Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[Cl-].[Br:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)([C:15](=[O:17])[CH3:16])C(OCC)=O)=[CH:6][CH:5]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[C:15](=[O:17])[CH3:16])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)(Cc1ccc(Br)cc1)C(C)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Temperature: 120 °C
Yield: 52 %

Procedure:
A mixed liquid containing LiCl (0.175 g, 4 mmol), ethyl 2,2-bis(4-bromobenzyl)-3-oxobutanoate (0.94 g, 2 mmol) and H2O (0.036 mL) in DMF (4 mL) was stirred under heating at 120° C. for 48 hours. The mixed liquid was then cooled to room temperature, water (10 mL) was added, and the resulting mixture was extracted with ethyl acetate. The resulting organic layer was washed with a saturated saline solution and then dried using MgSO4. The organic layer was concentrated under reduced pressure, and then purified using silica gel column chromatography, yielding the title compound (41) in a yield of 52%.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=2)[O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[C:34](OC)=[O:35])=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.CO>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]([NH:14][C:15]1[CH:40]=[CH:39][CH:38]=[C:17]([O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[CH2:34][OH:35])[CH:16]=1)=[O:13])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3CO)c2)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of methyl 6-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazole-7-carboxylate (200 mg, 0.369 mmol) produced in Example 46(iv) in tetrahydrofuran (8 mL) were added triethylamine (101 μL, 0.738 mmol) and isobutyl chloroformate (96 μL, 0.738 mmol) at 4° C., and the mixture was stirred at 4° C. for 30 min. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (2 mL), sodium borohydride (42 mg, 1.10 mmol) and methanol (2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (20 mL), washed successively with 1N hydrochloric acid (5 mL), 5% aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→60/40), and the obtained solution was concentrated under reduced pressure to give the title compound (108 mg, 55%) as a pale-yellow powder.
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:19]([O:12][CH2:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: OCC/C=C/Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC/C=C/Cc1ccccc1
Reaction time: 14 h
Yield: 95.3 %

Procedure:
To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation example 236, 3.8 g, 23.42 mmol) in CH2Cl2 (40 mL) was added pyridine (2.3 mL, 28.1 mmol) and pivaloyl chloride (3.5 mL, 28.1 mmol) at 0° C. under N2. The mixture was stirred for 14 h. The resulting mixture was diluted with CH2Cl2, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (5.5 g, 80˜95%)
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1.CO.Cl.[N:47]([O-])=O.[Na+]>O.Cl[Cu]>[N+:1](=[C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH2:3]1)=[N-:47]
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reactant: O=N[O-]
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C(=O)C(C)C(O)C(C)CCC1=C(C(=O)O)C(O)=C(C)CC1=[N+]=[N-])C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Temperature: 25 °C

Procedure:
A solution of 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid (1.28 g.) in 10 ml. methanol and 2 ml. of aqueous N HCl was cooled to 0° and a chilled solution of 150 mg. of NaNO2 in 1 ml. water was slowly added. To the solution was added 320 mg. of CuCl in 1 ml. of concentrated HCl. The reaction mixture was allowed to slowly warm up to room temperature and then diluted with water and extracted with ether. The ether extract was concentrated to a small volume and the crystallized product was collected by filtration, m.p. 137°-138°. [α]D -13.5° (0.7%, CH3OH).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]2.[OH:28]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]2)=[O:28]
Reactant: O=c1ccc2cc(OCCCCSc3ccc4ccccc4n3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc4ccccc4n3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(2- quinolyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH:25]4[CH2:31][CH:30]5[N:32](C(OCC)=O)[CH:27]([CH2:28][CH2:29]5)[CH2:26]4)[N:21]=3)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+]>CC(O)C.O>[CH:30]12[NH:32][CH:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]([C:22]1[N:21]=[C:20]([NH:19][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:12][N:11]=3)[S:24][N:23]=1)[CH2:31]2
Reactant: CCOC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(C(F)(F)F)cc3Oc3cccnc3C)n1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1ncccc1Oc1cc(C(F)(F)F)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Yield: 74.8 %

