Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:14][CH3:13]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2ccc(Br)cc12
Temperature: 120 °C
Yield: 90.7 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (12.12 g, 50 mmol) in methanol (200 mL) was added sodium methoxide (13.50 g, 250 mmol) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the methanol was removed under the vacuum and the residue was diluted with water. Then, the solids were collected by filtration and washed with water. After drying in air, 10.8 g (90.8% yield) of 6-bromo-4-methoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C10H8BrNO (M+) 236.9789, found 236.9784.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](=S)=[S:18].C(O)C.[K+].[Br-]>O>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]2[N:15]=[C:17]([SH:18])[NH:16][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(N2CCC(O)CC2)cc1N
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OC1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Yield: 62.3 %

Procedure:
6-Fluoro-5-(4-hydroxypiperidin-1-yl)-2-mercapto-1H-benzimidazole (4.5 g, 62%) was prepared by a similar procedure to that described in preparation 1 (step 5) using the diamine (6.0 g, 0.027 mol) (obtained in step 2 above), carbon disulfide (3.9 g, 0.052 mol), ethanol (30 mL) and water (5 mL). mp 268-269° C.; IR (KBr) 3397, 3124, 1487 cm-1 ; 1H NMR (DMSO-d6) δd 1.45-1.56 (m, 2H, CH2), 1.60-1.87 (m, 2H, CH2), 2.24 (s, 1H, SH), 2.64-3.92 (m, 2H, NCH2), 3.11-3.17 (m, 2H, NCH2), 3.30-3.60 (m, 1H, CH), 4.30 (brs, 1H, OH), 6.70 (d, J=7.4 Hz, 1H), 7.00 (d, J=12.6 Hz, 1H), 12.00 (brs, 1H, NH); Mass (m/z) 267 (M+.).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([N:17]=[C:18]1[N:22]3[CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH2:30][C@H:21]3[CH2:20][S:19]1)[CH:13]=[CH:12][CH:11]=2)=[O:5])C.[OH-].[Na+]>Cl>[C:4]([CH2:6][C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([N:17]=[C:18]1[N:22]3[CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH2:30][C@H:21]3[CH2:20][S:19]1)[CH:13]=[CH:12][CH:11]=2)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Temperature: 5 °C
Yield: 48 %

Procedure:
A solution of (S)-3-[(3-ethoxycarbonylmethylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (3.8 g) in 3 N hydrochloric acid (60 cc) is heated at 100° C. for 6 hours. After cooling, the pH of the solution is adjusted to 7 by adding 5 N sodium hydroxide solution, and the mixture is then extracted with methylene chloride (2×200 cc). The organic extracts are combined, dried over magnesium sulphate and then concentrated to dryness. The resulting residue is dissolved in a dimethylformamide/water mixture (2/1 by volume; 60 cc), the solution is heated to the boil, decolorising charcoal (0.3 g) is added and the mixture is filtered hot. After cooling at 5° C. for 20 hours, the crystals which have appeared are filtered off, washed with diisopropyl ether and then dried at 70° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(3-carboxymethylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (1.7 g), melting at about 200° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(O[CH:21]1[O:33][C@H:32]([CH3:34])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=O)C>>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[N:8]([C@@H:21]3[O:33][C@H:32]([CH3:34])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]3[O:23][C:24](=[O:26])[CH3:25])[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc([N+](=O)[O-])ccc21

Procedure:
5-nitro-N-(1-methylethyl)-1H-benzimidazol-2-amine (1.1 g) was coupled to 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose according to General Procedure II. The crude product was purified by flash chromatography (1:1 ethyl acetate/hexanes) to yield the title compound (0.420 g) as a mixture of 5,6 regioisomers. MS (AP): m/z 443 (M+Na).
Reaction SMILES: C([CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10])(C(OCC)=O)=O>Cl>[C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(=[O:10])[CH3:8]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc2ccccc2n1
Agent: Cl
Product: CC(=O)c1ccc2ccccc2n1
Yield: 96.1 %

