Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([C@H:27](OS(C)(=O)=O)[CH3:28])(=[O:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C@@H:27]([CH3:28])[C:24]([NH2:25])=[O:26])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C[C@@H](OS(C)(=O)=O)C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (100 mg, 0.32 mmol), methanesulfonic acid (R)-1-carbamoyl-ethyl ester (64 mg, 0.38 mmol) and potassium carbonate (67 mg, 0.48 mmol) were suspended in DMF (3 mL) and the reaction mixture stirred at RT for 24 h then at 50° C. for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected flash chromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid (59 mg, 48%). LCMS: RT=3.07 min; [M+H]+=383; 1H NMR (400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H, s), 7.85 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36 (9H, m). ee >99% (chiralpak IC, 1 mL/min, 20% ethanol in heptane, 50 min run)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1(=[O:16])=[O:15].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.CCOCC>[CH2:17]([NH:21][C:22]([NH:14][S:11]([C:10]1[C:4]2[S:3](=[O:16])(=[O:15])[N:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:12])=[O:13])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=O
Reactant: CN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1S(=O)(=O)N(C)C2
Reaction time: 16 h

Procedure:
A suspension of 13.0 g of 2-methyl-2,3-dihydro-1,2-benzisothiazole-7-sulfonamide-1,1-dioxide, 11.2 ml of butyl isocyanate and 13.8 g of potassium carbonate in 200 ml of dry methyl ethyl ketone was heated at reflux for 2 hours. 13.8 g of potassium carbonate was added and heating was continued for an additional 16 hours. The mixture was cooled, the solvent was decanted from the solids, concentrated in vacuo, the residue dissolved in ethyl acetate and washed with saturated aq. NaHCO3. The aqueous wash was added to the original solids diluted with water and acidified to pH ~3 with dilute HCl. The mixture was extracted with methylene chloride, the extract was washed with water and brine, dried and concentrated in vacuo leaving a solid which was slurried in ether and filtered to give 13.24 g of the title compound as a white powder, m.p. 162°-164° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH:7]2[NH2:17])[CH2:4][CH2:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][N:31]=[CH:32]3)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:2]1([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH:7]2[NH:17][C:25]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][N:31]=[CH:32]3)=[O:24])[CH2:3][CH2:4]1
Reactant: NC1CCc2cc(F)ccc2C1CC1CC1
Reactant: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccc2cnccc12)NC1CCc2cc(F)ccc2C1CC1CC1
Yield: 28.6 %

Procedure:
1-Cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (127 mg, 0.49 mmol), isoquinolin-5-yl-carbamic acid phenyl ester (150 mg, 0.49 mmol), and diisopropylethylamine (193 mg, 1.47 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (10-90% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea 71 (68 mg, 0.14 mmol). MS (MH+) 390; 1H NMR (CD3OD) δ 0.08-0.87 (m, 2H), 1.60-1.65 (m, 2H), 2.03 (m, 1H), 2.97 (m, 2H), 3.14 (m, 1H), 4.36 (m, 1H), 6.87 (m, 2H), 7.27 (m, 1H), 7.93 (t, 1H, J=2.6 Hz), 8.14 (d, 1H, J=2.7 Hz), 8.32 (d, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.6 Hz), 8.53 (d, 1H, J=2.2 Hz), 9.63 (s, 1H). HPLC Rt=3.63 min (10-90% water:acetonitrile gradient, 100% pure).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[Cl:39][CH2:40][C:41](Cl)=[O:42].[I-].[Na+].[C:46]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:48])[CH3:47]>CN(C=O)C.O>[ClH:39].