Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:38]=[CH:37][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].O>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:38]=[CH:37][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:22][CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25][CH2:26]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
1.6 ml (1.6 mmol) of a 1M aqueous solution of lithium hydroxide are added to a solution of 400 mg (0.8 mmol) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoate in 5 ml of tetrahydrofuran and the medium is stirred at ambient temperature for 20 h. After addition of water and of acetic acid up to a pH of 4, the reaction medium is extracted with ethyl acetate. The organic phase is dried over sodium sulphate then filtered and concentrated under vacuum. 400 mg (100%) of (S)-3-(4-but-2-ynyloxybenzoylamino)-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:44]1([CH:54]([NH2:56])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.CN1CCOCC1>CC(N(C)C)=O>[C:44]1([CH:54]([NH:56][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CC(N)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CC(NC(=O)c1cccc2c1cnn2-c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (40.0 mg, 0.156 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (89 mg, 0.23 mmol) were combined in a 20 mL vial and dimethylacetamide (DMA) (1 mL) was added. The yellow solution was stirred at room temperature for 10 minutes and then a solution of 1-(1-napthyl)ethylamine (40.1 mg, 0.234 mmol) and N-methylmorpholine (NMM) (0.086 mL, 0.78 mmol) in DMA (0.20 mL) was added. The mixture was shaken at room temperature for 16 hours then the solution was evaporated in vacuo. The crude product was purified by preparative reversed-phase HPLC to afford the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]4[CH:20]=[C:21]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[CH:15][C:8]=3[S:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Reactant: O=c1c2ccc(O)cc2sn1C1CCCC1
Product: O=C(O)c1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1
Yield: 35 %

Procedure:
2-Cyclopentyl-6-hydroxybenzo[d]isothiazol-3(2H)-one (0.094 g, 0.4 mmol) and methyl 3′-(bromomethyl)biphenyl-4-carboxylate (0.146 g, 0.48 mmol) were processed according to the general procedure described for Example 19 to afford 3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylic acid as a colorless solid in 35% yield over 2 steps (0.053 g, after HPLC purification). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (d, 2H, J=8.6 Hz), 7.83-7.79 (m, 5H), 7.70-7.69 (m, 1H), 7.51-7.42 (m, 2H), 7.45 (d, 1H, J=8.5 Hz), 5.34 (s, 2H), 4.49-4.47 (m, 1H), 1.86-1.76 (m, 2H), 1.75-1.57 (m, 6H). HRMS (ESI) calcd for C26H23NO4S [M+H]+: 446.1420. Found: 446.1420.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy]benzyl]-3-pyrrolyl]propionate (532 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (428 mg, yield: 85%). This was recrystallized from ethanol-hexane. Melting point: 139–140° C.
Reaction SMILES: Br[C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1.[CH3:16][O-:17].[Na+].CO>CO>[CH3:16][O:17][C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1
Reactant: Brc1nnc2n1C=Cc1ccccc1C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nnc2n1C=Cc1ccccc1C2

Procedure:
To a solution of 0.262 g of 3-bromo-11H-s-triazolo [3,4-b][3]benzazepine in 2 ml of methanol was added 1.0 ml of 2 N-sodium methoxide/methanol and the mixture was refluxed for one hour. The solvent was evaporated off and, following the addition of water, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residue was treated with isopropyl ether. By the above procedure was obtained 3-methoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate-n-hexane yielded colorless prisms, melting point: 161°-162° C. The infrared absorption spectrum of this product was identical with that of the compound obtained in Example 34.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]([Mg]Cl)([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH:11]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=1)[OH:12]
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Product: CC(C)C(O)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (283 mg, 1.55 mmol) and isopropylmagnesium chloride (1.55 mL, 3.10 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (4:1) as eluent. Orange solid. Yield: 138 mg, 40%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.82-0.93 (m, 3H), 1.02 (d, J=6.6 Hz, 3H), 1.95-2.08 (m, 1H), 4.46 (d, J=6.6 Hz, 1H), 7.39-7.44 (m, 1H), 7.45-7.50 (m, 2H), 7.68-7.75 (m, 2H), 7.96-8.01 (m, 2H), 8.57 (d, J=1.9 Hz, H); MS (ESI): m/z=228.26 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl>>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)c1
Reactant: CN(C)CCCl
Product: Cc1cc(C)cc(C(=O)c2c(-c3ccc(OCCN(C)C)cc3)oc3ccccc23)c1