Procedure:
A solution of 2-ethoxalylmethylcarbonylquinoline (32.24 g, 0.132 mol) in concentrated hydrochloric acid (300 mL) was refluxed for 4 h and concentrated in vacuo. The residue was dissolved in aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 20:1 to 7:1 hexane/ethyl acetate to give 21.72 g of 2-acetylquinoline (96%): 1H NMR (270 MHz, CDCl3) δ8.25 (d, 1H, J=8.6 Hz), 8.19 (dd, 1H, J=8.3, 1 Hz), 8.13 (d, 1H, J=8.6 Hz), 7.86 (dd, 1H, J=8.3, 1 Hz), 7.78 (td, 1H, J=8.3, 1 Hz), 7.64 (td, 1H, J=8.3, 1 Hz), 2.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([O:20]C)=[O:19])=[CH:8]1>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:11][CH:10]([CH2:17]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([OH:20])=[O:19])=[CH:8]1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Yield: 86.2 %

Procedure:
Into a 5000-mL 4-necked round-bottom flask was placed a solution of methyl 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxylate (110 g, 313.24 mmol, 1.00 equiv) in methanol/NaOH (40%) (1000 mL). The resulting solution was heated to reflux for 1.5 hours and concentrated under vacuum. Hydrogen chloride (2 mol/L) was used to adjust the pH to 4. The precipitates were collected by filtration, washed with 1×1000 mL of water and dried to afford 91 g (86%) of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxylic acid as a white solid.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>S(=O)(=O)(O)O.ClCCl>[C:17]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of benzoin with 15 ml of acetic anhydride and a few drops of sulphuric acid are added to a reactor with stirring and at room temperature (25° C.) for 15 hours. Water and dichloromethane are added to the reaction mixture. The organic phase is recovered after separating by settling, dried over sodium sulphate, filtered and then concentrated to dryness under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]CCCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:10])[CH3:11])[CH:5]=[C:6]([F:8])[C:7]=1[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(3,5-difluorophenyl)propan-2-ol (2.00 g, 11.6 mmol) in THF (46 mL) at −78° C., n-BuLi in hexanes (1.6 M; 18.2 mL, 29.0 mmol) was slowly added through a dripping funnel. When the addition was complete, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.11 mL, 34.8 mmol) was then added in one portion. The mixture was allowed to warm up room temperature and stirred for 1 h, then the reaction was quenched with water and the solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a colorless oil. LCMS calc. for C15H21BF2O3Na (M+Na)+ m/z=321.2. found: 321.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[C:2]=1[OH:12].[N:13]([O-])=[O:14].[Na+].[OH-].[Na+].OS(O)(=O)=O>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[C:3](=[O:11])[C:2]1=[O:12]
Reactant: O=N[O-]
Reactant: Oc1cc2ccccc2nc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2C(=NO)C1=O
Temperature: 0 °C
Yield: 62.6 %

Procedure:
To a solution of 50.1 mg (0.311 mmol) of 11a and 52.0 mg (0.753 mmol) of NaNO2 in 1.5 mL of aqueous 0.2N NaOH in an ice-bath was added dropwise 1 mL of aqueous 2N H2SO4. A red precipitate was observed. The mixture was stirred in the ice-bath for 2 h and at 25° C. for 4 h, filtered and washed with water, and dried to leave 37 mg (62%) of 14a as a red solid, mp 241°-242° C. 1H CDCl3 +DMSO-d6), 6.83 (m, 2), 7.069 (t, 1 J=7.2), 8.544 (d, 1, J=8.1), 11.228 (m, 1). MS, 190 (100, M+), 162 (50), 145 (65), 117 (30). High resolution MS, Calcd for C9H6N2O3 190.0375, found 190.0377.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[C@@H:14]([CH3:30])[O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:77])[C@@H:65]([NH2:76])[CH2:66][CH2:67][O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:77])[C@@H:65]([NH:76][C:27]([C:18]2[CH:17]=[C:16]([O:15][C@H:14]([CH3:30])[C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:31])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][O:68][CH2:69][C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Reactant: Cc1ccc2c(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1.0 g 4-[(R)-2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 30 ml DMF were added 1.2 g DIPEA, 319 mg HOAt and 450 mg EDC. After 5 minutes 1.1 g 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 16 h. The mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine. The crude product was used in the next reaction step. Yield: 2.8 g.
Reaction SMILES: C(C1C=CC=CC=1OC)(C)C.[Br:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[C:17]([Br:20])[C:18]=1[SH:19].[I:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[Br:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[C:17]([Br:20])[C:18]=1[S:19][C:31]1[CH:30]=[CH:29][C:28]([O:33][CH3:34])=[C:27]([I:26])[CH:32]=1
Reactant: COc1ccccc1I
Reactant: COC(=O)Cc1cc(Br)c(S)c(Br)c1
Agent: COc1ccccc1C(C)C
Product: COC(=O)Cc1cc(Br)c(Sc2ccc(OC)c(I)c2)c(Br)c1
Yield: 83.2 %

