Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][N:7]=[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][OH:26])=[CH:16][C:11]=2[O:10][CH2:9]1>O1CCCC1>[CH3:5][O:6][N:7]=[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]([OH:26])[C:3]([NH:2][CH3:1])=[O:4])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CON=C1COc2cc(OCc3ccccc3NO)ccc21
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N(O)c1ccccc1COc1ccc2c(c1)OCC2=NOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
0.38 g of methyl isocyanate was added to a solution of 2.0 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxyamine in 50 ml of tetrahydrofuran, and they were stirred at room temperature for 8 hours. The reaction liquid was concentrated under reduced pressure to obtain 2.3 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxy-N′-methylurea. This product was dissolved in 20 ml of N,N-dimethylformamide. 0.95 g of methyl iodide and 0.98 g of anhydrous potassium carbonate were added to the solution, and they were stirred at room temperature for 4 hours. The reaction solution was diluted with 200 ml of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 1.4 g of the title compound (having a m.p. of 109-112° C. and 1H-NMR data shown in the following table].
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([B-](F)(F)F)[CH:10]=[CH2:11].[K+].Cl[C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH2:11]([C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1)[CH:10]=[CH2:9]
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Reactant: C=CC[B-](F)(F)F
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCc1cc(C=O)cc2c1OC(C)C(=O)N2
Temperature: 115 °C
Reaction time: 48 h
Yield: 3.4 %

Procedure:
To a solution of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium allyltrifluoroborate (0.197 g, 1.330 mmol), and 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 5.00, 20 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 48 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (0.25 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The impure material was reconstituted in DMSO (1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 45-70% ACN:0.05% TFA (aq). The collected fractions were combined and the solvent was removed via rotary evaporation to provide the title compound as an off-white solid (0.007 g, 0.030 mmol, 3.41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.82 Hz, 3H) 3.38-3.42 (m, 2H) 4.82 (q, J=6.82 Hz, 1H) 5.06-5.12 (m, 2H) 5.91-6.01 (m, 1H) 7.28 (d, J=2.02 Hz, 1H) 7.42 (d, J=2.02 Hz, 1H) 9.82 (s, 1H) 10.93 (s, 1H). ESI-MS: m/z 232.2 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[C:21]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCCCCCCCC1
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Solvent: CCO
Product: O=C(c1ccccc1)N1CCc2nnc(NN=C3CCCCCCCCCCC3)cc2C1

Procedure:
A suspension of 2.7 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 1.8 g of cyclododecanone in 20 cc of absolute ethanol is heated on a water bath for 30 minutes, whereby a dissolution and reprecipitation clearly occurs. The resulting title compound is recrystallized from a mixture of 160 cc of methanol and 30 cc of dimethyl formamide. M.P. 222°-225° (decomp.).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:8][C:1]1[CH:2]=[C:3]([CH3:7])[CH:4]=[CH:5][C:6]=1[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: Cc1cccc(C)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCC(=O)O)c(C)c1
Yield: 92 %