Procedure:
Reaction of 2-p-hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran with 2-dimethylaminoethyl chloride by the procedure described in Example 7 gave the title compound.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:37](=[O:48])[NH:38][C@@H:39]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[CH3:40])[CH:26]=3)[C:21]2=[O:49])=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1.[CH:61]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62]1>O1CCCC1>[CH:61]1([S:64]([NH:67][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:21](=[O:49])[C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([C:37]([NH:38][C@@H:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH3:40])=[O:48])=[CH:24][CH:23]=3)(=[O:66])=[O:65])[CH2:63][CH2:62]1
Reactant: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)O)cc2c1)c1ccc(F)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)NS(=O)(=O)C3CC3)cc2c1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
CDI (13.50 mg, 0.083 mmol) was added to a stirred, room temperature mixture of (R)-5-(2-(4-fluorophenyl)-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (28 mg, 0.055 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at 70° C. for 2 h. DBU (0.017 mL, 0.111 mmol) and cyclopropylsulfonamide (10.09 mg, 0.083 mmol) were added, the resultant mixture was kept stirring at room temperature overnight. The mixture was concentrated, and the residue was purified via PTLC (Emerck 1 mm), eluted with CH2Cl2/MeOH=10:1 to give (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-2-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide (16 mg) as a white solid. LCMS [M+H]+=608. 1H NMR (500 MHz, DMSO) δ ppm: 9.06 (d, J=7.88 Hz, 1H), 8.20 (d, J=8.20 Hz, 1H), 8.15 (s, 1H), 7.36-7.50 (m, 6H), 7.18 (t, J=8.99 Hz, 2H), 6.69 (s, 1H), 5.22 (t, J=7.25 Hz, 1H), 3.16-3.19 (m, 1H), 2.87-2.94 (m, 1H), 2.26 (br. s, 2H), 2.16 (br. s, 2H), 1.51 (d, J=7.25 Hz, 3H), 1.43 (br. s, 3H), 0.98-1.05 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:24]=[N:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)cn1
Product: COc1cc(-c2ccc(C(F)(F)F)nc2)ccn1
Yield: 816.4 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol) were reacted according to the procedure of Example 5 (step a) to provide the title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255 [M+H].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH2:25])[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=1)[CH2:20][CH2:19]2
Reactant: NC1CCc2cc(F)ccc21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: O=[N+]([O-])c1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
2-Chloro-6-nitro-quinoline (2.7 g, 13 mmol) and rac-5-fluoro-indan-1-ylamine (CAS 148960-33-2, 3.9 g, 26 mmol) were heated at 130° C. for 24 h. The reaction mixture was purified by flash chromatography on silica gel (dichloromethane). rac-(5-Fluoro-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine was obtained as a yellow solid (2.99 g, 71%), MS: m/e=324.4 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:10][N:9]=1
Reactant: C#CCN(C)C
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CN(C)CC#Cc1nnc(Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A resealable pressure bottle was charged with dichlorobis(triphenyl-phosphine)palladium(II) (106 mg, 0.15 mmol), N,N-dimethylprop-2-yn-1-amine (0.13 ml, 1.5 mmol), 1,4-dichlorophthalazine (300 mg, 1.5 mmol), copper(I) iodide (29 mg, 0.15 mmol), TEA (4.2 mL, 30.1 mmol), and ACN (15.0 mL, 0.1M). The vessel was sealed and the mixture was stirred at overnight at 90° C. Next day the reaction was cooled to RT, filtered over celite, and the filtrate was concentrated under reduced pressure to afford a brown residue, which was purified by ISCO silica gel chromatography (5%-7% of 90/10/1 DCM/MeOH/NH4OH to afford 3-(4-chlorophthalazin-1-yl)-N,N-dimethylprop-2-yn-1-amine. MS m/z=246 [M+1]+. Calc'd for C13H12ClN3: 245.7.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[CH3:35][NH2:36]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[N:36][CH3:35])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Reactant: CN
Solvent: CO
Product: CN=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 90 %

