Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([P:9]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](Cl)(C)C>ClCCl>[CH2:11]([O:10][P:9]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[OH:13])[CH3:12]
Reactant: CCOC(C)(OCC)P(=O)(OCC)C1CCCO1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g of ethyl 1,1-diethoxyethyl(tetrahydrofuran-2-yl)phosphinate in 10 ml of dichloromethane containing 1% (b.v.) of ethanol is treated with 0.71 g of trimethylsilylchloride. The faintly cloudy solution is stirred overnight at room temperature after which time thin layer chromatography indicates complete reaction. Removal of the solvent in vacuo affords a colourless oil which after distillation yields P-tetrahydrofuran-2-yl-phosphonous acid ethyl ester, b.p. 90°/8×10-2 mbar
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]([CH2:18][C:19]4[N:28]=[C:27]([CH3:29])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[C:13]4=[N:30][CH2:31][CH2:32][N:12]4[C:11]=3[N:10]=[CH:9]2)=CC=1.C1C(=O)N([Br:42])C(=O)C1>CC#N>[Br:42][C:9]1[NH:8][C:16]2[C:15](=[O:17])[N:14]([CH2:18][C:19]3[N:28]=[C:27]([CH3:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[C:13]3=[N:30][CH2:31][CH2:32][N:12]3[C:11]=2[N:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Cn2cnc3c2C(=O)N(Cc2nc(C)c4ccccc4n2)C2=NCCN23)cc1
Solvent: CC#N
Product: Cc1nc(CN2C(=O)c3[nH]c(Br)nc3N3CCN=C23)nc2ccccc12
Reaction time: 1.5 h

Procedure:
To 5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 13 (386 mg, 1.16 mmol) in CH3CN (10 ml) was added NBS (268 mg, 1.51 mmol) at 0° C., stirred for 1.5 hr. Another 41 mg of NBS was added, stirred for 30 minutes. The reaction was quenched by adding water (15 ml), washed with DCM (2×15 ml). The organic phase was washed with HCl (1 M, 10 ml). The combined aqueous phase was concentrated and purified by flash chromatography (MeOHIDCM, MeOH contains 1% Et3N) to afford 2-bromo-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 14.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][O:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([C:37]2[N:46]([C:47]3[CH:52]=[CH:51][C:50]([CH:53]([CH2:55][CH3:56])[CH3:54])=[CH:49][CH:48]=3)[C:45](=[O:57])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:32][C:31]=1[CH3:58])(C(C)(C)C)(C)C>C1COCC1>[CH:53]([C:50]1[CH:49]=[CH:48][C:47]([N:46]2[C:45](=[O:57])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=[C:37]2[C:33]2[CH:32]=[C:31]([CH3:58])[C:30]([O:29][CH2:28][CH2:27][OH:26])=[C:35]([CH3:36])[CH:34]=2)=[CH:52][CH:51]=1)([CH2:55][CH3:56])[CH3:54]
Reactant: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccccc3c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Reaction time: 2 h

Procedure:
A 1 M solution of tetrabutyl ammonium fluoride in THF was added to a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one in THF at 0° C. The ice bath was removed, and stirring was continued at room temperature for 2 hours. The solvent was evaporated, and residue was taken in dichloromethane, concentrated and purified as described in Example 1 to give the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16].[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:38]2[CH2:39][CH2:40][CH:35]([C:31]3[CH:30]=[C:29]([NH:28][C:26](=[O:27])[CH:25]([CH3:24])[CH3:41])[CH:34]=[CH:33][CH:32]=3)[CH2:36][CH2:37]2)=[CH:18][CH:19]=1
Reactant: O=C(CCCCCCl)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 6-chloro-1-(4-fluorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 439.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:12]([CH3:14])([CH3:13])[CH:11]=[O:15]
Reactant: CC(C)C=O
Reactant: Fc1ccc(CCl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C=O)Cc1ccc(F)cc1Cl
Reaction time: 3 h
Yield: 57.9 %

