Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1.Br[C:20]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:20]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][N:21]=3)[N:14]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Reactant: OCc1ccnc(Br)c1
Product: Cc1ccncc1-c1ccc2cc(Nc3cc(CO)ccn3)ncc2c1
Yield: 44 %

Procedure:
The title compound was prepared following the procedures described for Example 13, using 7-(4-methylpyridin-3-yl)isoquinolin-3-amine and 2-bromopyridine-4-methanol, to yield 26.2 mg (44%) of (2-(7-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)pyridin-4-yl)methanol. LCMS (ESI): RT (min)=2.759, M+H=343.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.38 (d, J=4.9 Hz, 1H), 7.29 (s, 1H), 6.81 (d, J=5.1 Hz, 1H), 5.35 (t, J=5.7 Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][C:59]([N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:60]>>[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH2:58][C:59](=[O:60])[N:61]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: O=C(CBr)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCC(=O)N1CCCCC1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 75.4 %

Procedure:
Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 2-bromo-1-(piperidin-1-yl)ethanone (31 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (31 mg, 75%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 8.28 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.87 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J=8.6 Hz, 1H), 4.59-4.50 (m, 2H), 4.00-3.74 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69 (s, 1H), 3.60 (s, 6H), 3.40 (s, 3H), 3.35-3.25 (m, 4H), 3.12 (t, J=9.2 Hz, 1H), 2.54 (br s, 1H), 2.16 (s, 3H), 1.68 (br s, 2H), 1.62 (br s, 4H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 823 (M+H); HPLC 98.7% (AUC), tR 16.81 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[CH3:21][O:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccs1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(NC(=O)c3cccs3)nc2n1
Temperature: 4 °C
Yield: 77.9 %

Procedure:
The procedure is similar to that described in Example 1, starting with 2-thiophenecarboxylic acid (14 g) N,N'-carbonyldiimidazole (17.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (12.3 g). The product produced by precipitation in water (19.5 g; m.p. 216° C.) is dissolved in boiling ethanol (750 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-2-thiophenecarboxamide (15.6 g) is produced, m.p. 220° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[Cl:37]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:26][C:25]=3[Cl:37])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=C1CCC(c2ccc(OCCCNCC(O)COc3ccc(CCOCC4CC4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([O:24][CH2:25][CH2:26][O:27][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Br:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCOCc1ccccc1
Reactant: O=Cc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OCCOCc2ccccc2)cc1Br
Temperature: 130 °C

Procedure:
A mixture of 2-bromo-4-fluoro-benzaldehyde (32.0 g, 157 mmol), Na2CO3 (85.5 g, 788 mmol), and 2-benzyloxy ethanol (24.0 g, 158 mmol) in anhydrous DMSO (300 mL) were heated under N2 at 130° C. (bath temp) for 18 h. The reaction mixture cooled to rt, diluted with H2O (100 mL), and extracted with EtOAc The organic layer was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo The residue was purified by flash chromatography (hexane to 10% EtOAc in hexane) to give the title compound as a viscous liquid: yield 11.8 g (22%).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1.[P:52](Cl)([O:56]CC)[O:53][CH2:54][CH3:55].C1(C)C=CC=CC=1.CCOC(C)=O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:54]([O:53][P:52]([O-:56])[O:47][CH2:46][CH3:48])[CH3:55].[CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOP(Cl)OCC
Agent: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](N(C)C)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]5O)C[C@@H]34)[C@@H]2CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOP([O-])OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound Spinosyn H (351 mg, 0.489 mmol) was dissolved in dry pyridine (5 ml). DMAP (62 mg, 0.51 mmol) was added and stirring at RT under nitrogen was continued for 5 min. Diethyl chlorophosphite (157 mg, 0.145 ml, 1.0 mmol) was added. After 30 min. toluene (50 ml) and EtOAc (50 ml) were added. The solution was washed successively with brine (2×) and 5% aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was separated over a flash SiO2 column (100 g/EtOAc) to give compound 2'R)-(diethyl)phosphite of Spinosyn H; 306 mg, 75% CI MS m/z 838 (M+1); 1H-NMR (CDCl3) δ 6.69 (1H, bs), 4.40 (1H, m), 3.83 (4H, 2× CH2, m), 1.18 (6H, 2× CH3, m); Elemental Analysis: for C44H72NO12P calc. C 63.06, H 8.66, N 1.67 found: C 62.94, H 8.88, N 1.71.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH2:8][C:9]([OH:11])=O)[S:4][CH:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OC(C(F)(F)F)=O.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][C:32]2=[O:41])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC#N>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH2:8][C:9]([N:25]2[CH2:26][CH2:27][CH:28]([N:31]3[CH2:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:41])[CH2:29][CH2:30]2)=[O:11])[S:4][CH:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CN1C(=O)C(CC(=O)O)SC1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1C(=O)C(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)SC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-methyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (0.2 mmol, 50 mg), 3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one TFA salt (0.15 mmol, 49 mg) and DIPEA (0.375 mmol, 65.3 μl) in 4:1 CH3CN:DMF (0.5 ml) was added HATU (0.18 mmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=465.5; tR=2.18. 1H NMR (400 MHz, CDCl3) δ 7.34-7.22 (m, 5H), 7.12 (t, J=7.5 Hz, 1H), 7.00 (d, J=7.5 Hz, 2H), 6.95-6.89 (m, 2H), 6.61 (d, J=7.8 Hz, 2H), 5.46-5.41 (m, 1H), 4.70 (m, 1H), 4.56 (m, 1H), 4.26 (m, 3H), 3.86 (m, 1H), 3.50 (m, 1H), 3.32 (m, 1H), 3.12-3.08 (m, 1H), 2.89-2.73 (m, 1H), 1.69 (m, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[CH2:56]([C:63]1[S:67][C:66]([NH2:68])=[N:65][N:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>ClCCl>[CH2:56]([C:63]1[S:67][C:66]([NH:68][C:20]([C:19]2[CH:23]=[CH:24][C:16]([C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)=[O:21])=[N:65][N:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnc(Cc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Reaction time: 16 h

