Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10](=[O:11])[N:9]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:8][C@H:7]1[C:20]1([CH2:23][O:24][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:22][CH2:21]1)=[O:5])[CH3:2]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[C:10](=[O:11])[N:9]([C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8][C@H:7]1[C:20]1([CH2:23][OH:24])[CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Solvent: c1ccncc1
Product: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CO)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.3 %

Procedure:
A hydrogen fluoride-pyridine complex (10 mL) was added dropwise to a solution of (3R)-3-[1-(tert-butyldiphenylsiloxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-ylcarboxylic acid ethyl ester (2.81 g, 4.93 mmol) in pyridine (20 mL) at 0° C. over five minutes. The mixture was stirred at room temperature for 2.5 hours and then poured into ice water (150 mL), followed by extraction with ethyl acetate (300 mL). The resulting organic layer was washed with a 10% citric acid solution (100 mL), water (100 mL), and brine (100 mL) and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2→1:1→2:1) to give 1.378 g (84%) of the title compound as a pale yellow gummy solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)c1
Yield: 71.9 %

Procedure:
Following general procedure D, (6-bromo-4-(3-((dimethylamino)methyl)phenylamino)quinoline-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (81 mg, 72%) as a yellow-green solid. NMR (300 MHz, MeOD+TFA-d) δ 9.44 (s, 1H), 8.25 (dd, J=8.9, 1.9 Hz, 1H), 8.09-7.95 (m, 2H), 7.79-7.54 (m, 4H), 7.19 (dd, J=11.5, 2.3 Hz, 1H), 7.06 (s, 1H), 4.38 (s, 2H), 2.91-2.82 (m, 1H), 2.83 (s, 6H), 1.23-1.14 (m, 4H); ESI MS m/z 490 [C29H25ClFN3O2+H]+; HPLC 97.3% (AUC), tR=11.07 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:27]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[C:16]([C@@H:23]([OH:26])[CH2:24][OH:25])[N:15]=2)=[CH:10][CH:9]=1.[Cl:29][C:30]1[CH:51]=[CH:50][C:33]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[BH:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]3)=[CH:37][CH:36]=2)=[C:32]([F:52])[CH:31]=1>>[Cl:29][C:3]1[CH:2]=[CH:27][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[C:16]([C@@H:23]([OH:26])[CH2:24][OH:25])[N:15]=3)=[CH:10][CH:9]=2)=[C:5]([F:28])[CH:4]=1.[Cl:29][C:30]1[CH:51]=[CH:50][C:33]([O:34][C:35]2[CH:36]=[CH:37][C:38]([CH:41]3[BH:45][C:44]([CH3:46])([CH3:47])[C:43]([CH3:48])([CH3:49])[O:42]3)=[CH:39][CH:40]=2)=[C:32]([F:52])[CH:31]=1
Reactant: NC(=O)c1cc([C@@H](O)CO)nc(-c2ccc(Oc3cc(Cl)ccc3F)cc2)n1
Agent: CC1(C)BC(c2ccc(Oc3ccc(Cl)cc3F)cc2)OC1(C)C
Product: NC(=O)c1cc([C@@H](O)CO)nc(-c2ccc(Oc3ccc(Cl)cc3F)cc2)n1

Procedure:
(R)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl) pyrimidine-4-carboxamide (Compound Example No. 9) was prepared in a similar fashion to (R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl) pyrimidine-4-carboxamide (Compound Example No. 7) using 2-(4-(4-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,3-dioxaborolane (6) instead of 2-(4-(5-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,3-dioxaborolane (14). 1H NMR (400 MHz, CD3OD): 8.49 (2H, d, J=8.8 Hz), 8.03 (1H, s), 7.30 (1H, dd, J=2.8, 10 Hz), 7.18-7.10 (2H, m), 6.96 (2H, d, J=9.2 Hz), 4.73 (1H, dd, J=3.2, 5.6 Hz), 3.89 (1H, dd, J=3.6, 11 Hz), 3.75 (1H, dd, J=6.0, 11 Hz); LC/MS: m/z=404[M+H]+. Compound 6 was prepared according to Scheme 1 in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:26][CH3:27])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:26][CH3:27])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:36][CH2:35][CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:21])[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1
Reactant: NCCN1CCOCC1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)O)c3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)NCCN4CCOCC4)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.8 %

