Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC#N>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccnc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of 3-bromopyridine (4.82 mL, 0.05 mol), palladium acetate (0.22 g, 0.02 equiv.), tri-(o-tolyl)phosphine (0.61 g, 0.04 equiv.), methyl acrylate (9.01 mL, 2 equiv.), triethylamine (12.5 mL) and CH3CN (25 mL) was sealed in a bomb and heated to 100° C. for 3.5 hours. The mixture was cooled in an ice-bath, the bomb was vented and the reaction mixture was concentrated in vacuo. The residue was extracted with 0.5N HCl/Et2O (3×), the organic layer was backwashed with additional 0.5N HCl and the aqueous layers were combined, basified with saturated NaHCO3 and extracted with ether. The ether layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 7.89 g (97%) of methyl 3-(3-pyridyl)-2-propenoate.
Reaction SMILES: CO[C:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH2:14]1COCC1>>[CH3:14][O:11][CH2:10][CH:9]1[CH2:12][CH2:13][CH:6]([CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8]1
Reactant: C1CCOC1
Reactant: COC(C)(C)c1ccc(C=O)cc1
Product: COCC1CCC(C(C)C)CC1

Procedure:
In an autoclave, 405 g (2.5 moles) of the 4-(1-methoxy-1-methylethyl)-benzaldehyde obtained according to A, in 200 ml of THF, were flushed several times with nitrogen and hydrogen in the presence of 1 g of ruthenium hydroxide and then hydrogenated at 150° C. and under a hydrogen pressure of 300 bar until the pressure remained constant.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(Cl)Cl.CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])c4ccccc34)ccn2)CC1
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)c4ccccc34)ccn2)CC1

Procedure:
A solution of the urea product, obtained above, (130 mg, 0.32 mmol) in DCM/MeOH (1:1 v/v, 40 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm, 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (10 mL) and sat. aq NaHCO3 and the organic layer was separated and washed with brine (10 mL), dried and evaporated in vacuo to afford the title compound, Intermediate D6, as a red solid (87 mg, 69%); Rt 1.05 min (Method 2); m/z 378 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].[Mg+2].[Cl-].[Cl-].CCN(CC)CC.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])C(Cl)=O>C1COCC1.CCOC(C)=O>[F:21][C:22]1[CH:23]=[C:24]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A 2 L round bottomed flask was fitted with a mechanical stir motor and nitrogen inlet. To a 10° C. solution of potassium 3-ethoxy-3-oxopropanoate (55.15 g, 324 mmol) in THF (500 mL) was added MgCl2 (38.56 g, 405 mmol) and Et3N (45 mL, 324 mmol). The reaction mixture was allowed to warm to 23° C. and stir for 3 h. A solution of 3-fluoro-4-nitrobenzoyl chloride (˜162 mmol) in THF (200 mL) was added. The reaction turned yellow instantly and a precipitate formed. THF (200 mL) was added to ensure that stirring was not impeded. TLC analysis indicated that the reaction had gone to completion however the reaction was allowed to stir over night. The reaction was quenched with 2 N HCl (1 L) and extracted with EtOAc (2×500 mL). The organic layer was washed with saturated NaHCO3 (500 mL), H2O (300 mL) and brine (200 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The desired product (37.65 g, 147 mmol) was isolated by flash column chromatography in 91% yield (1:1 Hex EtOAc) as a yellow solid as a mixture of keto (75%) and enol (25%) tautomers. 1H-NMR (DMSO-d6) Keto tautomer δ 8.29 (dd, J=8.6, 7.4 Hz, 1H), 8.10 (dd, J=11.6, 2.0 Hz, 1H), 7.94 (m, 1H), 4.30 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H); Enol tautomer δ 12.44 (br s, 1H), 8.22 (app t, J=8.2 Hz, 1H), 8.05 (dd, J=12.6, 2.0 Hz, 1H), 7.90 (m, 1H), 6.22 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H); LCMS RT=3.14 min; MS {M+H]+=311.0.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([CH:39]=O)[CH:35]=[CH:34]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCO.C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[CH:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:39]([C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[C:29]([O:28][CH3:27])[CH:30]=[CH:31][CH:32]=4)[N:37]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cccc2ccc(C=O)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of tert-butyl (3S)-1-(2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.20 g, 0.53 mmol) and 8-methoxyquinoline-2-carbaldehyde (0.105 g, 0.53 mmol) in EtOH (10 mL) was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and iodobenzene diacetate (0.189 g, 0.59 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give tert-butyl (3S)-1-(2,2,2-trifluoro-1-(3-(8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.27 g, 93.4%) as off white solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)Cc1cccc(Cl)c1
Product: N#Cc1ccnc(-n2nc(Cc3cccc(Cl)c3)cc2O)c1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(3-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([NH2:20])=[C:15]([CH3:21])[C:14]=1[CH2:22][O:23]C(=O)C)[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.COC(=O)[C@@H](CC1C(CO)=C2C(=CC=1)N[N:42]=C2)CC(OC)=O>>[Cl:19][C:17]1[CH:18]=[C:13]([CH2:12][C@@H:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:4]([O:3][CH3:1])=[O:27])[C:14]([CH2:22][OH:23])=[C:15]2[C:16]=1[NH:20][N:42]=[CH:21]2
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Product: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CO)C(=O)OC
Yield: 99 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (2.21 g, 5.4 mmol) was converted to the title compound in a manner analogous to the preparation of 2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester. Material was obtained as amber solid in 99% yield. MS m/e (M+H)+=241.2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][N:34]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 4 h
Yield: 133.1 %