[C:46]([N:49]1[CH2:54][CH2:53][N:52]([CH2:40][C:41]([N:12]2[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]3[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=3)[C@H:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[O:42])[CH2:51][CH2:50]1)(=[O:48])[CH3:47]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N1CCN(CC(=O)N2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of the compound (175 mg) obtained in Example 1 and diisopropylethylamine (113 mg) in DMF (5 ml), chloroacetyl chloride (50 mg) was added at room temperature, and the reaction mixture was stirred for 1 hour. To the reaction solution, diisopropylethylamine (113 mg), sodium iodide (180 mg) and 1-acetylpiperazine (102 mg) were added and the reaction mixture was further stirred for 5 hours. To the reaction solution, water was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was treated with 4 N hydrogen chloride/ethyl acetate to obtain the title compound (150 mg) as colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]([NH2:42])[CH3:41])=[CH:36][CH:35]=1)([O-:33])=[O:32]>>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C@@H:40]([NH:42][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[CH:20]=[CH:21]3)=[O:30])[CH3:41])=[CH:38][CH:39]=1)([O-:33])=[O:32]
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1cccc(-c2ccccc2Cn2ccc3cc(C(=O)O)ccc32)c1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2ccc3cc(C(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:8][C:4]1[C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: Cc1cccc(N)c1[NH-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc12

Procedure:
The procedure used in Example 68 is followed. In a 250 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 5 g of (2-amino-6-methylphenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 100 ml of acetic acid. After cooling, bring to dryness under reduced pressure. Take the residue up in 25 ml of water then bring to pH=8 by addition of a saturated aqueous solution of sodium hydrogen carbonate. The precipitate that formed is filtered off, washed with water, and made into a paste with diisopropyl ether, and in this way, we obtain 4.7 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5](=[O:37])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(OCC)(=O)C.O>CC(C)=O.OS(O)(=O)=O>[CH:2]([C:3]1[CH2:4][S:5](=[O:37])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:1]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Yield: 39.4 %

Procedure:
As described in Belgian Patent 770,531, to a solution of 1.80 g (3.4 mmole) of benzhydryl 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 100 ml of acetone at 0° was added over the period of 2 min. 0.90 ml of 8N CrO3 in H2SO4 and the mixture was stirred at 0° for 5 min., then poured into a mixture of 300 ml ethyl acetate and 300 ml of water and the ethyl acetate layer was washed with water, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica with CHCl3 to yield 0.716 g of benzhydryl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide after crystallization from methanol; uv max (C2H5OH): 269 nm (4600), 292 nm (4300), and 355 nm (1760); nmr (dmso-d6): 3.75 and 4.32 (AB, 2 (JAB = 19 Hz), C2 -CH2), 3.88 (s, 2, α-thienyl CH2), 5.08 (d, 1 (J = 5 Hz), C6 -H), 6.18 (dd, 1 (J = 5 Hz, J' = 8.5 Hz), C -H), 7.17 (1, s, -CO2CH Ph2), 7.02 (d, 2 (J = 3.0 Hz), thiophene 3- and 5-H), 7.44 (10, s, phenyl-H), 8.72 (d, 1 (J = 8.5 Hz), amide N-H), and 9.85 (s, 1, aldehyde-H).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].Cl.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C=O)C.O>[O:12]1[CH2:13][CH2:14][N:9]([C:1]([C:2]#[C:3][CH2:4][CH3:5])=[O:7])[CH2:10][CH2:11]1
Reactant: C#CCCC(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC#CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A mixture of 4-pentynoic acid (210 mg, 2.14 mmol), morpholine hydrochloride (265 mg, 2.14 mmol), 1-hydroxybenzotriazol (338 mg, 2.50 mmol), WSC HCl (484 mg, 2.52 mmol), and triethylamine (0.37 ml, 2.65 mmol) in DMF (7 mL) was stirred for 1 h at room temperature. Water was added. The mixture was extracted with ethyl acetate-toluene, and the extracts were washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 1:1 to 1:5 hexane/ethyl acetate to give the title compound (325 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.OC[N:39]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]1=[O:49].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCN4C(=O)c5ccccc5C4=O)c(C)c3C)c2cc1OC