Procedure:
65.0 g of 2-chloro-4-fluorobenzyl chloride in 90 ml of toluene and 28.8 g of isobutyraldehyde are added dropwise, simultaneously but separately, with thorough mixing at 80° C. in the course of 30 minutes to a mixture of 1.9 g of tetrabutylammonium iodide, 155 g of 30% strength sodium hydroxide solution and 115 ml of toluene, and stirring is continued for 3 hours at 80° C. The organic phase is separated off, washed with three times 50 ml of water, dried, and concentrated (58.5 g) by short-path distillation (bp.=70°-90° C./0.3). Distillation gives 45.1 g of (2-chloro-4-fluorophenyl)-pivalaldehyde (bp.: 53°-55° C./0.1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[N:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24][CH3:25])=[CH:22][CH:23]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[N:6][CH:7]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C)cn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(C)cn2)cc1

Procedure:
A mixture of the dihydro-imidazole of step 3 (3. 95 g, 13.9 mmol) and p-toluenesulfonic acid monohydrate (785 mg, 4 mmol) in toluene (500 ml) was heated to reflux for 4–5 hours. The reaction mixture was cooled and 10 ml of triethylamine was added and the solvent removed-under reduced pressure. The crude mixture was purified by chromatography on silica gel using ethyl acetate to give the desired product which was used in the next reaction without further purification.
Reaction SMILES: [OH-].[Na+:2].[C:3]12([NH:13][C:14]([C:16]#[C:17][C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[Cl:27])[NH:20][C:19]=3[C:29]([O:31]CC)=[O:30])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.O>C(O)(C)C>[Na+:2].[C:3]12([NH:13][C:14]([C:16]#[C:17][C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[Cl:27])[NH:20][C:19]=3[C:29]([O-:31])=[O:30])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C#CC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(C#Cc1c(C(=O)[O-])[nH]c2cc(Cl)cc(Cl)c12)NC12CC3CC(CC(C3)C1)C2
Temperature: 60 °C
Yield: 93.6 %

Procedure:
Sodium hydroxide (59 mg) was added to a solution of Example 18 (170 mg) in isopropyl alcohol (5.4 ml) and the reaction was heated at 60° C. for 3 h. After cooling, water (6 ml) was added and the resulting yellow precipitate was filtered and washed well with more water, then dried to furnish the title compound (157 mg,) as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].CON(C)[C:23](=[O:25])[CH3:24]>>[CH:17]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[C:12]([C:23](=[O:25])[CH3:24])=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: CC(C)N(C(=O)c1ccc(C(F)(F)F)cn1)C(C)C
Reactant: CON(C)C(C)=O
Product: CC(=O)c1cc(C(F)(F)F)cnc1C(=O)N(C(C)C)C(C)C

Procedure:
Prepared in analogy to Example A17(b) from 5-Trifluoromethyl-pyridine-2-carboxylic acid diisopropylamide (CAS: 765298-31-5) and N-methoxy-N-methylacetamide instead of dimethylformamide. Orange solid. MS (m/e): 317.1 ([M+H]+, 100%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=[C:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)[CH2:18][CH3:19])[C:15]3[CH:27]=[CH:28][CH:29]=[N:30][C:14]=3[CH2:13][O:12][C:11]=2[CH:31]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=[CH:24][CH:25]=3)[CH2:18][CH3:19])[C:15]3[CH:27]=[CH:28][CH:29]=[N:30][C:14]=3[CH2:13][O:12][C:11]=2[CH:31]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc(NS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.34 mL, 4.36 mmol) is added dropwise to a solution of 3-[1-(8-fluoro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1.37 g, 3.96 mmol) and pyridine (0.35 mL, 4.36 mmol) in dichloromethane (10 mL) at 0° C. After 2 h, 7% aqueous sodium bicarbonate (20 mL) is added and the mixture stirred for 30 min, decanted, and the layers separated. The aqueous phase is washed with dichloromethane (2×20 mL). The organic phases are collected and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 1.98 g of crude product. The material is purified by flash chromatography, using Biotage® and eluting with hexane:ethanol (9:1) to afford 1.35 g (80%) of the title compound. LCMS m/e 425 [M−H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[O:24]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Temperature: 105 °C
Yield: 55.7 %

