Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH:29]([NH:31][NH:32][C:33]([C:35]1([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34])=O>ClCCl>[N:51]1([CH2:50][CH2:49][CH2:48][O:47][C:44]2[CH:43]=[CH:42][C:41]([C:35]3([C:33]4[O:34][CH:29]=[N:31][N:32]=4)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:46][CH:45]=2)[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: O=CNNC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1nnc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
Triphenylphosphine (0.203 g, 0.78 mmol), iodine (0.198 g, 0.78 mmol) and triethylamine (0.217 mL, 1.56 mmol) were dissolved in dichloromethane (5 mL). The mixture was stirred at room temperature for 10 minutes. N′-formyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbohydrazide (0.145 g, 0.39 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (25 mL). The organic was dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified using preparative HPLC on Fraction-Lynx® eluting with water:acetonitrile:trifluoroacetic acid (95:5:0.1) to provide the title compound (0.028 g, 20%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ1.78-1.85 (m, 4H), 2.05 (m, 2H), 2.30 (m, 2H), 2.56-2.60 (m, 4H), 2.60-2.70 (m, 4H), 3.59 (m, 2H), 3.90-4.05 (m, 4H), 6.90 (d, 2H), 7.20 (d, 2H), 8.30 (s, 1H). HRMS ESI+ m/z 358.2117 [MH]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][CH:17]2[CH2:22][CH2:21][C:20]([N:24](CC=C)CC=C)([CH3:23])[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1>O1CCOCC1.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>[NH2:24][C:20]1([CH3:23])[CH2:19][CH2:18][CH:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:22][CH2:21]1
Reactant: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1(N)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Temperature: 80 °C

Procedure:
To a solution of cyclopropyl{4-[4-(diallylamino)-4-methylcyclohexylamino]-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-3-yl}methanone (23 mg, 0.041 mmol) in dioxane (3 mL) was added Pd(PPh3)4 (5 mg, 0.004 mmol) and N,N-dimethylbartituric acid (32 mg, 0.205 mmol). The resultant mixture purged with N2 and heated to 80° C. for 16 h. The solution was allowed to cool to rt, diluted with ethyl acetate, filtered and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The purified product was concentrated, diluted with a saturated NaHCO3 solution, extracted with a mixture of CHCl3/isopropanol (3:1), and dried with Na2SO4 to obtain the desired product as the free base (5 mg, 25%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.39 (s, 1H), 8.45 (s, 1H), 8.28 (dd, J=8.7, 1.9 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.73 (s, 2H), 4.76-4.72 (m, 1H), 2.89-2.85 (m, 1H), 2.33-2.25 (m, 2H), 2.09-1.97 (m, 4H), 1.96-1.89 (m, 2H), 1.45 (s, 3H), 1.41-1.18 (m, 4H); ESI MS m/z 484 [C26H27Cl2N3O2+H]+; HPLC 98.6% (AUC), tR=11.05 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccc3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Tert-butyl(4-butoxy-2-isobutyl-1-oxo-6-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.34 g, 0.7 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from methanol-diisopropyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-phenyl-1(2H)-isoquinolinone hydrochloride (0.28 g, 96.6%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:4]=1[C:5]([NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6].[CH2:32](N(C(C)C)C(C)C)[CH3:33].ICC>ClCCl>[CH2:32]([N:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[C:20]([C:28]([F:31])([F:29])[F:30])=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:3]=2[O:2][CH3:1])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)[CH3:33]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCNC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: ClCCl
Product: CCN1CCCC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2C(F)(F)F)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of 25.mg (0.056 mmol) rac-2-methoxy-N-(3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide in 0.25 ml dichloromethane were added 19.7 ul (0.112 mmol) N-ethyldiisopropylamine and finally 6.0 ul (0.0728 mmol) iodoethane. The solution was stirred at room temperature for 20 hours. The solvent was removed in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 15 mg (58%) of the title compound as a colorless oil. MS (m/e): 475.2 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[S:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[N:3]=1.[CH2:21](N(CC)CC)[CH3:22].[B-](F)(F)(F)C=C.[K+].ClCCl>CC(O)C.C1COCC1>[CH3:20][C:18]1[N:19]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:21]=[CH2:22])=[N:3]2)[S:16][CH:17]=1
Reactant: Cc1csc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)O
Product: C=Cc1nn(Cc2nc(C)cs2)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Yield: 80.5 %

