Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([NH:35]C(=O)C)[CH:13]=[C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[Si](C(C)C)(C(C)C)C(C)C)[CH:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:39][O-:40].[Na+]>CO>[NH2:35][C:12]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:40][CH3:39])[CH:7]=2)=[O:9])[CH:15]=[C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)[CH:13]=1
Reactant: CC(=O)Nc1cc(C(=O)c2ccnc(Cl)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2cc(N)cc(-c3cccc4[nH]ccc34)c2)ccn1
Yield: 12.9 %

Procedure:
To N-[3-(2-Chloro-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-acetamide (Example 83, 0.150 g, 0.27 mmol) in 25 mL of anhydrous methanol was added 0.022 g (0.41 mmol) NaOMe. The reaction mixture was refluxed overnight. The methanol was removed under vacuum and water was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The crude product was purifed by preparative TLC using 10:1 methylene chloride:methanol to give 12 mg [3-amino-5-(1H-indol-4-yl)-phenyl]-(2-methoxy-pyridin-4-yl)-methanone. 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 8.22 (s, 1H), 7.38 (t, J=1.5 Hz, 1H), 7.34 (t, J=1.0 Hz, 1H), 7.32 (t, J=0.9 Hz, 1H), 7.21-7.16 (m, 4H), 7.13 (dd, J=5.1, 1.3 Hz, 1H), 7.10-7.07 (m, 2H), 7.00 (s, 1H), 6.62-6.59 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
A solution of 19 (2.5 g, 18 mmol) in DME (90 mL) was added 4-trifluoromethoxy phenyl boronic acid (1.1 mol eq, 4.46 g) and NaHCO3 (3 mol eq, 4.66 g) suspended in water (50 mL). The mixture was degassed under vacuum, then Tetrakispalladium was added (catalytic amount) and the reaction stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (100 mL). The aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to obtain 20B as a pale yellow crystals (96% Yield, 4.6 g, 17.4 mmol). 1HNMR (DMSO, 200 MHz) δ 7.5 (dd, 2H, J=2), 7.84 (dd, 1H, J=1.8), 8.31 (d, 2H, J=9.8), 8.54 (d, 1H, J=2), 8.93 (dd, 1H, J=1.9).
Reaction SMILES: [CH2:1]1[C:22]2[CH:5]([CH2:6][C:7]3[C:20]([CH:21]=2)=[CH:19][C:18]2[C:9](=[CH:10][C:11]4[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:8]=3)[CH2:4][CH2:3][CH2:2]1.[C:23]1(Cl)C(=O)C(Cl)=C(Cl)C(=O)[C:24]=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:18]3[C:9](=[CH:10]2)[CH:8]2[C:7]4[C:20]([CH:19]3[CH:23]=[CH:24]2)=[CH:21][C:22]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=4)=[CH:15][CH:14]=1
Reactant: C1=C2CCCCC2Cc2cc3cc4ccccc4cc3cc21
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1=CC2c3cc4ccccc4cc3C1c1cc3ccccc3cc12
Temperature: 50 °C
Yield: 85.8 %

Procedure:
A stirred mixture of the hexahydropentacene (221.78 g, 0.720 mol), chloranil (362.6 g, 1.475 mol) and 4 L toluene is kept at reflux for 2½h. The mixture is cooled to about 50° C. and 350 mL 33% sodium hydroxide solution is gradually added. The organic layer is separarted, while the aquous layer is washed with toluene. The combined toluene layers are filtered over aluminium oxide and are rotary evaporated. The residue is stirred with a mixture of 500 mL toluene and heptane. Filtration and washing gives 188.0 g of the product (0.618 mol, 86%). 1H-NMR (CDCl3): δ 5.35 (dd, 2H), 7.05 (dd, 2H), 7.4 (m, 4H), 7.75 (m, 8H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH2:21][CH2:20][N:19]([C:30](=[O:32])[CH3:31])[CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1[nH]n(C2CCCC2)c2nc(C3CCNCC3)nc(=O)c1-2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(c2nc3n(C4CCCC4)[nH]c(C)c-3c(=O)n2)CC1
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-methyl-6-(4-piperidinyl)pyrazolo[3,4-d]pyrimidin-4-one (0.79 g, 2.6 mmol), triethylamine (2.0 ml), and chloroform (25 ml) was added acetic anhydride (2.0 ml, 0.02 mol). The mixture was stirred for 3 hours and the solvent was removed in vacuo. The residue was treated with water and the product was collected by filtration to afford 0.8 g (90%) of 1-cyclopentyl-3-methyl-6-(1-acetyl-4-piperidinyl)pyrazolo[3,4-d]pyrimidin-4-one as white needles, m.p. 176°-178° C. when recrystallized from cyclohexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH3:2].[C:24]([O:28][C:29](=[O:42])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:41])[CH:39]=[CH2:40])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](/[CH:40]=[CH:39]/[C:38](=[O:41])[NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:42])=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Product: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1