Procedure:
0.6 g of trans-4-(4-tert-butoxycarbonylmethoxycyclohexyl)benzoic acid (1.79 mmol, 1 eq.) is placed in 8 mL of dichloromethane with stirring. 0.7 mL of diisopropylethylamine (4.49 mmol, 2.5 eq.), 0.275 g of hydroxybenzotriazole (1.79 mmol, 1 eq.) and 0.413 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.15 mmol, 1.2 eq.) are successively added, followed, after 10 minutes, by addition of 0.377 g of 5-benzyl-1,3,4-thiadiazol-2-amine (1.97 mmol, 1.1 eq.). After 16 hours, 0.137 g of hydroxybenzotriazole (0.895 mmol, 0.5 eq.) and 0.172 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mmol, 0.5 eq.) are added. After 18 hours, the medium is evaporated, diluted with ethyl acetate and washed three times with brine. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with a gradient of methanol in dichloromethane ranging from 0% to 2%. 0.09 g of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetate is obtained.
Reaction SMILES: C1([NH:4][C:5]2[C:10]([C:11]([NH:13][C:14]3[C:15](OC)=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=2)CC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>N1C=CC=CC=1>[CH3:20][C:19]1[C:14]2[NH:13][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][CH:7]=[N:6][C:5]=3[NH:4][C:15]=2[N:16]=[CH:17][CH:18]=1
Reactant: COc1nccc(C)c1NC(=O)c1cccnc1NC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2
Temperature: 90 °C
Yield: 91 %

Procedure:
A solution of 2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (0.3 g, 1 mmol) in 2 mL of dry pyridine under an argon atmosphere was treated with 2.2 mL of a 1.0M solution of NaHMDS. The solution was then warmed to 90° C. for 6 h. Upon cooling, the mixture was partitioned between EtOAc and 0.5N HCl. The EtOAc layer was then washed further with 0.5N HCl, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (1:1 EtOAc:Hexanes) to give 5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one in 91% yield (0.24 g).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].[CH3:19][C:20]1[C:28]([C@H:29]2[CH2:31][O:30]2)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][O:23][C:24]2=[O:32]>C(O)C>[OH:30][C@@H:29]([C:28]1[CH:27]=[CH:26][C:25]2[C:24](=[O:32])[O:23][CH2:22][C:21]=2[C:20]=1[CH3:19])[CH2:31][N:15]1[CH2:16][CH2:17][C:10]2([C:9](=[O:18])[N:8]([C:3]3[CH2:4][O:5][C:6](=[O:7])[C:2]=3[CH3:1])[CH2:12][CH2:11]2)[CH2:13][CH2:14]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: CCO
Product: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 140 °C

Procedure:
To a solution of 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17, 10 mg, 0.040 mmol) in ethanol (2 mL) in a microwave tube was added (S)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (I-4A, 9.9 mg, 0.052 mmol)) and the resulting solution was heated at 140° C. in microwave for 3 h. After concentration, the residue was purified by preparative TLC using 30% methanol/ethyl acetate to give the title compound. LC/MS, (M+1)+: 441.00, 1HNMR (500 MHz, CDCl3), δ7.840-7.804 (m, 2H), 5.304-5.240 (m, 4H), 5.134-5.107 (m, 1H), 4.066-4.038 (t, J=7.1 Hz, 2H), 3.185-3.161 (m, 1H), 2.8885-2.862 (m, 1H), 2.629-2.568 (m, 2H), 2.462-2.416 (m, 1H), 2.305 (s, 3H), 2.344-2.323 (m, 1H), 2.197-2.158 (t, J=7.1 Hz, 2H), 2.108-2.033 (m, 5H), 1.661-1.604 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16](C([Sn])=C(CCCC)CCCC)[CH2:17]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:15][C:3]1[C:2]([CH:16]=[CH2:17])=[C:12]([F:13])[C:11]([F:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CCOC(=O)c1cc(F)c(F)c(Br)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)cc(C(=O)OCC)c1F

