Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
4.85 g (22.56 mmol) of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one was dissolved in 60 ml of ethanol. 3.13 g (45 mmol) hydroxylamine hydrochloride was then added followed by 1.8 g (45 mmol) of NaOH in 15 ml of water. The mixture was refluxed for 20 hrs and was cooled to ambient temperature. The solvent was removed in vaccuo. The residue was diluted with ethyl acetate and washed with water and the organic layer was dried over sodium sulfate. The solvent was removed to give 4.28 g of product as a light yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH3:15].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:36][CH:35]=1)[CH3:15]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(O)c1ccc(Cl)cc1Br
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Neat methanesulfonyl chloride (0.40 mL, 5.1 mmol) was added to a 0° C., DCM solution (20 mL) of 1-(2-bromo-4-chlorophenyl)ethanol (1.2 g, 5.1 mmol) and Et3N (0.78 mL, 5.6 mmol) and the resulting mixture was allowed to warm to room temperature gradually. After 30 min, Et3N (0.78 mL, 5.6 mmol) and 4′-chloro-[1,1′-biphenyl]-4-amine (1.0 g, 5.1 mmol) were added sequentially and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][N:10]1[CH3:20].O1CCCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]1[CH3:20]
Reactant: CCOC(=O)c1cn(C)n(-c2ccccc2OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-n1c(=O)c(C(=O)O)cn1C
Yield: 83.2 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 2-(2-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.5 g, 9.2 mmol), tetrahydrofuran (6 mL), methanol (5 mL) and 4N aqueous sodium hydroxide solution (8 mL) as starting materials, the title compound (1.9 g, 85%) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:17][CH2:16]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:19][CH2:20]1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Yield: 77.3 %

Procedure:
To a solution of 700 mg (1.32 mmol) of 3-[1-(3-benzyloxycarbonylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in acetic acid was added 50 mg 10 % palladium-carbon, and the mixture was stirred for 5 hours in a hydrogen atmosphere at ambient temperature. The reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. The resulting crude crystals were recrystallized from ethanol to give 450 mg (1.02 mmol) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.C(Cl)(=O)OCC.[NH2:19][C:20]1[C:39]([Cl:40])=[CH:38][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][C@H:28]2[O:36][CH3:37])=[O:25])=[C:22]([O:41][CH3:42])[CH:21]=1>ClC(Cl)Cl.C(N(CC)CC)C>[NH2:19][C:20]1[C:39]([Cl:40])=[CH:38][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:4](=[O:6])[CH:3]([CH2:2][OH:1])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:29][C@H:28]2[O:36][CH3:37])=[O:25])=[C:22]([O:41][CH3:42])[CH:21]=1
Reactant: O=C(O)C(CO)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)C(CO)c2ccccc2)C[C@H]1OC
Reaction time: 0.75 h
Yield: 10 %

Procedure:
To a stirred suspension of 2.99 parts of α-(hydroxymethyl)benzeneacetic acid in 60 parts of trichloromethane were added dropwise first 1.82 parts of N,N-diethylethanamine and then 1.95 parts of ethyl carbonochloridate at a temperature below 5° C. Upon completion, stirring was continued for 45 minutes at this low temperature. The thus obtained solution was added dropwise to a solution of 5.35 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide in 45 parts of trichloromethane while the temperature was kept below 10° C. Upon completion, the whole was stirred for 20 hours at room temperature. The organic layer was washed with a sodium carbonate solution in water and with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile and a few drops of water. The product was filtered off and dried in vacuo at 30° C., yielding 0.76 parts (10.0%) of cis-N-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-α-(hydroxymethyl)benzeneacetamide; mp. 114.0° C. (compound 87).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:10][CH2:9][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 18 mmol of the compound from Example 1 in 10 milliliters of toluene was mixed with a solution of 5.0 grams (17.8 mmol) of benzophenone in 25 milliliters of anhydrous toluene. After 16 hours stirring at 25° C. the reaction mixture was slowly and cautiously hydrolyzed with gas evolution noted at 0° C. with 5 milliliters of 1N aqueous HCl. The separated organic layer was washed with aqueous NaHCO3, dried over anhydrous MgSO4 and evaporated. Gas chromatographic analysis and mass spectral identification of the components showed that the ketone had been consumed, but only traces of the desired 1,1-diphenyl-1-heptene had been formed. The principal outcome of the reaction was reduction: diphenylmethanol was separated and identified.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Br[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)=O>>[CH3:48][C:44]1([CH3:49])[CH2:45][CH2:46][CH2:47][N:42]([CH2:40][CH2:39][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:43]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCC(C)(C)C3)c(F)c2)c1