Yield: 17.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(hydroxymethyl)-1,3-isoindolinedione (41 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (14 mg, yield 17%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:15]=1)[C:9](N(OC)C)=[O:10])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:15]=[C:8]([CH:9]=[O:10])[CH:7]=[N:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cncc(C(=O)N(C)OC)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCOc1cncc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 16-3 (14.0 g, 66.5 mmol) and CH2Cl2 (200 mL) at -78° C. under argon was added DIBAL (1.0M hexanes, 90 ml) dropwise over 30 minutes. After 30 minutes, the solution was warmed to 0° C. for 1 hour. The reaction was quenched with 100 ml 1.0M Rochelle's salt, stirred for 1.0 hour and then extracted with Et2O. The organic layer was dried (MgSO4), and then concentrated to give the aldehyde 16-4 as a brown oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]([OH:28])=[O:27])=[CH:18]1)[CH2:14][CH2:15][CH3:16].C([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]#[N:44])=O.[O:45]1CCC[CH2:46]1>C(OCC)(=O)C.O>[CH2:13]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]([OH:28])=[O:27])=[C:18]1[CH:46]([OH:45])[C:35]1[CH:36]=[CH:31][C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]#[N:44])=[CH:33][CH:34]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C1CCOC1
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Reactant: N#Cc1ccccc1-c1ccccc1C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCCCn1c(C(O)c2ccc(-c3ccccc3C#N)cc2)c(C(=O)O)c2ccccc21
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a 3 liter 3-neck flask was added 1 liter of dry tetrahydrofuran and 48.4 ml diisopropylamine. The mixture was cooled to -50° C. under argon, and 216 ml of 1.6M of n-butyllithium (in hexane) was added dropwise over 5 minutes. The mixture was then allowed to warm to -10° C., and then recooled to -40° C. A solution of 30 g of 1-butylindole-3-carboxylic acid in 100 ml dry tetrahydrofuran was added dropwise over 5 minutes. The solution was stirred at -40° to -30° C. for 1 hour, and then recooled to -70° C. At once was added 28.61 g of 2-formyl-2'-cyanobiphenyl, and the mixture was stirred at -70° C. under argon for 2 hours. The mixture then was warmed to -20° C. and 500 ml of water was added while stirring. Ethyl acetate was then added to the mixture and the aqueous layer separated, which was extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with 1N HCl, and dried (MgSO4). The solvent was removed under reduced pressure, and the resulting material recrystallized from a mixture of ethyl acetate and hexane, to yield 36.4 g of 1-(n-butyl)-2-[1-hydroxy-1-(2"-cyanobiphenyl-4'yl)methyl]indole-3-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][N:8]=1.[CH3:11][C:12]([CH3:14])=[O:13]>O>[CH3:3][C:4]1[S:5][C:6]([CH:9]=[CH:11][C:12](=[O:13])[CH3:14])=[CH:7][N:8]=1
Reactant: CC(C)=O
Reactant: Cc1ncc(C=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cnc(C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An aqueous solution of 2% sodium hydroxide (3 ml) was added to a solution of 2-methyl-thiazole-5-carboxaldehyde (2.5 g) in acetone (20 ml) and water (10 ml). The mixture was stirred for 24 hours at ambient temperature, diluted with water (150 ml) and extracted with chloroform (2×50 ml). The organic layer was washed with water and then dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent gave 1-(2-methyl-5-thiazolyl)but-1-en-3-one as a low-melting point solid (1.4 g, 43%). Pmr spectrum (CDCl3 ; δ in ppm); 2.30 (3H, s); 2.72 (3H, s); 6.36 (1H, d); 7.56 (1H, d); 7.74 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:15]OS(OC)(=O)=O.[BH4-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Reactant: COS(=O)(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Temperature: 100 °C

Procedure:
