Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[CH:23][N:22]=[C:21]([NH:31][CH2:32][CH2:33][NH:34]C2N=CC(C#N)=CC=2)[N:20]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[CH:23][N:22]=[C:21]([NH:31][CH2:32][CH2:33][NH:34][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=2)[N:20]=1
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:2]([C:7]([N:9]2[CH2:14][CH:13]([NH:36][CH2:37][CH2:38][OH:39])[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Reactant: NCCO
Product: O=C(NCC1CCC(NCCO)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12

Procedure:
N-((1-(Biphenylcarbonyl)-5-(2-hydroxyethylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according general procedure N using N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and 2-aminoethanol. (ESI) 509 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]([F:27])([F:26])[CH2:22][C:23](O)=[O:24]>C(OCC)(=O)C.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[CH2:22][C:21]([F:27])([F:26])[F:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: O=C(O)CC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CC(F)(F)F)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 3,3,3-trifluoropropionic acid. m.p.: 201-204° C. (ethyl acetate/hexane)
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:21]([N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:21]([N:28]1[CH2:32][CH2:31][CH:30]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(N3CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.7 g (60.0 mmol) NaBH(OAc)3 and 2.3 mL acetic acid are added to a solution of 4.94 mL (50.0 mmol) piperidine and 8.03 mL (50.0 mmol) N-benzylpyrrolidinone in 200 mL THF. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:9][CH:10]=1)(=[O:3])=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Solvent: c1ccncc1
Product: COC(=O)CC1=C(C)C(=Cc2ccc(S(=O)(=O)NC(C)=O)cc2)c2ccc(OC)cc21
Yield: 50 %

Procedure:
A solution of 4a (100 mg) in pyridine (5 ml) was added acetic anhydride (2 ml). The mixture was heated at 110° for 1 hour and concentrated in vacuo. The crude mixture was purified via preparative tlc using 2000 μm silica gel plates developed with 30% ethyl acetate in chloroform. The isolated product was recrystallized from acetone-hexane to give pure Z methyl 1-[4-(N-acetylaminosulfonyl)phenyl]methylene-5-methoxy-2-methyl-1H-3-indenylacetate (55 mg, 50%): m.p. 172.5°-174.5° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:22][CH3:23])[CH2:5][C:4]1=[O:24])[CH3:2]>C(O)C.[OH-].[Na+]>[CH2:1]([C@@H:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:22][CH3:23])[CH2:5][C:4]1=[O:24])[CH3:2]
Reactant: CC[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O
Reaction time: 4.5 h

Procedure:
2β-Ethyl-17β-methoxy-5α-androstan-3-one (Step A) is dissolved in ethanol (95%, 13 ml.) followed by addition of sodium hydroxide (50%, 14 drops). After stirring at 20°-25° for 4.5 hrs. the mixture is extracted with diethyl ether, the diethyl ether extract is concentrated under reduced pressure to yield the title compound, which is recrystallized twice from methanol; m.p. 105°-107°; NMR (CDCl3) 0.77, 1.05, 3.20 and 3.33 δ.
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.Cl.[CH2:16](OCC)[CH3:17]>C(O)C>[OH:14][CH:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)[C:11]([O:13][CH2:16][CH3:17])=[O:12]
Reactant: CCOCC
Reactant: O=C(O)C(O)Cc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 0.5 g (2.74 mmol) of D,L 3-(4-hydroxyphenyl) lactic acid hydrate in 10 mL of ethanol was added a catalytic amount of concentrated hydrochloric acid. The mixture was heated at reflux for 2 hours then cooled to room temperature and concentrated under vacuum. The residue was dissolved in 50 mL of ether and washed with saturated aqueous sodium bicarbonate (1×50 mL) and brine (1×50 mL). The organic layer was removed, dried over magnesium sulfate, filtered and evaporated under vacuum to afford 0.54 g (2.57 mmol,94%) of the ethyl ether. 1H NMR (200 MHz,CDCl3): 1.26 (t,7 Hz,3H), 2.86 (dd;7,14 Hz;1H); 3.03 (dd;4,14 Hz; 1H), 4.19 (q,7 Hz,2H), 4.38 (dd;4,7 Hz;1H), 5.60 (br s,1H), 6.66 (d,8 Hz,2H), 7.03 (d,8 Hz,2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH3:22])\[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:27])(=O)=O>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH2:22][Cl:27])\[C:14]([OH:16])=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)O[C@H]1CC[C@H](O/N=C(/C(C)=O)C(=O)OC(C)(C)C)CC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H](O/N=C(\C(=O)O)C(=O)CCl)CC1

