Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])=[CH:18][CH:17]=1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2c[nH]c3c2C(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), p-anisidine (616 mg, 5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [EDCI] (959 mg, 5 mmol) in 50% aqueous 1,4-dioxane (10 mL) was stirred at ambient temperature for 17 h. After concentrating in vacuo, the residue was taken up in 10% methanol in ethyl acetate, washed with 1.3M hydrochloric acid then with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate afforded N-(4-Methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 1); mp 219°-220° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:22]=2[N:23]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:28][C:25]3[CH:26]=[CH:27][C:21]4[S:20][C:19]([CH3:18])=[N:23][C:22]=4[CH:24]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(C)(C)C)cc4)ncn3)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 2-methyl-benzothiazol-5-ol (0.14 g, 0.85 mmol, Aldrich) in DMF (10 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) at room temperature. The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (10 mL) was added to the residue, and the organic layer was washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After purifying the crude product by silica gel chromatography (4:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (5 mL). Water (8 mL) was added dropwise to this mixture, and a white precipitate fell out of solution, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 163–165° C. MS (ESI, pos. ion) m/z: 376 (M+1). Anal. Calcd for C23H21N3OS.(H2O)1/3: C, 69.26; H, 5.72; N, 11.01. Found: C, 69.19; H, 5.61; N, 11.03.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:13]=[C:12]([NH:14][S:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[N:11]=[C:10]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:9]=1)[CH3:6])C.[BH4-].[Li+]>C1COCC1>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][S:24][C:10]1[N:11]=[C:12]([NH:14][S:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)(=[O:16])=[O:17])[CH:13]=[C:8]([O:7][C@H:5]([CH3:6])[CH2:4][OH:3])[N:9]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(4-morpholinylsulfonyl)amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester, (the product of step i) (0.34 g), THF (8 mL) and 2M lithium borohydride in TIER (1 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and ammonium acetate/acetonitrile as the mobile phase) to give the title compound as a white solid. Yield: 0.25 g
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)/[C:9]1=[O:39])=O)(C)(C)C.[F:40][C:41]1[CH:42]=[CH:43][C:44]([CH3:56])=[C:45]([CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH:46]=1>C1(C)C=CC=CC=1>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[CH:18]2[CH2:50][C:49](=[O:51])[NH:48][CH:47]([C:45]3[CH:46]=[C:41]([F:40])[CH:42]=[CH:43][C:44]=3[CH3:56])[C:10]32[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:8][C:9]3=[O:39])[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 17.7 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-3-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.2 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (14 mmol) in toluene to give the title compound as a white solid (600 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.N>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5cc[nH]c35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc6cc[nH]c56)c34)n(-c3ccccc3)c(=O)c12
Yield: 11.4 %

Procedure:
(S)-2-(1-((5-(1H-Indol-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (91 mg, 0.14 mmol) was treated with trifluoroacetic acid (1.82 mL, 23.62 mmol) and a solution of ammonia (7N in methanol, 1.82 mL, 12.74 mmol) according to the method described in Example 27 to give 8 mg (11% yield) of the title compound. Purity 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:11]3[C:10]([I:25])=[N:9]2)=[N:6][CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+]>C1COCC1>[I:25][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH3:30])=[CH:7][N:6]=2)[N:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cn1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of tert-butyl 1-(5-aminopyridin-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (63) (1.1 g, 2.4 mmol) in dry THF (15 mL) was added HCHO (38% aqueous, 3.4 g, 3.6 mmol). The mixture was stirred at room temperature overnight and NaBH(OAc)3 (612 mg, 2.88 mmol) was introduced in several portions. The reaction mixture was stirred at room temperature for 5 h and then quenched with water (10 mL). The solvent was removed in vacuo. The residue was purified by column chromatography (silca gel, 0 to 10% ethyl acetate in dichloromethane) to provide tert-butyl 3-iodo-1-(5-(methylamino)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (64) (200 mg, 18%) as a yellow solid. LC-MS (ESI): m/z (M+1) 468.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[O:17])[CH2:27]2)=[N:23][CH:24]=1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Reactant: COc1ccc(-c2ccccc2C(=O)O)cc1
Product: COc1ccc(-c2ccccc2C(=O)N2CCC[C@@H](Nc3ncc(Br)cn3)C2)cc1

Procedure:
prepared by reaction of 4′-methoxy-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:30][NH:31][C:32](=[O:37])C(Cl)(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:32]([NH:31][CH3:30])=[O:37])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Solvent: CN(C)C=O