Procedure:
Ethyl 3-(5-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (69.5 mg, 0.130 mmol) was dissolved in iPrOH (5 mL) and potassium hydroxide (72.9 mg, 1.30 mmol) was added. The reaction was heated to reflux for 3 days. More KOH (72.9 mg, 1.30 mmol) was added and the reaction was heated for another 2 days. Water (˜10 drops) was added and the reaction was heated for 1 week. The solution was partitioned between saturated aqueous NH4Cl and CH2Cl2. The aqueous layer was extracted 3 times with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford crude 3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (45 mg, 0.0973 mmol, 74.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH:10]=1
Reactant: CC(C)I
Reactant: COC(=O)c1cc(F)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(F)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 1 (step a) from methyl 6-fluoro-1H-indazole-4-carboxylate (0.500 g, 2.58 mmol), sodium hydride (0.129 g, 3.22 mmol), and 2-iodopropane (0.386 mL, 3.86 mmol). The product was collected as a yellow solid (0.32 g, 52%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.57 Hz, 6H) 3.96 (s, 3H) 5.04 (quin, J=6.57 Hz, 1H) 7.61 (dd, J=9.60, 2.27 Hz, 1H) 8.03 (dt, J=8.46, 1.20 Hz, 1H) 8.41 (s, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([CH3:14])[CH2:9]2)=N)[CH3:4].C([OH:17])C>O>[CH2:3]([O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([CH3:14])[CH2:9]2)=[O:17])[CH3:4]
Reactant: CCOC(=N)C12CC1CN(C)C2
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)C12CC1CN(C)C2

Procedure:
Crude 3-methyl-3-azabicyclo[3.1.0]hexane-1-carboximidic acid ethyl ester dihydrochloride (obtained as described below) is boiled under reflux for 3 hours in 30 ml of ethanol and 0.6 ml of water. After evaporation, the resultant residue is made alkaline with an aqueous sodium bicarbonate solution. Extraction with methylene chloride gives the title compound (M.Pt. of napthalene-1,5-disulphonate 161°-165°).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[N:7]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:37])[CH2:15][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[N:7]4)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc2c(O)cccc2n1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: COc1ccc2c(OCC(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cccc2n1
Yield: 72.4 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 0.6 g of 5-hydroxy-2-methoxyquinoline and 1.93 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), in order to obtain 1.2 g of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline.
Reaction SMILES: [S:1]1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:6]2[C:5]3[S:1][CH:2]=[CH:3][C:4]=3[CH2:10][N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: c1cc2n(c1)Cc1ccsc1NC2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccsc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:5].[CH2:31](OC(OCC)OCC)C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:21][CH:20]=[C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)[CH:18]=2)[N:1]=[CH:31]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCN(C(C)C)CC3)ccc2N)c1
Reactant: CCOC(OCC)OCC
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(C(C)C)CC4)cc3c2=O)c1

Procedure:
Using an analogous procedure to that described in Example 1, methyl 3-{[2-amino-5-(4-isopropylpiperazin-1-yl)benzoyl]amino}-4-methylbenzoate was reacted with triethylorthoformate to give methyl 4-methyl-3-[6-(4 isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate; NMR Spectrum: (DMSOd6) 1.00 (d, 6H), 2.15 (s, 3H), 2.59 (m, 4H), 2.68 (m, 1H), 3.24 (m, 4H), 3.85 (s, 3H), 7.45 (d, 1H), 7.60 (m, 3H), 7.95 (m, 1H), 8.00 (m, 1H), 8.05 (d, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[O:11][C:12]2[C:18]([F:19])=[C:17]([CH2:20][C:21]([O:23]C)=[O:22])[CH:16]=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[O:11][C:12]2[C:18]([F:19])=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3c(C)cccc3Cl)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(Cl)c1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
To a solution of methyl (2-(2-chloro-6-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.45 g, 4.16 mmol) in THF/methanol (4:1, v/v 100 ml) was added 1N NaOH (40 ml). After stirring at room temperature for 17 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(2-chloro-6-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.30 g, 93%) as a colorless crystalline powder.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11]([N:13]([CH2:23][CH3:24])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=1)[CH3:12].[OH-].[Na+]>C(O)C>[CH2:23]([N:13]([CH2:11][CH3:12])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[C:16]([CH3:22])[CH:15]=1)[CH3:24]
Reactant: O=C1CCc2ccccc21
Reactant: CCN(CC)c1ccc(C=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)c1ccc(C=C2Cc3ccccc3C2=O)c(C)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
A solution of 50 g. (0.3785 mole) 1-indanone and 77.75 g. of 93% 4-diethylamino-2-methylbenzaldehyde in 150 ml. of ethanol was stirred and 94 ml. of a solution of warm (approx. 30° C.) 25% aqueous sodium hydroxide was added. This reaction mixture was heated to reflux for 45 minutes. A solid precipitate began appearing after 30 minutes. Next, the mixture was cooled to about 5° C. and the precipitate filtered and washed with petroleum ether. After air drying, the resulting solid was washed with water until the wash material was pH 7.0. The washed precipitate was recrystallized from 80% aqueous ethanol to yield 92.6 g. (80.1% yield) of 2-(4'-diethylamino-2'-methylbenzylidene)-1-indanone (m.p. 133.5°-134.5° C.), U.V. spectra and ε values are set forth in Table 3 below. The structure was confirmed by both infrared and nuclear magnetic resonance spectra.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8][C:9]([CH3:27])([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:10]([OH:17])([C:9]([CH3:27])([S:8][C:5]1[N:6]=[N:7][C:2]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[CH:3][CH:4]=1)[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: CC(C)(Sc1ccc(Cl)nn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(Sc1ccc(-n2cncn2)nn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 69.2 %