Procedure:
A flask was charged with the compound prepared in Example 302 (0.533 g), 1-bromobenzene (0.252 g), potassium tert-butoxide (0.252 g), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.056 mg), and bis(dibenzylideneacetone)palladium (0.037 g) and flushed with nitrogen gas. Toluene (30 mL) which was thoroughly purged with nitrogen gas was added and the reaction mixture heated at 105° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 10% ethyl acetate/hexane) to furnish the title compound (0.365 g) with the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([F:17])[C:12](=O)[N:11]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([F:17])[CH2:12][N:11]([C@@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(NC(=O)OC(C)(C)C)CCC[C@]2(F)C1=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@]2(F)CCC[C@@]2(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
(1R,5R)-1-(tert-Butoxycarbonylamino)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (3.69 g, 10.2 mmol) was dissolved in tetrahydrofuran (200 mL). A 1.20 M solution of a borane-tetrahydrofuran complex in tetrahydrofuran (42.4 mL, 50.9 mmol) was added dropwise under ice-cooling, and the mixture was stirred for two hours while gradually heating to room temperature. The solvent was evaporated under reduced pressure. Under ice-cooling, 90% aqueous ethanol (100 mL) and triethylamine (100 mL) were added to the residue, and the mixture was heated to reflux for two hours. The solvent was evaporated under reduced pressure, and then the residue was extracted with saturated sodium bicarbonate water and dichloromethane. Thereafter, the target substance was extracted from the aqueous layer with dichloromethane. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=95:5→90:10) to give 3.33 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([S:12](Cl)(=[O:14])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(O)(=O)C.O>[F:1][C:2]1[CH:11]=[C:10]([S:12]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:14])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(F)c2cccnc2c1O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(NCc1ccccc1)c1cc(F)c2cccnc2c1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A suspension of 5-fluoro-8-hydroxy-7-quinolinesulfonyl chloride (0.150 g) in 2 mL of THF is cooled to −78° C. and treated with benzylamine (0.186 mL). The mixture is allowed to warm to 25° C. over several hours, then diluted with 50 μL of glacial acetic acid and 2 mL of distilled water. The oil which forms is crystallized by scratching, and the resulting suspension is stirred for one hour. The solid is filtered, washed with two 2 mL portions of distilled water and dried in a stream of air to give 0.121 g of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:12]([O:10][C:5]1[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (5 g, 22.8 mmol) in DMF (100 ml) is added benzyl bromide (5.7 ml, 48 mmol) and cesium carbonate (11.9 g, 37 mmol). The reaction mixture is stirred at room temperature for 20 hours then diluted with water (150 ml) and extracted with EtOAc (2×150 ml), the organic portions are combined, washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give a waxy off-white solid. The solid is stirred in iso-hexanes (30 ml) for 30 minutes, filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH:17]1([C:20]2[C:21]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[C:21]([N:30]3[CH2:35][CH2:34][N:33]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:32][CH2:31]3)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 81.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (271 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (401 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1.O[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[O:11])=[CH:8][C:7]=2[O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Yield: 52.3 %

