Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]([NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:7].O.CO>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:10]([C:11]3[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)=[N:9][N:8]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: COc1cc(OC)cc(C(=O)NNC(=O)c2cc(OC)cc(OC)c2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1cc(OC)cc(-c2nnc(-c3cc(OC)cc(OC)c3)o2)c1
Yield: 83.5 %

Procedure:
A mixture of 20.5 g (0.057 mole) of N,N'-bis(3,5-dimethoxybenzoyl)hydrazine in 125 ml of phosphorus oxychloride was heated to reflux temperature. All material dissolved after a short time and the solution was held at reflux for 1 hr. before it was cooled and slowly poured into water. The damp precipitate was stirred with 250 ml of boiling methanol before the mixture was cooled and filtered to give 16.3 g (84%) of crude 2,5-bis(3,5-dimethoxyphenyl)-1,3,4-oxadiazole, mp 167°-170° C.; Crystallization of a small sample from methanol gave mp 173°-175° C. 1H NMR(acetone-d6): 3.98 (s, 12H), 6.83 (m, 2H), 7.43 (m, 4H). Anal. Calcd. for C18H18N2O5 : C, 63.15; H, 5.30; N, 8.18. Found: C, 62.73; H, 5.34; N, 7.98.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5](=[O:14])[C:4]1([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C(O)C>CO.C(Cl)(Cl)Cl.CO>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([OH:46])[CH2:41][CH2:42][N:43]([CH2:2][CH:3]3[CH2:7][N:6]([CH:8]4[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[C:5](=[O:14])[C:4]3([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:44][CH2:45]2)=[CH:36][CH:35]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C1N(C2CCCCC2)CC(CCl)C1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1N(C2CCCCC2)CC(CN2CCC(O)(c3ccc(Cl)cc3)CC2)C1(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 39 g. (0.106 mole) of 4-chloromethyl-1-cyclohexyl-3,3-diphenyl-2-pyrrolidinone, 58.5 g. (0.424 mole) of finely ground potassium carbonate, and 22.5 g. (0.106 mole) of 4-(4-chlorophenyl)-4-hydroxypiperidine in 300 ml. of ethanol was heated to 200° C. in a steel bomb for 66 hrs. During the heating the bomb was continuously rotated to produce mild stirring. The contents were filtered and the filtrate concentrated. The residue was heated in 250 ml. of ethylacetate and allowed to stand at room temperature overnight. The mixture was filtered. The filtrate was extracted with dilute hydrochloric acid and dilute sodium hydroxide. The ethylacetate was concentrated and the residue dissolved in ethanol and allowed to stand overnight. The resulting mixture was filtered and the filtrate concentrated. The residue was chromatographed on a 4.5 × 60 cm. silica gel column. The product was obtained from the column using a chloroform-methanol eluate containing increasing amounts of methanol. The product after isolation and crystallization from isopropanol melted at 222°-225° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:33])([CH3:32])[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH:17]=1)[C:10]([CH3:35])([CH3:34])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:33][C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:34])([CH3:35])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:32])[C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1)C(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
A mixture of 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.87 g, 1.8 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (35 mg, 4%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O4 (M+H)+: 452.57, observed: 452.1.
Reaction SMILES: C([Mg][Br:4])C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12].CO.[BH4-].[Na+].[CH2:17]1[CH2:21]OCC1>>[Br:4][C:10]1[N:5]=[C:6]([CH:11]([NH2:12])[CH2:21][CH3:17])[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccccn1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(N)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl magnesium bromide (3.0 mL, 3.0 mmol) was added dropwise over 10 min to a solution of the pyridine nitrile A466.2 (500 mg, 2.75 mmol) in THF (5 mL) at room temperature under a nitrogen atmosphere. After strring for 30 min at room temperature, the reaction mixture was then cooled to 0° C. and anhydrous methanol added (2.75 mL) followed by sodium borohydride (15 mg, 3.0 mmol). The mixture was allowed to warm to room temperature over 1 hr before quenching with saturated ammonium chloride solution (10 mL) and stirring overnight at room temperature. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried (MgSO4), evaporated in vacuo and purified by column chromatography using 10% MeOH in ethyl acetate as eluant to yield A466.3 (237 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 0.87 min, M+H+=217.15
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCN4CCc5ccccc5C4)cc3)noc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
Combine 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (200 mg, 0.595 mmol), 1,2,3,4-tetrahydroisoquinoline (0.08 mL, 0.595 mmol), potassium carbonate (181 mg, 1.31 mmol), potassium iodide (10 mg, 0.06 mmol) and 4% aqueous acetonitrile. Stir at 70° C. for 18 hours and cool to room temperature. Filter the reaction mixture and wash the solids with dichloromethane. Evaporate the filtrate to give the title compound as a brown solid (130 mg, 56% Yield). Purity by LC/MS=68%, [M+H]+=389.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccnc(CCl)c1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cc(C(F)(F)F)ccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 81.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-4-trifluoromethylpyridine (0.67 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.79 g) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:3][N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6]/[C:7]/1=[N:8]\[O:9][CH3:10].Cl.O1CCOCC1>CO>[CH3:10][O:9]/[N:8]=[C:7]1/[CH:2]([CH3:1])[CH2:3][NH:4][CH2:5][CH2:6]/1
Reactant: CO/N=C1\CCN(C(=O)OC(C)(C)C)CC1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CO/N=C1\CCNCC1C
Reaction time: 8 h
Yield: 147.1 %