Procedure:
A mixture consisting of 1.6 g (3.9 mmol) of (+)-3-(6-chloropyridazin-3-ylthio)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 1.0 g (14.5 mmol) of 1,2,4-triazole, 1.0 g (7.2 mmol) of potassium carbonate, 2.2 g (14.7 mmol) of sodium iodide, and 20 ml of acetonitrile was heated at reflux for 116 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and to the residue was added a saturated sodium chloride aqueous solution, followed by extraction with dichloromethane. The organic layer was washed successively with 10% sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution and dried. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of chloroform and methanol (100:1). The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and methanol to obtain 1.2 g (70%) of (+)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-(6-(1H-1,2,4-triazol-1-yl)pyridazin-3-ylthio)butan-2-ol as a colorless crystal.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[C:29]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])(=[O:31])[CH3:30]>>[C:29]([NH:32][CH:33]([CH2:34][CH2:35][S:36][CH3:37])[C:38](=[O:39])[S:18][CH2:17][C:16](=[O:19])[C@:15]1([OH:25])[C@:20]2([CH3:24])[C@H:12]([C@H:11]3[C@:2]([F:1])([CH:22]([OH:23])[CH2:21]2)[C@:3]2([CH3:28])[C:8](=[CH:7][C:6](=[O:27])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][C@@H:14]1[CH3:26])(=[O:31])[CH3:30]
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CSCCC(NC(C)=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@@]21C
Yield: 53.4 %

Procedure:
The title compound (0.38 gm) was prepared from 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.50 gm) and N-acetyl-L-methionine (0.70 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reaction time: 8 h

Procedure:
4-tert-Butoxycarbonylamino-3-nitrobenzoic acid methyl ester (1.11 g, 3.75 mmol) was dissolved in ethyl acetate-methanol (1:1) (30 ml). Next, 10% palladium-carbon powder (200 mg, 5 mol %) was added to the aqueous solution under a nitrogen atmosphere, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain 3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3=O)cn2)c1=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
A reaction vessel was charged with 332c (946 mg, 3.2 mmol) in 40 mL of anhydrous 1,4-dioxane, 3,5-dibromo-1-methylpyridin-2(1H)-one (1.11 g, 4.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.16 mmol), Xantphos (185 mg, 0.32 mmol), and Cs2CO3 (2.6 g, 8.0 mmol). After three cycles of vacuum/Argon flash, it was stirred at 110° C. for 4 h. The reaction mixture was filtered and the filtrate was evaporated in vacuum. The crude was purified by silica-gel column chromatography eluting with 50:1 methylene chloride/methanol to afford 332d as a yellow solid (706 mg, 46%). MS: [M+H]+ 479.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 85 %

Procedure:
As described for example 89, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (144 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, using morpholine instead of 2,2,2-trifluoroethylamine, to the title compound (142 mg, 85%) which was obtained as a white solid. MS: m/e=414.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25](O)=[O:26])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:8]=[C:7]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:6]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([NH:23][C@H:24]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([N:2]([CH3:3])[CH3:1])=[O:26])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:8]=[C:7]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:6]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)CC4)nc(N)n2)CC1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@H](Cc3ccccc3)C(=O)N(C)C)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from dimethylamine (2.0 M solution in THF), (S)-2-(7-(2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-carboxamido)-3-phenylpropanoic acid, triethylamine, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. Analytic LCMS (M+H)+: m/z=543.2.