Procedure:
Under nitrogen, to a solution of the product of Step 2 (31 mg, 85 μmol) in DMF (2 mL), was added [2-(4-morpholinyl)ethyl]amine (23 mg, 170 mmol), HOBT (35 mg, 0.26 mmol), HBTU (49 mg, 0.13 mmol), followed with 4-methylmorpholine (30 μL, 0.26 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated, residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O, containing 0.1% TFA), to afford the title compound as a pale yellow solid (53 mg, 90%). %). 1H NMR (400 MHz, DMSO) δ ppm 9.74 (t, 1H, 4.4 Hz), 9.28 (s, 1H), 8.73 (t, 1H, 5.2 Hz), 8.16 (s, 1H), 7.87 (s, 1H), 7.73 (d, 1H, 8.0 Hz), 7.56 (d, 1H, 7.2 Hz), 7.49 (d, 1H, 7.6 Hz), 6.96 (s, 2H), 4.72 (q, 2H, 7.2 Hz), 4.41 (s, 2H), 4.00 (d, 2H, 11.2 Hz), 3.53-3.68 (m, 6H), 3.30 (bs, 2H), 3.14-3.17 (m, 2H), 1.42 (t, 3H, 7.2 Hz). MS (ES+) m/e 477 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:14]=[CH:13][C:12]3[N:15]=[C:16]([C:20]4[C:21]([NH2:25])=[N:22][O:23][N:24]=4)[N:17]([CH2:18][CH3:19])[C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>CN(C=O)C.O.CCOC(C)=O>[NH2:25][C:21]1[C:20]([C:16]2[N:17]([CH2:18][CH3:19])[C:11]3[CH:10]=[C:9]([O:8][C:4]4[CH:3]=[C:2]([NH:1][C:39](=[O:40])[C:38]5[CH:42]=[CH:43][C:35]([O:34][CH3:33])=[CH:36][CH:37]=5)[CH:7]=[CH:6][CH:5]=4)[N:14]=[CH:13][C:12]=3[N:15]=2)=[N:24][O:23][N:22]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(OC)cc4)c3)cc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 20.5 %

Procedure:
To a 0° C. solution of 0.10 g of the product of Example 3 (0.30 mmols) in DMF (1.0 mL) was added 0.041 mL of triethylamine (0.30 mmols) and 0.056 g of 4-methoxybenzoylchloride (0.33 mmols). The reaction mixture was allowed to warm to rt and stirred for 23 h. The reaction mixture was diluted with 1 mL of water and 5 mL of EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and concentrated to a partial volume. Methanol was added, and a solid precipitated from the solution. The precipitate was filtered off and dried and the crude product was purified by silica gel chromatography to provide the title compound as a white powder (0.029 g, 21%). MS (ES+) m/e 473 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[N:11][OH:12])([NH2:10])[CH3:9].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1>[C:8](=[N:11][OH:12])([NH2:10])[CH3:9].[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)([O-:12])(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(N)=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 130.5 %

Procedure:
Triethylamine (3 ml, 2.18 g, 0.022 mol) was added to acetamide oxime (1.5 g, 0.02 mol) in tetrahydrofuran (THF) (45 ml). To the mixture, p-toluenesulfonyl chloride (Tosylchloride, TsCl) (4.2 g, 0.022 mol) was added in small portions (generating heat intensively). The mixture was allowed to react at room temperature for 45 mins. and the precipitates were collected by filtration. THF was distilled off under reduced pressure, and water was added to the resultant residue. The residue was extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and isopropyl ether was added to the residue to separate crystals. The crystals were filtered off is and dried to give acetamide-oxime-tosylate (3.2 g, yield; 69.2%).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:35][CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[OH:38]>>[Cl:45][C:41]1[CH:40]=[C:39]([C@@H:37]([OH:38])[CH2:36][NH:35][CH:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][S:16]([C:13]4[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:33])=[CH:11][CH:12]=4)(=[O:18])=[O:17])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH:44]=[CH:43][CH:42]=1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: Cl
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4cccc(Cl)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzensulfonamide (which was obtained in Example 225) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 278 as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=6.9 Hz, 3H), 1.20-1.50 (m, 10H), 1.75-1.90 (m, 2H), 2.50-2.80 (m, 5H), 3.00-3.15 (m, 2H), 3.40-3.50 (m, 2H), 4.60 (dd, J=8.1, 3.8 Hz, 1H), 6.29 (t, J=5.7 Hz, 1H), 6.77 (d, J=9.1 Hz, 2H), 6.85 (d, J=9.1 Hz, 2H), 7.25-7.50 (m, 8H), 8.94 (s, 1H), 9.55 (brs, 1H); MS (ES) m/z: 628.1 (MH+); HRMS Calcd. for C32H43ClN5O4S(MH+): 628.2748. Found: 628.2718.
Reaction SMILES: C([Li])CCC.[CH2:6]([S:13][C:14]1[N:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:25]Br>O1CCCC1>[CH2:6]([S:13][C:14]1[N:18]=[C:17]([Br:25])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CSc2ncn(-c3ccccc3)n2)cc1
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1nc(SCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C

