Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:24][N:25]=[C:26]=[S:27].O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@:7]2([C:26](=[S:27])[NH:25][CH3:24])[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: O=[S@@]1CCCC[C@@H]1c1cccnc1
Reactant: CN=C=S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=S)[C@]1(c2cccnc2)CCCC[S@]1=O
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A stirred suspension of (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (50.0 g) in dry tetrahydrofuran (500 ml) is treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (281 ml;1M) at between -5° C. and +5° C. The resulting suspension is stirred for 15 minutes at between -5° C. and +50C. and then it is treated with a solution of methyl isothiocyanate (20.26 g) in dry tetrahydrofuran (63 ml) at between -5° C. and +50C. The mixture is stirred at between -5° C. and +5° C. for 30 minutes and then it is treated with water (500 ml). The aqueous phase is then washed with dichloromethane (2×150 ml), The aqueous solution is then treated with charcoal, filtered, neutralised by treatment with dilute hydrochloric acid (2N) and filtered, to give (1R,2R)-2-(3-pyridyl)-N-methyltetrahydro-2H-thiopyran-2-carbothioamide 1-oxide (50.64 g), in the form of a white powder, m.p. 215°-216° C., enantiomeric excess greater than 99.6%. [NMR (CDCl3):- 1.6(m,1H), 1.7(m,2H),2.2(m, 1H),2.3(m, 1H),2.9(m,1H), 3.0(m,1H),3.1 (d,3H),3.7(m,1H),7.3(m,1H), 8.1 (m,1H),8.3(m,1H),8.5(m,1H),8.7(m,1H)]; specific rotations (sodium D line) -205° (c=1, 28° C., CHCl3); -281° (c=1, 31° C., EtOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=O)[CH2:8][O:7][C:6]=2[CH:12]=1.[CH3:13][Mg+].[Br-].[BH4-].[Na+].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:13])[CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: C[Mg+]
Reactant: O=C1COc2cc(F)ccc2N1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1COc2cc(F)ccc2N1
Temperature: 65 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a stirred solution of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (I-22, 1 g, 5.98 mmol) in THF (25 mL) at 0° C. was added 3M CH3MgBr (8 mL, 24 mmol). After additon, the cooling bath was removed and the mixture was heated to 65° C. for 4 h. The reaction mixture was quenched with acetic acid (10 mL) at 0° C. and NaBH4 (568 mg, 15 mmol) was added to the solution. The resulting solution was stirred at rt for overnight. Subsequently, 3N aqueous NaOH solution was cautiously added until pH value of the mixture was adjusted to 10.0. The basic solution was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over neutral alumina (petroleum ether/EtOAc, 0-15% EtOAc) to afford 135 mg (14%) of 7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (I-23) as a brown oil. 1H NMR (400 MHz, DMSO) δ 6.45-6.55 (m, 3H), 4.16-4.19 (m, 1H), 3.73-3.77 (m, 1H), 3.44-3.51 (m, 2H), 1.17 (d, J=6.34 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30]>CCOCC>[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30].[CH3:17][N:18]1[C:22]([C:3](=[N:2][CH3:1])[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CN=C(Cl)c1ccc(C)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CN=C(c1ccc(C)cc1)c1c(C)cc(CC(=O)OC)n1C
Temperature: 25 °C
Yield: 61 %