Procedure:
Following the procedures of Example 1, but substituting 2-iodoanisole for 2-isopropylanisole, methyl 3,5-dibromo-4-mercaptophenylacetate (1 g) was reacted with 2-iodoanisole (0.7 g) to yield the thioether, methyl 3,5-dibromo-4-(3-iodo-4-methoxyphenylthio)phenylacetate (1.4 g) which in turn was oxidized to methyl 3,5-dibromo-4-(3-iodo-4-methoxyphenylsulfonyl)phenylacetate, MP: 127°-129° C. The acetate was saponified to the acid, 3,5-dibromo-4-(3-iodo-4-methoxyphenylsulfonyl)phenylacetic acid, MP: 158°-162° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[CH:1]1([NH:7][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[O:45][C:46](=[O:48])[CH3:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: NC1CCCCC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Cyclohexylamine (0.159 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.134 g, 0.294 mmol, 55%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:22][C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([NH:30][C:31]2[CH:39]=[C:38]3[C:34]([CH2:35][CH2:36][N:37]3C(OC(C)(C)C)=O)=[CH:33][CH:32]=2)=[O:29])=[CH:13][CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[NH:37]1[C:38]2[C:34](=[CH:33][CH:32]=[C:31]([NH:30][C:28]([C:24]3[S:25][CH:26]=[CH:27][C:23]=3[NH:22][CH2:21][C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:11]=[CH:12][CH:13]=3)=[O:29])[CH:39]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(NC(=O)c3sccc3NCc3ccnc4ccccc34)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2c(c1)NCC2)c1sccc1NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of TFA/CH2Cl2 (3 mL, 1:1, v:v) was added tert-butyl 6-({[3-[(quinolin-4-ylmethyl)amino]thien-2-yl]carbonyl}amino)indoline-1-carboxylate (40 mg, 0.08 mmol) and the resulting mixture was stirred at rt. After 1 h, the solution was neutralized with 3N NaOH and diluted with EtOAc. The aqueous phase was removed and the organic phase was washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to yield N-2,3-dihydro-1H-indol-6-yl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide as a yellow solid. MS (ES+): m/z 401 [M+1]. 1H NMR (CDCl3, 400 MHz): δ3.00 (t, J=8.4 Hz, 2H), 3.58 (t, J=8.4 Hz, 2H), 4.99 (d, J=6.4 Hz, 2H), 6.54 (d, J=5.6 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 7.46 (d, J=4.4 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 8.03 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.85 (d, J=4.4 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccnc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
The mixture of 2-[(quinoline-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (49) (220 mg, 0.61 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (50) as a pale yellow solid (98 mg, 48%).
Reaction SMILES: C[Mg]I.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2(C#N)[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.CC[O:19][CH2:20][CH3:21]>>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2([C:20](=[O:19])[CH3:21])[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: N#CC1(c2cccc(Cl)c2)CCC1
Agent: C[Mg]I
Product: CC(=O)C1(c2cccc(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methylmagnesium iodide (138 ml of 3M solution in ether) was added dropwise to a stirred solution of 1-(3-chlorophenyl)cyclobutanecarbonitrile (53 g) in ether (100 ml) under nitrogen at 0° C. The mixture was stirred at ambient temperature for 24 hours. The resulting solid was collected by filtration, washed well with ether, then added in portions to an ice-cold mixture of water (200 ml) and concentrated hydrochloric acid (125 ml). The resulting yellow suspension was heated at 95° C. for 1 hour with occasional stirring, and then cooled to ambient temperature. The product was extracted into ether (5×100 ml) and the combined extracts washed with water (2×100 ml), dried over magnesium sulphate and the solvent removed in vacuo to give an oil which was distilled to give 1-[1-(3-chlorophenyl)cyclobutyl]ethanone (47.5 g), b.p. 108°-109° C./2 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)ccc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Cl)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