Yield: 50.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:13][C:14]=2[C:15]([O:17]CC)=[O:16])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:13][C:14]=2[C:15]([OH:17])=[O:16])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C(C)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Temperature: 65 °C
Yield: 91.9 %

Procedure:
To a solution of ethyl 4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (1.42 g, 0.00373 mol) in tetrahydrofuran (30.2 mL, 0.373 mol) and methanol (6.04 mL, 0.149 mol) was added sodium hydroxide (1.0N in water, 29.8 mL, 0.0298 mol), and the resulting cloudy mixture was heated at 65° C. for 5 hours. The reaction was cooled to room temperature, diluted with water, and adjusted to pH 3.0 via addition of 1N aqueous HCl. The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford 4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (121) (1.21 g, yield 92%) as a white solid. LCMS: (FA) ES+ 353; 1H NMR (400 MHz, DMSO) δ 12.70 (bs, 1H), 7.37-7.34 (m, 2H), 7.33-7.30 (m, 2H), 5.09 (q, J=7.2, 1H), 3.69-3.76 (m, 4H), 3.48-3.39 (m, 4H), 1.49 (d, J=6.8, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:4][C:3]=1[OH:20].[N:21]#[C:22]Br.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[NH2:21][C:22]1[O:20][C:3]2[CH:4]=[C:5]([CH2:8][CH2:9][C:10]3[N:11]=[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]4[CH:19]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: Cc1ccn2cc(CCc3ccc(N)c(O)c3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccn2cc(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (1.5 g) and cyanogen bromide (0.7 g) in ethanol (25 ml) was stirred for 2 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with potassium carbonate and the mixture was extracted with a solution of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by alumina column chromatography eluting with a solution of chloroform and methanol (19:1, V/V). The fractions containing object compound were concentrated to give 2-amino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.44 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:23])[NH:7][C:6]=1[CH:24]=O)=[O:4].Cl.[NH2:27]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:24]([C:6]1[NH:7][C:8]([CH3:23])=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])#[N:27]
Reactant: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C=O)=C2C(=O)OC)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C#N)=C2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
In 16 ml of acetic acid was dissolved 1.87 g (5.5 mmol) of 3,5-dimethoxycarbonyl-2-formyl-1,4-dihydro-6-methyl-4-(3 -ethynylphenyl)pyridine obtained in Example 15. Thereto were added 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.67 g (8.2 mmol) of sodium acetate. The admixture was stirred for 2.5 hours at room temperature. Then 1.96 g (19.2 mmol) of acetic anhydride was added thereto, and the admixture was reacted for 1.5 hours at room temperature, further for 4 hours at 95°-100° C. After completing the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue. After neutralization of the reaction mixture with saturated solution of sodium hydrogencarbonate, the reaction mixture was extracted with ethyl acetate several times. The organic layer thereof was washed with water, dehydrated and concentrated. The residue was purified by subjecting to silica gel column chromatography [eluent: benzene-ethyl acetate (10 : 1)] and recrystallized from the mixture of ethyl acetate and n-hexane to give 1.2 g of the desired compound as yellow prism crystals (yield: 66.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([CH2:15][CH3:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][C:5]3([CH2:15][CH3:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]3=[O:14])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(3-chloropropyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-Furoyl chloride (118 μL, 1.2 mmol) was added to a stirred solution of Compound 26 (287 mg, 0.8 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried and recrystallized by hexane and ether to yield 340 mg (90%) of white solids. M.P. 146° C. 1H NMR (DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.97 (m, 4H), 5.47 (s, 2H), 6.66 (t, J=2.5 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.23 (d, J=7.4 Hz, 1H), 7.29-7.33 (m, 3H), 7.44 (d, J=1.3, 8.7 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 1H). EIMS m/z 475 (M+23). Anal. (C27H24N4O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14](=[O:18])(=[O:17])[CH2:15][CH2:16][C:12]=3[N:11](C(OC(C)(C)C)=O)[C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[Sn](C)(C)C.ClN1C(=O)CCC1=O.[I-:43].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14](=[O:18])(=[O:17])[CH2:15][CH2:16][C:12]=3[NH:11][C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[I:43]