Procedure:
N-Methyl 4-methylbenzimidoyl chloride (5.44 g, 32.5 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform (13 ml) and chlorosulfonic acid (0.38 g, 3.2 mmole). The reaction was placed under a nitrogen atmosphere and stirred at room temperature. Methyl 1,4-dimethyl-1H-pyrrole-2-acetate (5.39 g, 32.3 mmole) was added and the reaction was stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The phases were separated, and the organic phase was extracted with saturated aqueous sodium bicarbonate and water, then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting red-brown viscous liquid was dissolved in absolute ethanol and treated with 70% perchloric acid (5.1 g, 35.5 mmole). The solution was cooled and treated with ether to induce crystallization. The solid was isolated by filtration, washed with cold ethanol, and air dried to yield 7.86 g (61%) of the title compound, m.p. 119°-124° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=3)[C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[O:20])(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:34]([F:37])([F:36])[F:35])=[N:3]1.CN1C(C2SC(S(Cl)(=O)=O)=CC=2)=[CH:42][C:41](C(F)(F)F)=N1>>[CH2:41]([O:27][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:31]=[CH:32][CH:33]=[C:16]([NH:15][S:12]([C:10]3[S:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([C:34]([F:35])([F:37])[F:36])[CH:5]=4)=[CH:8][CH:9]=3)(=[O:14])=[O:13])[CH:17]=2)=[CH:23][CH:24]=1)[CH3:42]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)Nc2cccc(C(=O)Nc3ccc(C(=O)O)cc3)c2)s1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4cc(C(F)(F)F)nn4C)s3)c2)cc1

Procedure:
4-{3-[5-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonlyamino]-benzoylamino}-benzoic acid, MS (ISP): m/e=549.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonyl chloride and yielded 4-{3-[5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[N:1]1([CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: c1ccc2c(c1)CCCN2
Product: CCOC(=O)C(=CN1CCCc2ccccc21)C(=O)OCC
Temperature: 130 °C

Procedure:
A mixture of tetrahydroquinoline (13.32 g, 100 mmol) and diethyl ethoxymethylenemalonate (21.62 g, 100 mmol) is heated to 130° C. using a Dean-Stark apparatus. After 1 hour the reaction mixture was concentrated to give the title compound as a brown oil. ESMS m/z 304 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]5)[CH2:35][CH2:34]4)=[C:29]([C:46]#[N:47])[CH:28]=3)=[O:25])[CH:20]=[N:19]2)=[CH:14][CH:13]=1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]([CH3:23])=[C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:40][CH2:41][C:42](=[O:45])[CH2:43][CH2:44]5)[CH2:35][CH2:34]4)=[C:29]([C:46]#[N:47])[CH:28]=3)=[O:25])[CH:20]=[N:19]2)=[CH:16][CH:17]=1
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCC(O)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCC(=O)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (0.1 ml) and dimethyl sulfoxide (0.2 ml) in methylene chloride (30 ml) were added under ice-cooling 1-(4-chlorophenyl)-N-[3-cyano-4-[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide synthesized in Example 189 and triethylamine (0.9 ml), and the mixture was stirred at the same temperature for 1 h. To a reaction mixture was added aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform:methanol=20:1) to give the title compound (0.2 g), melting point: 213° C.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH2:17][CH3:18].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CCCCO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 99 %

Procedure:
Ferulic acid (5 g) and then n-butyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for about 2 hours. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×8.5 cm; 70 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound (6.25 g, 99%) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][N:7]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A solution of 1.9 g (0.011 mole) of 3-cyclobutylaminopropanoic acid ethyl ester in 7 mL of acetonitrile was added dropwise to a mixture of 1.74 g (0.09 mole) of 2,4-dichloro-5-nitro-pyrimidine and 2.07 g (0.021 mole) of potassium bicarbonate and 20 mL of acetonitrile at ambient temperature over 45 mins. The mixture was stirred for 2.5 hours, then diluted with 45 mL of ethyl acetate. The mixture was filtered, concentrated under reduced pressure and the residue purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) to give 1.7 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-propanoic acid ethyl ester (IV-23).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CCO>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH3:11])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc([C@@H](C)NS(C)(=O)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc([C@@H](C)NS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
Dissolve N-[(1R)-1-(4-acetylphenyl)ethyl]methanesulfonamide (15 g, 62 mmol) in EtOH (155.4 mL) and cool with an ice bath. Add sodium borohydride (1.2 g, 31.1 mmol) and stir the resulting mixture in the ice bath for 2 h. Quench the reaction with H2O (20 mL) and concentrate under reduced pressure. Dilute the residue with EtOAc (90 mL) and H2O (50 mL). Separate the layers and wash the organic layer with brine (2×50 mL), dry over MgSO4; filter; and concentrate the filtrate under reduced pressure to provide a residue. Purify and separate isomers using chromatography conditions K (see below) collecting the second eluting isomer as the title compound (2.01 g, 13%). MS (m/z): 261 (M+18).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[OH-].[K+].[CH2:12]([OH:14])[CH3:13]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:14])[CH:13]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=3)[S:9][C:3]=2[CH:4]=1
Reactant: CCO
Reactant: Nc1ccc(Cl)cc1S
Agent: [K+]
Agent: [OH-]
Product: O=C1Nc2ccc(Cl)cc2SC1c1ccc(Cl)cc1