5-Chloro-2-fluoroaniline (25 g, 172 mmol) was added to conc. hydrochloric acid (150 mL, 37%). The mixture was cooled (−10° C.) and a solution of sodium nitrite (11.9 g, 172 mmol) in water (193 mL) was added slowly (<-5° C.). This done, a solution of tin(II)chloride (118 g, 618 mmol) in conc. hydrochloric acid (116 mL) was added slowly (−6° C.). The mixture was stirred for 1 h, filtered through Celite® and the filter cake washed extensively with water. The filtrate was adjusted to pH 14 with conc. sodium hydroxide solution and the suspension extracted with diethylether. Organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was removed in vacuo to yield the title compound as yellow solid (22.9 g, 83%), EI-MS: m/e=160.0 (M+).
Reaction SMILES: N#N.[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][C:6]([CH:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:10](OC)=[O:11])=[CH:5][CH:4]=1.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:8]=[CH:7][C:6]([C@@H:9]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[CH:10]=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(-c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A 100 mL 2-necked round bottom flask was equipped with a septum, N2 inlet and 2.6 g (7.4 mmol) of the (R)-(-)-methyl acetate of Example O dissolved in 45 mL of dry toluene. The solution was cooled to -78° C. (CO2 /acetone), and 9 mL (9 mmol) of a 1.0M solution of DIBAL-H in toluene was added slowly (5 min.) with stirring. The reaction mixture was stirred for 1 h at -78° C. and poured into a mixture of 100 g of ice and 100 mL of CHCl3. The reaction flask was rinsed with 100 mL of CHCl3 and the mixture was stirred vigorously for 30 min. After separation of the CHCl3 layer, the aqueous phase was washed with 100 mL of CHCl3 (emulsion!) and the combined CHCl3 extracts were washed once with brine 80 mL, dried (Na2SO4) and concentrated leaving 2.3 g (95%) of the title aldehyde as a colorless oil which was not further purified: 1H-NMR (CDCl3)δ9.54 (d, J=2.1 Hz, 1H), 7.63-7.35 (m, 9H), 5.05 (d, J=2.1 Hz, 1H), 0.97 (s, 9H), 0.14 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][CH2:36][O:37][CH2:38][CH3:39])[CH2:12]1)[C:8](=[O:40])[NH:7]2)=[O:5])C.C1COCC1.CO.[Li+].[OH-]>ClCCl.CO>[CH2:38]([O:37][CH2:36][O:35][CH:11]1[CH2:10][CH:9]2[N:13]([C:14](=[O:34])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]3[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]2=[O:40])[CH2:24]3)[CH2:12]1)[CH3:39]
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCOCOC1CC2C(=O)NC3(C(=O)O)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Yield: 101.9 %

Procedure:
A solution of the ester 21g (0.775 g, 1.39 mmol) in 1:1:1 THF-Methanol-aq. 1M LiOH (36 ml) was stirred at rt for 3.5 h after which TLC (95:5 and 9:1 dichloromethane-methanol) and LC-MS indicated complete conversion into the carboxylic acid. The reaction mixture was then concentrated into approximately ⅓ of the volume, then diluted with water (10 ml) and acidified to approx. pH 4 using aq. 10% citric acid (60 ml) upon which a precipitate formed. The mixture was washed with ethyl acetate (3×25 ml) and the combined organic layers were washed with brine (2×50 ml), then dried (Na2SO4), filtered and concentrated. The residue was concentrated from toluene (3×10 ml) which gave the crude title compound as an off-white foam (0.75 g, quantitative). LR-MS: Calcd for C28H40N3O7: 530. Found: 530 [M−H].