Procedure:
m-Xylene 10f (98%, 5.5 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 42 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11f were obtained in 92% yield. 1H-NMR: 7.66 (d, 1H, Ar--H); 7.07 (d, 2H, Ar--H); 3.22 (t, 2H, CH2CH2COOH); 2.77 (CH2CH2COOH); 2.49 (s, 3H, CH3); 2.35 (s, 3H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[CH3:11].[H-].[Na+].I[CH3:20]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+].O.[Na+].[Cl-]>[CH3:20][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[CH3:11]
Reactant: CI
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(C)c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of ethyl 7-hydroxy-3-methyl-1H-indazole-5-carboxylate (Anti-Cancer Drug Design 1997, 12, 555) in DMF (25 mL) at 0° C. was added 60% oil dispersion of NaH (152 mg, 3.81 mmol). The mixture was stirred for 1 hour before the dropwise addition of a solution of iodomethane (0.54 g, 0.24 mL, 3.8 mmol) in DMF (3 mL). The mixture was kept at 0° C. for several hours before allowing the mixture to warm to room temperature and stirred overnight. The reaction was diluted with EtOAc, saturated aqueous NaHCO3, water and saturated aqueous NaCl. The organic extract was dried over Na2SO4, filtered and concentrated. The material was purified by silica gel chromatography (80 g column) eluting with a 0-30% EtOAc/hexanes gradient to provide ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (294 mg, 33%).
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C:15]([CH3:21])([CH3:20])[CH2:16][C:17](O)=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[BH4-].[Li+].Cl>O1CCCC1.CO>[C:7]([O:11][C:12](=[O:13])[NH:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][OH:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CCO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
At 0° C., ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) (cf. Schoen et al. J. Med. Chem., 1994, vol. 37, p. 897-906, and references cited herein) and triethylamine (1.92 ml, 13.8 mmol) in tetrahydrofuran (10 ml). The solution was stirred for 40 min at 0° C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 ml). The liquid was immediately cooled to 0° C. A 2M solution of lithium borohydride in tetrahydrofuran (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0° C. for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0° C. and methanol (5 ml) was added. 1N Hydrochloric acid (100 ml) was added and the solution was extracted with ethyl acetate (2×100 ml, 3×50 ml). The combined organic extracts were washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl aceteate/heptane (1:2) to give 1.84 g of 3-hydroxy-1,1dimethylpropylcarbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[Si:12]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=CC1C=CC=CC=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C.S(=O)(O)[O-].[Na+]>ClCCl>[Si:12]([O:29][CH2:30][CH2:31][CH2:32][CH:33]1[O:10][CH:8]1[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](OCCCC=Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCC1OC1c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
3-Chloroperbenzoic acid (2.14 g) was added to a solution of 5-(t-butyldiphenylsilyloxy)-1-phenyl-1-pentene (3.30 g) in dichloromethane (65 ml) at ambient temperature and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into a mixture of diethyl ether and 5% aqueous sodium bisulfite (100 ml). The organic layer was separated, washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, and evaporated in vacuo to give (2R*, 3R*)-3-[3-(t-butyldiphenylsilyloxy)propyl]-2-phenyloxirane (3.45 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.BrCC1C=CC=C(F)C=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: N#Cc1ccc(COc2cccc(N)c2)cc1

Procedure:
3-Nitro-phenol was reacted with 4-bromomethyl-benzonitrile according to the procedure from Example 199A substituting 4-bromomethyl-benzonitrile for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:11]=[C:10]2[N:12]([CH2:24][CH3:25])[C:13]([C:15]([N:17]([CH:21]3[CH2:23][CH2:22]3)[CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:14][C:9]2=[C:8]2[N:26]([CH3:29])[CH:27]=[N:28][C:7]=12)=O.[C:30]([NH2:33])(=[S:32])[CH3:31]>CN(C=O)C>[CH:18]1([N:17]([CH:21]2[CH2:23][CH2:22]2)[C:15]([C:13]2[N:12]([CH2:24][CH3:25])[C:10]3=[N:11][C:6]([NH:5][C:3]4[N:33]=[C:30]([CH3:31])[S:32][CH:2]=4)=[C:7]4[N:28]=[CH:27][N:26]([CH3:29])[C:8]4=[C:9]3[CH:14]=2)=[O:16])[CH2:20][CH2:19]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=O)CCl)nc21
Reactant: CC(N)=S
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3csc(C)n3)nc21
Temperature: 80 °C
Yield: 6.6 %