Procedure:
A suspension of 2-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-4-methylthiazole (0.414 g, 1.03 mmol) in IPA/THF (4:1; 15 mL) was degassed with argon, treated with triethylamine (0.433 mL, 3.10 mmol), potassium trifluoro(vinyl)borate (0.416 g, 3.10 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.0845 g, 0.103 mmol). The mixture was heated at 90° C. for 14 hours under argon. The mixture was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (10-75% EtOAc in hexanes) to provide 4-methyl-2-((4-nitro-3-vinyl-1H-indazol-1-yl)methyl)thiazole (0.249 g, 80% yield) as an amber gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:9][C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:14])[C:7]=2[CH:8]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Solvent: O
Product: COc1ccc2[nH]c3ccccc3c(=O)c2c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
Polyphosphoric acid (50 gm) was heated to 160° C. under a nitrogen atmosphere. N-(4-methoxyphenyl)anthranilic acid (4.89 gm; 20 mmol) was added and the mixture stirred at 160° C. for 15 minutes. The reaction was cooled rapidly in an ice bath and water added to give a greenish yellow precipitate. This was filtered off, washed with water, then dilute sodium bicarbonate solution and again with water. The solid was finally dried at 50° C. under vacuum to give 3.67 gm (81%) of 2-methoxyacridone. δH (200 MHz, DMSO-d6) 3.86 (3H, s), 7.23 (1H, t), 7.55 (5H, m), 8.22 (1H, d), 11.7 (1H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].O.CO>C(OCC)(=O)C>[CH:25]1([C:23]([C@H:14]2[CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C:20]2[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH2:8][CH2:9]4)=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)C3CCCCC3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)C1CCCCC1
Yield: 8200 %

Procedure:
A mixture of methyl-17β-cyclohexylcarbonyl-estra-1,3,5(10)-triene-3-carboxylate (0.14 g, 0.34 mmol), K2CO3 (0.2 g, 1.45 mmol), water (3.0 mL) and methanol (30 mL) was heated at reflux overnight. The reaction mixture was then concentrated. The residue was diluted with water, acidified with dilute HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried, and concentrated. The resulting solid was washed with CH3CN and isolated by filtration from boiling ethyl acetate to give, 0. 11 g of the title compound. mp 280°-285° C. (softened at 260° C.).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][CH2:23][NH:24]C(=O)OCC2C=CC=CC=2)=[N:19][CH:20]=1)=O)C1C=CC=CC=1.[H][H]>CO>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[N:19][CH:20]=1
Reactant: O=C(NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)nc1)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: NCCCc1ccc(CCCN)nc1
Yield: 104.4 %

Procedure:
A solution of 2,5-di(3-benzyloxycarbonylaminoprop-1-ynyl)pyridine (8-1) (8.0 g) in methanol (160 mL) was hydrogenated under 20 psi of hydrogen gas pressure in the presence of 5%-Pd/Al2O3 (1.1 g) for 16 hours. The catalyst was filtered through Solka-flok and washed with methanol. The filtrate and wash were combined and concentrated under reduced pressure to give 12-1 (3.56 g) as a crystalline compound; m.p. 116-119° C.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+].[OH-].[Na+]>CN(C)C=O.O1CCCC1.CO>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:3]/[N:4]=[C:5](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:39][CH:38]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Under a nitrogen atmosphere, sodium hydride (60%; oily; 127 mg) was added to a solution of methyl (E)-4-hydroxyimino-4-phenylbutyrate (661 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After addition of 1N hydrochloric acid (5 ml), an aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried (over MgSO4) and concentrated. The residue was subjected to a silica gel column chromatography and an oily product was obtained from an eluate with ethyl acetate-hexane (1:3, volume ratio). This was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), a 1N aqueous solution of sodium hydroxide (5 ml) was added thereto and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 1N hydrochloric acid (5.5 ml) and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried (over MgSO4) and concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (907 mg; yield: 60%). The powder X-ray crystal diffraction pattern is shown in FIG. 1. Melting point: 126-127° C. (decomposition).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][CH:18]=1>>[OH:23][C:19]([C:15]1[CH:14]=[C:13]([C:4]2[C:3]([CH:1]=[O:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][CH:16]=1)([C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1cccc(-c2ccccc2C=O)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 87.1 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 2-formylphenylboronic acid (0.50 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.02 g), the amorphous title compound (0.93 g) was obtained.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:22]([CH:26]1[CH2:31]CC(O)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+].C(O)C>CO>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:28][CH2:27][CH:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:31][CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)C1CCC(OC(=O)C(C#N)=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 67 %

Procedure:
139 g (0.5 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 200 ml of 4-tert-butylcyclohexanol and 10 g of Na2CO3 were reacted together at 182° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 4 h, the reaction mixture was diluted with 300 ml of methanol and filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 130 g (67%) of 4-tert-butyl-cyclohexyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 302 nm; E11 (MeOH) 324]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12](=[O:15])(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:9][C@H:4]([CH2:3][CH3:2])[CH2:12][OH:15]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC[C@H](CO)Nc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C