Procedure:
Key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (II) can be prepared according to Scheme 6. Starting with commercially available 2-bromo-ethanol (XXIX), silylation with tert-butyldimethylsilyl chloride provides (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (XXX). Alkylation of the potassium enolate of (4-bromo-phenyl)-acetic acid ethyl ester with XXX furnishes 2-(4-bromo-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (XXXI). Heck reaction of XXXI with (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester gives key building block 2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-hydroxy-butyric acid ethyl ester (II).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:8]=1)C.[Li+].[OH-]>C1COCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[N:8]=[C:7]([CH2:6][CH:5]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[C:4]([OH:33])=[O:3])[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Br)cc2)cc1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was added LiOH (14 mg, 0.6 mmol, 3 equiv) in 2:1 THF/H2O (1 mL). After 3 h at 45° C., the mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the title compound (66 mg, 79 %). HPLC: Rt=4.25 (Method A). MS (ESI): mass calculated for C26H23BrN2O2, 474.09; m/z found, 475/477 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.40 (d, J=8.5 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 7.19-7.05 (m, 7H), 7.01 (d, J=8.5 Hz, 2H), 6.23 (s, 1H), 4.10 (dd, J=9.6, 5.5 Hz, 1H), 3.53 (dd, J=14.8, 9.6 Hz, 1H), 3.13 (dd, J=14.8, 5.5 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: N[C:2]1C(N)=CC=CN=1.C[O:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].OC1C=C(O)C=CC=1C(OC)=O.C(Cl)C#C>>[OH:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:2])=[O:14]
Reactant: Nc1cccnc1N
Reactant: C#CCOc1ccc(C(=O)O)c(OC)c1
Agent: C#CCCl
Agent: COC(=O)c1ccc(O)cc1O
Product: C#CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
A mixture of 10.9 g of 2,3-diaminopyridine (IIa) and 20.6 g of 2-methoxy-4-propargyloxybenzoic acid (m.p.142°; obtainable by the reaction of methyl 2,4-dihydroxybenzoate with propargyl chloride to give methyl 2-hydroxy-4-propargyloxybenzoate (m.p. 100°); reaction of this with methyl iodide to give methyl 2-methoxy-4-propargyloxybenzoate (m.p. 88°) and hydrolysis) is added in portions with stirring to 500 ml of POCl3. The mixture is boiled for 4 hours, concentrated, and the residue is treated with 375 ml of 10% hydrochloric acid. The precipitated 2-(2-methoxy-4-propargyloxyphenyl)imidazo(4,5-b)pyridine hydrochloride ("M") is filtered off. M.p. 247° (from methanol).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(N=C=NC2CCCCC2)CCCC[CH2:28]1>CCO.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C/C(=C\c1ccc(C(=O)O)s1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1

Procedure:
A suspension of 0.161 g (0.437 mmol) of 5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylic acid, (Compound 3, 0.03 g, 0.655 mmol) in EtOH, 0.099 g (0.48 mmol) of 1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate washed with water and brine. The organic layers were combined and dried (MgSO4), The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8]I)(=[O:5])=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)CCCI
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
To a solution of 3-iodo-propane-1-sulfonic acid dimethylamide (600 mg) in DMF (10 mL) was added potassium phthalimide (590 mg) and the reaction heated at 100° C. for 16 h. After cooling to room temperature, the reaction was partitioned between dichloromethane (30 mL) and water (30 mL). The organic layer was washed with aqueous brine solution (3×30 mL), dried (MgSO4) and reduced in vacuo to give 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propane-1-sulfonic acid dimethylamide as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14].CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([CH2:12][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(C)Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CC(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
562.9 g. (4.08 moles) of N-isopropylaniline is rapidly added to a solution of the crude product of Step 1 in 500 ml. of dimethylformamide stirred at 50° C. under nitrogen. The reaction mixture is stirred at 100° C. under nitrogen for 10 hours and allowed to cool to room temperature overnight. The reaction mixture is heated to 60° C., 2 l of water is added, and the mixture is cooled to 10° C. The obtained solids are collected, washed twice with 500 ml. portions of water and dissolved in 550 ml. of 95% ethanol at 75° C. The solution is cooled to 0° C., and the obtained solids are collected, washed three times with 100 ml. portions of 95% ethanol and vacuum dried at 35°-40° C. for 4 hours to obtain the 95.3% pure yellow product (466 g. (80.2% (two steps))), m.p. 78°- 81° C.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>CCCCCC.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 44 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 0.293 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (+) isomer and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent gives 0.24 g of the expected product after crystallization from a DCM/iso ether mixture. αD25 =+127° (c=0.24; chloroform).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:20])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.552 g, 4.0 mmole), 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.77 g, 8.0 mmole), and 60% sodium hydride in mineral oil (0.176 g, 4.4 mmole) in dimethylformamide (150 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=136–137° C.; MS (−) ESI m/z=358 (M−H)−. Analysis for C16H13ClF3NO3 Calculated: C: 53.42; H, 3.64; N, 3.89. Found: C: 53.37; H, 3.57; N, 3.67.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18](O)[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10]=23)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH2:18][CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (+/−)-methyl [9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pytrolo[1,2-a]indol-1-yl]acetate (see Example 14, 85 mg) in CH2Cl2 were added trifluoroacetic acid (0.5 mL) and triethylsilane (0.2 mL). The mixture was stirred for 1 hour at r.t. and solvent was removed. The residue was purified by silica gel chromatography eluted with 30% EtOAc/hexane to give 70 mg of the title compound as a white foam which has hydrolyzed following the procedures described in Step 10 of Example 7.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[C:5]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]([F:16])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[CH3:9])#[N:2].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:19]([C:18]1[O:23][C:4]2[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:6]([F:16])[C:5]=2[N:17]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: Cc1c(C#N)c(O)c(NC(=O)C(C)(C)C)c(F)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2nc(C(C)(C)C)oc2c1C#N
Temperature: 25 °C
Yield: 0.1 %

