Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[N:23]=[C:24]4[C:29](=[C:30]5[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]5)[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12][C@:11]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:37][C@H:10]2[CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH3:44][C:45]1[O:49][N:48]=[C:47]([C:50](O)=[O:51])[CH:46]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:44][C:45]1[O:49][N:48]=[C:47]([C:50]([NH:1][C@@H:2]2[C:16](=[O:17])[N:15]3[CH2:18][C@H:19]([O:21][C:22]4[N:23]=[C:24]5[C:29](=[C:30]6[C:35]=4[CH:34]=[CH:33][CH:32]=[CH:31]6)[CH:28]=[CH:27][CH:26]=[CH:25]5)[CH2:20][C@H:14]3[C:13](=[O:36])[NH:12][C@:11]3([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:37][C@H:10]3[CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:51])[CH:46]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Reactant: Cc1cc(C(=O)O)no1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-amino-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate, Hydrochloric Acid (Example 18b, 5.00 g, 8.24 mmol), 5-methylisoxazole-3-carboxylic acid (1.15 g, 9.06 mmol) and 2-(3H41,2,31triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (3.44 g, 9.06 mmol) in dichloromethane (82 ml) was added N-ethyl-N-isopropylpropan-2-amine (5.03 ml, 28.8 mmol). The mixture was stirred at rt for 2 h, and then quenched with saturated aqueous sodium carbonate solution. The organic layer was washed with 1N HCl, separated, filtered, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to provide a white foam. This material was purified flash chromatography on silica gel (4:1 dichloromethane/ethyl acetate) to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (4.5 g, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[CH3:38][C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH3:38][C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][S:42]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:10]2[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:29][CH:28]=1)(=[O:44])=[O:43]
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: CC(C)(C)CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (50 mg, 0.11 mmol) was dissolved in dichloromethane (3.0 ml), cooled to 0° C. and triethylamine (20 μl, 0.13 mmol) was added to the mixture. The resulting mixture was cooled to −78° C. and 3,3-dimethylbutane-1-sulfonyl chloride (25 mg, 0.13 mmol) was carefully added. The reaction was stirred at −78° C. for 2 h. Water was added to the reaction, the product extracted with dichloromethane and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (46 mg, 69%) as a solid.
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: O=C(CBr)N1CCCCC1
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
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: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2:21].[Na+].[Na+].C(=O)(O)[O-].[Na+].O>ClCCl>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[SH:21]
Reactant: [S-2]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1cc([N+](=O)[O-])ccc1S
Temperature: 125 °C
Yield: 100.8 %

Procedure:
2-Fluoro-5-nitroaniline (1 g, 6.41 mmol), sodium sulfide nonahydrate (1.7 g, 7.05 mmol), sodium bicarbonate (600 mg, 7.05 mmol) and water (15 mL) were combined and heated in the microwave at 125° C. for 5 min. After cooling, dichloromethane was added, and the organic layer was washed with 2M aqueous hydrochloric acid and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 1.1 g (33%) of the title compound.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:34])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[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)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1C
Product: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(F)cnc32)cc1
Temperature: 140 °C
Yield: 65.4 %

Procedure:
Cyclohexylamine (6.14 mL, 53.65 mmol) was added to a stirred solution of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (74) (10 g, 26.82 mmol) in xylene and heated at 140° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase was washed by water and brine, then dried over Na2SO4 and evaporated to yield 7.46 g (65%) of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexyl amide (92) as white solids. MP: 176° C.; 1H-NMR (DMSO-d6): δ 1.25-1.41 (m, 5H), 1.54 (m, 1H), 1.66 (m, 2H), 1.87 (m, 2H), 3.68 (s, 3H), 3.86 (m, 1H), 5.51 (s, 2H), 6.81 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 8.31 (d, J=8.0 Hz, 1H), 8.83 (s, 1H), 10.24 (s, 1H); EIMS m/z 426 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:32]=[CH:31][C:23]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO.[Pd]>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:23]1[CH:31]=[CH:32][C:20]([C:17]2[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[O:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccccn5)cc4)no3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccccn4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 22 h
Yield: 5.6 %

