol-dichloromethane) to give the title compound (179 mg, yield 75%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:8][C:7]([O:16]CC1C=CC3C(=CC=CC=3)N=1)=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CS(C)=O.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH3:45]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(CC(=O)NN)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Reaction time: 4 h
Yield: 68.5 %

Procedure:
A solution of 310 mg (1 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 62) in 25 mL of DMSO was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil and after 0.25 hours, 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 4 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with CH2Cl2 →4% MeOH/CH2C2, to give 290 mg (68% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (0.685 mmol) and 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF was stirred for 22.5 hours. The mixture was diluted with water, made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in EtOH and precipitated with ether to give 50 mg (47% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid, mp, 160° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10.0 g, 45.0 mmol) in methylene chloride (200 mL) was added 4-fluoro-benzylamine (6.19 g, 49.5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (21.9 g, 49.5 mmol) and N,N-diisopropylethylamine (15.7 mL, 90.1 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (300 mL), washed with water (300 mL) and brine (2×200 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide as a beige solid (13.5 g, 90% yield). MS (M+H)+=330; Rt=136 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH:4]1[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.[CH3:20]N(CN(C)C)C.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH:4]1[C:13](=[CH2:20])[C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: O=C1CC(c2ccc(Cl)cc2Cl)Oc2ccccc21
Reactant: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Product: C=C1C(=O)c2ccccc2OC1c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3 g (10 mmol) of the 2',4'-dichloro flavanone and 27 ml of bis-(dimethylamino)methane was stirred at room temperature; 27 ml of acetic anhydride was added dropwise over 15 minutes. A slight temperature rise occurred. One hour later the reaction was partitioned between 200 ml of ether and 200 ml of cold H2O. The aqueous phase was separated, washed with two 250 ml portions of ether, and discarded. The combined ether extracts were washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and evaporated. The residual oil was chromatographed on 200 g of silica gel, eluting with benzene. This gave 2.5 g of 2',4'-dichloro-3-methylene flavanone, isolated as a solid, m.p. 86°-87° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>>[CH3:44][N:45]([CH3:49])[C:46]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:47]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CN(C)C(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([C:26](=[O:40])[NH:27][CH2:28][C:29]4[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=4[CH2:35][CH2:36][CH3:37])[C:23]([CH3:41])=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[C:23]([CH3:41])=[C:24]([CH:25]=3)[C:26]([NH:27][CH2:28][C:29]3[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=3[CH2:35][CH2:36][CH3:37])=[O:40])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a stirred solution of tert-butyl(1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-(((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl) pyridine-2-yl)piperidin-4-yl)carbamate (0.4 g, 0.00051 mol) in DCM (10 mL) at 0° C., TFA (10 mL) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (80 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (60 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.315 g, 92.1%) which was used as such for next reaction.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45](C(Cl)=O)=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:19][CH2:18]2)=[O:21])=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C(=O)c3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (6 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (15 ml), and the solution was added triethylamine (2 ml, 14.35 mmol). To the solution, 4-chlorobenzoyl chloride (150.7 mg, 0.86 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether-ethyl acetate to afford (S)-(4-chlorophenyl)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]methanone (282 mg, yield 85%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(N3CCC(n4ccc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)indoline (75 mg, 0.2 mmol) in THF (3 mL) was added DDQ (54 mg, 0.24 mmol). The resulting mixture was stirred at room temperature for 30 min and was poured into EtOAc (30 mL). The organic layer washed with Na2CO3(aq) (30 mL), H2O (30 mL), dried (Na2SO4), and filtered. The solvent was removed and the resulting residue purified by column using 80-90-100% EtOAc/(CH2Cl2/hexane=1/1) as the eluent to yield 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-1H-indole, which was then converted to its corresponding HCl salt.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 4 (34.29 g, 94.60 mmol) in tetrahydrofuran (234 mL) and methanol (234 mL) was added 1 N aq sodium hydroxide (473 mL). The solution was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 3 N aqueous hydrochloric acid was added dropwise to pH 2. The resulting slurry was filtered, and the solid was washed with water (300 mL, then 100 mL). The solid was dried by azeotropic removal of water first with toluene, then heptane (7×100 mL), followed by heating to 70° C. under reduced pressure to afford (+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid (Intermediate 5). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1 H), 8.02 (d, J=8.4 Hz, 2 H), 7.84 (d, J=8.4 Hz, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 7.66-7.58 (m, 3 H), 7.40 (t, J=7.6 Hz, 1 H), 5.56 (dd, J=6.0, 8.6 Hz, 1 H), 2.49 (s, 3 H), 2.24-2.10 (m, 1 H), 2.08-1.95 (m, 1 H), 1.66-1.52 (m, 1 H), 1.52-1.39 (m, 1 H), 1.03 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.N1C=CC=CC=1.O>C(Cl)Cl>[F:7][C:8]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[B:18]1[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: CC1(C)OB(c2cc(N)cnc2Oc2ccc(F)cc2F)OC1(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cnc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
Ethylsulfonyl chloride (50 uL, 52 mmol) was added to a stirred solution of 6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (163 mg, 0.5 mmol) and pyridine (113 uL) in DCM (2.4 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with water (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid. LCMS (M+H)+=441.
