Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.B(Cl)(Cl)Cl.[C:14](Cl)([CH3:16])=[O:15].[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+]>C(Cl)Cl.CCCCCCC>[NH2:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:14]([C:16]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)=[O:15]
Reactant: COc1cccc(N)c1
Reactant: CC(=O)Cl
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccc(C(=O)c2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step D) To a solution of 21.8 g (172 mmol) of m-anisidine in 800 mL of CH2Cl2 cooled to −50° C., was added 172 mL (172 mmol) of 1M BCl3 in heptane over 20 min to produce an amber colored mixture which was stirred 1 h. To this mixture was added 12.2 mL (172 mmol) of AcCl and 22.9 g (172 mmol) of AlCl3. The mixture was allowed to warm to room temperature overnite, poured into ice water, the solution adjusted to pH 9 using 10% aqueous NaOH and was extracted repeatedly using EtOAC. The combined organic extracts were washed with brine, dried (MgSO4), concentrated and the resulting solid recrystallized from the minimal amount of MeOH in CH2Cl2/hexanes (50%) to afford 13.4 g (47%)of slightly impure 2-amino-4-methoxybenzophenone as a crystalline solid. The solid could be taken directly into the next reaction or purified to absolute purity over SiO2 (eluted with 0% to 14% MeOH/CH2Cl2): 1H NMR (500 MHz, CDCl3) δ 2.50 (s, 3H), 3.79 (s, 3H), 6.05 (d, J=2.4 Hz, 1H), 6.21 (dd, J=8.8, 2.4 Hz, 1H), 6.38 (m, 2H), 7.62 (d, J=8.8 Hz, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][C:17]#[N:18])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[C:19]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:15][CH2:16][C:17]#[N:18])[C:12]3[C:4]([C:5]=2[CH:6]=1)=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)=[O:29])([OH:24])=[O:23]
Reactant: Cc1ccc2c(c1)c1ccccc1n2CCC#N
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1cc(C(=O)c3ccccc3C(=O)O)ccc1n2CCC#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound prepared in step (a) (0.03 mole), phthalic anhydride (0.03 mole) and 50 ml. of benzene were stirred in an ice bath. Aluminum chloride (0.065 mole) was slowly added to the mixture, and after addition, the mixture was stirred for 30 minutes at 0°C. and then warmed to 50°C. and stirred for 3 hours. After cooling, 3N hydrochloric acid was added to decompose the aluminum complex. The yellow solid that formed was filtered and stirred in warm dilute ammonium hydroxide. The hydroxide solution was filtered, and the filtrate was neutralized with dilute hydrochloric acid. The solid obtained upon neutralization was recrystallized from xylene to give 3-(o-carboxybenzoyl)-6-methyl-9-cyanoethylcarbazole as white crystals, melting point 190°C.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([NH:16][C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][C:29]=4[O:43][CH3:44])[N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:45])[C:8]([CH3:46])=[CH:7]1)C.C1COCC1.O[Li].O>CO>[CH2:41]([O:40][P:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:19]2[N:18]=[C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:10]=3[C:9](=[O:45])[C:8]([CH3:46])=[CH:7][N:6]4[CH2:5][C:4]([OH:47])=[O:3])[C:22]([C:23]([F:24])([F:26])[F:25])=[CH:21][N:20]=2)=[C:29]([O:43][CH3:44])[CH:30]=1)([O:37][CH2:38][CH3:39])=[O:36])[CH3:42]
Reactant: CCOC(=O)Cn1cc(C)c(=O)c2c(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)cccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3c(=O)c(C)cn4CC(=O)O)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
A solution of ethyl[5-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-3-methyl-4-oxoquinolin-1(4H)-yl]acetate (Example 300, 41 mg, 0.061 mmol) in MeOH (0.5 mL), and THF (0.5 mL) was charged with LiOH H2O (25.6 mg, 0.61 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The material was purified by prep TLC (5% MeOH in DCM) to give 24.1 mg of the desired product (yield: 61%). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (m, 6H), 1.99 (s, 3H), 3.24 (d, J=21.2 Hz, 2H), 3.78 (s, 3H), 3.99 (m, 2H), 6.90 (d, 1H), 7.03 (s, 1H), 7.43 (s, br, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.94 (s, br, 1H). 8.36 (s, 1H), 8.51-8.56 (m, 2H). MS (ES+): m/z 651.19 [MH+]. HPLC: tR=1.32 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C@@H:11]([CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:15]([C@H:9]1[CH2:10][C@H:11]([CH3:14])[C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H]1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: C[C@H]1C[C@H](C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)N(Cc2ccccc2)C1=O