Procedure:
tert-Butyl (Z)-2-(trans -4-acetoxycyclohexyloxyimino)3-oxobutyrate (327 mg, 1 mmol) was reacted with sulphuryl chloride (0.8 ml) in glacial acetic acid (2 ml) by an analogous procedure to that described in Example 57d to give the crude title compound.
Reaction SMILES: C(O[CH2:5][C:6]1[NH:7][C:8]([C:15](=[O:17])[CH3:16])=[C:9]([CH3:14])[C:10]=1[C:11](=O)[CH3:12])(=O)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>ClC(Cl)C>[C:15]([C:8]1[C:9]([CH3:14])=[C:10]2[C:6]([N:7]=1)=[CH:5][C:20]1[C:19]([N:18]=[C:26]3[C:21]=1[CH:22]=[CH:23][CH:24]=[CH:25]3)=[C:11]2[CH3:12])(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1[nH]c(C(C)=O)c(C)c1C(C)=O
Reactant: c1ccc2[nH]ccc2c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(=O)C1=Nc2cc3c(c(C)c2=C1C)N=c1ccccc1=3
Yield: 34.9 %

Procedure:
To a solution of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole (0.200 g) and indole (0.098 g) in dichloroethane (90 cm3) was added Montmorillonite K10 clay (0.30 g). The mixture was stirred and heated at reflux for 80 h. After cooling the clay was removed by filtration and the filtrate concentrated to ca 20 cm3 in vacuo. The crude product was removed by filtration and then chromatographed on silica. Elution with chloroform-methanol (60:1) yielded 0.08 g of the title compound as a yellow solid m.p. 258°-260° C., m/z (EI) 276 (M+) δH ([2H6 ]-DMSO) 2.58 (3H, s, COCH3), 2.88 (3H, s, CH3), 2.92 (3H, s, CH3), 7.05 (1H, m, 8-H), 7.38 (2H, m, 6-H, 7-H), 7.85 (1H, s, 10-H), 8.08(1H, J, 8 Hz, 9-H), 10.6 (1H, s, NH), 11.17 (1H, s, NH). (Found: C, 77.0; H, 5.74; N, 9.76; C18H16N2 O. 0.14 EtOAc requires C, 77.2; H, 5.98; N, 9.70%.)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[NH:9][C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[N:11][C:7]=2[CH:6]=1)=O.O.[NH2:25][NH2:26].O>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:10]1[NH:9][C:8]2[CH:22]=[CH:23][C:5]([C:3]([NH:25][NH2:26])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Product: NNC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Yield: 15 %

Procedure:
2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (20 mg, 0.057 mmol) and hydrazine hydrate 0.2 ml was heated to reflux until reaction completion, then put cool water, diluted with ethyl acetate. The organic phase was separated, washed with brine and water, dried over anhydrous MgSO4. The resultant crude was filtered and concentrated under reduced pressure to afford 2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid hydrazide as a solid (3 mg, 15% yield).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2=[CH:15][CH:16]=[CH:17][C:11]3=[C:12]2[N:7]([CH2:8][CH2:9][CH2:10]3)[CH2:6]1)[CH2:2][CH3:3].[CH2:18](I)[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2=[CH:15][CH:16]=[CH:17][C:11]3=[C:12]2[N:7]([CH2:8][CH2:9][CH2:10]3)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCNC1Cc2cccc3c2N(CCC3)C1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CCC)C1Cc2cccc3c2N(CCC3)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
A mixture of 2,3,6,7-tetrahydro-N-propyl-1H,5H-benzo(ij)quinolizin-2-amine (2.33 g, 0.01 mol), propyl iodide (5.16 g, 0.03 mol) and anhydrous potassium carbonate (3 g, 0.02 mol) in dimethylformamide (75 mL) was stirred for 5 hours at 90° C. At this time additional propyl iodide (1.72 g, 0.01 mol) and potassium carbonate (0.05 g, 0.0036 mol) were added and the reaction was continued for an additional 2 hours. The reaction was cooled, filtered to remove inorganic material, and the solvent was removed under reduced pressure. The product was partitioned between ethyl acetate (800 mL) and 4N sodium hydroxide (20 mL, 0.08 mol), the organic layer concentrated, filtered, and chromatographed on silica gel in 5-30% ethyl acetate:hexane to give 2.19 g of 2,3,6,7-tetrahydro-N,N-dipropyl-1H,5H-benzo(ij)quinolizin-2-amine.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[C:22]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:21]=1)[CH3:18]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCCC2)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCCC2)c1
Temperature: 150 °C
Yield: 46.5 %

Procedure:
A microwave flask was charged with 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (48 mg, 0.17 mmol), 1-[3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (54 mg, 0.17 mmol), and K2CO3 (59 mg, 0.43 mmol). Dioxane (2.1 ml) and water (0.5 ml) were added, and the solution was vacuum degassed under argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (14 mg, 0.02 mmol) was added, and the reaction mixture was heated (150° C.) in a microwave reactor for 45 minutes. The reaction mixture was filtered through a plug of celite using ethyl acetate. The filtrate was transferred to a separatory funnel and shaken with water (20 ml). The organic phase was collected and the aqueous phase back extracted with ethyl acetate (2×15 ml). The organic phases were combined, dried (MgSO4), filtered and stripped to provide a viscous semi-solid. This material was purified by preparative TLC, eluting with 4.8% methanol in methylene chloride to afford 31 mg of 1-[2-(3-ethoxy-5-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow powder. MP 236-237° C., M+H=393.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:18]=1[CH:19]=O>>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:18]=1[CH2:19][C:10]1[S:11][C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Product: CC(C)Cc1nn(C)c(=O)c2cc(Cc3c(F)cccc3Cl)sc12
Yield: 4.3 %

Procedure:
Prepared from 5-methyl-7-(2-methylpropyl)thieno[2,3d]pyridazin-4(5H)one (example 6 step b 1.00 g) and 2chloro-6-fluorobenzaldehyde (0.96 g) according to the is procedure of Example 14. The crude product was purified by preparative normal-phase HPLC with gradient dichloromethane/ethanol elution followed by recrystallisation from isohexane to give the title compound (0.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8]([CH2:24][C:25](O)=[O:26])([CH2:20][C:21](O)=[O:22])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B#B.O>O1CCCC1>[OH:26][CH2:25][CH2:24][C:8]1([CH2:20][CH2:21][OH:22])[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[C:14]=2[CH2:15][C:16]2[C:7]1=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1]
Reactant: COc1cccc2c1C(=O)c1c(OC)cccc1C2(CC(=O)O)CC(=O)O
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1Cc1c(OC)cccc1C2(CCO)CCO

Procedure:
To 4,5-dimethoxy-10-oxo-9,10-dihydroanthracene-9,9-diacetic acid (9.9 g.) in dry tetrahydrofuran (300 ml.) is added with stirring, in an atmosphere of nitrogen, diborane in tetrahydrofuran (1M, 100 ml.). The reaction mixture is refluxed for 72 hours, cooled, and water (100 ml.) is added. The tetrahydrofuran is evaporated and the remaining suspension is filtered, the residue is washed successively with aqueous sodium bicarbonate, water, a little isopropanol, and petroleum ether (b.p. 60°-80°C.) to give 9,9-di-(2-hydroxyethyl)-4,5-dimethoxy-9,10-dihydroanthracene, m.p. 193°-196°C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:4]
Reactant: O=C(NCCCCCCO)C(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCCCCNC(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To 2.1 gm (10.1 mmole) of the 6-trifluroacetamido-1-hexanol in 40 ml of methylene chloride was added 3 gm (10.64 mmole) of pyridinium dichromate and 4.4 gm of 3 Angstrom molecular sieves, and the reaction was allowed to proceed with stirring for 3 hours at 23° C. After addition of 250 ml of ethyl acetate, the reaction mixture was filtered through a small bed of silica gel 60 and concentrated in vacuo. Flash chromatography using 50% (v/v) ethyl acetate in hexane afforded 1.48 gms (70%) of 6-trifluroacetamido-1-hexanal. ##STR19##
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:4]=1.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:18]1[CH2:19][CH2:20][O:21][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:30])([F:1])[F:29])[N:8]=[CH:7][N:6]=3)=[CH:11][CH:12]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3cc(C(F)(F)F)ncn3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)c1cc(Nc2ccc([C@@H]3CNCCO3)cc2)ncn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(R)-tert-Butyl 2-(4-(6-trifluoromethylpyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (130 mg, 0.3 mmol) was dissolved in dioxane (1.2 ml) and a solution of HCl in dioxane (4 M, 1.15 ml, 4.59 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (R)—N-(4-(morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine hydrochloride (96 mg, 87%) as a light yellow solid. MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:25]=[C:26]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:27]=[CH:28][CH:29]=1>>[C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:21][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10]1)(=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cccc(C(=O)c3ccccc3)c2)C1

Procedure:
(jj) In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with (3-bromomethyl-phenyl)-phenyl-methanone [J.Med.Chem. 1984, 27 (12), 1682-1690] there was obtained tert-butyl (3RS,4RS)-3-(3-benzoyl-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate as a yellowish liquid; MS: 490 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:31](=[O:32])[C:30]([CH3:33])=[CH:29][N:18]([C@@H:19]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:21]([N:26]=[N+:27]=[N-:28])[CH2:20]2)[C:17]1=[O:34].CCN(CC)CC>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:13][CH2:14][CH2:15][N:16]2[C:31](=[O:32])[C:30]([CH3:33])=[CH:29][N:18]([C@@H:19]3[O:25][C@H:22]([CH2:23][OH:24])[C@@H:21]([N:26]=[N+:27]=[N-:28])[CH2:20]3)[C:17]2=[O:34])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN)c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCNC(=O)CCc2ccc(O)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mg 3-(4-hydroxyphenyl)-propionic acid N-hydroxysuccinimideester (HPP:NOS) in MeOH was mixed with 10 mg of 3-AE-AZT (Example 27) dissolved in 100 ul MeOH. The mixture was stirred 30 minutes at room temperature, followed by addition of 2.5 ul of Et3N. This mixture was incubated overnight at room temperature, and then chromatographed by TLC on silica gel-F 250 um using the solvent system CHCl3 /MeOH/HOAc (90+10+1). The following Rf values were observed upon visualization by UV at 254 nm: 3-AE-AZT, 0.034;NOS, 0.28; product, 0.35; HPPA, 0.37; andHPP:NOS, 0.55. The product, unlike 3-(4-hydroxyphenyl)propionic acid (HPPA), was an effective inhibitor of polarization in a FPIA for AZT.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[CH:7]=[C:6]2[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([I:26])=[C:6]2[C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(I)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (800 mg, 2.38 mmol) in DMF (8.6 mL) at room temperature was added a solution of N-iodosuccinimide (585 mg, 2.6 mmol) in DMF (5.6 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, and then with sat. aq. NaHCO3 and then dried and concentrated. The residue was triturated with hexane to provide 1-cyclopropylmethyl-6-ethoxy-3-iodo-2-(4-nitro-phenyl)-1H-indole (1.061 g, 96%) as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-5 (170 mg, 0.51 mmol), 1N NaOH (5 mL), and CH3OH (10 mL) was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C., neutralized with 1N HCl (5 mL), and then concentrated. The solid was extracted with CHCl3 and the combined extracts concentrated to give 3-6 as a gelatinous solid.
Reaction SMILES: [CH2:1]1[CH:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[CH:3]=[N:2]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[CH2:1]1[CH:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[CH:3]=[N+:2]1[O-:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=NCC2c3ccccc3CCc3cccc1c32
Solvent: ClC(Cl)Cl
Product: [O-][N+]1=Cc2cccc3c2C(C1)c1ccccc1CC3

Procedure:
To a cold solution (5° - 15° C) of 1,7,8,12b-tetrahydrobenzo[1,2]-cyclohepta[3,4,5-de]isoquinoline (2.7 g) in chloroform (30 ml), a solution of m-chloroperbenzoic acid (2.3 g) in 20 ml of chloroform is added dropwise. The reaction mixture is allowed to stand at room temperature (i.e., 20° - 25° C) for 30 minutes. The reaction mixture is then washed with 15% ammonium hydroxide and water. The reaction mixture is dried (MgSO4) and concentrated to yield an oily residue. The oily residue is crystallized from benzene/hexane to give the title compound, mp 156° - 158° C.