Procedure:
To a solution of 4-(2-chloroacetamido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (58.5 mg, 0.141 mmol) in DMF (176 μL) was added thioacetamide (12.71 mg, 0.169 mmol). The vial was capped and the reaction mixture was heated at 80° C. 3 h. The reaction mixture was concentrated in vacuo. The crude residue was taken up in MeOH and purified by prep-HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(2-methylthiazol-4-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (4.05 mg, 6.6% yield) was isolated as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: C#CCNC(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 2-amino-3-fluoro-N-prop-2-ynyl-benzamide and 2,4,5-trichloro-pyrimidine in an analogous manner to Example 308b. Product isolated as an orange solid (1.22 g, 28%). m.p.=209-213° C.; LCMS (m/e) 339 (M+H); 1H-NMR (CDCl3, 400 MHz); 9.07 (bs, 1H), 8.23 (s, 1H), 7.40-7.30 (m, 3H), 6.40-6.32 (m, 1H), 4.25-4.18 (m, 2H), 2.32-2.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])[CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)C2CCCCC2)CCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-chloro-4-(2-methylpiperazin-1-yl)phthalazine (JK-2, 752 mg, 2.86 mmol) was dissolved in DMF (8 mL) and N,N-diisopropylethylamine (1.5 mL). Cyclohexanecarbonyl chloride (0.498 mL, 3.72 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-75% ethyl acetate gave an off-white foam. MS (M+H)+=373.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:15]=12.[CH3:28][C:29]1[N:33]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:31][C:30]=1[CH:53]=[O:54]>O1CCCC1.CCCCCC.O>[OH:54][CH:53]([C:30]1[N:31]=[CH:32][N:33]([C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:29]=1[CH3:28])[CH:24]1[C:23](=[O:27])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c2n(c3ccccc13)C(=O)CCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.89 g) in tetrahydrofuran (30 ml) at -70° C. under a nitrogen atmosphere was added 1.64M n-butyllithium in hexane (11.5 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (3.39 g) in tetrahydrofuran (39 ml) over 15 minutes. The mixture was stirred at -70° C. for 30 minutes, and a solution of 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde (6.0 g) in tetrahydrofuran (75 ml) was added dropwise over 20 minutes. After the mixture was stirred at -70° C. for further 55 minutes, it was diluted with water and extracted with methylene chloride. The organic layer was washed with water twice and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10 -methylpyrido[1,2-a]indol-6(7H)-one. The product was a mixture of two diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][NH2:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][CH2:26][NH:27][CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of the product from step (i) (1.61 g), N-(tert-butoxycarbonyl)-ethylenediamine (1 g) and sodium triacetoxyborohydride (2.12 g) in dichloromethane (20 ml) was stirred at room temperature for 3 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Yield 1.28 g.
Reaction SMILES: F[C:2]1[CH:3]=C(C2C=CC(OCCCCCCCC)=C(F)C=2)C=C[C:7]=1O.[CH2:25]([C@H:30]1[CH2:33][C@H:32]([C:34]([Cl:36])=[O:35])[CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:25]([CH:30]1[CH2:31][CH:32]([C:34]([Cl:36])=[O:35])[CH2:33]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:7][CH2:2][CH3:3]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Reactant: CCCCC[C@H]1C[C@H](C(=O)Cl)C1
Product: CCCCCCCCC1CC(C(=O)Cl)C1
Yield: 120.8 %

Procedure:
Except that 0.60 g of the crude 3,3 '-difluoro-4-hydroxy-4'-octyloxybiphenyl obtained in Example 5- (c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.4 g of the crude trans-3-pentylcyclobutanecarboxylic acid chloride obtained in (d) above in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=2/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.84 g (yield 91.1%) of 3,3'-difluoro-4-octyloxybiphenyl-4'-yl trans-3-pentylcyclobutanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:25])[CH2:14][CH:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11]C.[NH2+]1CCOCC1.C(OC1C=CC(C(=O)CC(N2CCOCC2)C([O-])=O)=CC=1OC)CCC.[NH2+]1CCOCC1.C(OC1C=CC(C(=O)CC(N2CCOCC2)C(O)=O)=CC=1OC)C=C.C(OC1C=CC(C(=O)CC(N2CCOCC2)C([O-])=O)=CC=1OC)C.[NH2+]1CCOCC1>>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13](=[O:25])[CH2:14][CH:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]([OH:18])=[O:17])=[CH:4][C:3]=1[O:2][CH3:1])[CH3:11]
Reactant: CCCOc1ccc(C(=O)CC(C(=O)[O-])N2CCOCC2)cc1OC
Agent: C1COCC[NH2+]1
Agent: C=CCOc1ccc(C(=O)CC(C(=O)O)N2CCOCC2)cc1OC
Agent: CCCCOc1ccc(C(=O)CC(C(=O)[O-])N2CCOCC2)cc1OC
Product: CCOc1ccc(C(=O)CC(C(=O)O)N2CCOCC2)cc1OC