Procedure:
A stirred solution of Example 23 (0.5 g, 1.0 mmol) in MeOH was refluxed with methylamine (1.6 mL, 1.5 equiv., 33% in EtOH) for one hour. Evaporation in vacuo gave (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][Br:18])=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
3.00 g (10.41 mmol) 6-bromo-2-p-tolyl-benzoxazole are stirred together with 1.90 g (10.68 mmol) N-bromosuccinimide, 10.00 mg (0.04 mmol) dibenzoylperoxide and 60 ml carbon tetrachloride for 2 h at 90°. The reaction mixture is filtered through kieselguhr, then the solv. is eliminated by rotary evaporation in vacuo and the residue is recrystallised from petroleum ether.
Reaction SMILES: CO[C:3](=[O:18])[C@@H:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:5]([OH:9])[CH2:6][CH2:7][CH3:8].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:4]([C:3](=[O:18])[NH:23][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([OH:9])[CH2:6][CH2:7][CH3:8])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)CN
Product: CCC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)C
Yield: 84 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-hexanoic acid methyl ester (D94) (1.57 g, 6.02 mmol, 1 equiv) was refluxed in iso-butylamine (10 ml) for 2 h. The solution was concentrated in vacuo and the residue purified by flash chromatography on silica gel to give ((1S,2R)-2-hydroxy-1-isobutylcarbamoyl-pentyl)-carbamic acid tert-butyl ester (G33) (1.52 g, 84%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:4]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(C)C)(C)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:12][C:25]([NH:24][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[S:26])[CH:13]=[CH:14][CH:15]=2)[CH:4]=1
Reactant: COc1ccnc(-c2cccc(N)c2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: COc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)aniline (357 mg) in acetone (5 ml) was added benzoyl isothiocyanate (0.252 ml), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added diisopropyl ether, and the precipitate was collected by filtration and dried to give N-(3-(4-methoxypyridin-2-yl)phenyl)-N′-benzoylthiourea (462 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=2)[CH3:22])=[N:6][CH:7]=1.[CH3:34][NH2:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[CH:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:35][CH3:34])=[O:29])=[CH:32][CH:33]=2)[CH3:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(C)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Reactant: CN
Product: CNC(=O)c1ccc(OC(C)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
Prepared from hydrolysis of methyl 4-(1-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}ethoxy)benzoate (EXAMPLE 137.1) followed by methylamine coupling, using a similar procedure as described in the preparation of examples 132.11.1 and B2.11.2. MS: M+H=484.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1.[Br-].[CH:19]1([Zn+])[CH2:21][CH2:20]1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: [Zn+]C1CC1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(C2CC2)cn1
Temperature: 80 °C

Procedure:
To a solution of benzyl 5-bromopicolinate (876 mg, 3.0 mmol) in THF (10 mL) was added Pd(PPh3)4 (173 mg, 0.15 mmol) under N2. After addition of a solution of cyclopropylzinc bromide in THF (0.5 M, 10 mL), the mixture was heated at 80° C. for 3 hours and then cooled to room temperature. The reaction mixture was quenched with sat. H4Cl (aq) and extracted with EtOAc (5×). The organic layer was washed with sat. NaHCO3(aq.), brine, and dried (MgSO4). The product benzyl 5-cyclopropylpicolinate (510 mg) was obtained by silica gel chromatography (elution with 0-15% EtOAc/Hex, then 15% EtOAc/Hex).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[S:16]1[C:20]2[CH:21]=[C:22]([C:25]([N:27]3[CH2:34][CH2:33][C:32]4([CH3:36])[CH2:35][CH:28]3[CH2:29][C:30]3[CH:40]=[CH:39][C:38](O)=[CH:37][C:31]=34)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.C(N(CC)CC)C.N>CN(C)C1C=CN=CC=1.ClCCl>[S:16]1[C:20]2[CH:21]=[C:22]([C:25]([N:27]3[CH2:34][CH2:33][C:32]4([CH3:36])[CH2:35][CH:28]3[CH2:29][C:30]3[CH:40]=[CH:39][C:38]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:37][C:31]=34)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(O)cc31)C2
Agent: CN(C)c1ccncc1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc31)C2
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.77 mL) is added to a solution of benzothiazol-6-yl-(8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone (1.24 g; for synthesis see Example 92), triethylamine (3.4 mL), and 4-dimethylaminopyridine (10 mg) in dichloromethane (12 mL) chilled to −10° C. under argon atmosphere. The solution is stirred at ca. −5° C. for 30 min and then at room temperature overnight. The reaction solution is added to ice-cold water and then concentrated aqueous ammonia solution is added. The resulting mixture is extracted with dichloromethane, the combined organic extracts are washed with water and dried (MgSO4). The solvent is removed under reduced pressure to give the crude product that is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[C:34]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:13]([C:3]3[CH:4]=[N:5][C:6]4[C:11]([C:2]=3[OH:1])=[C:10]([OH:12])[CH:9]=[CH:8][CH:7]=4)=[O:15])[CH2:27][CH2:28]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)c1cnc2cccc(O)c2c1O
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cnc2cccc(O)c2c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.2 g) is added to a solution of 4,5-dihydroxyquinoline-3-carboxylic acid (0.7 g), which is prepared according to the method described in Japanese Patent First Publication No. 65874/1981, in dry dimethyl sulfoxide (30 ml) and the mixture is stirred at room temperature for 30 minutes. 4-(4-Diphenylmethyl-1-piperazinyl)butylamine (2.2 g) is added to the reaction mixture and the mixture is stirred at room temperature for 6 hours, and thereto is added water (about 200 ml), and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is subjected to silica gel column chromatography, followed by elution with chloroform - methanol (30 : 1). The obtained crystals are recrystallized from isopropyl alcohol to give the desired compound (0.72 g). m.p. 215° to 218° C.