Procedure:
1,1-Dimethylethyl(4E)-3-methyl-4-[(methyloxy)imino]-1-piperidinecarboxylate (197 mg) was dissolved in methanol, treated with 4.0 N HCl/dioxane (4 mL) and stirred overnight. The reaction was then concentrated to provide the product as a white solid (170 mg). The crude material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C(N(CC)CC)C.C(O)C>O>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 98.1 %

Procedure:
A mixture of 1-(3-(benzyloxy)pyridin-2-yl)thiourea (prepared according to Example 2, Steps A and B) (8.00 g, 30.8 mmol), 2-(4-bromo-3-oxobutyl)isoindoline-1,3-dione (12.8 g, 43.2 mmol; prepared according to J. Med. Chem. (1992) 35, 3239-3246), triethylamine (7.31 mL, 52.4 mmol), and ethanol (200 mL) was heated at reflux for 2 hours. The reaction mixture was cooled, diluted with water (200 mL), filtered, washed several times with water and hexanes, and dried. The product was recrystallized the solid from hexanes:methylene chloride (1:1, 250 mL) to afford 2-(2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)ethyl)isoindoline-1,3-dione (13.8 g, 98.0% yield) as a white powder. 1H NMR (d6-DMSO) δ 9.93 (bs, 1H), 7.80-7.87 (m, 6H), 7.57 (d, 2H), 7.35-7.43 (m, 4H), 6.89 (m, 1H), 6.70 (s, 1H), 5.25 (s, 2H), 3.88 (t, 2H), 2.91 (t, 2H). Mass spectrum (apci) m/z=457 (M+H).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[CH:15]=[C:16]([C:18]3[O:23][C:22](=[O:24])[C:21]([CH3:25])=[C:20]([OH:26])[C:19]=3[CH3:27])[O:17][C:13]=2[CH:12]=1)([OH:10])=[O:9].[C:30](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:25][C:21]1[C:22](=[O:24])[O:23][C:18]([C:16]2[O:17][C:13]3[CH:12]=[C:11]([C:8]([O:10][CH3:30])=[O:9])[CH:29]=[CH:28][C:14]=3[CH:15]=2)=[C:19]([CH3:27])[C:20]=1[OH:26]
Reactant: CC(=O)O
Reactant: Cc1c(-c2cc3ccc(C(=O)O)cc3o2)oc(=O)c(C)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(-c3oc(=O)c(C)c(O)c3C)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyldiazomethane (2 M hexane solution, 85 μl) was added to a mixed solution of 6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (50 mg) in MeOH (5 ml) and toluene (1 ml), and the mixture was stirred at room temperature for 10 minutes. After adding acetic acid to the reaction solution for quenching of the excess trimethylsilyldiazomethane, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH =9/1) to obtain 3,5-dimethyl-4-hydroxy-6-(6-(methoxycarbonyl) benzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23](F)=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35][O-:36].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([O:36][CH3:35])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(1-t-Butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (300 mg) was dissolved in 3 ml of DMF, followed by the addition of 32 mg of 55% sodium hydride under ice cooling. After the resultant mixture was stirred for 10 minutes, 72 mg of sodium methoxide was added. The mixture thus obtained was stirred further for 18 hours at room temperature. The reaction mixture was diluted with chloroform and then washed successively with 10% aq. citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness, whereby 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained. It was used directly in the reaction of the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=O)(C)(C)C>>[N:1]1([C:20]([C:19]2[CH:23]=[CH:24][C:16]([CH2:15][NH2:14])=[CH:17][CH:18]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Product: NCc1ccc(C(=O)N2CCCCC2)cc1
Yield: 100 %