Procedure:
In 30 ml of toluene was dissolved 3.04 g of ethyl 3-bromo-2,4,5-trifluorobenzoate, and to the solution were added 5.11 g of tributylvinyltin and 0.25 g of tetrakis(triphenylphosphine) palladium (0), after which the resulting mixture was heated under reflux for two hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=100:1), to obtain a colorless, oily ethyl 2,4,5-trifluoro-3-vinylbenzoate. The oily product thus obtained was dissolved in a mixed solvent of 62 ml of methanol and 12 ml of methylene chloride, and thereafter, at -50° C., an ozone gas was blown thereinto for three hours and subsequently a nitrogen gas was blown thereinto for 30 minutes. The temperature of this solution was elevated to -20° C., and thereafter, 0.81 g of sodium borohydride was added thereto, after which the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was added to a mixed solvent of 400 ml of ethyl acetate and 600 ml of ice water and the pH was adjusted to 1 with 6N hydrochloric acid, after which the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=4:1), to obtain 1.70 g of a colorless, oily ethyl 3-hydroxymethyl-2,4,5-trifluorobenzoate.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:3][CH:2]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH:14]1([C:17]([N:9]2[CH2:10][CH:11]3[C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=4)([CH2:12]3)[CH2:8]2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(C23CNCC2C3)cc1
Product: Cc1ccc(C23CC2CN(C(=O)C2CC2)C3)cc1

Procedure:
In a like manner 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane (Example 32) is reacted with cyclopropanecarbonyl chloride to give 3-cyclopropanecarbonyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane which is reduced as above to give 3-cyclopropylmethyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 180°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26]C)[CH:20]=[C:19]3[C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:9])([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[C:19]3[C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-c2ccc(C)s2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)s1
Temperature: 60 °C
Yield: 86.1 %

Procedure:
To a solution of (4-Chloro-phenyl)-[2-methoxy-4-(5-methyl-thiophen-2-yl)-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (0.137 g, 0.288 mmol) in THF (3.2 ml) was added concentrated hydrogen chloride (HCl, 0.314 ml) dropwise. The mixture was heated at 60° C. for 24 hours. After cooling to room temperature, THF was removed. The aqueous solution was adjusted to pH=˜9 with 40% aqueous NaOH. The yellow solid was precipitated out. After filtration and washed with ethylacetae obtained 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(5-methyl-thiophen-2-yl)-1H-quinolin-2-one (0.115 g, 0.248 mmol, 86%yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([NH2:22])=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=O)=[CH:6][CH:5]=1.[CH3:25][NH:26][S:27](Cl)(=[O:29])=[O:28].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:25][N:26]1[S:27](=[O:29])(=[O:28])[NH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][N:19]=3)[CH:14]=[CH:13][C:12]=2[CH:10]1[C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(OC(F)(F)F)cc2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(OC(F)(F)F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 55.2 %

Procedure:
In a similar fashion using route 27 general procedure 70, 7[(4-trifluoromethoxyphenyl)carbonyl]-8-aminoquinoline (Intermediate 378) (100 mg, 0.31 mmol), N-methylsulfamoyl chloride (Intermediate 213) (105 mg, 1.0 mmol) and NaBH4 (14 mg, 0.34 mmol) in pyridine (4 ml) gave the title compound (70 mg, 56%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[C:10]1[N:14]([CH2:15][CH2:16][C:17]([O:19]C)=O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.C1(P([N:45]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl.C(N=C=NCCCN(C)C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:13]=3[N:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:45]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCC(=O)OC)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)NC3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.3 %

Procedure:
To a stirred solution of methyl 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propanoate (1.00 g, 2.15 mmol) and diphenylphosphoryl azide (1.39 mL, 6.46 mmol) in toluene (11 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (966 μL, 6.46 mol) at room temperature. After 12 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-35% ethyl acetate/n-hexane gradient mixture. A solution of the obtained compound was stirred in the presence of 1.9% palladium on fibroin (200 mg) under hydrogen atmosphere at room temperature for 17 h. The catalyst was removed and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (8 M, 0.5 mL) was added at room temperature. After 15 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (973 mg, 5.08 mmol) was added at room temperature. After 6 h, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (155 mg, 1.02 mmol) was added. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-35% ethyl acetate/n-hexane gradient mixture to afford the desired product as pale yellow solid (334 mg, 0.801 mmol, 39%).