Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:19][CH3:20])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Yield: 85 %

Procedure:
To a solution of 5-nitrosalicylic acid (10.8 g) in ethanol (100 ml) was added concentrated sulfuric acid (92.0 g) at room temperature and the mixture was heated under reflux for 7.5 hours. After neutralization with aqueous sodium hydroxide, the reaction mixture was extracted with ethyl acetate. The extractant was washed with saturated aqueous sodium hydrogencarbonate, 0.5M hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (10.7 g, yield 85%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10])#[N:2].C([OH:28])C.OO.[OH-].[Na+]>O>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=1)=[O:10])(=[O:28])[NH2:2]
Reactant: COc1ccc(CC#N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 484 mg of 5-cyanomethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 10 ml of ethanol, 0.6 ml of 30% aqueous hydrogen peroxide and 5 ml of 0.1 mol/l sodium hydroxide, and the mixture was stirred for 1 hour at 50° C. Then, 0.6 ml of 30% aqueous hydrogen peroxide and 5 ml of 0.1 mol/l sodium hydroxide were added again and the mixture was stirred for 30 minutes at 50° C. The reaction mixture was poured into water and extracted with ethyl acetate. After washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence, the organic layer was dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=100:1 to 50:1) to obtain 318 mg of 5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:31])[N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: C1CCNC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N4CCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and pyrrolidine.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:6])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24](Cl)[N:23]=[CH:22]2.CN(C=O)C>O1CCOCC1.CCOC(C)=O>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([NH:6][C:3]1([CH3:2])[CH2:5][CH2:4]1)[N:23]=[CH:22]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: CC1(N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(Nc2ncc3cccc(Br)c3n2)CC1
Temperature: 125 °C
Yield: 92.9 %

Procedure:
A mixture of 1-methylcyclopropanamine hydrochloride (Small Molecules Inc.; 0.32 g, 2.96 mmol), DIEA (1.37 mL, 7.89 mmol) and 8-bromo-2-chloroquinazoline (0.48 g, 1.97 mmol) in 5 mL of dioxane was heated in a microwave at 125° C. for 45 min. LCMS indicated the presence of starting material (8-bromo-2-chloroquinazoline). The reaction mixture was treated with 2 mL of DMF and heated in a microwave at 130° C. for 35 min. It was diluted with 50 mL of EtOAc, washed with 5 mL of water followed by 5 mL of brine. The organic layer was concentrated and the residue was stirred in 2 mL of ether and 10 mL of hexanes. The solid was filtered and dried to give 8-bromo-N-(1-methylcyclopropyl)quinazolin-2-amine (499a; 0.51 g, 1.83 mmol, 93% yield) in about 80% purity. This material was used in next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1H, br.), 8.05 (1H, dd, J=7.6, 1.2 Hz), 7.95 (1H, s), 7.83 (1H, d, J=7.4 Hz), 7.16 (1H, t, J=7.7 Hz), 1.51 (3H, s), 0.78 (2H, m), 0.65 (2H, m). MS (ESI, pos. ion) m/z: 278.1/280.1 (M+1).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4].Cl.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:25][CH2:26]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3ccncc3)CC1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
Compound 24 (42.0 mg, 0.101 mmol) obtained in Example 24, and 4-chloropyridine.hydrochloride (22.6 mg, 0.151 mmol) were dissolved in ethanol (0.5 mL), and the mixture was stirred at 140° C. for 2 hours under microwave (CEM; Discover, 300 watts) irradiation after adding triethylamine (140 μL, 1.01 mmol). The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography, and crystallized from diisopropylether to give the title compound (Compound 25) (17.0 mg, 40%).
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH:37]([CH3:39])[CH3:38])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][C:20]=1[Br:36])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[Br:36][C:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][N:11]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C@H:10]([C:9]([OH:40])=[O:8])[CH:37]([CH3:38])[CH3:39]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)O)C(C)C