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
(-)-4-(5-Chloro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman ##STR60## (-)-4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminocarbonyl-aminosulfonyl)-7-methoxychroman is prepared analogously to Example 1 from optically active 4-(5-chloro-2-methoxybenzamido methyl)-6-sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point: 239° C.; [α]D20 : -59.8° (c=1, DMF); HPLC: ee 98.5%.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].O>C(O)C>[CH2:1]([NH:3][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCN
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Solvent: CCO
Solvent: O
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A 70% aqueous ethylamine solution (40 ml) was added to a solution (70 ml) of 7-chloro-6-nitro-4(3H)-quinazolone (6.31 g, 28.0 mmol) in ethanol and the mixture was heated with stirring at 110° C. for 4 hours in a sealed tube. After cooling to room temperature, the reaction mixture was poured into water and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and dried to give the title compound (2.6 g, 39%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][S:27]([NH:30][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:4]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)(=[O:29])=[O:28]
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 ml scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methanesulfonamide (9.00 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.20 (m, 2 H), 1.43-1.57 (m, 2 H), 1.74-1.91 (m, 5 H), 2.17-2.26 (m, 2 H), 2.41-2.46 (m, 1 H), 6.95-7.22 (m, 1 H), 7.23-7.44 (m, 2 H), 7.64-7.82 (m, 2 H), 11.68 (s, 1 H), 13.98 (s, 1 H); MS (ESI) m/z 430 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[S:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=3)=[CH:18][CH:19]=2)=[N:12][N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nnc(-c2ccc(O)cc2)s1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (1 g, 3.5 mmol) in methanol (9 mL) containing NaHCO3 (1.2 g, 13.9 mmol) and di-t-butyldicarbonate (Boc2O; 1.5 g, 7.0 mmol) was stirred for 5 h. The resulting mixture was filtered and the filtrate concentrated. The residue was dissolved in CH2Cl2 (48 mL) and treated with 0.5 M NaOCH3 in methanol (8.3 mL). After stirring at room temperature for 1 h, the volatiles were removed under vacuum to yield tert-butyl ((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate. To a solution of tert-butyl((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (1.01 g, 2.89 mmol), dimethylformamide (16 mL) and potassium carbonate (1.36 g, 9.86 mmol) was added 3-fluorobenzylbromide (0.61 mL, 4.93 mmol), and the mixture was stirred at room temperature overnight. After 24 h, the resulting mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, heptane:EtOAc) to yield tert-butyl((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate. 1H NMR (400 MHz, CDCl3) δ 7.87-7.92 (m, 2H), 7.33-7.42 (m, 1H), 7.14-7.23 (m, 2H), 7.01-7.08 (m, 3H), 5.13 (s, 2H), 4.68-4.77 (m, 2H), and 1.48 (s, 9H); MS (ES+) 416 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH3:18][C:19]1([CH3:30])[CH2:23][C:22](=O)[CH:21]([C:25](OCC)=[O:26])[CH2:20]1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[OH:10][C:9]1[C:8]2[C:22]3[CH2:23][C:19]([CH3:30])([CH3:18])[CH2:20][C:21]=3[C:25](=[O:26])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCOC(=O)C1CC(C)(C)CC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CC(C)(C)C3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 13.5 g. of 5-(3-methyl-2-octyl)-resorcinol and 10.5 g. of 4,4-dimethyl-2-carboethoxycyclopentanone [Canadian J. of Chem. 47, 1982-1988 (1969)] in 59 ml. of benzene was added 4.3 ml. of phosphorous oxychloride with stirring and refluxing for 6 hours. After the red solution was allowed to stand at room temperature for 8 hours, it was added to an ice and sodium carbonate solution. The colorless mixture was extracted with ether, dried over magnesium sulfate and concentrated. The mixture was extracted with cold pentane and the pentane was discarded. The residue [9-hydroxy-7-(3-methyl-2-octyl)-2,2,-dimethyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c] [l]benzopyran] was obtained as a gummy solid.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C:8]2[CH:13]=[N:12][CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cncnc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Oc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
5-(p-Methoxyphenoxy)pyrimidine (7.7 g) was dissolved in dichloromethane and the solution, maintained at a temperature of -70° to -78° C., was treated by the dropwise addition of boron tribromide (7 ml). The stirred solution was allowed to warm to room temperature and after standing overnight the dichloromethane solution was washed with a cold saturated aqueous solution of sodium bicarbonate (100 ml). The dichloromethane solution was then dried, treated with charcoal and the solvent removed by distillation under reduced pressure. The residue was washed with diethyl ether to give 5-(p-hydroxyphenoxy)pyrimidine (0.4 g) m.p. 158° C. which was characterised by p.m.r. spectroscopy.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH2:31](O)[CH2:32]C>[Ni]>[Cl:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]2[N:10]([C@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@@H:7]([CH2:22][OH:23])[CH2:8]3)[C:31]([CH3:32])=[N:19][C:12]=2[CH:13]=1
