Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24]N5CCCCC5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.IC.C(=O)([O-])[O-].[K+].[K+].C(O[CH2:44][CH3:45])(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:45]5[CH2:44][CH2:14][N:13]([CH3:22])[CH2:8][CH2:7]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(ON3CCCCC3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C)CC3)cc2c1=O
Reaction time: 19 h

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(piperidin-yloxy)quinazolin-3(4H)-yl]benzamide (0.3 g), iodomethane (0.044 ml) and potassium carbonate (0.397 g) were stirred in DMF (2 ml) for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. The residue was dissolved in methylene chloride (2 ml) and stirred with PS-isocyanate resin (1.25 mmol/g) (0.28 g) and MP-carbonate (2.89 mmol/g) (0.488 g) for 19 hours and then filtered and concentrated to yield the title compound (0.129 g) as a cream solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.70 (m, 2H), 1.97 (m, 2H), 2.13 (s, 3H), 2.19 (s, 3H), 2.22 (m, 2H), 2.60 (m, 2H), 2.85 (m, 1H), 4.55 (m, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.59 (s, 1H), 7.72 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.17 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[NH:9][CH3:10])(C)(C)C>Cl>[C:11]([N:8]([CH2:7][C:6]([OH:28])=[O:5])[NH:9][CH3:10])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: CNN(CC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Product: CNN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.7 %

Procedure:
1 L, two-neck, round-bottomed-flask was fitted with a glass stopper and reflux condenser connected to a calcium tube. (N-Fmoc-N′-methyl-hydrazino)-acetic acid t-butyl ester (20 g, 52 mmol) was added. A solution of HCl (150 mL, 4 M solution in dioxane) was added slowly with vigorous stirring in an ice water bath. The reaction mixture was stirred at RT over 1 day. The solution was concentrated completely under reduced pressure at 40° C. A saturated aq. NaHCO3 solution (100 mL) was added and the aqueous layer was washed with diethyl ether (100 mL). Conc. HCl was added dropwise slowly at 0° C. (pH 2-3). The mixture was extracted and the organic layer was retained (500 mL, MC). The solution was dried with sodium sulfate and evaporated in vacuo. The residue was purified by recrystallization with n-hexane and ethyl acetate to give (N-Fmoc-N′-methyl-hydrazino)-acetic acid (12 g, 72%). 1H-NMR (DMSO-d6) δ 12.38 (s, 1H), 8.56 (b, 1H), 7.89˜7.86 (d, J=9 Hz, 2H,), 7.70˜7.67 (d, J=9 Hz, 2H,), 7.43˜7.29 (m, 4H), 4.29˜4.27 (d, J=6 Hz, 2H), 4.25˜4.20 (t, J=6 Hz, 1H), 3.47 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[O:28][CH3:29])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:32])=[CH:12][C:13]([CH3:31])([CH3:30])[NH:14]2.[OH-].[Na+].C(OCC)(=O)C>C(O)C.[Zn]>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([O:28][CH3:29])=[C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:33]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:34])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:31])([CH3:30])[CH:12]=[C:11]3[CH3:32])[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 110 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-5-nitrophenyl)-2,2,4-trimethyl -1,2-dihydroquinoline (Compound No. 14-48, 100.4 mg, 0.217 mmol) was dissolved in 4N aqueous NaOH solution (405 μL, 1.62 mmol)-ethanol (5 mL), and zinc (292.9 mg, 4.48 mmol) was added thereto, and then the reaction mixture was stirred at 110° C. overnight. Ethyl acetate (20 mL) was added to the reaction mixture and the unsoluble materials were filtered. After ethyl acetate (50 mL) was added to the filtrate, the whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (12.1 mg) as a yellow amorphous product. (Yield 13%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH2:18]1[C:20]2([CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]2)[CH2:19]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][CH:23]2[CH2:24][CH2:25][C:20]3([CH2:18][CH2:19]3)[CH2:21][CH2:22]2)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1
Reactant: OCC1CCC2(CC1)CC2
Reactant: O=C(O)c1cnc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of a 2,4-dichloroprimidine-5-carboxylic acid (440 mg) in THF (4.0 mL) are added t-BuOK (potassium tert-butoxide) (5.7 mmol) and spiro[2.5]oct-6-ylmethanol (2.3 mmol) in THF (1.0 mL) at 0° C. After stirring at 0° C. for 1.5 h, the reaction is quenched by the addition of sat. aq. NaHCO3. The mixture is washed with ether. The aqueous layer is acidified to pH 2 with sat. aq. KHSO4, then extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude title compound.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:19]([C:21]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:11])[F:13])=[O:22])[N:20]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=429.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:25]=[N:26][C:27]4[CH:33]=[C:32]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])[CH:31]=[C:30]([CH3:42])[C:28]=4[N:29]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[OH:49][C:43]([C:45]([F:48])([F:47])[F:46])=[O:44].[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[C:32]1[CH:31]=[C:30]([CH3:42])[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([S:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)(=[O:16])=[O:15])=[CH:22][CH:21]=3)[N:25]=[N:26][C:27]=2[CH:33]=1
Reactant: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCNCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
4-{4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.0696 g, 0.111 mmol, 1 equiv) was diluted with DCM (5 mL) and treated with TFA (0.051 mL, 0.664 mmol, 6 equiv). The resulting red solution was stirred at ambient temperature for 6 hours. Additional 6 equivalents of TFA were then added and the reaction was stirred for 12 hours. The solvents were then evaporated and the resulting solids collected and dried to yield a yellow powder (0.062 g, 99% yield). MS (ESI+): m/z=528.9, LC retention time: 2.70 min. 1H NMR (DMSO-d6): δ 2.72 (s, 3H), 3.13 (m, 4H), 3.22 (m, 4H), 7.53 (m, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.84 (d, J=8.7 Hz, 2 H), 8.20 (d, J=1.7 Hz, 1H), 8.32 (d, J=8.8 Hz, 2H), 8.62 (bs, 2H), 11.53 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17].CC(=O)OCC>CC#N>[Cl:17][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CSc1ncc(OCC2CC2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ncc(OCC2CC2)c(Cl)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To the title compound of step 2 (29.00 g, 136.79 mmol) and N(CH3)4Cl (22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL), was added POCl3 (123.93 g, 820.74 mmol). The mixture was stirred at r.t. for 30 min and at 70° C. for 1 h. After concentration under vacuum, EA extractive work up and silica gel chromatography (PE: EA=50:1-5:1) gave the title compound (20 g, 63.6% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.56 (s, 3H), 1.33-1.28 (m, 1H), 0.72-0.70 (m, 2H), 0.41-0.37 (m, 2H). LCMS: 230.9 (M+1)+
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:43]2[CH2:50][CH2:49][CH2:48][C@H:44]2[C:45](O)=[O:46])=[O:42])=[CH:36][CH:35]=1>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:45]([C@@H:44]1[CH2:48][CH2:49][CH2:50][N:43]1[C:41](=[O:42])[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=1)=[O:46]
Reactant: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: Nc1ccccc1SCc1ccccc1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)Nc2ccccc2SCc2ccccc2Br)cc1
Reaction time: 1 h

