Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:4]=1[C:5]([C:7]1[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.C(OC(=O)C)(=O)C.[CH3:34][N:35]([CH3:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[CH:37]=1>Cl>[CH3:43][N:42]([CH3:44])[C:38]1[CH:37]=[C:36]([N:35]([CH3:45])[CH3:34])[CH:41]=[CH:40][C:39]=1[C:5]1([C:4]2[CH:19]=[CH:20][C:21]([N:23]([CH3:24])[CH3:25])=[CH:22][C:3]=2[N:2]([CH3:26])[CH3:1])[C:7]2[C:8](=[CH:12][CH:13]=[C:14]([N:16]([CH3:17])[CH3:18])[CH:15]=2)[C:9](=[O:10])[O:11]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)O)c(C(=O)c2ccc(N(C)C)cc2N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccc(N(C)C)cc32)c(N(C)C)c1

Procedure:
A mixture of 2-(2,4-bis(dimethylamino)benzoyl)-4-(dimethylamino)benzoic acid or the 5-(dimethylamino) isomer thereof (10 g.), N,N,N'-tetramethyl-m-phenylenediamine (2.30 g.) and acetic anhydride (50 ml.) was warmed (at 30°-35° C.) during one hour. More N,N,N',N'-tetramethyl-m-phenylenediamine (1.15 g.) was added and warming was continued. The mixture was diluted with dilute hydrochloric acid (10%) and ice and filtered. The filtrate was made alkaline. Crystallization of the product from toluene afforded 3,3-bis(2,4-bis(dimethylamino)phenyl)-5-(dimethylamino)phthalide (I: X=Y2 =Y4 =Z5 =(CH3)2N, Z4 =Z6 =Z7 =H) (m.p. 188°-192° C.) or the 6-(dimethylamino) isomer thereof.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:32][C:23]3[CH:22]=[C:21]([CH2:18][CH2:19][CH3:20])[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: CCCc1cc(CNCCN2CCN(c3ccc(OC)cc3)CC2)nn1-c1ccccc1
Yield: 41.3 %

Procedure:
Compound 39 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1([C@@:18]23[CH:25]=[CH:24][C:23](=[O:26])[N:22]2[C@@H:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][O:19]3)[CH2:17][CH2:16]1.O>C(Cl)Cl>[CH:15]1([C@@:18]23[C@H:25]([N:12]4[CH2:13][CH2:14][CH:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]4)[CH2:24][C:23](=[O:26])[N:22]2[C@@H:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:20][O:19]3)[CH2:17][CH2:16]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: O=C1C=C[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C1CCN([C@@H]2CC(=O)N3[C@@H](c4ccccc4)CO[C@]23C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To a mixture of 4-(2-methoxyphenyl)piperidine (0.951 g, 4.97 mmol) and (3S,7aR)-7a-cyclopropyl-3-phenyl-2,3-dihydropyrrolo[2,1-b]oxazol-5(7aH)-one (preparation #24) (1.0 g, 4.1 mmol) was added water (0.8 mL, 44 mmol). After about 5 minutes, DCM (5 mL) was added. All the solids dissolved. The reaction mixture was stirred at room temperature for about 16 hours. Purification on a Biotage silica gel column eluting with DCM/EtOAc (1:0 to 1:1) afforded (3S,7R,7aR)-7a-cyclopropyl-7-(4-(2-methoxyphenyl)piperidin-1-yl)-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (1.29 g, 2.98 mmol) as a white solid. RP-HPLC (Table 1, Method a) Rt 2.14 min; m/z: (M+H)+ 433.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.097 mmol), 5-aminovaleric acid (740 mg, 6.32 mmol), and NaOMe solution (10 mL, 4.86 mmol) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 19 mg of the title compound. MS: (+) m/z 549.31 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].[NH:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:18])[C:12]=2[CH:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:8][S:5]([CH2:4][CH2:3][CH2:2][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][NH:9]2)(=[O:7])=[O:6]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)CCCOc1cccc2[nH]ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
1-Chloro-3-(methanesulfonyl)-propane (160 g) was added to 1H-indol-4-ol (108.77 g) in 1 L MeCN, and 338 g K2CO3 and 13.36 g KI were added. The reaction mixture was stirred overnight at 80° C., then cooled and filtered through celite. The filtrate was vacuum distilled and solvent replaced with DCM (700 mL). The mixture was filtered, and the solvent removed in vacuo and replaced with MeOH (600 mL). The solvent was partially removed in vacuo at 40° C. and crystallization occurred. After cooling, additional MeOH was added and the slurry was filtered. The collected solid was rinsed with cold MeOH and dried overnight at 35° C. in vacuo under N2 to provide 4-(3-methanesulfonyl-propoxy)-1H-indole (82%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25].[OH-].[Li+]>O1CCCC1.CO.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1F)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1F)CCC3
Yield: 49.4 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-fluorobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (345 mg, 0.787 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was treated with 1 M aqueous lithium hydroxide solution (25 mL) at room temperature for 19 h. The mixture was diluted with water and methanol and filtered. The filtrate was concentrated in vacuo and the residue dissolved in water and acidified with concentrated hydrochloric acid. The resulting precipitate was collected via vacuum filtration, washed with water, and air-dried to provide 165 mg (50%) of the title compound as a yellow solid. Recrystallization (methanol/water) provided an analytical sample as a yellow green solid: mp 246-249° C. (dec). 1H NMR (DMSO-d6) δ 12.94 (bs, 1H), 7.73 (bs, 1H), 7.44 (bs, 1H), 7.33 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.37 (t, J=7.6 Hz, 1H), 5.59 (s, 2H), 4.63 (s, 2H), 2.92 (t, J=7.3.Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 2.44 (s, 3H), 1.97 (quintet, J=7.3 Hz, 2H); MS ES+ m/e 425 (p+1); IR (KBr, cm−1) 3450, 1619, 1225.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([NH2:10])=O)(=[O:4])=[O:3].S(Cl)(Cl)=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[C:8]#[N:10])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C(N)=O)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: CS(=O)(=O)c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 61.3 %

Procedure:
In a 3-neck 500 mL round-bottomed flask, 3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (7 g, 1 eq.) was dissolved in DMF (70 mL, 10 Vol) and added thionylchloride (3.8 mL, 2.0 eq.) and reaction mixture was refluxed to 90° C. for 12 h. The progress of the reaction was followed by TLC analysis on silica gel with 30% ethyl acetate -Hexane as mobile phase and visualization with UV, SM Rf=0.20 and Product Rf=0.35. Reaction mixture was brought to room temperature and quenched into the ice-water slurry (300 mL) and neutralized with sodium bicarbonate solution. Compound was extracted in the ethyl acetate (100 mL×3). Organic layer was washed with brine solution (100 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 5.0 g of crude compound, yield (95.0%). The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×20 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 15% to 20% ethyl acetate in hexane. Compound started eluting with 15% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (4 g), Yield (62%); Mass: (ES−) 247.97 (M−1).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[NH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)=[O:37])[CH2:32][CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[NH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)=[O:37])[CH2:32][CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (570 mg, 0.820 mmol) (obtained as described in Reference Example 51(5)) in anhydrous tetrahydrofuran (17 ml) were added successively acetic acid (56 μl, 0.984 mmol) and a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (984 μl, 0.984 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:3)→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (360 mg, yield 95%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N+:7]([CH3:10])([CH3:9])[CH3:8])(=O)[OH:2].C(O)(=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+]>>[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[C:1]([O:4][CH2:5][CH2:6][N+:7]([CH3:10])([CH3:9])[CH3:8])(=[O:2])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]
Reactant: C[N+](C)(C)CCOC(=O)O
Reactant: O=C(O)c1ccccc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: C[N+](C)(C)CCOC(=O)c1ccccc1O

Procedure:
To an aqueous solution containing 28.5 grams of choline carbonate is added 13.8 grams of salicylic acid and 12.6 grams of sodium sulfite. The mixture is stirred until complete solution is achieved and the ebullition of gases cease. The solution of choline salicylate sodium sulfite thus formed is sufficiently pure to be used for further pharmaceutical manufacture. The compound choline salicylate sodium sulfite may be obtained by removing the solvent under high vacuum with the aid of gentle warming. The compound is a colorless crystal, that is highly hygroscopic, rapidly absorbing water on exposure to the atmosphere. An 0.1 molar solution of choline salicylate sodium sulfite has a specific electrical conductivity of 8.16 × 10-3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12]3)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12]3)=[CH:7][CH:2]=1
Reactant: O=C(O)c1cnc2ccc(Oc3ccnc(Cl)c3)cc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cnc2ccc(Oc3ccncc3)cc2c1
Temperature: 25 °C

Procedure:
To a mixture of 6-[(2-chloropyridin-4-yl)oxy]quinoline-3-carboxylic acid (Int-31, 0.358 g, 1.19 mmol) and palladium (10% on carbon 0.07 g) in ethanol (5 mL) was added triethylamine (1 mL, 7.2 mol). The reaction flask was carefully evacuated and backfilled with an atmosphere of hydrogen from a balloon. After stirring at room temperature under hydrogen over night the flask was carefully purged with nitrogen and the suspension filtered through Celite. The filtrate was concentrated and used as obtained in the following step. LC-MS: (FA) ES+ 267.
Reaction SMILES: [CH:1](OCC)=[O:2].[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:10][CH2:9][C:8]1=[O:25]>ClC1C=CC=CC=1>[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]([CH:1]=[O:2])[CH2:9][C:8]1=[O:25]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCOC=O
Solvent: Clc1ccccc1
Product: CN1C(=O)CN(C=O)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 68.6 %

Procedure:
6 ml. of ethyl formate are added to a solution of 1.4 g. (5 mmoles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 5 ml. of chlorobenzene, and the reaction mixture is maintained at the boiling point of the solvent for 3 hours. Thereafter the solvent is evaporated under reduced pressure, and the oily residue is solidified by treating it with 20 ml. of dry ether. 108 g. (68.6 %) of 1-methyl-4-formyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 167°-169° C. The melting point does not change after recrystallization from ethanol. Rf2 = 0.5.
Reaction SMILES: [CH2:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:9][CH:10]=[CH2:11])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[C:12]1([C:4]([CH2:9][CH2:10][CH3:11])([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCC(CC=C)(C(=O)OC)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(CCC)(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A solution of the product of Example 1A (7.5 g, 32.61 mmol) in ethyl acetate (125 mL) was treated with 10% palladium on carbon (600 mg) and stirred at 25° C. under hydrogen gas for 18 hours. The solution was filtered through Celite® and the filtrate was concentrated in vacuo to give the title compound (7.63 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.27 (m, 5 H), 3.64 (m, 3 H), 1.96 (m, 4 H), 1.08 (m, 4 H), 0.89 (t, J=7.17 Hz, 6 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31]>C1COCC1>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([CH:30]=[O:31])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@]12CCc3c(C=O)cccc3[C@H]1CN(Cc1ccccc1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
cis-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.561 mmol, 200 mg) was dissolved in THF (5 ml) and the resulting solution was cooled to −78° C. Butyllithium (2.5 M in hexanes)(2.81 mmol, 1.123 ml) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. N,N-Dimethylformamide (8.42 mmol, 0.777 ml, 734 mg) was added and the reaction mixture was stirred at −78° C. for a further 2 h and then quenched by the addition of saturated aqueous ammonium chloride solution and allowed to warm to room temperature. The resulting biphasic solution was separated and the aqueous phase was further extracted with ether (2×). The combined organic extracts were dried over magnesium sulphate, filtered and the solvent removed in vacuo. The crude product was purified by silica column chromatography (eluting with heptane—50:50 EtOAc:Heptane) to afford cis-2-benzyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole-6-carbaldehyde (95 mg), 1H NMR (400 MHz, CDCl3) ppm 10.29 (1H, s, CHO), 7.67-7.61 (1H, m, Ar—H), 3.62-3.55 (2H, m, NCH2Ph), 3.32-3.04 (4H, m, 4×CH), 2.73 (1H, d, CH), 2.49 (1H, d, CH), 2.30 (1H, t, CH), 1.88-1.78 (1H, m, CH), 1.53-1.45 (1H, m, CH), 1.20 (3H, s, CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[C:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([CH:22]2[CH2:23][CH2:24]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=C(c2ccccc2)C2CC2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Yield: 102.4 %

Procedure:
[4-(2-Cyclopropyl-2-phenyl-vinyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (94 mg, 0.28 mmol) is dissolved in methanol (1.5 mL) and DCM (1.5 mL). Then 5% palladium on carbon (59 mg, 0.028 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give 97 mg of the crude product which is used in the next step without purification.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH:7]3[NH:14][C:15]3[C:20]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[CH:19][N:18]=[C:17]4[NH:31][CH:32]=[CH:33][C:16]=34)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2].[H][H]>[Pd].CO.O1CCOCC1>[C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH:7]3[NH:14][C:15]3[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[C:17]4[NH:31][CH:32]=[CH:33][C:16]=34)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)C12CC3CC(C1)C(Nc1c(C(=O)OCc4ccccc4)cnc4[nH]ccc14)C(C3)C2
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)C12CC3CC(C1)C(Nc1c(C(=O)O)cnc4[nH]ccc14)C(C3)C2
Yield: 80.2 %

Procedure:
10% Palladium on carbon (50% wet) (40 mg) was added to a solution of benzyl 4-[(5-carbamoyladamantan-2-yl)amino]-1H-pyrrolo-[2,3-b]pyridine-5-carboxylate (183 mg) in methanol (5 ml) and 1,4-dioxane (5 ml), and hydrogenated under hydrogen atmosphere for 5 hours. Resulting precipitates were dissolved by tetrahydrofuran and filtered out the catalysts. The filtrates were evaporated in vacuo to give 4-[(5-carbamoyladamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (117 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)ccc1O

Procedure:
In 100 ml of acetone is dissolved 15 g (0.0824 moles) of ethyl 2,5-dihydroxybenzoate, 13.9 g (0.110 mole) benzyl chloride and 34.1 g (0.247 mole) potassium carbonate. The mixture is heated to its reflux temperature and maintained at reflux for 22 hours. The solution is filtered and the residue is washed with acetone. The filtrate and washings are concentrated, and the residue is dissolved in diethyl ether. The ether extracts are washed twice with water then with saturated sodium chloride solution and finally dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the solution is evaporated to provide a suspension of product which is triturated with hexane and dried to provide a solid. The solid is recrystallized from hexane to provide ethyl 5-benzyloxy-2-hydroxybenzoate, m.p. 71.5°-73° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[C:14](Cl)(Cl)=[O:15].C1C=CC=CC=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[O:7][C:14](=[O:15])[NH:9][N:8]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
The reactions of Equation 37 above can be run according to similar procedures described in U.S. Pat. No. 4,259,104; Golfier and Milcent, J. Heterocycl. Chem., 10, 989 (1973); and R. Madhavan and V. Srinivasan, Indian J. Chem., 7, 760 (1969). Thus, in reaction 37a, a 2-nitrobenzhydrazide XLVIII is reacted with phosgene in an aprotic solvent such as benzene at ambient temperature for about 10 hours, followed by addition of two mole equivalents of triethylamine and heating at reflux for about 2 hours to form 2-(2-nitrophenyl)-1,3,4-oxadiazolin-5-one of Formula (LI). In reaction 37b, LI is reacted with phosphorus pentachloride in phosphorus oxychloride or with phosphorus pentabromide in phosphorus oxybromide at 25° to 80° C. for about 5 hours to form (Xk"'). And in reaction 37c, Xk"' is reacted with sodium methoxide or sodium ethoxide in a solvent such as methanol or tetrahydrofuran at 0° to 30° C. for about 0.5 to 5 hours to form Xk"".