Procedure:
Methane sulfonyl chloride (10 mg, 0.09 mmol) was added to cold (0-5° C.) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (35 mg, 0.08 mmol) and Et3N (10 mg, 0.1 mmol) in DCM (1 mL); stirring was continued at 25-35° C. for 4 h. Reaction mixture was diluted with DCM, washed with water, aqueous NaHCO3 solution followed by brine to afford the crude compound, which was purified by preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 10% MeOH in CHCl3 as eluent) to afford 53.63 mg of the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:34])[C@@H:23]([CH3:33])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:32])([CH3:31])[CH:28]=[CH:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[OH:36].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:34])[C@@H:23]([CH3:33])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:32])([CH3:31])[C@H:28]5[O:36][C@H:29]5[CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H]3O[C@H]3C[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 70.3 %

Procedure:
To a solution of Compound (41b) (40 mg, 0.08 mmol) in 4 ml of dichloromethane was added 15 mg (0.18 mmol) of sodium hydrogen carbonate under ice-cooling. To the resulting suspension was added 25 mg (0.116 mmol) of 80% m-chloroperbenzoic acid, and the mixture stirred for 18.5 hours at room temperature. To the reaction mixture were added 0.5N aqueous sodium thiosulfate solution and an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; chloroform:methanol=100:1) to give 28 mg (85%) of Compound (43b).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[CH:15]1([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate 90.3 g, 1.5 mmol) in dichloroethane (10 mL) was add cyclopropylamine (0.13 mL, 1.95 mmol), sodium triacetoxyborohydride (0.48 g, 2.26 mmol) and a few drops of acetic acid. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with NaHCO3 solution. The organic phase was separated and then dried over MgSO4. Following concentration, the residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 4.03 (d, J=12.21 Hz, 2 H), 2.79 (m, 3 H), 2.14 (m, 1 H), 1.91 (d, J=12.55 Hz, 2 H), 1.69 (m, 2 H), 1.46 (m, 9 H), 1.27 (m, 2 H), 0.47 (m, 2 H), 0.36 (m, 2 H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([CH:8]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])[CH3:7])[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].O>C(OCC)(=O)C>[CH2:1]([O:4][N:5]=[C:6]([CH:8]([N:10]([C:11]1[C:12]([CH3:18])=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17])[C:27](=[O:28])[CH2:26][Cl:25])[CH3:9])[CH3:7])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C=CCON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a solution of 3-(2,6 -dimethylphenylamino)-2-butanone O-allyl oxime (4.5 g) in 75 ml ethyl acetate and 1.6 g pyridine was added dropwise 2.3 g chloroacetyl chloride. The mixture was stirred for 15 minutes, and poured into 1 liter of water. The organic phase was collected, diluted with 100 ml ether, washed with water, dried (MgSO4), treated with silica gel and stripped of solvent to yield 4.9 g yellow oil. The oil was chromatographed on silica gel (125 g) with elution by 3:1 CH2Cl2 :hexane followed by 5% acetone:CH2Cl2, to yield 2.5 g of the title product. This compound is tabulated as Compound No. 20 in Table I.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([N:40]([CH3:44])[C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:45][C:46]([F:51])([CH3:50])[C:47](O)=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([N:40]([CH3:44])[C:28]1[CH:29]=[CH:30][C:31]([NH:32][CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[C:26]([NH:25][C:47](=[O:48])[C:46]([F:51])([F:45])[CH3:50])[CH:27]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(F)F)c1
Reaction time: 8 h

