Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH2:5][N+:6]([O-])=[O:7].C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][N:3]=[C:4]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:5]1=[N:6][OH:7]
Reactant: CON=C(C[N+](=O)[O-])c1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C1C(=NO)Oc2ccccc21
Temperature: 92.5 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
71.8 g of 1-(2-hydroxy-phenyl)-2-nitro-ethanone O-methyl-oxime are added to a solution of 121 g (0.342 mol) of sodium bicarbonate in 700 ml of water. Within 30 minutes, the mixture is heated to 90-95° C., on which undissolved starting material melts and reacts and the product crystallizes out. The mixture is cooled to 20° C. and the product is filtered off, washed with 500 ml of water a little at a time and air-dried. 57.4 g (91.3% of theory) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime are obtained as a mixture of two stereoisomers.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:13]([CH3:15])=[CH2:14]>C(OCC)(=O)C.[Pd]>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH:13]([CH3:15])[CH3:14])[C:2]=1[OH:1])[C:6]#[N:7]
Reactant: C=C(C)c1cc(C#N)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C#N)cc(N)c1O
Reaction time: 14 h

Procedure:
To a solution of 4-hydroxy-3-isopropenyl-5-nitrobenzonitrile (4.135 g, 20.25 mmol) in ethyl acetate (100 ml) was added 1.2 g of Pd/C. The resulting mixture was degassed and flushed with nitrogen, and then degassed and flushed with hydrogen using a double balloon. The reaction was stirred under hydrogen for 14 h, and then diluted with ethyl acetate, filtered through a pad of Celite and concentrated. The residue was purified by flash column chromatography using a Horizon Biotage, 65i Si column, eluting with 1 column volume of dichloromethane, followed by a linear gradient of ethyl acetate in dichloromethane from 0% to 50% over 10 column volume. It was then repurified by flash column chromatography using a Horizon Biotage, 65i Si column, eluting with 1 column volume of 5% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 5% to 100% over 10 column volumes to afford the title compound. Mass spectrum (ESI) 177.4 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:18]1=[O:19].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[O:17][C:18](=[O:19])[CH:20]2[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=c1ccc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Oc2ccccc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
N-Benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine (1.54 mL, 0.00600 mol) in methylene chloride (0.50 mL) was added to a mixture of coumarin (0.731 g, 0.00500 mol) and of trifluoroacetic acid in DCM (1M, 10 mL) at rt. The resulting mixture was stirred at rt for 1 h and was then washed with NaHCO3 (2 mL) and brine (2 mL) successively. The organic phase was dried (over Na3SO4), filtered, and concentrated. The residue was purified by CombiFlash (ethyl acetate/hexane 20%) to give the desired product (0.99 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:1][C:2]3[C:3](=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][CH:11]=3)[N:12]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(O)c1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COC(=O)c1cccc2oc(-c3ccc(OC)cc3)nc12
Yield: 18 %

Procedure:
Methyl 2-(4-methoxyphenyl)benzoxazole-4-carboxylate was prepared from methyl 3-hydroxyanthranilate and 4-methoxybenzoyl chloride as described in Step A of Example 1. The product was obtained as an off-white solid in 18% yield. δ 8.29 (m, 2H), 8.01 (dd, J=7.8, 1.0 Hz, 1H), 7.74 (dd, J=8.1, 1.0 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.03 (m, 2H), 4.06 (s, 3H); 3.91 (s, 3H); MS (ESI) m/z 284 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:17]O)[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[Br:19]P(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:5]=[C:4]([CH2:17][Br:19])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Oc2ncc(CBr)cc2Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A solution of the product from Example 60B (0.73 g, 2.309 mmol) in dichloromethane (11.55 mL) under nitrogen was treated dropwise with tribromophosphine (0.218 mL, 2.309 mmol), stirred for one hour and poured into ice water and the pH was adjusted to pH 9 by addition of solid sodium bicarbonate added portionwise. An emulsion formed that was partially removed by filtration. The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4) filtered, and concentrated to afford the title compound (0.75 g, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].O=S(Cl)[Cl:15]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc(C(=O)Cl)cc1F
Yield: 99 %