Reactant: CCCO
Reactant: CC(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ni]
Product: Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1C[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
(1R, 2S, 3R, 5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (1.29 g, 2.78 mmol) in n-propanol (100 mL) was shaken with Raney nickel (Aldrich, slurry in water, 200 mg wet) under hydrogen (40 psi) on a Parr shaker for 4 hours. Catalyst was filtered off with Celite and the volatiles were evaporated in vacuo. The residual oil was refluxed in 96% formic acid (45 mL) for 5 hours. Concentrated hydrochloric acid (5 mL) was added and reflux continued for an additional 4 hours. Volatiles were evaporated in vacuo and the residue was dissolved in 1N sodium hydroxide (10 mL). The solution was stirred at ambient temperature for 18 hours, neutralized with acetic acid, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 15% methanol-chloroform gave (1R, 2S, 3R, 5R)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (236 mg, 26%), m.p. 198°-200° C.; 1H-NMR(DMSO-d6)δ: 8.30 and 7.72 (both s, 1 each, 2 aromatic CH), 5.0-4.8 (m, 3, 2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH2OH), 4.2-4.1 (m, 2, 2 OCH), 3.8-3.5 (m, 2, CH2O), 2.58 (s, 3, CH3), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH2); mass spectrum(CI): 331(M+1); [α]20589 -13.5°, [α]20578 -13.9°, [α]20546 -15.9°, [α]20436 -30.3° (c=0.251, methanol).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[C:3]=1[O:13][CH3:14].[C:15]1([C:21]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:22]2[CH:26]=[C:25]([CH:27]=[O:28])[N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][O:13][C:3]1[C:4]([CH2:10][O:11][CH3:12])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:27]([C:25]1[N:24]=[CH:23][N:22]([C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]=1)[OH:28]
Reactant: COCc1ccc(OC)c(Br)c1OC
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: COCc1ccc(OC)c(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1OC
Yield: 48 %

Procedure:
Starting from 1-bromo-2,6-dimethoxy-3-methoxymethylbenzene and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The reaction product is purified by chromatography on silica and is present in the form of a glassy lac. Yield: 48% of theory.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[N:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:2]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Fc1cccc(Cl)c1
Reactant: c1ccc(-c2nc[nH]n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(-n2cnc(-c3ccccn3)n2)c1
Temperature: 100 °C

Procedure:
2-(1H-1,2,4-Triazol-3-yl)pyridine (1.0 g, 6.8 mmol), potassium carbonate (1.88 g, 13.6 mmol) and 1-chloro-3-fluorobenzene (0.89 g, 6.8 mmol) were stirred in DMF (20 mL) at ambient temperature. The resulting reaction mixture was heated at 100° C. for 16 h, after which time it was quenched with H2O (50 mL) and diluted with EtOAc (200 mL). The EtOAc solution was washed with H2O (3×100 mL), then brine (100 mL) and dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexanes: EtOAc (40:60) to afford 2-[1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]pyridine as a white solid which was then dissolved in dichloromethane (5 mL) and precipitated as the hydrochloride salt (M.p.=221–223° C.) upon treatment with 1M HCl in diethyl ether (5 mL).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:31](=[O:32])[CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: O=C(Cc1ccccc1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 27 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (described in Example 8b) and phenylacetyl chloride, the title compound was obtained as a white solid (70%), mp 199.8°-202.1° C.; MS(CI): 423 (M+H); NMR (300 MHz,DMSO-d6): 1.37(m, 2H), 1.67(m, 2H), 2.26(m, 2H), 2.45(s, 2H), 2.93(m, 2H), 3.36(s, 2H), 3.53(m, 1H), 4.30(s, 1H), 6.91(m, 4H), 7.17-7.28(m, 9H), 7.95(d, 1H, J=8.4 Hz).
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O-])=O.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>O>[N:20]1([CH2:19][CH2:18][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH2:6])=[CH:10][CH:11]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
A stirred DMF suspension (5 mL) of 4-nitrophenol (0.5 g, 3.6 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.92 (5.4 mmol) and K2CO3 (1.24 g, 9 mmol) was heated at 80° for 3 hr. After cooling to RT, the reaction was diluted with H2O and extracted 3× with EtOAc. The combined EtOAc layers were washed 2× with H2O and dried over MgSO4. After concentration under vacuum, the resulting residue was chromatographed on silica gel, Gradient elution CH2Cl2 to 10% MeOH/CH2Cl2 eluted the 1-(2-(4-nitrophenoxy)ethyl)pyrrolidine (560 mg) as an orange oil. Further purification employing reverse phase chromatography (MeOH/H2O/0.1% TFA) yielded 413 mg of a yellow oil. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished following the procedure described in Example 6 step C. MS (ESI) 207 (M+H)+.