Procedure:
HATU (1.44 g, 3.78 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylacetamide (1.00 g, 3.60 mmol) (for preparation, see Example 1, steps B to E) were added to a solution of 2,2-difluoropropanoic acid (0.40 g, 3.60 mmol) and DIPEA (0.75 mL, 4.32 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred overnight. The solvent was concentrated and the crude product was recovered in EtOAc. The organic was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield: 1.00 g (75%); MS (ESI) (M+H)+: 370.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[NH2:17].[Cl:18][CH2:19][C:20](Cl)=[O:21]>CC1C=CC=CC=1>[Cl:18][CH2:19][C:20]([NH:17][C:3]1[C:4]([CH3:16])=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:2]=1[CH3:1])=[O:21]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CCl
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 20 parts of 2,6-dimethyl-4-(phenylmethoxy)benzenamine and 270 parts of methylbenzene were added portionwise 10.9 parts of 2-chloroacetyl chloride (exothermic reaction, the temperature rose to 30° C.). Upon complete addition, the reaction mixture was stirred for 1 hour at reflux temperature. After cooling, the precipitated product was filtered off and dried, yielding 23.8 parts (89%) of 2-chloro-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]acetamide; mp. 165.3° C. (int. 71).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[F:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)=[N:20][C:19]=2[CH:32]=1.O>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:28]([NH:29][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:27][CH:26]=3)=[N:20][C:19]=2[CH:32]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(OCc2nc3cc(F)ccc3s2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(OCc2nc3cc(F)ccc3s2)cc1
Reaction time: 1 h
Yield: 55 %

Procedure:
0.09 ml of triethylamine and 0.07 ml of butyryl chloride were added to a solution of 150.8 mg of 4-(5-fluorobenzothiazol-2-ylmethoxy)aniline [prepared as described in step (b) above] in 3 ml of methylene chloride cooled in an ice-water bath. The temperature of the resulting mixture was then elevated to room temperature and the mixture was stirred for 1 hour. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was recrystallized from a mixed solvent of methylene chloride and hexane to give 104.5 mg (yield 55%) of the title compound as a solid having a melting point of 201° to 202° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[CH:10]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(F)cc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 2-amino-4-fluorobenzoic acid (Aldrich, 2.0 g) and pyridine-4-carbaldehyde (1.21 ml) in 1,2-dichloroethane (20 ml) was added sodium triacetoxy-borohydride (4.1 g). The reaction mixture was stirred at room temperature for 18 hours. Silica gel was added and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (elution with EtOAc/methanol 19/1, v/v) and gave the title compound (1.04 g). 13C-NMR (DMSO-d6) δ 169.1, 166.2, 152.5, 149.6, 148.2, 134.6, 121.9, 107.6, 102.1, 97.7, 44.6.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[C:37](=[O:49])[N:38]([C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:35])=[CH:29][C:28]=3[F:50])=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[O:51][CH3:52])C1C=CC=CC=1.Br.CCOCC>CC(O)=O>[F:50][C:28]1[CH:29]=[C:30]([NH:33][C:34]([C:36]2[C:37](=[O:49])[N:38]([C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)[CH:39]=[CH:40][CH:41]=2)=[O:35])[CH:31]=[CH:32][C:27]=1[O:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([OH:15])=[C:17]([O:51][CH3:52])[CH:18]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1O
Reaction time: 1.17 h
Yield: 58.9 %

Procedure:
A mixture of N-(4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide trifluoroacetic acid salt (40 mg, 0.056 mmol) and HBr in HOAc (3 mL of 33% solution) was allowed to stay at rt for 70 minutes. Ether (25 mL) was added to the reaction mixture, stirred for 20 minutes, and the solid was filtered and dried to obtain the product (17 mg, 59%) as a light brown solid. 1H NMR (DMF-d7) δ 12.35 (s, 1H), 8.94 (d, 1H, J=6.6 Hz), 8.70 (d, 1H, J=7.7 Hz), 8.23-7.50 (m, 12H), 7.12 (d, 1H, J=6.6 Hz), 6.84 (m, 1H), 4.17 (s, 3H); MS(ESI+) m/z 516.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([N:21]1[CH2:22][CH2:23][CH:19]([CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][C:13]=2[O:24][CH3:25])[N:10]=[CH:9][N:8]=[C:7]3[NH:6][C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=2[F:29])[CH2:20]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNC1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCN(C(C)=O)C1
Yield: 63 %

Procedure:
Using a procedure similar to that described in Example 38, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazoline hydrochloride (300 mg; prepared as described in Example 33-starting material) was reacted with acetic anhydride to give the title product (194 mg, 63%); 1H NMR Spectrum (DMSO d6+CD3COOD) 1.71-1.90 (m, 1H); 1.93-1.94 (m, 3H); 2.00-2.20 (m, 1H); 2.66-2.86 (m, 1H); 3.18-3.31 (m, 1H); 3.43-3.72 (m, 3H); 3.93 (m, 3H); 4.04-4.18 (m, 2H); 7.15-7.32 (m, 2H); 7.42-7.53 (m, 2H); 7.78-7.80 (m, 1H); 8.35-8.37 (m, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH:4]3[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]3)=[CH:14][CH:13]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCCC(O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC3CCCC(=O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 15 h
Yield: 82.8 %

Procedure:
To a solution of 3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.40 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.43 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.33 g, 84%).