Procedure:
A mixture of 4-cyano-3-fluoro-benzoic acid (2.0 g, 12.12 mmol) in SOCl2 (20 mL) was refluxed for 2 h, and SOCl2 was removed in vacuo to give 4-cyano-3-fluoro-benzoyl chloride (2.2 g, 99%). The crude was carried to the next step without further purification.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:8]([CH:16]=1)[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:8]([CH:16]=1)[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydroxide solution (0.2 N) was added to 3-(5-amino-2-hydroxybenzoyl)propionic acid (2.4 g) until all the solid had dissolved. Acetic anhydride (3.0 ml) was quickly added to the solution (pH 10) with vigorous stirring at 10°-15°C, after which the pH reading was in the range 4-5, and stirring was continued for a further 60 minutes. The precipitated solid was collected and washed with water and a second crop was obtained by evaporation of the filtrate and addition of water to the residue. The combined solids were recrystallised from ethanol to give 3-(5-acetamido-2-hydroxybenzoyl)propionic acid (2.2g, 76%), m.p. 205°-206°C.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:19]([CH:15]3[CH2:16][CH2:17][CH2:18][N:13]([C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:38])=[O:2])=[CH:9][CH:8]=4)=[O:12])[CH2:14]3)([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[C:20](=[O:29])[NH:21]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester (0.24 g, 0.44 mmol) (from Example 63 supra) in tetrahydro furan (2.5 mL) was added the suspension of lithium hydroxide monohydrate (0.18 g, 4.4 mmol) (Aldrich). The mixture was stirred at room temperature for overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH<5 with dilute HCl, then extracted with ethyl acetate several times. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>O1CCCC1.O>[Br:12][C:5]1[C:4]([OH:11])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(O)c1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2,3-dimethoxy-phenol (6 g, 38.70 mmol) in tetrahydrofuran (30 mL) at 25° C., was added N-bromosuccinimide (6.89 g, 38.70 mmol) and the resultant reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6-Bromo-2,3-dimethoxyphenol as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2o1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Temperature: 150 °C
Yield: 34.1 %

Procedure:
To a solution of 4-amino-1-cinnamylpiperidine (1.3 g, 6 mmol) and triethylamine (1.6 mL, 7.2 mmol) in dry acetonitrile (125 mL) was added trifluoromethanesulfonic acid 6-bromo-2-oxo-2H-chromen-4-yl ester (2.23 g, 6 mmol). About 5 mL of solution was added to each of 25 dry microwave vials equipped with stir bars. The vials were capped and each was heated at 150° C. for 5 minutes in the microwave. The solutions were combined, concentrated and dissolved in chloroform. The solution was washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the desired compound (900 mg, 34%) as a yellow solid. MS (ESI(+)Q1MS m/z 440 (M+2H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.57-1.67 (m, 2H), 1.89-1.95 (m, 2H), 2.13 (m, 2H), 2.92 (m, 2H), 3.13 (m, 2H), 3.50 (m, 1H), 5.28 (sd, 1H), 6.35 (dt, 1H), 6.56 (d, 1H), 7.24-7.47 (m. 7H), 7.74 (dd, 1H), 8.45 (d, 1H).
Reaction SMILES: [NH2:1][C:2]([C:6]([CH3:10])([CH3:9])[C:7]#[N:8])=[CH:3][C:4]#[N:5].N[OH:12].Cl>CO>[NH2:5][C:4]1[O:12][N:1]=[C:2]([C:6]([CH3:10])([CH3:9])[C:7]#[N:8])[CH:3]=1
Reactant: CC(C)(C#N)C(N)=CC#N
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC(C)(C#N)c1cc(N)on1
Temperature: 40 °C
Reaction time: 7 h
Yield: 66.2 %

Procedure:
To 3-Amino-4,4-dimethyl-pent-2-endinitrile (10.0 g, 74 mmol) in MeOH (150 mL) is added NH2OH.HCl (10.0 g, 144 mmol). The mixture is stirred at 40° C. for 7 h, concentrated, suspended in isopropyl acetate (100 mL) and washed with 4 N aq. NaOH (2×100 mL) and brine (50 mL). The extracted org. layer is concentrated to provide 7.40 g of 2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile. Yield: 66%; ESI-MS: 152 [M+H]+; 1H-NMR (DMSO-d6): 1.6, 5.1, 6.8 ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1.[Br:10][CH:11](Br)C1C=CC=C(F)N=1>>[Br:10][CH2:11][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1
Reactant: Fc1cccc(CBr)n1
Reactant: Fc1cccc(C(Br)Br)n1
Product: Fc1cccc(CCBr)n1

Procedure:
Fractions 2 and 3 were >96% pure 2-bromomethyl-6-fluoropyridine and were therefore combined. Fraction 4 was composed of a 1:1 mixture of 2-bromomethyl-6-fluoropyridine and 2-dibromomethyl-6-fluoropyridine. The nmr spectra was consistent with the proposed structure for Fractions 2 and 3.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ethyl 6-methyl-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)phenyl)-1,4-dihydropyrimidine-5-carboxylate (7.9 g, 20 mmol) in carbon tetrachloride (100 mL) was added NBS (3.74 g, 21 mmol) under N2 at 60° C. The reaction mixture was stirred at 60° C. for 10 minutes, and cooled to 25° C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (6.64 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]([CH2:44][CH3:45])[C:39](=[O:46])[CH:38]=1>>[CH2:44]([N:40]1[C:41]([CH3:43])=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39]1=[O:46])[CH3:45]
Reactant: CCn1c(C)cc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCn1c(C)cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1-ethyl-6-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.211 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.17 (s, 3H), 1.49 (s, 9H), 1.57 (d, 3H), 2.22 (m, 4H), 2.37 (m, 1H), 2.84 (m, 1H), 5.60 (m, 1H), 5.91 (s, 1H), 7.06 (d, 2H), 7.27-7.40 (m, 5H), 7.68 (d, 1H), 7.24 (d, 2H), 8.09 (d, 1H), 8.90 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)[N:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46]>CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:31][CH:30]=3)[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnn34)CC2)cc1
Solvent: CO
Product: CN(C)CCNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
A solution of toluene-4-sulfonic acid 4-[4-amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl ester (5.0 mg, 0.0088 mmol), N,N-dimethyl-1,2-ethanediamine (1 mL, 0.009 mol) in MeOH (1 mL) was heated in microwave reactor at 300 watt, 100° C. for 2 h. The solvent and excess amine were removed in vacuo, and the material was purified by silica gel chromatography, eluting with 5% (7N NH3 in MeOH) in DCM. HPLC: tR=1.99 min. (OpenLynx, polar—5 min). MS (ES+): m/z 486.19 (100) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Yield: 99.5 %