Reaction SMILES: C(O[C:4](=[NH:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.N[C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][C:30]=1[NH2:31])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]>>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][C:15]1[CH:28]=[CH:29][C:30]2[NH:31][C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:11][C:13]=2[CH:14]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Product: CCOC(=O)Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2[nH]1
Yield: 71 %

Procedure:
Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 2-(3,4-diaminobenzyl)isoindole-1,3-dione under conditions similar to that set forth in Example 2(b) to provide ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylacetate (71% yield); 1H-NMR (300 Mhz, DMSO-d6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J=9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:24]([NH:32][NH2:33])[N:23]=[C:22]([S:34][CH3:35])[N:21]=2)=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:34][CH3:35])[N:23]3[C:2](=[O:4])[NH:33][N:32]=[C:24]3[C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:16][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CSc1nc(NN)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n[nH]c(=O)n12
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a stirred solution of triphosgene (2.08 g, 7.04 mmol) in THF (10 mL) at room temperature under argon was added a suspension of 4-(4-chlorophenyl)-6-hydrazinyl-2-(methylthio)-5-phenylpyrimidine (3.52 mmol) in THF (5 mL). The reaction mixture was stirred overnight. Analysis by HPLC/MS indicated that no starting material remained. The reaction mixture was cooled to 0° C. in an ice bath and ice water (50 mL) was added. After stirring for 30 min, the solid precipitate was collected and further washed with water (50 mL). After drying, the title compound (1.25 g) was obtained as an off-white solid. HPLC/MS: retention time=3.51 min, [M+H]30 =369.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[N:4]=1)[NH2:2].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[F:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]2[N:4]3[C:5]4[C:10]([CH:11]=[CH:12][C:3]3=[N:1][N:2]=2)=[CH:9][C:8]([S:13][C:14]2[CH:15]=[C:16]([C:20]3([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=4)=[CH:31][CH:30]=1
Reactant: N#CC1(c2cccc(Sc3ccc4nc(NN)ccc4c3)c2)CCOCC1
Reactant: O=Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccc(F)cc6)n54)c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5i (203 mg, 0.54 mmol) was suspended in CH2Cl2. 4-Fluorobenzaldehyde (0.07 mL, 0.65 mmol) was added, and the reaction was stirred at room temperature for 4 hours. Iodobenzene diacetate (176 mg, 0.54 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction was adsorbed onto silica gel and concentrated, and then purified by silica gel chromatography (20-100% EtOAc in hexanes, followed by 0-10% MeOH in EtOAc) to give the desired product, 5j.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([NH:23][C:24]([CH3:29])([C:26](O)=[O:27])[CH3:25])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:26](=[O:27])[C:24]([NH:23][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:29])[CH3:25])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of proline-tert-butyl ester (47) (2.00 g, 12 mmol, in CH2Cl2 (15 ml) was added N-carbobenzyloxy-2-methylalanine (3.05 g, 13 mmol), HOBT (2.36 g, 17 mmol) and EDC: (3.43 g, 18 mmol) and the solution was stirred at room temperature under N2 for 48 hours. The solvent was evaporated, the crude material dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a white solid (4.68 g, 100%). 1H-NMR (500 MHz, CDCl3) δ 1.20-2.15 (m, 4H), 1.43 (s, 9H), 1.59 (d, 6H), 3.21-3.79 (m, 2H), 4.35 (br s, 1H), 4.82-5.19 (m, 3H), 5.74 (br s, 1H), 7.17-7.49 (m, 5H). Analytical HPLC (C18 column) 10.66 min. LC-MS (ES+) m/e=391.3 (M+H).