Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8]C(=O)C(F)(F)F)[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[N:4]=1)[CH3:2].[OH-].[Na+].O>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 5-ethyl-3-(4-iodobenzyl)-2-trifluoroacetylimino-1,3,4-thiadiazoline (44.1 g) in tetrahydrofuran (300 ml) was added 2N sodium hydroxide (100 ml), followed by stirring at room temperature overnight. Water (300 ml) was added to the reaction mixture, followed by extraction with chloroform (250 ml) twice. The organic layers were washed with a saturated aqueous sodium hydrogencarbonate and were dried over anhydrous magnesium sulfate, followed by removal through distillation. The oily substance so obtained was crystallized from diisopropyl ether, whereby 32.3 g of the title compound was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[CH:7]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=O.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH3:37])=[CH:27][C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH:22]=[CH:23][CH:24]=1.N1CCCCC1>C(O)C>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][C:28]([C:27]1[CH:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:3]([C:4]([NH2:6])=[O:5])=[C:1]([NH2:2])[N:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:38])([F:17])[F:39])[CH:20]=2)[C:26]=1[CH3:37])=[O:29]
Reactant: N#CCC(N)=O
Reactant: CC(=CC(=O)OCC[Si](C)(C)C)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1=C(C(=O)OCC[Si](C)(C)C)C(c2ccc(C#N)cc2)C(C(N)=O)=C(N)N1c1cccc(C(F)(F)F)c1

Procedure:
To a solution of 0.45 g (5.40 mmol) 2-cyanoacetamide in 5 ml ethanol are added 0.71 g (5.40 mmol) 4-formylbenzonitrile, a solution of 1.87 g (5.40 mmol) of the compound of Example 40A in 6 ml ethanol and 0.16 g (1.89 mmol) piperidine. The mixture is stirred under reflux for 3.5 hours. The reaction mixture is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 2000 μl; number of injections: 8). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Br:1]Br.[CH3:3][NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1>C(O)(=O)C.C(#N)C>[CH3:3][NH:4][N:5]=[C:6]([Br:1])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CNN=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: CNN=C(Br)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 61 %

Procedure:
9.5 g (0.06 mol) of bromine were added dropwise at (-5) to (-7)° C. to a solution of 10 g (0.06 mol) of 4-chlorobenzaldehyde (N-methyl)hydrazone in 50 ml of acetic acid and 20 ml of acetonitrile. After the mixture had been stirred for 3 hours, the product which had precipitated was separated off and washed with a small amount of pentane. Yield: 61%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:7])[CH:5]=[CH2:6]>>[CH3:1][N:2]([CH2:6][CH2:5][C:4]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])[CH3:3]
Reactant: C=CC(=O)OCCN(C)C
Reactant: CNC
Product: CN(C)CCOC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Anhydrous dimethylamine (19.8 grams) was added dropwise to 2-(N,N-dimethylamino)ethyl acrylate (31.5 grams) in a magnetically-stirred, ice-cooled reaction vessel at such a rate that the temperature did not exceed 40°C. The addition of dimethylamine was complete in about 10 minutes. After allowing the reaction mixture to stir overnight at room temperature, it was subjected to reduced pressure (about 20 mm. Hg) to remove unreacted dimethylamine. Gas-liquid chromatographic analysis indicated that the residue product was 96.5 percent pure. The structure of the product, ##EQU18## was verified spectroscopically (nuclear magnetic resonance and infrared) and by elemental analysis. Anal. Calc'd. for C9H20N2O2 : C, 57.4; H, 10.6; N, 14.9. Found: C, 57.3; H, 10.5; N, 14.8. This product is designated herein as Amine Catalyst X.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([O:20]CC(Cl)(Cl)Cl)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl>CN(C)C=O.O.[Zn]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CSC[C@H]12
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)O)=CSC[C@H]12
Reaction time: 3 h

