Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CS[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:18][N:17]=1>>[CH3:13][C:4]1[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reaction time: 6 h
Yield: 77 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.73 g), was fused with 2-methylthio-5-(4-chlorobenzyl)-4-pyrimidone (0.75 g) at 160°-170° C. and heating was continued for 6 hours. The mixture was cooled and recrystallised from chloroform/petroleum-ether (b.p. 60°-80° C.), to give 2-[4-(3-methyl-5-bromopyrid-2-yl)butylamino]-5-(4-chlorobenzyl)-4-pyrimidone (1.0 g) m.p. 149°-150° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1.[N+]([O-])(O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1
Reactant: COCc1nc(CO)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: COCc1nc(C=O)c[nH]1

Procedure:
A 145.9 gm. portion of 2-methoxymethyl-4-imidazolemethanol and 137 ml. of concentrated HNO3 are reacted as described in Example 15. After adjusting the pH to 7.0 with concentrated aqueous Na2CO3, the solution is concentrated under vacuum. Extraction of the residue three times with hot ethanol gives, after combining and concentrating the extracts, a yellow gum. This gum is chromatographed on silica gel. Fractions 7-15 are combined and recrystallized from 120 ml. of isopropanol, treated with charcoal and the desired product is recovered, m.p. 100°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:10].BrC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[F:1][C:2]1[CH:9]=[C:8]2[C:5](=[CH:4][C:3]=1[Cl:10])[CH:6]=[N:17][CH:16]=[CH:15]2
Reactant: Brc1ccc2cnccc2c1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: Fc1cc2ccncc2cc1Cl

Procedure:
Starting from 4-Fluoro-3-chlorobenzaldehyde, the title compound was synthesized by the protocol described for 6-Bromo-isoquinoline (3). Rt=0.77 min (Method A). Detected mass: 182.1/184.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.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>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:29]1
Reactant: OB(O)c1ccoc1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccoc4)n3)cnc2n1
Temperature: 90 °C
Yield: 95.1 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (from Example 34) (200 mg, 0.49 mmol), 3-furanboronic acid (111 mg, 0.98 mmol), K3PO4 (457 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 9 mol %) in DMA (6 ml) was heated at 90° C. for 45 min under N2. The reaction was concentrated under reduced pressure while azeotroping with xylene (3×30 ml). EtOAc (50 ml) and H2O (50 ml) were added and the organics separated and concentrated under reduced pressure while loading onto MgSO4. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 as the eluent gave 3-[2-(furan-3-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (203 mg, 94%): m/z (ES+) 435 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=3)[CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])C(=O)OC(C)(C)C)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:32]=[CH:31][CH:30]=[C:16]([CH2:17][NH:18][CH2:26][CH2:27][O:28][CH3:29])[CH:15]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of 75 (440 mg, 0.6 mmol) in DCM (10 mL), TFA (145 μL, 1.9 mmol) was added and the reaction was stirred for 12 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluent MeOH/EtOAc (1:10), to afford the title compound 76a (227 mg, 63% yield) as a light yellow solid. 1H NMR (DMSO) δ (ppm): 8.54 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.02-8.0 (m, 2H), 7.93 (d-t, J=2.0 Hz, 1H), 7.55-7.53 (m, 4H), 7.34-7.32 (m, 4H), 7.29-7.26 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 4.19 (s, 2H), 3.81 (s, 1H), 3.57 (t, J=4.9 Hz, 2H), 3.33 (s, 2H), 3.29 (s, 3H), 3.08 (t, J=4.9 hz, 2H), 2.84 (q, J=2.2 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][N:8]([CH2:14][CH3:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH2:7][N:8]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:14][CH3:15])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 75 °C

Procedure:
Cyclopropanecarboxylic acid (5-bromo-2-iodo-benzyl)-ethyl-amide (6.0 g, 14.7 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (5.2 g, 16.2 mmol), and potassium carbonate (5.09 g, 36.8 mmol) were combined in DME (50 mL) and water (20 mL) under nitrogen. The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.74 mmol) was added, and the reaction was heated to 75° C. The reaction was monitored by analytical LCMS and an additional portion of the boronic ester (0.500 g, 1.56 mmol) was added to push the reaction to completion. When the starting material was consumed, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[CH:10]([OH:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CO[C:41](OC)([CH3:43])[CH3:42]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:10]([CH2:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[O:21][C:41]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(O)Cc1ncccc1C(=O)O
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)C(Cc2ncccc2C(=O)O)OC1(C)C
Temperature: 40 °C