Reactant: CC(C)(C)OC(=O)N1C2=C(C(=O)COC2)C(c2ccc(F)c([Sn](C)(C)C)c2)C2=C1CCS2(=O)=O
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C1COCC2=C1C(c1ccc(F)c(I)c1)C1=C(CCS1(=O)=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
The product from Example 1I (0.023 g, 0.038 mmol) in 1% acetic acid in methanol (25 mL) was treated with N-chlorosuccinimide (0.010 g, 0.077 mmol) and sodium iodide (0.011 g, 0.077 mmol), stirred for 10 minutes, treated with pulverized sodium thiosulfate pentahydrate (0.020 g, 0.080 mmol), stirred for 10 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 mL), stirred at ambient temperature for 15 minutes and concentrated to dryness. The residue was retreated with trifluoroacetic acid (3 mL), heated gently on a steam bath for 1 minute, allowed to cool to ambient temperature and concentrated to dryness. The residue was purified by chromatography on silica gel (2% methanol and then 5% methanol in methylene chloride) to provide the title compound (0.0156 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[O:45]=[C:39]1[CH:38]([N:30]2[C:29](=[O:46])[C:28]3[C:33](=[CH:34][CH:35]=[CH:36][C:27]=3[CH2:26][NH:25][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:32]=[C:31]2[CH3:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a stirred solution of (4-fluoro-phenyl)-acetic acid (0.23 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (480 mg, 76% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.83 min (99.2%); mp, decomposed at 290° C.; 1HNMR (DMSO-d6) 2.12-2.19 (m, 1H, CHH), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, ArCH2), 4.68-4.83 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.09-7.72 (m, 7H, Ar), 8.36 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.58, 41.36, 41.70, 56.48, 114.89 (d, JC-F=21 Hz), 117.69, 124.72, 125.58, 130.86 (d, JC-F=7 Hz), 132.45 (d, JC-F=3 Hz), 133.82, 140.68, 148.44, 154.80, 160.91, 161.00 (d, JC-F=242 Hz), 169.50, 170.15, 172.59. LCMS MH=437; Anal Calcd For C23H21N4O4F: C, 63.30; H, 4.85; N, 12.84; F, 4.35. Found: C, 63.25; H, 4.66; N, 12.73; F, 4.21.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[N:26]1([S:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1N2C=CC=NC2=C(C(O)=O)C=1.C(Cl)(=O)C(Cl)=O.NC1C=CC=CC=1>C1COCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[N:26]1([S:32]([C:35]2[CH:36]=[C:37]([NH:41][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cnn2cccnc12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II as follows: to a stirred solution of a pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 mmol) in THF (4 ml) was added at room temperature DMF (2 drops), the solution was cooled to 0° C. and oxalylchloride (1.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 h and evaporated to dryness. The precipitate was dissolved in pyridine (6 ml) and, while stirring at room temperature, 4-dimethylaminopyridine (1 mmol) and an aniline derivative (1 mmol) was added. The reaction mixture was allowed to stir at room temperature for 16 h, evaporated to dryness and the crude product purified by flash chromatography on silica gel (20 g, dichloromethane/methanol) to yield the product as a light yellow solid, which was further purified by crystallization from methanol/hexane. MS (ISP) 580.1 [(M−H)−]; mp 221° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1Cl)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18]C(F)(F)C(NCC1OCCNC1)=O.FC1C=CC(CCl)=CC=1>>[F:18][C:16]1[CH:15]=[CH:14][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]2)=[CH:3][CH:2]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Agent: Fc1ccc(CCl)cc1
Product: NCC1CN(Cc2ccc(F)cc2)CCO1

Procedure:
Intermediate 21 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 4-fluorobenzyl chloride, followed by deprotection to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.C([O-])(=O)C.[Na+].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29]>C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:29]1
Reactant: NNc1ccccc1Cl
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a mixture of 12.96 g of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione, 8.56 g of sodium acetate and 40 ml of acetic acid was added 11.26 g of 2-chlorophenylhydrazine hydrochloride at room temperature. The mixture was stirred at 60° C. for 1 hour, and concentrated under reduced pressure. After the reaction mixture was concentrated under reduced pressure and water was poured into the residue, the mixture was extracted with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 18.43 g of 1-(2-chlorophenyl)-5-(2-furyl)-3-trifluoromethyl-1H-pyrazole of the formula: