Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[F:10][C:11]1[CH:12]=[C:13]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH:14]=[CH:15][C:16]=1[F:17]>CO>[F:10][C:11]1[CH:12]=[C:13]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32](/[CH:35]=[N:8]\[OH:9])=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1cccnc1)c1cc(/C=N\O)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.44 ml, 5.43 mmol) and hydroxylamine hydrochloride (75 mg, 1.09 mmol) were added to a solution of 2-([(3,4-difluorophenyl)methyl]oxy)-5-formyl-N-3-pyridinylbenzamide (may be prepared by Example 80; 200 mg, 0.54 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 30 min. The mixture was evaporated under reduced pressure to half volume. The mixture was diluted with water (20 ml) and filtered. The solid was washed with water (20 ml)/methanol (5 ml) and air dried under vacuum to yield the title compound as a white solid. 167 mg.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14](O)=[CH:13][C:12](O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:8]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: O=c1c(-c2ccccc2)coc2ccccc12
Yield: 28.4 %

Procedure:
Prepared according to the general procedure using genistein (300 mg, 1.11 mmol), K2CO3 (307 mg, 2.22 mmol), acetone and MeI (0.139 mL). Purified by flash column chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 15 (70 mg, 22%) as an off-white solid. Analytical data for isoflavone 15: 1H NMR (500 MHz, DMSO) δ 12.96 (s, 1H), 9.62 (s, 1H), 8.41 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 6.41 (s, 1H), 3.86 (s, 3H); 13C NMR (125 MHz, DMSO) δ 181.1, 165.9, 162.4, 158.2, 158.1, 155.1, 130.9, 123.2, 121.7, 115.8, 106.1, 98.7, 93.1, 56.8; LCMS: Mass calculated for C16H12O5, [M+H]+, 285. Found 285.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Cl>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([Cl:38])[CH:40]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1cccc(Cl)c1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccc(Cl)c3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-chlorobenzyl chloride (0.38 mL) as starting materials, 5-benzyloxy-N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[OH:9])[CH2:4][CH2:3]1.BrCC1C=C[C:26]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=CC=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:34][N:32]1[N:31]=[N:30][C:29]([CH2:26][N:2]2[CH2:7][CH2:6][CH:5]([CH:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=3)[OH:9])[CH2:4][CH2:3]2)=[N:33]1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1nnc(CN2CCC(C(O)c3ccc(OC(F)(F)F)cc3)CC2)n1

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 3, using 7.0 grams (0.026 mole) of 4-piperidyl[4-(trifluoromethoxy)phenyl]methanol, hydrochloride, 6.8 grams (0.026 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetraazole (prepared in a manner analogous to that of Steps A-C of Example 4), and 9.9 grams (0.077 mole) of N,N-diisopropylethylamine in about 40 mL of DMSO. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Na+].Br[CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6].C[O-].[Na+].[CH2:12]([SH:15])[CH2:13][SH:14].Cl>CCO.O>[CH2:12]([S:15][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[CH2:13][S:14][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6]
Reactant: O=S(=O)([O-])CCBr
Reactant: SCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCSCCSCCS(=O)(=O)O
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a solution of 2-bromoethylsulfonate sodium salt (25.6 g, 125 mmol) and sodium methoxide (8.03 g, 149 mmol) in EtOH (350 mL) at 0° C. was added, dropwise, a solution of 1,2-ethanedithiol (5.00 mL, 59.4 mmol) in EtOH (25 mL). The reaction mixture was allowed to warm to room temperature, and then heated to reflux for 48 hours. Next, the mixture was cooled to room temperature, and then acidified with 2 N HCl to pH 1-2. The resulting suspension was heated to 75° C. and water was slowly added in small portions until a clear solution was obtained. The reaction mixture was then cooled to room temperature, and then to 5° C. The resulting white precipitate was filtered off, washed with cold EtOH and dried, giving 11.9 g (64.6%) of Compound 4 as a white powder. 1H NMR (500 MHz, D2O) δ 3.27 (t, J=9.3, 6.4 Hz, 4H), 3.06-2.99 (m, 4H), 2.98 (s, 4H). 13C NMR (126 MHz, D2O) δ 51.11, 31.09, 25.58.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.Br[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Nc1ccc(Cl)nc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(Cl)nc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-aminopyridine (12.85 g, 0.1 mol) and N-(2-bromoethyl)phthalimide (25.4 g, 0.1 mol) were stirred together at ambient temperature (20° C.). The resulting mixture was heated to 120° C. and held at that temperature for 30 minutes whilst vigorous stirring was maintained. The mixture was allowed to cool, and when the temperature had reduced to 60° C., methanol (250 ml) was added and stirring was maintained until a homogeneous solution was obtained. The solution was then cooled to ambient temperature (20° C.), silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm) (50 g) was added and the mixture was evaporated to dryness. The title product, (N-(N-(6-chloro-3-pyridyl)-2-aminoethyl)phthalimide, was isolated from the dried mixture by flash chromatography on a silica column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), and with 2% w methanol in dichloromethane as eluent, as a buff solid (7 g, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane, N-methyl-4-piperidone (5 g) was added to the mixture, followed by 12 g NaBH(OAc)3 and 1 mL of glacial ACOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (200 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford an orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.32.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][O:46][C:47]4[C:56]5[C:51](=[CH:52][C:53]([O:57][CH3:58])=[CH:54][CH:55]=5)[N:50]=[CH:49][CH:48]=4)=[N:43][N:44]=3)[N:41]=2)[CH:33]=[CH:32][C:31]=1O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][O:46][C:47]4[C:56]5[C:51](=[CH:52][C:53]([O:57][CH3:58])=[CH:54][CH:55]=5)[N:50]=[CH:49][CH:48]=4)=[N:43][N:44]=3)[N:41]=2)[CH:33]=[CH:32][C:31]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(O)c(F)c5)nn34)ccnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(OCCN6CCOCC6)c(F)c5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-hydroxyethyl)morpholine (0.0964 ml, 0.788 mmol), triphenylphosphine (0.238 g, 0.909 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenol (0.253 g, 0.606 mmol)(prepared according to General Method A) in THF (10 mL) was added DEAD (0.144 ml, 0.909 mmol). Stirred at room temperature for 1 h. Concentrated. Purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=531.2 [M+1]+. Calc'd for C28H27FN6O4: 530.5.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[C:20]([CH2:30]C(C)C)=[C:21](C)C=CC=2S([O-])(=O)=O)[CH:16]=[CH:17][CH:18]=1>[OH-].[Na+]>[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([CH3:30])[CH2:21][N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC1CNCC(C)O1
Reactant: COCOc1cccc(-c2c(S(=O)(=O)[O-])ccc(C)c2CC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: COCOc1cccc(CC(C)CN2CC(C)OC(C)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
2,6-Dimethylmorpholine (10.0 g) was heated to 100° C. with stirring, and 3-(m-methoxymethoxyphenyl)-2-methylpropyl-p-toluenesulfonate (5.0 g) was dropwise added thereto in 1 hour. The reaction mixture was aged at 100° C. for 2 hours with stirring, cooled to room temperature, and after addition of 15% aqueous sodium hydroxide (50 ml), extracted with diethyl ether (50 ml×3). The organic layer was combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 4-[3-(m-methoxymethoxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine (1.2 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[N:19]=[C:18]([CH:30]([CH3:32])[CH3:31])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:30]([CH3:32])[CH3:31])=[N:19][N:20]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (86.5 g, 486 mmol) was added in portions to the pyrazole (164 g, 486 mmol, Step A) in DMF (1l) at 0° C. under an atmosphere of N2. This mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was poured into H2O (1 l) and the resulting precipitate was collected and washed with water. The product was dried overnight to give 184.1 g (91%), mp 146°-147° C. (hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[C:10]([CH:35](OCC)[O:36]CC)[N:9]=2)=[C:4]([F:42])[C:3]=1[O:43][CH3:44].CC#N>O>[NH2:15][C:12]1[C:13]([F:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:43][CH3:44])[C:4]=2[F:42])[N:9]=[C:10]([CH:35]=[O:36])[CH:11]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C=O)cc(N)c2F)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2.117 g, 3.44 mmol), CH3CN (15 mL), water (15 mL) and 1 normal (N)H2SO4 (7.5 mL) was placed in an oil bath and heated to 80° C. After 2 h at 80° C., an aliquot of the reaction mixture was partitioned between EtOAc and 10% sodium bicarbonate (NaHCO3) and analyzed by high-performance liquid chromatography (HPLC) and TLC (80/20 hexanes/EtOAc). TLC and HPLC analyses showed only a trace of the starting material remaining (˜2% by HPLC) and essentially one, more polar product.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH2:42])([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH:42][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:25])([CH3:27])[CH3:26]
Reactant: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (180 mg, 0.494 mmol), 4-(3-aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.741 mmol) and diisopropylethylamine (128 mg, 0.988 mmol) in 1,4-dioxane (3 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 197 mg of 4-{3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-4-ethylpiperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving the material (197 mg, 0.329 mmol) in MeOH (25 mL) and dichloromethane (12 mL) and bubbling anhydrous hydrogen chloride gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (184 mg, 98% yield). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M(free base)+H].
Reaction SMILES: [F:1][C:2]([F:44])([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([F:43])=[CH:35][CH:34]=1)[CH2:3][NH:4][C:5]1[C:6]([F:32])=[C:7]([CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([CH3:31])=[N:19][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:21][CH:22]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1.CO.C(Cl)Cl>Cl.C(Cl)Cl>[ClH:11].[NH2:23][C:20]1[N:19]=[C:18]([CH3:31])[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]([Cl:11])=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:44])[C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]([F:43])=[CH:35][CH:34]=3)[C:6]=2[F:32])=[CH:22][CH:21]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.6 %

Procedure:
A solution of 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)}methyl)acetamide (10 mg, 16 μmol), as prepared in the preceding step, in HCl (0.5 mL, 4.0 M in 1,4-dioxane) was stirred for 2 hours at ambient temperature. A solution of MeOH/DCM (25%, 0.4 mL) was added, and the mixture continued to stir overnight. The solvents were evaporated, and the resulting brown residue was flash chromatographed on silica gel eluting with MeOH/DCM (2.5, 5, and 10%) to give a solid product. It was treated with HCl solution (0.01 mL, 4.0 M in 1,4-dioxane, 40 μmol) in DCM (0.5 mL), stirred for 5 minutes, and the solvents evaporated to give the title compound (6.2 mg, 69% yield) as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.4 Hz, 1H), 8.17-8.14 (m, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.73-7.64 (m, 4H), 7.20 (dd, J=10.0, 8.3 Hz, 1H), 6.82-6.79 (m, 1H), 6.49 (t, J=9.1 Hz, 1H), 4.24 (s, 2H), 4.10-4.02 (m, 2H), 3.66 (d, J=2.3 Hz, 2H), 2.49 (s, 3H). Mass spectrum (LCMS, ESI) calc'd for C27H24ClF4N4O (M+H): 531.1. Found: 531.6.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:23]>>[NH2:23]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1

Procedure:
When 2-benzoyl-benzo[b]thiophen-3-ol was reacted with the following reagents in place of ammonium acetate under the conditions of Example 35, the title compound was obtained, characterized in each case by its thin-layer chromatogram, mixed melting point, elemental analysis and IR spectrum, with the yields shown to the right below:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[CH:22]=[CH:21][O:20][CH:19]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[CH:22]=[CH:21][O:20][CH:19]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccoc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccoc1
Yield: 66.1 %

Procedure:
8.0 g of ethyl 3-(4-fluorobenzoylamino)-3-(3-furylcarbonyl)propionate, 40 ml of chloroform and 20 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 5.0 g of ethyl 2-[2-(4-fluorophenyl)-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 65.8%
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one and (S)-1-pyrrolidin-2-yl-methanol in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)C(C)O3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)C(C)O3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 24hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes. was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give crystals, which were recrystallized from ethanol-ethyl acetate to give N-[4-[hydroxy(1-oxidopyridin-2-yl)-methyl]phenyl]-6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (Compound 203) (129 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].C(OC)(OC)OC>>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[O:19][CH2:18][CH2:17][O:7]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: OCCO
Solvent: COC(OC)OC
Product: Oc1ccc(C2(c3ccc(O)cc3)OCCO2)cc1
Reaction time: 18 h

Procedure:
2,2-bis(4-hydroxyphenyl)-1,3-dioxolane was prepared by the procedure of Example 5 by mixing together, in a reaction flask fitted with a mechanical stirrer, thermometer, and variable take-off distillation head, 99 gm of 4,4'-dihydroxybenzophenone (97% pure, 0.448 mole), 269 gm of ethylene glycol (4.3 moles), 96 gm of trimethyl orthoformate (0.91 mole), and 150 gm of montmorillonite clay (K-10, United Catalysts) and heating the reaction mixture at 70° to 90° to give slow distillation of the reaction by-products. After about 18 hours, 66 gm of distillate had been collected, an additional 64 gm of trimethylorthoformate (0.60 mole) was added to the reaction mixture, and the reaction continued. After a total of 24 hours reaction time, NMR analysis of a reaction sample showed about 2.23 mole ratio of ketal product to ketone starting material; after a total of 48 hours reaction time, NMR analysis of a second reaction sample showed the mole ratio was about 19 (about 95% conversion to ketal product). The reaction mixture was heated for an additional 8 hours and then cooled; NMR analysis again showed about 95% conversion.