Procedure:
2-(4-(5-(4-(Benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenoxy)pyridine (310 mg, 376 μmol) was placed in a single neck round bottom flask, suspended in methanol (5.0 mL) and THF (5.0 mL) and 10% Pd/C (0.5 mg, 5.0 μmol) was added. A condenser was placed on top of the flask and then sealed. The solution was stirred under H2 at 55° C. for 22 hours. While hot, the solution was filtered through Celite washed with additional methanol and the solvent was removed under reduced pressure. The solid residue was purified by silica gel column chromatography (EtOAc/Hex 1:2) to give the product as a white solid (7 mg, 3%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.00 (2H, d, J=8.8 Hz), 7.14 (1H, d, J=8.2 Hz), 7.05 (1H, ddd, J=7.3, 5.0, 1.0 Hz), 7.32 (2H, d, J=8.8 Hz), 7.92 (1H, ddd, J=8.8, 8.2, 2.0 Hz), 8.03 (2H, d, J=8.8 Hz), 8.11 (2H, d, J=8.8 Hz), 8.21 (1H, ddd, J=5.0, 2.0, 1.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 112.2 (CH), 114.1, 116.3 (CH), 119.7 (CH), 121.5 (CH), 122.4, 128.7 (CH), 130.1 (CH), 140.5 (CH), 147.6 (CH), 156.6, 162.1, 162.4 167.6, 175.5. MS (FAB+): 332 (MH+). HRMS for C19H13N3O3 (MH+): calculated: 332.1035; found 332.1049.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([C@H:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([C@H:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:18]([O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Benzyl bromide (4.40 g, 25.7 mmol) was added dropwise to a mixture of (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (4.00 g, 12.9 mmol) and Cs2CO3 (4.20 g, 12.9 mmol) in DMF (80 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (80 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1 to 4:1) to afford (2S,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (3.7 g, 66% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>>[C:17]([C:9]1[C:10]([C:13]([F:15])([F:16])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[C:4]([CH2:1][CH2:2][CH3:3])=[CH:12]2)#[N:18]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: COC(=O)C(C)Br
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)C(=O)OC

Procedure:
Synthesized in a manner similar to Example 1 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromopropanoate: MS (ESI): m/z 339 (MH+).
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH2:3][CH2:4][SH:5].[C:7](#[N:10])[CH:8]=[CH2:9].[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1>>[C:12](#[N:19])[CH2:13][CH2:14][S:5][CH2:4][CH2:3][CH2:2][CH2:1][S:6][CH2:9][CH2:8][C:7]#[N:10]
Reactant: SCCCCS
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: C=CC#N
Agent: [OH-]
Product: N#CCCSCCCCSCCC#N

Procedure:
4,9-Dithiadodecanedinitrile was prepared according to the procedure of Example 1 using 1,4-butanedithiol (20.0 g; 0.16 moles), acrylonitrile (17.0 g; 0.32 moles) and benzyltrimethylammonium hydroxide (40% in methanol; 1 ml) as the catalyst.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1>>[OH:19][C:3]1[CH:2]=[C:11]([C:6]2[CH:5]=[C:17]3[C:12](=[CH:8][CH:7]=2)[C:13]([C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:14]([OH:18])[CH:15]=[CH:16]3)[CH:10]=[CH:9][CH:4]=1
Reactant: COc1ccc(OB(O)O)cn1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Product: COc1ccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)cn1
Reaction time: 3 h
Yield: 84 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with 6-methoxypyridin-3-ylboric acid (48.6 mg, 0.32 mmol, 1 eq) according to method A in 3 h. Purification by column chromatography with hexane/ethyl acetate 8/2 yields the desired compound in a yield of 84%, 92 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1B1OC(C)(C)C(C)(C)O1)=[O:5])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:41])[CH2:33][NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:28][CH:27]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:41])[CH2:33][NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:30][CH:31]=1)=[O:5])[CH3:2]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(I)cc1
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)c(C#N)c(CC)n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Reaction time: 3 h