Procedure:
A solution of 2.4 g (4 mmol) of N-[(3-bromo-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester in 90 ml of dioxane is hydrogenated at 5 bar and at room temperature with the addition of 1.2 g of Pd/C (10%) until the calculated amount of hydrogen has been absorbed. After evaporation of the filtered solution, the evaporation residue is dissolved in 2N sodium hydroxide solution and extracted with ether, and the aqueous phase is rendered acidic with 2N hydrochloric acid. The title compound is obtained by extracting with ethyl acetate, drying and evaporating as a colourless foam (Rf 0.40, system A2), FAB-MS: m/e=514 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH2:10][CH2:9][N:8]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[N:5][N:4]=[N:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12][CH:7]1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnnn2C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnnc1C1CC(C(=O)O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
1-Benzyl 4-ethyl 2-(1-methyl-1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (1.14 g, 2.93 mmol) (from reference compound 36, step 6) was dissolved in THF (10 mL) and water (10 mL) and LiOH (0.280 g, 11.69 mmol) was added. The mixture was stirred at room temperature for 30 min and then diluted with water and acidified with 2 M HCl. The aqueous phase was extracted 3 times with EtOAc, the combined organic phase dried over Na2SO4 and evaporated to yield 1-(Benzyloxycarbonyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-4-carboxylic acid (990 mg, 98%). 1H NMR (400 MHz, cdcl3) δ 1.89-2.01 (m, 1H), 2.15-2.24 (m, 1H), 2.27-2.36 (m, 1H), 2.50-2.61 (m, 1H), 2.78 (p, 1H), 3.68-3.80 (m, 1H), 3.91-4.09 (m, 4H), 5.08 (q, 2H), 5.44 (t, 1H), 7.23-7.39 (m, 5H). MS m/z 346 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH2:26]([NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.1 %

Procedure:
To a solution of 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.7 g) in methanol (7 ml) were added benzaldehyde (229 mg) and acetic acid (130 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano-borohydride (135 mg). The mixture was stirred for 30 minutes at room temperature, to which was added ethyl acetate ester (50 ml). The mixture was washed with water and dried over anhydrous MgSO4, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography to give the object 2-benzylamino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.91 g) as a colorless oily compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][O:32]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CCCCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCC1CO1)c1c(F)ccc(F)c1F

Procedure:
[7-(4-chloro-benzenesulfonyl)-7-(2,3,6-trifluoro-phenyl)-1-heptene (0.65 g, 1.6 mmole) and mCPBA (77%, 0.71 g, 3.2 mmole) were stirred in 50 mL DCM for 5 hours. 2 g Na2S2O3 in 100 mL water were added to quench excess mCPBA. The organic layer was separated, washed with 1N NaOH solution (50 mL), brine (50 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (Gradient from 0/100 to 40/60 in 40 minute, 0.52 g, 77%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, j=8.05 Hz, 2H), 7.45 (d, j=8.05 Hz, 2H), 7.15 (m, 1H), 6.83 (m, 0.5), 6.74 (m, 0.5H), 4.58 (dd, j=5.1 and 6.5 Hz, 1H), 2.84 (m, 1H), 2.71 (t, j=4.4 Hz, 1H), 2.41 (dd, j=2.9 and 5.1 Hz), 2.45 (m, 1H), 2.34 (m, 1H), 1.25-1.55 (m, 6H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][N:12]2[C:18](=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:20]1(/[CH:30]=[CH:31]\[C:32](O)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1(/[CH:30]=[CH:31]\[C:32]([N:15]2[CH2:16][CH2:17][C:18](=[O:19])[N:12]([CH2:11][CH2:10][CH2:9][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C\c1cccc2ccccc12
Agent: Cl
Product: O=C(/C=C\c1cccc2ccccc12)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described for example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (Z)-3-naphthalen-1-yl-acrylic acid gave the title compound as light yellow foam. MS: 420.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=1[Cl:25])[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[C:19]([Cl:25])[CH:20]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2Cl)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)c(Cl)c2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (3′-chloro-4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]([OH:15])[CH2:12][CH2:13][OH:14].O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:14][CH2:13][CH2:12][CH2:11][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: OCCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: OCCCOCc1ccccc1
Temperature: 100 °C
Yield: 65 %