5-Bromo-8-nitroisoquinoline (216.9 g, 0.86 mol) was added in portions during 10 min to a solution of dimethylsulphate (750 ml). Some heat was developed. The mixture was heated at 100° C. for 10 minutes. 5-Bromo-2-methyl-8-nitroquinolinium methyl sulphate precipitated. The mixture was cooled on ice and diethyl ether (1 l) was added. The crude mixture was filtered and crystals were isolated. The salt was solved in acetic acid (1.5 l). To the ice-cooled mixture was added: sodium borohydride (47 g, 1.24 mol) over 4 hours. The temperature was kept below 30° C. The crude mixture was evaporated and sodium hydroxide (2 l, 1 M) was added. The crystals were filtered. Yield 205.2 g (88%). Mp 85-87° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1.[C:31]([Al](CC)CC)#[N:32]>ClCCl.C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]2)([C:31]#[N:32])[CH3:23])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC[Al](C#N)CC
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(C(C)(C#N)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To tert-butyl piperidin-4-ylmethylcarbamate (0.527 g) and 1-(biphenyl-4-yl)ethanone (0.483 g) in dichloromethane (6.2 mL) was added titanium (IV) isopropoxide (0.720 mL). The reaction mixture was stirred at room temperature for 24 hours. A 1.0 mol/L solution of cyanodiethylaluminum (2.46 mL) in toluene was then added dropwise and the reaction mixture was stirred at ambient temperature for another 24 hours. It was then quenched with saturated sodium bicarbonate and diluted with dichloromethane. The biphasic mixture was filtered, and the layers of the filtrate were separated. The aqueous layer was extracted with dichloromethane, and the combined organics were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexanes=85:15) to obtain the title compound (0.565 g) having the following physical data.
Reaction SMILES: C1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][C:13]=2[CH:14]=[O:15])[N:10]([CH3:16])[C:9](=[O:17])[CH2:8][CH2:7]3)CC1.[C:18]([O-])(=[O:20])[CH3:19].[NH4+].CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[CH2:18]([O:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]=[O:15])[N:10]([CH3:16])[C:9](=[O:17])[CH2:8][CH2:7]2)[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CN1C(=O)CCc2cc(C3CC3)c(C=O)cc21
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: [NH4+]
Solvent: CC#N
Product: CCOc1cc2c(cc1C=O)N(C)C(=O)CC2

Procedure:
The title compound was prepared according to the procedure used for the preparation of 6-cyclopropyl-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.47 (3H, t, J=7.0 Hz), 2.65 (2H, m), 2.93 (2H, m), 3.36 (3H, s), 4.14 (2H, q, 7.1 Hz), 6.81 (1H, s), 7.42 (1H, s), 10.45 (1H, s). m/z (APCI+) 233.9 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.167 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH:13]=O)=[CH:5][NH:6]2.[NH2:15][CH:16]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH2:13][NH:15][CH:16]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][NH:6]2
Reactant: N#Cc1ccc(Br)c2c(C=O)c[nH]c12
Reactant: CCOC(=O)C(N)C(OCC)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NCc1c[nH]c2c(C#N)ccc(Br)c12)C(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 4-bromo-3-formyl-1H-indole-7-carbonitrile (1.08 g, 4.34 mmol), ethyl 2-amino-3,3-diethoxypropanoate (prepared according to the procedure of U.S. Pat. No. 7,470,680; 1.780 g, 6.94 mmol), and molecular sieves (2.17 g, 2 g) in 1,2-dichloroethane (79 mL) and THF (29.6 mL) at 0° C. was treated with sodium triacetoxyborohydride (2.57 g, 12.14 mmol) and the resulting mixture was stirred at room temperature overnight. After 24 h, LCMS residual starting material, so additional sodium triacetoxyborohydride (1.38 g, 1.5 eq.) and molecular sieves (2 g) were added and stirring was continued for 4 h more. The mixture was diluted with EtOAc and filtered through a CELITE® pad and the solids were washed with EtOAc. The filtrates were diluted with EtOAc and washed with NaHCO3 (aq) and brine, dried and concentrated to afford a dark-colored oil. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexane (gradient from 15:85 to 100:0) to provide the desired product as a brown syrup (0.67 g, 35% yield). LCMS (M+H)+ m/z 438.2, 440.2.