Procedure:
To a solution of 43 mg (0.1 mmole) of trichloroethyl cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate in 6 ml of dimethylformamide and 6 l ml of acetic acid is added over a 1.5 hr period 250 mg (3.8 mmole) zinc dust. The mixture is stirred vigorously for 3 hrs and then diluted with 50 ml of water. The mixture is acidified with dilute HCl, filtered and extracted with ethyl acetate. The organic phase is extracted with 5% NaHCO3 which is acidified and reextracted into ethyl acetate. The final extracts are washed with brine, dried, and evaporated to give cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.Cl[CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:26][CH2:27][CH2:28][S:29]3(=[O:31])=[O:30])=[CH:3][C:4]=2[CH3:24])=[O:9])[CH2:15][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1

Procedure:
Using (4-amino-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (833 mg) described in Preparation Example 148 and 3-chloropropane-1-sulfonyl chloride (0.42 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (624 mg) was obtained.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH2:14][O:13][CH2:12][CH2:11][C:10]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>CCO.O.C(Cl)(Cl)Cl.[Pd]>[CH:1]([N:4]1[C:8]([C@@H:9]2[C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][O:13][CH2:14]2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccnn2C(C)C)COCC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCOC[C@@H]1c1ccnn1C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
To a solution of ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (100 mg, 0.38 mmol) in EtOH (2 mL) was added Pd/C (50 mg), then it was charged with H2 (1 atm) and stirred at room temperature for 3 days, Mass spec shows about 50% conversion. The mixture was then added a solution of NH4CO2H (200 mg) in water (2 ml) and additional Pd/C, and the mixture was further heated at 75° C. for 1.5 h, after cooled to room temperature, the reaction was diluted with EtOH, pd/C was filtered off, and the filtrate was concentrated to give crude oil, which was diluted with CHCl3, organic layer was washed with Sat. NaHCO3, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=65:35) to give (±)ethyl(3S,4R)-3-(1-isopropyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-carboxylate (70 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH2:11][OH:12])[CH:10]=1.N1C=CN=C1.Cl[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl>[C:23]([Si:20]([O:12][CH2:11][C:9]1[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=[CH:7][C:8]=1[CH3:13])([CH3:22])[CH3:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOc1ccc(C)c(CO)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
[5-(methoxymethoxy)-2-methyl-phenyl]methanol (Intermediate 173, 1.9 g, 10 mmol) was dissolved in dichloromethane (10 ml) to give a colourless solution. 1H-imidazole (1.137 g, 16.7 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (2.095 g, 13.9 mmol) were added. The reaction mixture immediately became a white suspension and was stirred at room temperature for 30 minutes. The reaction mixture was quenched with 10 ml of water and diluted with 10 ml of dichloromethane. Two phases were separated through a separating funnel. The organic phase was dried over Na2SO4 and evaporated under vacuum and the residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 50:50 as eluents affording the title compound (2.9 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:9]O)=[CH:4][CH:3]=1.C(N(S(F)(F)F)CC)C.[OH-].[NH4+].CCCCCCC.C(OC(=O)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][O:25][C:12]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:11]2)=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CO)c1ccc(F)cc1)c1ccc([C@H]2CNCCO2)cc1
Agent: CCN(CC)S(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Fc1ccc([C@@H]2COC(c3ccc([C@H]4CNCCO4)cc3)=N2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.2 %