Procedure:
Add 4-cyano-5-ethyl-1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.22 g, 0.65 mmol, prepared in preparation 50), to propane-2-sulfonic acid [2-(4-iodo-phenyl)-propyl]-amide (0.20 g, 0.65 mmol, can be prepared as in J. Med. Chem., 43, 4354 (2000)), [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(1H) complex with methylene chloride (1:1) (0.013 g, 0.016 mmol), and 2M aqueous sodium carbonate (1.35 mL, 2.7 mmol) in DMF and heat to 80° C. After 3 hours, cool and pour into water. Extract with ethyl acetate. Wash the combined organics with water, and brine, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (ES+)=446.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1[CH:22]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Product: COc1ccc(/C=C/C(=O)c2cc(C)ccc2O)c(OCc2ccccc2)c1OC
Yield: 72.3 %

Procedure:
2-Hydroxy-5-methylacetophenone (690 mg, 2.53 mmol) and 2-benzyloxy-3,4-dimethoxybenzaldehyde (460 mg, 3.03 mmol) was reacted according to the same procedure as Preparation 1 to give 740 mg (Yield 76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22](N)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].C([N:27](CC)CC)C.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=1)[C:38](Cl)=[O:39]>ClCCl>[S:15]1[C:10]2[CH2:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[N:6]([C:4]([C:3]3[C:2]([Cl:1])=[CH:23][CH:22]=[CH:21][C:20]=3[C:34]3[C:33]([F:32])=[CH:41][C:37]([C:38]([NH2:27])=[O:39])=[C:36]([CH3:42])[CH:35]=3)=[O:5])[CH2:12][C:11]=2[CH:13]=[CH:14]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccsc3Cc3ncccc32)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(Cl)c2C(=O)N2Cc3ccsc3Cc3ncccc32)c(F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2 mmol of 5-(2-chloro-4-aminobenzoyl)-4,10-dihydro-5H-pyrido[3,2-b]thieno[2,3-e]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1 mmol of 5-fluoro-2-methylbenzoyl chloride. After stirring at room temperature overnight, the mixture is washed with H2O, 1M NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed to give the product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 124.9 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (100 g, 0.52 mol) in anhydrous THF (550 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (210 mL, 0.52 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (120 g, 0.44 mol) in anhydrous THF (500 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (178 g), which was used immediately for next step without purification.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[CH3:33][O:34][CH2:35][CH2:36]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CCO.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:36][CH2:35][O:34][CH3:33])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: COCCBr
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CCCCc1nnc(OC2CCN(CCOC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 0.2 mmol, 97 mg) in EtOH (2 mL) was added 2-bromoethyl methyl ether (0.6 mmol, 57 μL), and potassium carbonate (0.6 mmol, 83 mg). The mixture was stirred at 60° C. for 3 hours, then cooled to room temperature, and filtered through celite. The celite cake was washed with DCM. The organic layers were combined and condensed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (2 mL), 1N HCl in ether (2 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (52 mg). LCMS: m/z 469 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.31-7.40 (3 H, m), 7.06-7.10 (2 H, m), 5.38-5.57 (1 H, m), 4.39-4.44 (1 H, m), 3.53-3.78 (4 H, m), 3.43 (3 H, s), 3.25-3.42 (4 H, m), 2.96-3.02 (2 H, m), 2.04-2.55 (4 H, m), 1.97-2.02 (2 H, m), 1.78-1.83 (2 H, m), 1.29-1.62 (8 H, m), 1.22-1.30 (2 H, m), 0.80 (3 H, t).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:13])=[N:6][C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].O>C(OCC)C>[Cl:13][C:5]1[C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][N:8]=[C:7]([CH:10]([F:12])[F:11])[N:6]=1
Reactant: CC(=O)c1cnc(C(F)F)nc1Cl
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cnc(C(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
0.4 g of 5-acetyl-4-chlorodifluoromethylpyrimidine was dissolved in 10 ml of dry diethyl ether, then, an excess of a borane ammonia complex was added under cooling with ice, and the mixture was stirred overnight at room temperature. After addition of water, extraction with diethyl ether was carried out. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.32 g of the desired product as a viscous liquid. nD19.9 1.4899