Procedure:
n-Butyllithium (50 ml) was added dropwise to a stirred solution of 3-benzylthio-1-phenyl-1,2,4-triazole (31.8 g) in dry tetrahydrofuran (200 ml) at -70° C. Bromine (19 g) was added and the reaction mixture was allowed to warm to room temperature and then quenched with water. After washing with brine, the organic phase was dried and evaporated to give a yellow oil. Purification by chromatography over silica with dichloromethane and petroleum ether afforded the desired product as a pale yellow oil.
Reaction SMILES: [ClH:1].C([C:4]1[CH:13]=[C:12](OCC2C=CC(C3C=CC=CC=3C3N=NN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OCC(OCC)=O)[N:10]=2)[N:5]=1)C>C(O)C>[ClH:1].[N:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:4]=1
Reactant: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Agent: Cl
Solvent: CCO
Product: c1cnc2cccnc2c1
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (1.6 ml) was added to a suspension of 2-ethyl-6-(ethoxycarbonylmethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (0.61 g) in ethanol (9.7 ml) and the resulting solution was stirred for three hours. The precipitated solid was collected by filtration and recrystallised from methanol to give 2-ethyl-6-(ethoxycarbonylmethoxy)-4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine hydrochloride (0.139 g), as a white powder, m.p. 191°-193° C.; NMR (d6 -DMSO): 1.0(t,3H), 1.4(t,3H), 3.1(q,2H), 4.0(q,2H), 5.0(s,2H), 5.6(s,2H), 7.2(d,2,H), 7.6(m,8H), 8.7(d,1H); mass spectrum (+ve FAB, DMSO/NBA): 511 (M+H)+.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([CH3:21])[C:18]([O-])=[O:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:74]([F:77])([F:76])[F:75])([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[CH3:21][CH:17]([CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([F:22])([F:2])[F:23])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[C:18]([N:71]1[CH2:70][CH2:69][CH:68]([NH:67][C:64]2[CH:65]=[CH:66][C:61]([N+:58]([O-:60])=[O:59])=[C:62]([C:74]([F:77])([F:75])[F:76])[CH:63]=2)[CH2:73][CH2:72]1)=[O:19]
Reactant: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-methyl-propionic acid lithium salt (70 mg; 0.22 mmol, prepared in accordance with Example 63), diisopropylethyl amine (87 μL; 0.50 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (76 mg; 0.20 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (63 mg; 0.20 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 60 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (64 mg; 0.11 mmol). The structure was confirmed using Protocol I-A. Calculated mass=588; observed mass=588; HPLC retention time=3.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.BrB(Br)Br.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[O:7])=[CH:28][CH:29]=1
Reactant: COc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1c(=O)cc(-c2cccc(O)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 0 °C

Procedure:
Interm. (b 7-g) (6.8 g) was added to DCM (210 ml), stirred at 0° C. Tribromoborane (67.3 ml) was added dropwise and the reaction mixture was stirred at 0° C. for 15 minutes. The mixture was brought to room temperature, stirred at room temperature for 30 minutes and K2CO3 10% was added. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 6.6 g of 6-(4-chlorobenzoyl)-4-(3-hydroxyphenyl)-1-methyl-2(1H)-quinolinone (interm. 7-h) (quantitative yield; used in next reaction step, without further purification).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:13](#[N:17])[CH2:14][C:15]#[N:16]>N1CCCCC1.C(O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[OH:12])[CH:7]=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C#N)cc(I)c1O

Procedure:
A preferred method of synthesis of (E)-1-cyano-3-(3-iodo-4,5-hydroxyphenyl)acrylonitrile (Compound 2) is as follows: The compound was prepared as described in Ohmichi et al., 1993, Biochemistry 32:4650 in two steps. First, 3-methoxy-4-hydroxy-5-iodobenzylidene malononitrile was prepared by adding 3 drops of piperidine to 1.4 g of 5-iodovanillin and 0.4 g of malononitrile in 25 ml of ethanol and refluxing the mixture for 4 hours. 0.8 g (49% yield) of a yellow solid resulted.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:32][CH3:33])[CH:13]([C:22]1([C:25](OC(C)(C)C)=[O:26])[CH2:24][CH2:23]1)[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[Si:15]([O:14][CH:13]1[C:22]2([CH2:24][CH2:23]2)[C:25](=[O:26])[NH:11][C@H:12]1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C1(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-(tert-butyldimethylsilyloxy)butyl)cyclopropanecarboxylate (1.18 g) in methanol (20 mL) was added 10% palladium carbon (150 mg), and the mixture was stirred at room temperature for 18 hr under a hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in methanol (20 mL). Sodium methoxide (230 mg) was added and the mixture was refluxed for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless oil (yield: 397.8 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](O)=[N:8][NH:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: COc1ccc2c(O)n[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(Cl)n[nH]c2c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 37.7 %