Procedure:
A solution of 1.8 g of the ester of Example 1, 25 ml of N sodium hydroxide solution, 25 ml of water and 100 ml of methanol was heated at 70°-75° C. for 90 minutes and the methanol was then evaporated. 100 ml of water and 10 ml of dimethylformamide were added to the mixture which was then heated to reflux. 4 ml of acetic acid were added thereto and the mixture was held in an ice bath for an hour and was then vacuum filtered. The recovered crystals were washed with water and dried to obtain 1.715 g of 2-(7-chloro-4-quinolinylamino)-5-fluoro-benzoic acid melting at 341°-342° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
5.5 of 3-trifluoromethylbenzoyl chloride were dropped slowly onto 15 ml of an aqueous solution containing 2.0 g of glycine and 2.1 g of sodium hydroxide, and then, after the dropwise addition was complete, the reaction solution was heated at 70° C. for 2 hours, with stirring. The mixture was allowed to stand to cool, and then the reaction solution was washed with ethyl acetate, the aqueous layer was neutralized with 8N hydrochloric acid, and the crystals which separated out were filtered to afford 4.6 g of the title compound, after drying.
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH3:9][O:10][CH2:11][C:12]([NH:18][CH3:19])=[CH:13][C:14]([O:16][CH3:17])=[O:15]>C(O)(=O)C>[OH:7][C:4]1[CH:3]=[C:2]2[C:1](=[CH:6][CH:5]=1)[N:18]([CH3:19])[C:12]([CH2:11][O:10][CH3:9])=[C:13]2[C:14]([O:16][CH3:17])=[O:15]
Reactant: CNC(=CC(=O)OC)COC
Reactant: O=C1C=CC(=O)C=C1
Solvent: CC(=O)O
Product: COCc1c(C(=O)OC)c2cc(O)ccc2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.9 %

Procedure:
3.1 g of 1,4-benzoquinone (28.7 mmol) was dissolved in 50 ml of acetic acid to which was subsequently added dropwise 2.28 g (14.3 mmol) of methyl 4-methoxy-3-methylamino-2-butenoate and the mixture was stirred for 5 hours at room temperature. After the solvent was distilled off under reduced pressure, the resulting residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column chromatography (eluent: hexane-ethyl acetate, 2:1) to obtain 0.78 g of the title compound with a yield of 22%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70.4 %

Procedure:
Using 5-methylsalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([PH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([O:9][C:10](=[O:13])[CH:11]=[CH2:12])[CH3:8]>>[CH2:1]([P:6]([CH2:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:13])[CH2:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:13])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCP
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCP(CCC(=O)OCC)CCC(C)C

Procedure:
Using the procedure of Example 1, isopentyl phosphine is reacted at 70°-90° C. with ethylacrylate to give isopentylbis(carbethoxyethyl)phosphine. The latter is oxidized with hydrogen peroxide and hydrolyzed with aqueous dilute hydrochloric acid to give the corresponding acid, isopentylbis(β-carboxyethyl)phosphine oxide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.CN1CCOCC1>CN(C=O)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH:5]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCc1cccnc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(Cc3cccnc3)c2)OC1(C)C
Temperature: 100 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 3-picolyl chloride (prepared from the hydrochloride salt using a pre-swelled suspension of morpholinomethyl polystyrene in DMF) according to Method AC (heating to 100° C. under microwave irradiation for 2 h) and was isolated as a brown oil (71%). LCMS (ES+) 286 (M+H)+, RT 1.98 minutes (Method 1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C@H:12]2[C@@H:18]([CH2:19][NH:20][S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22])[O:17][CH2:16][CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].[Cl-].[NH4+]>CO>[Cl:4][C:5]1[CH:6]=[C:7]([C@H:12]2[C@@H:18]([CH2:19][NH:20][S:21]([CH2:24][CH2:25][O:2][CH3:1])(=[O:23])=[O:22])[O:17][CH2:16][CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C[O-]
Reactant: C=CS(=O)(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COCCS(=O)(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 28% solution (5 ml) of sodium methoxide in methanol was added dropwise to a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-{[(ethenylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (235 mg) in methanol (1 mL), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (215 mg).