Procedure:
To a solution of 2-amino-5-chlorothiophenol (4.49 g) in ethanol (30 ml) is added 96 % potassium hydroxide (1.63 g), and the mixture is distilled to remove ethanol. The resulting solid material is suspended in toluene (70 ml) and thereto is added methyl ° -bromo-4-chlorophenylacetate (7.38 g), and the mixture is refluxed overnight. The reaction mixture is concentrated, and the resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 7-chloro-2-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (6.58 g) as crystals. M.p. 230°-233.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCCCCO
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Product: CCCCCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Yield: 52.8 %

Procedure:
2 g of 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.5 g of potassium hydroxide, 4.2 g of oxalyl chloride and 20 ml of n-pentanol are treated in the same manner as described in Example 17. 1.3 g of n-pentyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained. Yield: 52.8%
Reaction SMILES: ICC.Br[CH:5]([CH2:10][CH3:11])[C:6](OC)=O.BrC1C=C(Cl)C(O)=C(Cl)C=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:6][CH:5]2[CH2:11][CH2:10]2)=[C:25]([F:30])[CH:24]=1
Reactant: CCC(Br)C(=O)OC
Reactant: Oc1ccc(Br)cc1F
Agent: Oc1c(Cl)cc(Br)cc1Cl
Solvent: CCI
Product: Fc1cc(Br)ccc1OCC1CC1

Procedure:
The title compound was prepared analogously to Step 1 in Example A(52), where iodoethane was substituted instead of methyl α-bromobutyrate and 4-Bromo-2,6-dichloro-phenol was substituted instead of 4-Bromo-2-fluorophenol of that example.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:45])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18](CC3C=CC(OC)=CC=3)[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[N:9]=[C:8]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([NH:4][C:5](=[O:45])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:14]=2)[N:9]=[C:8]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(CCCN2CCCCC2)c2ccc3nc(-c4cccc(OC)c4)n(CC(=O)NC(C)C)c(=O)c3c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(-c2nc3ccc(NCCCN4CCCCC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Reaction time: 18 h
Yield: 28.6 %