Procedure:
Benzyl chloride (104 g, 1.0 m) was added dropwise to a solution of KOH (112 g, 2.0 m) in 100 ml of xylene and 304 g of 1,3-propanediol at 50° C.-60° C. The solution was then heated at 100° C. for 2 hours. Water (400 ml) was added to the cooled solution and the mixture was extracted twice with 600 ml of methylene chloride. The combined methylene chloride extracts were washed three times with 400 ml of water, dried over MgSO4, filtered and evaporated to a yellow oil which was distilled under vacuum. The 98° C.-106° C. (1.5 mm) fraction was collected to give 88.7 g of 3-benzyloxypropanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].O=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[Sn](Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[NH2:8][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccsc1N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2sccc2c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alternatively, a mixture of 2-amino-3-thiophenecarbonitrile (2.5 g, 20.13 mmol), ethyl 3-oxobutanoate (2.80 mL, 22.15 mmol) and SnCl4 (4.73 mL, 40.3 mmol) in toluene (135 mL) was stirred at RT for 30 min, and then refluxed for 2 h. The mixture was then basified with 6M NaOH (ca. 25 mL), diluted with 10% MeOH in DCM (40 mL), and the mixture filtered through celite. The organic layer of the filtrate was then separated and the aqueous layer re-extracted with 10% MeOH in DCM (50 mL×3). The combined organic layers were dried and concentrated. The residue was then purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in DCM, to give the title compound. Another batch of 2-amino-3-thiophenecarbonitrile (2.5 g, 20.13 mmol) was subjected to the same procedure and the products from each reaction were combined to give the title compound (2.36 g).
Reaction SMILES: [Br-].[C:2]([CH2:4]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[C:58]([CH2:63][CH2:64][C:65]#N)[CH:57]=[CH:56]2>C1COCC1>[O:51]=[C:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](=[O:41])[N:43]1[CH2:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[C:58]([CH:63]=[CH:64][CH2:65][CH2:4][C:2]#[N:3])[CH:57]=[CH:56]2
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CCCC=Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
The compound (675.0 mg) obtained in Example 123-1 was suspended in anhydrous THF (30 ml) and cooled with ice. Then, the suspension was added with a 2 mol/l lithium diisopropylamide/heptane solution (0.825 ml), followed by stirring at room temperature for 1 hour. Then, the solution was gradually added with a solution prepared by suspending the compound (327.9 mg) obtained in Example 119-7 in anhydrous THF (20 ml), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (268.0 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22]#[N:23])=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1N)(=[O:3])[CH3:2].C(ON=O)(C)(C)C>O1CCCC1>[C:1]([C:4]1[C:5]([C:22]#[N:23])=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N

Procedure:
To a stirred solution of 4-acetyl-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.4 g) in tetrahydrofuran (2 ml) was added dropwise t-butylnitrite (0.0262 ml). The mixture was heated under reflux for 30 minutes. The reaction mixture was applied to a silica gel (1 g) column and eluted with tetrahydrofuran to provide the title compound as white solid, m.p. 166-168° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][N+:4]([O-:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:14](O)([OH:19])[C:15]([F:18])([F:17])[F:16].O>C(OC)(C)(C)C>[CH3:1][CH:2]([CH3:7])[CH:3]([N+:4]([O-:6])=[O:5])[CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)C[N+](=O)[O-]
Reactant: OC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil, which was used without further purification.
Reaction SMILES: O.[F:2][C:3]([F:19])([C:9](=O)[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:20]([SH:24])[CH2:21][CH2:22][SH:23]>C(Cl)Cl>[S:23]1[CH2:22][CH2:21][CH2:20][S:24][C:9]1([C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([F:19])([F:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(F)(F)C(=O)C(F)(F)C(=O)OCC
Reactant: SCCCS
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(F)(F)C1(C(F)(F)C(=O)OCC)SCCCS1
Reaction time: 18 h

Procedure:
Dissolve 12.1 mmol of the product of Example 6 in 50 mL of methylene chloride and cool in an ice/water bath under argon. Add 6 g of powdered activated 3A molecular sieves, 18.2 mmol of 1,3-propanedithiol, and then 2.4 mmol of BF3Et2O. Stir for 18 h in the cold, then filter the reaction, washing with ether. Add 100 mL of ether and wash with saturated sodium bicarbonate, water, and brine, and dry over MgSO4. Purify by silica gel chromatography using ether/hexane as eluant to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](I)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([C:34]1[O:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:37]5[O:38][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(I)cc34)c2)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(-c5ccc(C=O)o5)cc34)c2)no1
Temperature: 55 °C
Yield: 87 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea from the previous step (0.21 g, 0.4 mmol), 5-formylfuran-2-ylboronic acid (0.07 g, 0.51 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.035 g, 0.05 mmol), and 1.0 M Na2CO3 solution (3 mL) in EtOH (2 mL) and 1,2-dimethoxyethane (3 mL) was heated at 55° C. for 1 hour. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 30-60% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}urea as solid (0.172 g, 87%). 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.53 (br, 1H), 8.80 (d, 1H), 8.78 (s, 1H), 7.32 (dd, 1H), 8.07 (d, 1H), 7.67 (m, 2H), 7.34-7.54 (m, 3H), 7.07 (d, 1H), 7.01 (d, 1H), 5.94 (s, 1H), 1.32 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12]([O-])(=O)[CH3:13].[Na+].C(I)C.CN(C)C=O>O>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[OH:11])[CH3:13]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(F)cc1O

Procedure:
4-Fluoro-2-hydroxy-benzoic acid (10.8 g, 0.07 mol), sodium acetate (6.9 g, 0.084 mol), ethyl iodide (55 g, 0.35 mol) and dimethylformamide was stirred at ambient temperature for 48 h. The mixture was poured into water and extracted with n-hexane. The solution was filtered through a plug of silica gel and evaporated. The residue was almost pure product and was used directly in the next step. Yield 10.2 g, 80%.