Procedure:
To a solution of 2-[3-tert-Butoxycarbonylamino-4-(2-fluoro-phenyl)-2-hydroxy-butyl]-nicotinic acid (13 g, 32 mmol) in 500 mL of 2,2-dimethoxypropane and 500 mL of acetone at 0° C. is added boron trifluoride diethyl etherate (3.2 mL, 25 mmol). The reaction is heated at 40° C. overnight after which time the solvent is removed under reduced pressure. The resultant residue is then partitioned between dichloromethane and water and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: c1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazol (0.71 ml, 10 mmol) in dry THF (20 ml) was added dropwise 1.6 M-BuLi in hexane (6.9 ml, 11 mmol) under argon at -78° C. The reaction mixture was stirred at -78° C. for 0.5 hr and Bu3SnCl (3.1 ml, 11 mmol) was added dropwise. After stirring for 1 hr at -78° C. and for 1 hr at room temperature, the mixture was concentrated, triturated with water (50 ml) and extracted with diethylether (100 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure to give (33) as colorless oil.(3.7 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:22])[CH2:18]S(C)=O.[Al]>O.O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:22])[CH3:18]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)CS(C)=O)c1Cl
Agent: [Al]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0 h
Yield: 60.6 %

Procedure:
1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone (2.0 g, 5.61 mmol) is dissolved in 100 ml of 10% water/tetrahydrofuran and cooled to 0° C in an ice bath. Aluminum amalgam is prepared by addition of aluminum foil (1.5 g, 56.1 mmol) to 350 ml of 2% aqueous mercuric chloride. After 15 seconds, the liquid is decanted, and the foil is washed twice with absolute ethanol followed by tetrahydrofuran. The freshly prepared aluminum amalgam is added to the reaction mixture which is then stirred for 30 minutes at 0° C. The reaction mixture is filtered through celite, and the solids are washed with tetrahydrofuran. The filtrate is evaporated, and the residue is taken up in ether. The ether solution is washed with 100 ml of water and dried over magnesium sulfate. Evaporation of the solvent gives a yellow solid which is recrystallized from diethyl ether/hexane. Yield (1.0 g, 60%) of 1-[2-[(2,6-dichloro-3 -methylphenyl)amino]phenyl]ethanone; mp 122°-125° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.F[C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:15]2[CH:16]=[N:17][CH:18]=[CH:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)s1
Reactant: O=C(O)c1ccncc1F
Product: Cc1ccc(CNc2cnccc2C(=O)O)s1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from 5-methylthiophen-2-ylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.27 (br s, 1H), 7.84 (br s, 1H), 7.57 (d, 1H, J=4.8 Hz), 6.87 (d, 1H, 3.2 Hz), 6.65 (d, 1H, J=2.3 Hz), 4.65 (s, 2H), 2.38 (s, 3H). [M+H] calc'd for C12H12N2O2S, 249; found 249.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24](Br)[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([N:37]4[C:36](=[O:38])[C:35]5=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]5[C:33]4=[O:43])[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 3.01 g of 5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(1-bromoethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole in 10 mL of N,N-dimethylformamide, 1.26 g of potassium phthalimide was added and the resultant mixture was stirred at 80° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 20 mL of water was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate (70 mL×1). The organic phase was washed with water (20 mL×1) and then dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (a gradient from 1:10 to 1:5) to obtain 2.80 g of the objective substance as a colorless resinoid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1([CH3:29])[O:3][C:4](=[CH:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(=CC(=O)O)O1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A solution of the crude (Z)-2,2-dimethyl-5-(tert-butyldiphenylsilyloxycarbonyl methylene)-1,3-dioxolan-4-one (52.4 mmol) in tetrahydrofuran (200 ml) was treated with acetic acid (13 ml) followed with 50 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue with toluene gave 6.3 g (70% yield for three steps) of the title material as a white solid (>95% pure by 1HNMR).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[NH:46][C:47](OC1C=CC([N+]([O-])=O)=CC=1)=[O:48])[C:39]([O:41][CH3:42])=[O:40]>C(N(CC)CC)C.C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:47]([NH:46][C:45]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[O:35][CH3:34])=[O:48])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 150 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate in 0.140 mL of triethylamine and 3.0 mL of THF was added 155 mg of methyl 3-methoxy-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate prepared in the same manner as in Production Example 11, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)-3-methoxybenzoate as a crude product (yellow foamy substance, 297 mg). ESI+: 652
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[NH2:1][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1
Reactant: CC1c2ccc(OCCCBr)cc2C1CN1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1c2ccc(OCCCN)cc2C1CN1CCCCC1