Procedure:
To a solution of N-isopropyl-2-[6-[(4-methoxybenzyl)-(3-piperidin-1-ylpropyl)amino]-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 3r) (44 mg, 0.07 mmol) in ethanol (7 mL) was added 10% Pd/C (−25 mg, catalytic). The mixture was stirred under an atmosphere of hydrogen (50 p.s.i.) for 18 h. The mixture was filtered through CELITE™ and concentrated in vacuo. The resulting oil was purified by chromatography on a silica gel with methanol:dichloromethane (1:9, v/v) as eluent. The resultant yellow solid was further purified using preparatory HPLC to yield N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-(3-piperidin-1-ylpropylamino)-4H-quinazolin-3-yl]acetamide (EXAMPLE 13a) (9 mg, 0.02 mmol, 24%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC=CC=1.Cl.[N:24]([O-])=[O:25].[Na+]>O.C(O)C>[C:11]([C:7]1[CH:8]=[C:9]([N:24]=[O:25])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: Oc1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 500 ml round flask equipped with a thermometer, stirrer and nitrogen inlet was added 2,6-ditertbutylphenol (50 g, 0.243 moles) and ethanol (95%, I00 ml). The solution was stirred until all of the phenol dissolved. The solution was then cooled to 0° C and concentrated hydrochloric acid (26.3 g, 0.267 moles) was slowly added. A solution of sodium nitrite (17.56 g, 0.254 moles) in water (75 ml) was then added dropwise so as to keep the temperature of the reaction between 0 °and 10° C. (1 hr). The solution became quite thick and more ethanol was added accordingly, for efficient stirring. After the addition was completed, the reaction mixture was stirred for 1 hr and it was then poured into a beaker of ice water (~5 L). The yellow green precipitate was filtered off washed, with water and air dried. The yield was 98 wt%. (210-213° C.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:17][C:16]=2[F:29])=[C:10]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=2)[CH:9]=1>>[Cl:7][C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][C:16]=2[F:29])=[C:10]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=2)[CH:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(Cl)cc2-c2ccc(CC)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2cc(Cl)sc2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((5-chloro-3-(4-ethylphenyl)thiophen-2-yl)methoxy)-3,5-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H-NMR (300 MHz, CD3OD) δ 7.27 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.92 (s, 1H), 6.72 (t, J=8.4 Hz, 2H), 5.01 (s, 2H), 3.29 (t, J=6.6 Hz, 2H), 2.54-2.64 (m, 4H), 1.68-1.78 (m, 2H), 1.18 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H21C1F2O2S, 235.0 (M-C9H9F2O2). found 235.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)(O)[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:12]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(CCO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h
Yield: 88 %

Procedure:
10.4 g (20.5 mmole) of 4-(t-butyldimethylsilyloxy)-2-(3,4-dichlorophenyl)-1-[N-(t-butoxycarbonyl)-N-(2-hydroxyethyl)amino]-2-butanol [prepared as described in step (b) above] and 8.03 g (30.6 mmole) of triphenylphosphine were dissolved in 180 ml of anhydrous toluene and a solution of 5.33 g (30.6 mmole) of diethyl azodicarboxylate in 20 ml of toluene was added dropwise under a nitrogen atmosphere at room temperature. The mixture was then stirred for 2 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The mixture was then washed with a saturated aqueous solution of sodium chloride. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 23:2 to 9:1 by volume as the eluent, to obtain 8.85 g of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8]C(C)C.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1
Yield: 82 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 82% yield, as colourless solid. 1H-NMR (CDCl3) 8.48 (d, 1H, J=1.98 Hz); 8.08 (d, 2H, J=8.25 Hz); 8.03 (dd, 1H, J=8.49, 2.01 Hz); 7.33 (d, 2H, J=8.25 Hz); 7.07 (d, 1H, J=8.49 Hz); 2.66 (t, 2H, J=7.5 Hz); 1.71-1.61 (m, 2H); 0.95 (t, 3H, J=7.29 Hz).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])#[N:2].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21].[H-].[Na+]>C1COCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([CH:3]([C:1]#[N:2])[C:4]2[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=2)[C:9]#[N:10])=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: N#CCc1ccc(F)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C#N)c2ccc(F)c(C#N)c2)nnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold solution of 5-(cyanomethyl)-2-fluorobenzonitrile (1 eq) and 3,6-dichloro-4-isopropylpyridazine (1.3 eq) (Reference: Org. Prep.+Proc. Int. 1988, 20, 117 and U.S. Pat. No. 4,628,088, 1986) in THF (38 mL, 0.1 M) was added portionwise NaH (1 eq). The reaction was stirred at 0° C. for 15 min and then warmed to RT and stirred for 2 hrs. The reaction was quenched with a sat. aq. NaHCO3 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by silica gel chromatography, eluting with petroleum ether:EtOAc (8:2) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ: 7.80-7.79 (2H, m), 7.49 (1H, s), 7.31-7.29 (1H, m), 5.63 (1H, s), 3.34-3.28 (1H, m), 1.36-1.29 (6H, m). MS (ES) C16H12ClFN4 required: 314/316. found: 315/317 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39]Br>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:39][CH2:38][O:37][CH3:36])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: COCCBr
Product: COCCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[1-(2-methoxyethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2-bromoethyl methyl ether following General Procedure S.