Procedure:
Coupling of (2R,4S)-1-Benzyl-4-methyl-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[N+:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[C:34]2[CH:38]=O)([O-:28])=[O:27]>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:34]3[C:33]4[C:37](=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=[CH:31][CH:32]=4)[NH:36][CH:35]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c([N+](=O)[O-])cccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 518.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.077 g, 0.022 mmol) in methanol (2.0 mL) was added with 7-nitro-1H-indole-3-carboxaldehyde (0.038 g, 0.020 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.054 g, 50%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.O>FC(C1C=CC=CC=1)(F)F.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:16])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: CC(=O)Oc1ccc(CBr)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 4-methyl-3-(trifluoromethyl)phenyl acetate (6.04 g) and 75% benzoyl peroxide (0.45 g) in (trifluoromethyl)benzene (60 mL) was added N-bromosuccinimide (5.42 g), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.6 g).
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=1[N:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C@@H:25]([CH3:32])[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:18]1=[O:43].Cl.[CH3:45][O:46][NH2:47]>O1CCCC1>[CH3:45][O:46][NH:47][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([CH3:6])=[C:8]([N:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[C@@H:25]([CH3:32])[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:18]2=[O:43])[CH:9]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3cccc4ccccc34)[C@@H](C)CN3CCCC3)c2=O)c1
Reactant: CON
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3cccc4ccccc34)[C@@H](C)CN3CCCC3)c2=O)c1
Yield: 70.2 %

Procedure:
A solution of iso-propylmagnesium chloride (2M in diethyl ether, 1.2 mL) was added dropwise to a stirred mixture of 4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid, methyl ester (Example 158b, 90 mg), O-methylhydroxylamine hydrochloride (65 mg) and tetrahydrofuran (2 mL) at room temperature. After 15 min the reaction was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (65 mg). MS: APCI(+ve) 526 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1)[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(I)=CC=1[Cl:44]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[C:23]([Cl:44])[CH:22]=1)[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Reactant: Clc1cc(I)ccc1Br
Product: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 5a, using 4-bromo-3-chloro-iodobenzene at Stage 2 of Scheme 4. m/z 520 [M+H]+.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O.[OH-].[K+].[CH2:11](Br)[CH3:12]>CO>[CH2:11]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([NH2:7])=[O:6])[CH3:12]
Reactant: CCBr
Reactant: CC(=O)CC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C(C)=O)C(N)=O
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a 500 mL, 5-necked flask, equipped with a circulating jacket, a thermometer, a nitrogen blanket line atop a condenser, an addition funnel, a syringe pump, and a mechanical stirrer, were charged 101.1 g of acetoacetamide (1.00 mol), 100 mL of deionized water and 100 g of methanol. The mixture was stirred at ambient temperature until all solids were dissolved. A 45% aqueous potassium hydroxide solution (99.6 g, 0.80 mol) was then added to the above solution through the addition funnel over a period of 5 minutes. The resulting mixture was stirred for 30 minutes and then cooled to 15° C. Ethyl bromide (130.8 g, 1.20 mol) was added to the mixture through the syringe pump over a period of 30 minutes. The resulting mixture was stirred at 15° C. for 16 hours. All volatiles were then removed at 60° C./20 mmHg. The solid residue was dissolved in 300 mL of water and extracted with chloroform. A total of six chloroform extractions were performed (60 mL+5×200 mL). The first extraction contained a high level of 2,2-diethylacetoacetamide and was discarded. The remaining extraction solutions were combined. After chloroform was removed in vacuo, 67.7 g of 2-ethylacetoacetamide was obtained. Crude yield: 66% (based on KOH charge).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][CH:4]=1
Reactant: CCCCCCCCC(=O)O
Reactant: c1ccc(-c2cnco2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
(188) A solution of 2-(oxazol-5-yl)pyridine (117 mg, 0.80 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.88 mmol, 0.35 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.60 mmol, 3.2 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.80 mmol, 152 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with nonanoic acid (2 equiv, 1.60 mmol, 253 mg, 0.28 mL) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 8.0 mmol, 1.02 g, 0.70 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of nonanoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)nonan-1-one (188) (94 mg, 0.33 mmol, 41% yield) as a light brown powder: mp 56-57° C.; 1H NMR (CDCl3, 250 MHz) d 8.61 (br d, J=4.4 Hz, 1H), 7.84-7.71 (m, 3H), 7.29-7.22 (m, 1H), 3.05 (t, J=7.3 Hz, 2H), 1.79-1.66 (m, 2H), 1.42-1.16 (m, 10H), 0.88-0.77 (m, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.4, 157.3, 153.1, 150.0, 146.2, 137.0, 126.8, 124.0, 120.3, 39.0, 31.7, 29.2, 29.0, 24.0, 23.9, 22.5, 14.0; IR (KBr) umax 2922, 2856, 1705, 1697, 1600, 1420, 1381 cm−1; MALDI-FTMS (DHB) m/z 287.1744 (C17H22N2O2+H+ requires 287.1754).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[O:30][N:29]=1)([CH3:27])[CH3:26].C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:31]2[O:30][N:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[CH:32]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)on1)C(F)(F)F
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.4 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (76 mg, 0.24 mmol) described in Example 115B in anhydrous THF (1.5 mL), was added 4-chlorophenyl 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from Example 267A (84 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (15 mg, 0.12 mmol). The mixture was stirred at rt for 6 h. To the suspension was added diethyl ether. Sonication and filtration afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea (88.8 mg, 69%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.17 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.56 (d, J=9 Hz, 1H), 7.43-7.48 (m, 1H), 7.30-7.36 (m, 3H), 6.19 (s, 1H), 3.99 (s, 6H), 1.49 (s, 6H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][CH2:6][N:7]=C=NCC.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N)CC1>C(Cl)Cl.CCOCC>[CH:6]1([NH:7][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:22])[CH2:4][CH2:5]1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CNC(=O)OCc1ccccc1)NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
23.1 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) are added while stirring to 24 g of N-benzyloxycarbonyl-glycine and 8 ml of cyclopropylamine in 240ml of methylene chloride and the mixture is stirred at room temperature for 4 hours. The mixture is taken up in ether and washed with 1N hydrochloric acid, with bicarbonate solution and with water. After drying and evaporating the ether phase there are obtained 23 g of benzyloxycarbonylamino-acetic acid cyclopropylamide.
Reaction SMILES: [CH2:1]([C:4]1([O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:8]([O:9][CH3:10])[C@H:6]1[OH:7])[OH:5])[CH:2]=[CH2:3].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:1]([C:4]1([O:14][C@H:13]([CH2:15][O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:11]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:8]([O:9][CH3:10])[C@H:6]1[O:7][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:5])[CH:2]=[CH2:3]
Reactant: C=CCC1(O)O[C@H](CO)[C@@H](O)[C@H](OC)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OC)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Allyl-3-O-methyl-glucopyranose (4.5 g) was dissolved in anhydrous DMF (120 mL) and sodium hydride (1.84 g, 50% dispersion in oil) was added thereto. The resulting solution was stirred for 0.5 hours at 0° C. Benzyl bromide (6.8 mL) was added dropwise at 0° to 5° C. and the reaction mixture was then stirred for 4 hours at room temperature. The reaction mixture was quenched by adding methanol, diluted with dichloromethane (250 mL) and washed with water (3×250 mL), dried over Na2SO4, filtered and evaporated. The material was purified by chromatography on silica gel using hexane-ethyl acetate (5:1) as eluent. The evaporated fractions from column were crystallized from a mixture of dichloromethane and hexane to provide for allyl-3-O-methyl-2,4,6-tri-O-benzyl-glucopyranose (8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.CN.Cl.[BH3-][C:19]#[N:20].[Na+]>CO>[CH3:19][NH:20][CH:11]1[CH2:12][CH2:13][CH:8]([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCC(Oc2ccncc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCC(Oc2ccncc2)CC1
Reaction time: 3 h
Yield: 21 %

Procedure:
4-(Pyridin-4-yloxy)cyclohexanone (1.15 g, 6.052 mmol, 1.0 eq.) was dissolved in MeOH (15 ml); CH3NH2.HCl (490 mg, 7.263 mmol, 1.2 eq.) was added and stirring was carried out for 3 hours at RT. NaCNBH3 (760 mg, 12.105 mmol, 2.0 eq.) was added in portions at 0° C. and the mixture was stirred for 16 hours at RT. After monitoring by TLC, the reaction mixture was concentrated under reduced pressure and the residue was taken up in water (50 ml) and extracted with 10% MeOH in DCM (2×75 ml). The combined org. phases were dried over sodium sulfate, concentrated and purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 21% (270 mg, 1.310 mmol)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=1.C>O1CCOCC1>[F:18][C:2]([F:1])([F:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=1)=[O:16])(=[O:13])=[O:12]
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1CCC(F)(F)F
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2CCC(F)(F)F)nc(OC)n1

Procedure:
5.6 g of 2-(3,3,3-trifluoropropyl)-phenylsulfonylisocyanate and 3.12 g of 2-amino-4,6-dimethoxy-1,3,5-triazine are stirred up in 60 ml of absolute dioxane at 70°-80° C. for 2 hours. The mixture is subsequently treated with active charcoal, filtered, and concentrated by evaporation to about 1/5 of the volume. There crystallise from the residue, after the addition of ether, 6.8 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-(4,6- dimethoxy-1,3,5-triazin-2-yl)-urea, m.p. 177°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1)#[CH:12]
Reactant: COc1ccc(C=O)cc1F
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166.5 %

Procedure:
To the mixture of 3-fluoro-4-methoxybenzaldehyde (0.589 g, 3.0 mmol), potassium carbonate (1.8 g, 13.0 mmol) in methanol (65 mL) at room temperature was added slowly dimethyl 1-diazo-2-oxopropylphosphonate (1.4 g, 7.2 mmol). The resulting mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to provide 4-ethynyl-2-fluoro-1-methoxybenzene (622) (0.750 g, 76.9%) as a colorless oil.