Procedure:
A mixture of 118 g (0.74 mole) of 3,4-difluoronitrobenzene and 85 g (0.95 mole) of R-(+)-2-amino-1-butanol was dissolved in 400 mL of absolute ethanol. To this solution was then added 62.2 g (0.74 mole) of sodium bicarbonate. The suspension was stirred and heated at reflux temperature for 12 h when TLC indicated complete conversion of the 3,4-difluoronitrobenzene. After cooling to room temperature, the reaction mixture was filtered with the aid of additional ethanol and the ethanol was then evaporated. The crude product thus obtained was distilled under reduced pressure (10–112° C., 2 mm Hg) to afford (2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol as a red solid. Yield, 162 g (96%). [α]D=+95.4 (CHCl3, c 22.7); 1H NMR (CDCl3) δ7.88 (1H, dd, J=2.4, 8.9), 7.76 (1H dd J=2.4, 11.7), 6.66 (1H, dd, J=8.7), 4.88 (1H, m), 3.76 (1H dd, J=4.2, 11.2), 3.68 (1H, dd J=4.2, 11.2), 3.52 (1H, m), 2.63 (1H, bs), 1.70 (1H, m), 1.59 (1H, m), 0.97 (3H, t, J=7.5). 13C NMR: ppm 150.1, 147.7, 142.8, 142.7, 136.1, 122.3, 110.9, 110.7, 109.5, 63.6, 55.8, 24.4, 10.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=1)[CH2:10][C:9]([CH3:20])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39](Cl)([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27].O>CCOCC.C([Cu])#N>[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39]([CH:8]2[C:7]3[C:11](=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[CH:10]=[C:9]2[CH3:20])([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1=Cc2cc(C(C)(C)C)cc(-c3ccccc3)c2C1
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccccc3)cc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 14.5 g (55.4 mmol) of 5-tert-butyl-2-methyl-7-phenyl-1H-indene in 400 ml of ether cooled to −78° C., 22.2 ml (55.5 mmol) of 2.5 M nBuLi in hexanes was added. This mixture was stirred overnight at room temperature, then cooled to −78° C., and 200 mg (2.23 mmol) of CuCN was added. The resulting mixture was stirred for 30 min at −20° C., then cooled to −78° C., and a solution of 21.2 g (55.4 mmol) of (6-tert-butyl-5-methoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)dimethylsilane in 200 ml of ether was added. This mixture was stirred overnight at room temperature, then 1 ml of water was added. The obtained mixture was passed through a short layer of silica gel 60 (40-63 um), the elute was evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um; eluent: hexanes-dichloromethane=10:1, vol., then 3:1, vol.). This procedure gave 24.5 g (72%) of yellowish glassy solid.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:42]>C(OCC)(=O)C.CC(O)C>[ClH:42].[F:35][C:12]1[C:11]([CH2:10][NH:8][CH3:6])=[CH:15][N:14]([S:16]([C:19]2[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(C(=O)OC)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of methyl 5-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}-2-furoate (260 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 177 mg, 78%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]1[C:19](F)=[CH:18][C:17]([NH2:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[F:13][C:14]1[C:19]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][C:17]([NH2:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: OCCCN1CCCCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(OCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.3 mL of 3-piperidin-1-ylpropan-1-ol in 16 mL of N,N-dimethylformamide (DMF) is cooled to 0° C. with an ice bath. 345 mg of sodium hydride (60% in suspension in oil) are added in small portions. The suspension obtained is added dropwise to a suspension containing 500 mg of 4,5-difluoro-2-nitrophenylamine and 724 mg of sodium bicarbonate in 15 mL of DMF. The reaction medium is stirred for one hour at ambient temperature and then heated for 1 hour at 90° C. The cooled reaction medium is treated with 70 mL of ethyl acetate and 70 mL of distilled water. The aqueous phase is extracted with 70 mL of ethyl acetate. The combined organic phases are washed with 100 mL of distilled water and 100 mL of a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is concentrated to dryness in a rotary evaporator and the crude is then purified by chromatography on a 50 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 300 mg of 4-fluoro-2-nitro-5-(3-piperidin-1-ylpropoxy)phenylamine are isolated in the form of a yellow oil which crystallizes. Analytical LC/MS: Tr=2.26 min, [M+H]+=298.04 DAD=87%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH2:29][CH:30]=O)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[F:19][C:20]1[CH:21]=[C:22]([CH2:29][CH2:30][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: O=CCc1ccc([N+](=O)[O-])c(F)c1
Product: O=C1CN(CCc2ccc([N+](=O)[O-])c(F)c2)CCN1CCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (3-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 417 [M+1]+.