Procedure:
Sodium azide (1.49 g) is added to a stirred solution of 5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3 g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reaction mixture is refluxed overnight, poured into water and extracted with ether. The organic extract is washed with sat'd aqueous NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: Fc1ccccn1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccccn2)c2ccccc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (45.7 mg, 1.142 mmol, 60% dispersion in mineral oil) was added to a solution of methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) in DMF (2283 μl) at RT. After 30 min, 2-fluoropyridine (99 μl, 1.142 mmol) was added to the mixture and the resulting suspension was heated at 120° C. for 14 h. The reaction mixture was diluted with DMF, filtered, and purified by HPLC to afford the title compound as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[C:13]([CH3:18])=[N:14][CH:15]=[CH:16][CH:17]=1>>[CH3:10][O:11][C:12]1[C:13]([CH3:18])=[N:14][C:15]([N+:6]([O-:9])=[O:7])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccnc1C
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold mixture of 3 ml. of concentrated sulfuric acid and 3 ml. of fuming nitric acid, was added 0.5 g. of 3-methoxy-2-methylpyridine over 5 minutes. After warming spontaneously to room temperature the mixture was heated at 55°-60° C. for 6 hours. The mixture was cooled and added to 35 ml. of ice-water. After stirring 2 hours, the precipitate was collected and dried to give 3-methoxy-2-methyl-6-nitropyridine, m.p. 99°-100.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C>C(O)C.[Zn]>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(N)cc23)CC1
Yield: 54 %

Procedure:
Zinc (3.28 g, 50.46 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-indole (2 g, 5.04 mmol) in ethanol (500 mL). Acetic acid (30 mL) was then added dropwise with stirring while the reaction was cooled in a ice water bath. The resulting solution was stirred for 2 hours at room and then filtered. The filtrate cake was washed with ethanol, and the collected filtrate was concentrated in vacuo. The residue was purified by column chromatography using a 10:1 methanol/ammonia solvent system to afford 1 g (54%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-5-amine as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2].CO[C:23](OC)([N:25]([CH3:27])[CH3:26])[CH3:24]>>[CH3:26][N:25]([CH3:27])[C:23]([CH3:24])=[CH:2][C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:5]=1)=[O:3]
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COC(C)(OC)N(C)C
Product: CC(=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O)N(C)C
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A slurry of 3-acetyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.369 g, 1.30 mmol) in N,N-dimethylacetamide dimethylacetal (3.5 mL, 18.3 mmol) was heated under microwave conditions at 120° C. for 5 min. After this time, the reaction was cooled to room temperature and concentrated onto silica gel. The crude product was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give 3-[3-(dimethylamino)but-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.314 g, 68%) as a yellow foam.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)c1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC1=Cc2cc(Sc3cccc(O)c3)ccc2OC1(C)C
Yield: 67.3 %

Procedure:
6-(3-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (3.5 g) (see Preparation 6) was dissolved in dry 2,4,6-collidine (15 ml), anhydrous lithium iodide (3 g) was added and the mixture was heated under reflux under a nitrogen atmosphere for 24 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The-organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue chromatographed on silica eluting with a solvent gradient of 1:1 hexane:dichloromethane changing to dichloromethane to yield 6-(3-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.25 g) as an oil.