Procedure:
Use the General Procedure 6-1, using piperidine (373 mg, 4.4 mmol) and 4-(tert-butoxycarbonylamino-methyl)-benzoic acid to give the title compound as a white solid (1.03 g, 100%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:23]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNCCC(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
2.132 g (10.1 mmol) 3,3-diphenylpropylamine (Aldrich, Milwaukee, Wis.) was added to a mixture of 0.853 g (5.11 mmol) ethyl bromoacetate (Aldrich) and 2.7 g (19.57 mmol) potassium carbonate in 14 ml acetonitrile at rom temperature. The mixture was stirred under argon for 18 hours. The reaction mire was filtered, the solvent evaporated and the residue chromatographed on a silica gel column with 40% ethyl acetate in hexanes to give 1.05 g (yield 69%) N-[(3,3-diphenyl)propyl]glycine ethyl ester (Compound A22) as an oil. NMR spectra of the product showed: 1H NMR (CDCl3, 300 MHz) 7.40-7.10 (m, 10 H), 4.14 (q, 2 H),4.03 (t, 1 H),3.33 (s, 2 H), 2.56 (t, 2 H), 2.24 (dt, 2 H), 1.22 (t, 3 H); 13C NMR (CDCl3, 75 MHz) 172.44, 144.66, 128.43, 127.75, 126.15, 60.63, 50.93, 48.80, 47.92, 35.85, 14.17. 0.019 g of A28 was also isolated from the silica gel column.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+].[K+].[Br-]>CN(C=O)C.O>[CH3:21][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 18 h

Procedure:
4-Nitrobenzyl chloride (5.0 g, 29.1 mmole) and sodium p-toluenesulfinate (6.8 g, 37.9 mmole) were dissolved in 50 mL of dry DMF. The mixture was stirred at about 23° for about 18 hours then diluted with water. The sulfone crystallized from the aqueous mixture and was filtered. The sulfone was purified by recrystallization from ethanol to give a pale yellow crystalline solid, mp 188°-190° (7.6 g, 25.9 mmole, 89%): IR (KBr) 2994, 1598, 1514, 1490, 1342, 1312, 1304, 1148, 824 cm-1 ; 1H NMR (CDCl3) δ 2.44 (s, 3H), 4.38 (s, 2H), 7.27 (m, 4H), 7.53 (d, J=8.3 Hz, 2H), 8.13 (d, J=8.3 Hz, 2H); MS m/e 292 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:25]1([CH:24]=[CH:23][C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)C=Cc3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cinnamoyl chloride (1.7 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours and then poured into ice water and excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl 3-phenyl-2-propenoate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O.[CH3:12][N:13]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2=[CH:17][CH:18]=[C:19]3[C:23]([NH:22][CH2:21][CH2:20]3)=[C:15]2[CH2:14]1>C1(C)C=CC=CC=1.C(Cl)Cl>[N:6]1([N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16]4[CH:24]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:25][N:13]([CH3:12])[CH2:14][C:15]4=3)[CH2:20][CH2:21]2)[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: O=C1CCCN1
Reactant: CN1Cc2c(ccc3c2NCC3)C(c2ccccc2)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1Cc2c(ccc3c2N(N2C=CCC2)CC3)C(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of 1.9 ml (0.02 mol) of phosphorus oxychloride in 6 ml of toluene is added dropwise to a solution of 3.4 g (0.04 mol) of pyrrolid-2-one in 8 ml of toluene at a temperature between 2° and 0° C., with stirring and cooling. The mixture is stirred at room temperature for 11/2 hours and left to stand overnight. A solution of 5.2 g (0.02 mol) of 8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole in 10 ml of toluene and 20 ml of CH2Cl2 is then added. The CH2Cl2 is distilled off and the reaction mixture is stirred at a temperature between 75° and 80° C. for 8 hours, with stirring. The solid which has precipitated is filtered off with suction, and 2N NaOH and H2O are added in order to convert it into the free base. The aqueous phase is extracted with CH2Cl2, the CH2Cl2 phase is dried and the solvent is removed. The residue is chromatographed on silica gel 60 from E. Merck, Darmstadt) using an eluent mixture of CH2Cl2 /MeOH (2:1), and on aluminum oxide (aluminum oxide 90 from E. Merck, Darmstadt) using an eluent mixture of CH2Cl2 and MeOH (20:0.25). The product is dried in a desiccator over P2O5 under a water pump vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2C=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:29])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O.[C:48]([Cl:52])(Cl)(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:48]([Cl:52])=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[C:10]([Cl:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc2c(ccn2-c2ccccc2)c1O
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Cl)c2c(c(Cl)cn2-c2ccccc2)c1O