Procedure:
In an analogous manner, morpholinium 4-(3-methoxy-4-n-propoxyphenyl)-2-morpholino-4-oxobutyrate, m.p. 110°; morpholinium 4-(4-n-butoxy-3-methoxyphenyl)-2-morpholino-4-oxobutyrate, m.p. 120°; 4-(4-allyloxy-3-methoxyphenyl)-2-morpholino-4-oxobutyric acid, m.p. 166°; morpholinium 4-(4-ethoxy-3-methoxyphenyl)-2-morpholino-4-oxobutyrate, m.p. 131°; 4-(4-ethoxy-3-methoxyphenyl)-2-morpholino-4-oxobutyric acid, m.p. 157° are prepared from the corresponding acetophenones.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CN(C=O)C.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>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: OB(O)Oc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
2-Bromo4-nitrotoluene (2.16 g, 10.00 mmol) and phenylboric acid (1.46 g, 12.00 mmol) were dissolved in anhydrous DMF (25 mL) under nitrogen. To this mixture was added Pd(Ph3P)4 (0.58 g, 5%). The mixture was heated at 100° C. overnight. The solution was poured onto 1N HCl and extracted with Et2O. The crude product was chromatographed on silica gel using hexanes as eluent. After recrystallization from ethanol, the desired product (1.23 g) was obtained as pale orange needles: m.p. 69-71° C.; 1H NMR (CDCl3) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (5H, m), 8.07-8.10 (2H, m); 13C NMR (CDCl3) d 20.68, 121.96, 124.51, 127.78, 128.41, 128.83, 131.06, 139.06, 139.44, 142.97, 143.48, 146.05; Anal. Calc. for C13H11NO2, C: 73.26, H: 5.20, N: 6.57; Found, C: 73.10, H: 5.12, N: 6.50; m/z (EI) 213; HRMS Calc. for C13H11NO2, 213.0790; Found, 213.0793.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:4]=[C:5]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@]23CCN(C)C[C@H]2c2ccccc2O3)c1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]2(c3cccc(O)c3)Oc3ccccc3[C@@H]2C1
Yield: 94.8 %

Procedure:
A mixture of 3.50 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(3-methyoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 3.62 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was heated at 140° under a drying tube for 41/2 hours. The cooled reaction mixture was diluted with 350 ml of water and the pH adjusted to 7 by slow addition of 2N HCl with stirring. The mixture was extracted with ether (2×300), and the combined extracts were washed with water (3×300 ml), dried over anhydrous Na2SO4, and evaporated in vacuo to provide 3.16 g (94.8%) a solid foam. This material was boiled and triturated with a small amount of ether. After cooling to 0°, the resulting solid was filtered off, washed with cold ether, and dried to afford 2.58 g (77.4%) of crystalline solid, m.p. s 157, 158°-160°.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][C:15]2[C:16]([CH3:31])=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH2:33][CH2:34][CH2:35][O:36][CH3:37])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][C:8]1[CH:9]=[C:10]([N:13]([CH3:32])[CH2:14][C:15]2[C:16]([CH3:31])=[N:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCc1cc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
0.125 g (0.24 mmol) of the above prepared (2-(3-methoxy-propyl)-4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 1.44 ml of THF/EtOH=1/1, treated with 0.72 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt produced finally 0.102 g of the title compound as off-white crystals of mp. 72–73° C.