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (DCC) (705 g) in dichloromethane (1400 ml) was added over 30 minutes to a stirred solution of 2-(2-bromophenylmethylthio)aniline (see Bull. Chem. Soc. Japan, 48, 2323 (1975)) (957 g) and (S)-1-(4-methoxyphenylacetyl)proline (see Preparation 24) (900 g) in dichloromethane (5.5 L). The mixture was stirred at 25°-35° C. for one hour and filtered. The filtrate was evaporated under reduced pressure to give the desired product as a brown gum which was used directly in Preparation 22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:20]=2[N:19]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:18]2[NH:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:21]=3[N:22]=2)[C@H:10]([CH3:14])[CH2:9]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol from step (a) above (96 mg, 0.4 mmol) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (71 mg, 0.32 mmol, Example 1c) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[Se](=O)=[O:10]>O1CCOCC1>[CH3:7][C:3]1[C:2]([CH:8]=[O:10])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=[Se]=O
Reactant: Cc1cccnc1C
Solvent: C1COCCO1
Product: Cc1cccnc1C=O
Yield: 37.3 %

Procedure:
2,3-Lutidine (1.0 g, 9.33 mmol) was refluxed in a 1,4-dioxane (20 ml) solution in the presence of selenium dioxide (1.24 g, 11.2 mmol) in an argon atmosphere for one hr. The temperature of the reaction solution was then returned to room temperature, and the reaction solution was filtered. The solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:2) to give 422 mg (37.3%) of 3-methylpyridine-2-carbaldehyde as a colorless liquid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCN1CCCCCC1=O
Yield: 84.8 %

Procedure:
Following example 10, 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 44.2 g (0.2 M) of 1-bromodecane on 19 hr. reflux gave 38 g (84.7%) of product; b.p. 158°-163 °/0.25-0.3 mm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([Cl:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCN(Cc1ccccc1)C2
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 81 %

Procedure:
7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene [Ozdowska et al Rocz. Chem. Ann. Soc. Chim. Pol. 50, 1771 (1976)] 95.0 g, 15.9 mmol) was added to POCl3 and the mixture heated to 100° C. for 1 h. The reaction was cooled, concentrated under reduced pressure and the residue quenched with ice. After neutralising with K2CO3 the product was extracted with CH2Cl2,, the organic layer washed with H2O, dried over MgSO4 and evaporated to give the subtitle compound as a brown oil (3.33 g, 81%). Rf 0.45 (CH2Cl2/MeOH/0.88NH3 92/7/1, v/v).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:15]([C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]=1)#[N:16].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH:17]1[C:15]#[N:16])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)Cc1ccccc1
Reactant: COc1ccc2c(c1)CCC=C2C#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(C(=O)Cc1ccccc1)C1CCc2cc(OC)ccc2C1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCl--NH3M/Z: 395 (M+NH4)+.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:19])[C:8](=[O:18])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:19])[C:8](=[O:18])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)N(c1ccccc1)C(=O)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1C(=O)N(c2ccccc2)c2cc(O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 6-methoxy-1-phenyl-1H-indole-2,3-dione (50 mg, 0.20 mmol) and BBr3 (418 mg, 1.67 mmol) in CH2Cl2 (6 mL) was stirred at 0° C. for 1 hour. The crude product was purified by preparative TLC [Eluent: EtOAc/hexane (1:1)], giving the desired product (13 mg, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)C2CCCCC21