Procedure:
To a solution of the product from Step B (1 g, 6.1 mmol) in pyridine (0.5 mL, 6.1 mmol) was added phosphorous oxychloride (0.9 mL, 9.2 mmol) and the mixture heated at 130–140° C. for 5 h. The reaction mixture was cooled to 70° C. and poured onto ice (100 g). After standing for 24 h, the solid was collected and dried to give a cream-colored solid (0.42 g): ES/LCMS m/z 181 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Cl:19][CH2:18][CH2:17][CH2:16][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12]
Reactant: ClCCCBr
Reactant: O=C1CCc2cc(F)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)ccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A reaction flask was charged with 6-fluoro-3,4-dihydro-1H-quinolin-2-one (0.180 g, 1.09 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.048 g, 1.20 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 1-bromo-3-chloropropane (0.180 g, 1.14 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (92LH79) (0.193 g, 73%). 1H NMR (CDCl3) δ 7.02-6.88 (m, 3H), 4.09-4.05 (m, 2H), 3.61 (t, J=6.3 Hz, CH2), 2.87 (t, J=6.7 Hz, CH2), 2.65-2.61 (m, 2H), 2.16-2.09 (m, 2H); 13C NMR (CDCl3) δ 169.8, 158.4 (J=242.9 Hz), 135.7 (J=2.7 Hz), 128.5 (J=7.7 Hz), 115.7 (J=8.1 Hz), 115.1 (J=22.7), 113.8 (J=22.3 Hz), 42.6, 40.3, 31.5, 30.1, 25.5.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]#[N:10])[CH:3]=1.[N:11]([O-])=O.[Na+]>Cl>[NH2:10][C:9]1[C:4]2[C:5](=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[NH:6][N:11]=1
Reactant: O=N[O-]
Reactant: N#Cc1cc(Br)ccc1N
Agent: Cl
Agent: [Na+]
Product: Nc1n[nH]c2ccc(Br)cc12

Procedure:
Twenty grams of 4-bromo-2-cyanoaniline is treated with concentrated hydrochloric acid and sodium nitrite; the resulting diazo compound is reacted with stannous chloride in concentrated hydrochloric acid at 0° C. Working up as in Example 2 gives 3-amino-5-bromoindazole.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C@@H:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C@@H:16]4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:4]C[CH2:2]1.C1(O)CCCC1>>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:2][CH2:4][CH2:5]1
Reactant: c1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c(OC2CCCC2)c1
Agent: OC1CCCC1
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OC2CCC2)c1

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole and substituting cyclobutanol for cyclopentanol while making non-critical variations the title compound was obtained as 193 mg (37%) of a tan solid: mp 182.0-184.5° C. 1H NMR (400 MHz, CDCl3) δ 7.85 (br s, 1H), 7.35-7.28 (m, 3H), 7.18-7.14 (m, 1H), 7.04-7.00 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 4.63-4.56 (m, 1H), 3.10-3.07 (m, 2H), 2.98-2.95 (m, 2H), 2.87-2.84 (m, 2H), 2.47-2.41 (m, 2H), 2.37-2.32 (m, 2H), 2.02-2.00 (m, 2H), 1.74-1.72 (m, 1H), 1.64-1.59 (m, 1H); HRMS (FAB) calcd for C22H24N2O+H1: 333.1967 found 333.1960.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:28][NH2:29])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.[BH4-].[Na+]>CO.[NH4+].[Cl-]>[CH3:40][O:39][C:37](=[O:38])[C:36]1[CH:41]=[CH:42][C:33]([CH2:31][NH:29][CH2:28][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(CNC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
[(S)-1-Aminomethyl-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-carbamic acid tert-butyl ester (640 mg, 1.44 mmol) was stirred with methyl 4-formylbenzoate (237 mg, 1.44 mmol) in CH3OH (3 ml) at rt for 2 h. NaBH4 (58 mg, 1.44 mmol) was added. The mixture was stirred at rt for 20 min. Several drops of saturated aqueous NH4Cl were added. The mixture was then partitioned between CH2Cl2 and water (20 ml/20 ml). The organic layer was concentrated to give 4-{[(S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propylamino]-methyl}-benzoic acid methyl ester (650 mg, 76%).