Procedure:
N-(5-Cyano-2-fluoro-4-hydroxy-6-methylbiphenyl-3-yl)-2,2-dimethylpropionamide (I-238) (124 mg, 0.38 mol) was dissolved in toluene (5 ml), and at room temperature, paratoluenesulfonic acid monohydrate (20 mg, 0.11 mmol) was added. The reaction liquid was heated under reflux under nitrogen atmosphere for 4.5 hours. After cooling to room temperature, the solution was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was separated, this was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=9:1) to obtain the entitled compound (106 mg, 90%) as a white solid.
Reaction SMILES: BrC1C=CC=C[C:3]=1[C:8]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[O:12][CH:11]([CH3:13])[CH2:10][O:9]1.[OH:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:8]1([CH2:3][O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:12][CH:11]([CH3:13])[CH2:10][O:9]1
Reactant: CC1COC(c2ccc(Cl)cc2Cl)(c2ccccc2Br)O1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1COC(COc2cccnc2)(c2ccc(Cl)cc2Cl)O1
Reaction time: 18 h

Procedure:
A mixture of 2-(bromophenyl)-2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolane (10 g.), 3-hydroxypyridine (3.8 g.) and potassium carbonate (5.5 g.) in N,N-dimethylacetamide (90 ml.) was refluxed with stirring for 18 hours. After the mixture was allowed to cool, it was poured into water and extracted with toluene. The toluene fraction, thereby obtained, was washed with 5% aqueous sodium hydroxide and evaporated to yield 3-[[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolan-2-yl]methoxy]pyridine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=O)CCC1=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH2:43].C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:19][OH:20])=[N:43][CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccccn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=NCc1ccccn1)NO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde-oxime ((i.e. the product of Example 1 Step 2, 177 mg, 0.42 mmol) in DMF (4 mL) was added N-chlorosuccinimide (67 mg, 0.50 mmol) and the mixture was stirred at 70° C. bath temperature for 30 min. After cooling to 0° C., picolylamine (85 mg, 0.79 mmol) and triethylamine (145 mg, 1.44 mmol) was added. The mixture was allowed to war to room temperature over night and was then poured on ice water. The pH was adjusted to 7 by addition of NH4Cl and the resulting precipitate was filtered off. The crude product was then purified by column chromatography on SiO2 (CH2Cl2: MeOH=96:4) to give the title compound (75 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27](SC)[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[NH:28]([C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:26][CH3:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN=C(Nc1ccccc1)SC
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=NC)Nc3ccccc3)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and methyl N′-methyl-N-phenylcarbamimidothioate (11.5 mg, 0.064 mmol) were mixed in 0.3 ml DMF. Triethylamine (25.5 ml, 0.183 mmol) was added. The mixture was then cooled in an ice-bath and mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 5 mg, yield 18% of the desired product.
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([CH3:12])[N:6]=1>O1CCOCC1>[Cl:4][C:5]1[N:6]=[C:7]([CH3:12])[N:8]=[C:9]([NH2:1])[CH:10]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(N)cc(Cl)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Ammonia, 2.0 M in methyl alcohol (6.0 mL, 12 mmol) was added to a stirred yellow suspension of 4,6-dichloro-2-methylpyrimidine (Aldrich) (0.487 g, 3 mmol) in 1,4-dioxane (10.0 mL) at room temperature. The resulting mixture was sealed and stirred at 70° C. overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with SiO2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 10% MeOH in DCM) to give 6-chloro-2-methylpyrimidin-4-amine (0.25 g, 58%) as a white solid. MS (API-ES) m/z 144 (M+H)+.