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepine-2,5-dione (3.6 g) in acetic acid (50 ml) is hydrogenated for 120 hours at 3 atmospheres pressure using platinum oxide (1.2 g) as catalyst. The catalyst is filtered off and the filtrate evaporated under reduced pressure. The residue is distributed between dichloromethane (200 ml) and saturated aqueous sodium bicarbonate (100 ml). The dichloromethane solution is washed with water (50 ml), dried over sodium sulfate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel eluting with 0-50% ethyl acetate in toluene. The fraction eluting with 50% ethyl acetate in toluene is collected to give 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2,5-dione used without further purification for the next synthetic step.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][NH:11][C:10]=2[CH:14]=1)=O)C.O.[NH2:16][NH2:17]>C(O)C>[NH:11]1[C:10]2[CH:14]=[C:6]([C:4]([NH:16][NH2:17])=[O:3])[CH:7]=[CH:8][C:9]=2[N:13]=[CH:12]1
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2nc[nH]c2c1
Yield: 88 %

Procedure:
30 g of 1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (0.16 mol) and 150 mL anhydrous ethyl alcohol were added to a three-necked bottle, to which 50 mL of 80% hydrazine hydrate was added. After refluxing for 4 h, the ethyl alcohol was evaporated under reduced pressure and water was added to the residual solution to isolate a solid. After sucking filtration and drying, 24.9 g solid was obtained. Yield: 88%. MS: 177 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(OCc2cccc(F)c2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(F)c4)c3C2=O)C(=O)N1
Yield: 89.8 %

Procedure:
A mixture of 3-(3-fluoro-benzyloxy)-phthalic acid (1.9 g, 6.7 mmol), alpha-amino-glutarimide hydrochloride (1.2 g, 7.0 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-fluoro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (2.3 g, 89% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.22 min (99.9%); mp, 241-243° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H, CHH), 2.55-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.11 (dd, J=6, 12 Hz, 1H, CH), 5.40 (s, 2H, CH2), 7.15-7.87 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.11, 113.61, 113.90, 114.52, 114.80, 115.71, 116.70, 120.13, 122.96, 122.99, 130.49, 130.60, 133.25, 137.05, 139.08, 139.18, 155.21, 160.59, 163.81, 165.33, 166.74, 169.89, 172.73. Anal Calcd For C20H5N2O5F: C, 62.83; H, 3.95; N, 7.33; F, 4.97. Found: C, 62.72; H, 3.75; N, 7.27; F, 5.02.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:12]=[CH:13][C:14]=1[NH:15]C(=O)C(F)(F)F)#[N:8]>CO.O>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])=[CH:10][C:9]=1[C:7]#[N:8]
Reactant: N#Cc1cc(NC(=O)c2ccccc2F)ccc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1cc(NC(=O)c2ccccc2F)ccc1N

Procedure:
Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-(2,2,2-trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture is refluxed overnight. After removing the solvent under reduced pressure, the residue is suspended in water and extracted with dichloromethane. The organic extracts are pooled, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]#[N:12])[C:2]1=2.CC([OH:17])(C)C.[OH-].[K+]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([NH2:12])=[O:17])[C:2]1=2
Reactant: N#CCc1cccc2ccsc12
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)Cc1cccc2ccsc12

Procedure:
Add benzo[b]thiophene-7-acetonitrile (1.9 g, 11.0 mmol) to 2-methyl-2-propanol (20 mL). Heat to reflux under nitrogen and add potassium hydroxide pellets (7.4 g, 132 mmol). Stir and reflux under nitrogen for 30 minutes. Pour solution off of the excess potassium hydroxide and dilute with ethyl acetate. Wash with a 1:1 mixture of aqueous saturated sodium chloride, aqueous saturated sodium hydrogen carbonate. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Rinse the solid with cold diethyl ether and dry under vacuum to obtain the title compound as an off-white solid.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.[C:10]1([CH3:23])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[NH:18]>C(O)C>[CH3:7][C:6]1[N:21]=[C:20]([NH:19][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:23])=[NH:18])[NH:22][C:4](=[O:9])[CH:5]=1
Reactant: Cc1ccccc1NC(=N)NC(=N)N
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(=O)[nH]c(NC(=N)Nc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxobutyric acid ethyl ester (2.6 grams, 0.020 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-(o-tolyl)biguanide (3.8 grams, 0.020 mol; obtained from Aldrich Chemical Co.) in anhydrous ethanol (20 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with cold ethanol (0° C.). The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-o-tolylguanidine as a colorless solid (3.50 grams, 68 percent yield): mp=260° C.; Exact mass calculated for C13H15N5O=257.1277. Measured Low. Resolution Mass Spectrum (MAB/LR/N2)=257.1.