Procedure:
A solution of 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.300 g, 1.048 mmol), benzyl 2-hydroxyacetate (0.174 g, 1.048 mmol), EDC (0.603 g, 3.14 mmol), and DMAP (0.128 g, 1.048 mmol) in DCM (25 ml) was stirred at RT for 2 hours. The mixture was diluted with DCM and washed with HCl 1N and NaHCO35%. The organic phase was dried over Na2SO4, the solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 75:25). A further purification by trituration with EtOH was required to obtain 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoate (0.238 g, 0.548 mmol, 52.3% yield, MS/ESI+ 434.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(Cl)[Cl:21].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:21])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: ClC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a N2 purged round bottom flask was added 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (2.10 g, 7.20 mmol) and anhydrous CHCl3 (30 mL). The solution was cooled to 0° C. prior to the addition of oxalyl chloride (1.3 mL, 14 mmol) and anhydrous DMF (1 mL). The reaction solution was stirred 1 h under N2. The solution was concentrated under reduced pressure on the rotavapor to afford 2.4 g crude product. The crude acid chloride was used without further purification in the next reaction step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[C:36]1([NH:42][CH2:43][CH2:44][NH2:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:45][CH2:44][CH2:43][NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)CCCCC(=O)O)cc1OC
Reactant: NCCNc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)CCCCC(=O)NCCNc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
6-[2-(3,4-Dimethoxyphenyl)ethylamino]-6-oxohexanoic acid (6.0 g, 0.019) was dissolved in dry dichloromethane (200 ml) and triethylamine (2.28 g, 0.021 mole), and ethyl chloroformate (1.86 ml, 0.019 mole) added at 0°. After 1 hour at 0° N-phenyl-1,2-ethanediamine (2.64 g, 0.019 mole) was added and the mixture stirred at room temperature for 18 hr. After washing with water and drying (Na2SO4), the reaction mixture was evaporated and the residue recrystallised from ethyl acetate to give the sub title compound (5.3 g) mp 109°-11°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]2[C:17]=1[CH3:18].C([Li])(C)(C)C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>C(OCC)C.CCCCC>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:8]1[CH:7]=[CH:6][N:5]2[C:17]([CH3:18])=[C:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 1 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 40 ml of diethyl ether is treated dropwise at −78° C. with 8 ml of a 1.5 molar solution of t-butyllithium in n-pentane. The mixture is stirred for 15 min and then treated with 3.3 ml of tri-n-butyltin chloride. The internal temperature is then allowed to rise to room temperature, the mixture is poured onto ice water and extracted three times with ethyl acetate, the combined extracts are washed with a little water and dried over potassium carbonate, the solvent is stripped off in vacuo and the oil obtained is chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) as an eluent. 1.3 g of 7-tributylstannyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine are obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([O:8][NH:9][C:10](=[O:12])[CH3:11])=[O:7])([CH3:4])[CH3:3].[CH3:13][N:14]=[C:15]=[O:16]>C(N(CC)CC)C.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:13][NH:14][C:15]([N:9]([O:8][C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10](=[O:12])[CH3:11])=[O:16]
Reactant: CN=C=O
Reactant: CC(=O)NOC(=O)NC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(=O)N(OC(=O)NC(C)(C)C)C(C)=O

Procedure:
N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide (8.7 grams), methyl isocyanate (3.2 grams), and a few drops of triethylamine were stirred at room temperature in 150 ml of methylene chloride for about 12 hours. The solvent was then removed under vacuum leaving an oily residue which was dissolved in hot toluene. Upon cooling, a white crystalline material separated and was collected by filtration. The white crystals were recrystallized from toluene leaving a residue which was mixed with about 50 ml of water for two hours. This mixture was then filtered, and the insoluble material was dried in a vacuum leaving the desired N-((methylamino)carbonyl)-N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide, m.p. 142°-144° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:32]1([C:30]2[NH:29][N:28]=[C:27]([NH:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([N:11]([CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)[CH2:12][C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[N:25]=3)[CH:31]=2)[CH2:34][CH2:33]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: c1cncc(CNCc2cccc3[nH]ccc23)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cncc(CN(Cc2cccc3[nH]ccc23)c2nccc(Nc3cc(C4CC4)[nH]n3)n2)c1
Temperature: 140 °C
Yield: 3153.2 %

Procedure:
A 5 mL microwave tube was charged with N-(1H-indol-4-ylmethyl)-1-(3-pyridyl)methanamine (200 mg, 0.843 mmol, 2 equiv.), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol) and n-butanol (1.2 mL). DIPEA (5 equiv., 276.98 mg, 2.1216 mmol, 0.371 mL) was added, and the reaction mixture was heated to 140° C. for 17 h in an oil bath. The reaction was filtered and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC to afford 5836 mg (32%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1H-indol-4-ylmethyl)-N2-(3-pyridylmethyl)pyrimidine-2,4-diamine (II-10) as a light brown solid.