Procedure:
A mixture of 4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (270 mg, 0.956 mmol), NCS (269 mg, 2.01 mmol) and BzOOBz (12 mg, 0.048 mmol) in carbontetrachloride (4 mL) was refluxed for 30 min. Then the reaction was cooled and concentrated, the resulting mixture was purified by column to give the desired product (173 mg). The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=11.8 (s, 1H), 7.6-7.3 (m, 6H), 4.52 (q, 2H, J=6.8 Hz), 1.47 (t, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)=[C:8]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[CH3:28][Mg]Cl.[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:26][C:23]1([CH3:27])[CH2:24][CH2:25][C:20]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:28])[CH3:2])=[CH:9][C:8]=2[NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[CH:21][CH2:22]1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)c[nH]2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2ccc(C(C)(C)O)cc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [5-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 31, step (d), 30.0 mg, 0.0828 mmol) in 2 mL of THF at −78° C. under Ar was added methyl magnesium chloride (58 μL, 0.17 mmol, 3.0 M in THF). The resulting mixture was warmed to RT and stirred for 0.5 h. Treated with 10 mL of saturated NH4Cl aqueous solution followed by 10 mL of brine, the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were dried with Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (2-3% MeOH/DCM) to give 29.0 mg (93%) of the title compound as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 14.22 (s, 1H), 9.76 (s, 1H), 8.32 (s, 1H), 8.12 (d, 1H, J=1.8 Hz), 7.25 (dd, 1H, J=8.1, 1.8 Hz), 7.14 (d, 1H, J=8.1 Hz), 5.65 (m, 1H), 2.16-2.29 (m, 2H), 1.87-1.98 (m, 2H), 1.47 (t, 2H, J=6.2 Hz), 1.43 (s, 6H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H26N4O2, 379.2 (M+H), found 379.0.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=[O:22])[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.[H-].[Na+].I[CH3:28]>CN(C)C=O.O>[CH3:28][N:19]1[CH:20]=[C:15]([CH:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:13]=[CH:14][C:4]3[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]2=3)[C:16](=[O:22])[NH:17][C:18]1=[O:21]
Reactant: CI
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=O
Reaction time: 16 h

Procedure:
A solution of the product of example 22 step (iv) (0.68 g) in dry N,N-dimethylformamide (10 ml) was treated in one portion with sodium hydride (60% dispersion by wt, 0.086 g). After 1 hr iodomethane (0.13 ml) was added and the solution was stirred for 16 hr. The reaction mixture was diluted with water (50 ml) and the mixture was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification was by chromatography eluting with 50-60% acetone in isohexane.