Procedure:
N—((R)-1-(4-Fluorophenyl)-2-hydroxyethyl)-4-((S)-morpholin-2-yl)benzamide (14.4 mg, 0.042 mmol) was dissolved in dichloromethane (0.4 ml) and diethylaminosulfur trifluoride (DAST) (6.74 mg, 0.042 mmol) was added. The reaction mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was poured over crushed ice mixed with 25% ammonium hydroxide solution (10 ml) and the solution was extracted twice with dichloromethane (2×10 ml). The combined organic layer was dried over MgSO4 and evaporated to give a sticky solid. Addition of heptane/ethy lacetate 4:1 and some drops of dichloromethane gave a white solid which was isolated by filtration and dried in vacuo to afford the product as a white solid (5.1 mg, 37%): MS (ISP): 327.2 ([M+H]+).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[F:8][C:9]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:10]=1[CH2:11][N:12]1[C:20]2[CH2:19][CH:18]([CH3:21])[NH:17][CH2:16][C:15]=2[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:13]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>O>[F:8][C:9]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:10]=1[CH2:11][N:12]1[C:20]2[CH2:19][CH:18]([CH3:21])[N:17]([C:3](=[O:4])[CH3:2])[CH2:16][C:15]=2[C:14]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[N:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1Cc2c(c(-c3ccc(F)cc3)nn2Cc2ccc(F)cc2F)CN1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1Cc2c(-c3ccc(F)cc3)nn(Cc3ccc(F)cc3F)c2CC1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (7a) (0.53 g, 1.35 mmol), acetic anhydride (5.5 ml) and pyridine (5.5 ml) was stirred at 25° C. for 16 h. The mixture was poured on 50 ml water, extracted with 150 ml ethyl acetate, the combined organic layers were washed with 3 times 0.5 N NaOH (50 ml) and once with brine, dried over MgSO4, filtrated and evaporated to dryness. The crude product was silica gel chromatography (eluting with heptane/ethyl acetate) to give 156 mg of 1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (8z).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][NH:28][CH3:29].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:28]([CH3:29])[CH3:27])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CNC
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)N(C)C)cc2)=C(C)C1=O
Yield: 17.2 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and dimethylamine hydrochloride (62 mg, 0.75 mmol) and triethylamine (76 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (38 mg, 0.10 mmol, yield 18%).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:17][CH:16]=1
Reactant: CC(=O)C(Cl)=NNc1ccccc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccccc1)Sc1ccc(Cl)cc1
Yield: 23.5 %

Procedure:
The reaction of 951 mg (4.85 mmol) of 1-chloro-1-[(phenyl) hydrazono]-2-propanone with 864 mg of 4-chlorothiophenol and 840 ul of triethylamine in 15 ml of ethanol as Example 11 yielded 347 mg of 1-[(4-chlorophenyl)thio]-1-[(phenyl)hydrazono]-2-propanone, mp 111°-113° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C@@H:8]([NH2:38])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:13][CH:14]=1)[NH:38][S:48]([CH3:47])(=[O:50])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CC(=O)Nc2ccc([C@H](N)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)OC(C)(C)C)NS(C)(=O)=O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of (R)-3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid tert-butyl ester [100 mg, Reference Example 7(a)], dichloromethane (10 ml) and triethylamine (38 mg) was stirred at ambient temperature and then treated with methanesulphonyl chloride (22 mg). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane (20 ml) and then washed with hydrochloric acid (20 ml, 1M), then with saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was dried over magnesium sulphate and then evaporated to give the title compound (55 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][C:15]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:44][C:41]3[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=3)=[N:14][C:15]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(OCc3ccccc3)cc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(OCc4ccccc4)ccc23)n[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To (7-(benzyloxy)-4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone (380 mg, 0.97 mmol) in DMF (10 mL) at rt were added DIEA (500 uL, 2.90 mmol), 5-methyl-1H-pyrazol-3-amine (280 mg, 2.90 mmol), and KI (161 mg, 0.97 mmol). After stirring at 40° C. for 18 h, the solution was cooled and diluted with water. After standing at 0° C. for 1 h, the precipitate was collected by filtration and dried under reduced pressure to afford (7-(benzyloxy)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone as a yellow solid (365 mg, 83%) 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.30 (s, 2H) 6.48 (s, 1H) 7.33-7.44 (m, 8H) 7.50-7.52 (m, 2H) 8.07 (m, 2H) 8.65 (m, 1H) 10.53 (s, 1H) 12.18 (s, 1H). LC-MS (ESI) m/z 454 (M+H)+
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol) and DIPEA (190 μL, 1.09 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (21 μL, 0.27 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:TBME, 0-100%) affording 766 (39 mg, 26%). LCMS (method I): RT 3.74 min, [M+H]+ 555.2. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.28-7.24 (2 H, m), 4.27 (4 H, brd s), 3.97 (1 H, d, J=13.24 Hz), 3.92 (3 H, s), 3.79 (4 H, t, J=4.61 Hz), 3.50-3.47 (2 H, m), 3.28-3.26 (2 H, m), 3.08 (3 H, s), 3.05-2.95 (4 H, m), 2.35-2.25 (1 H, m), 1.98-1.95 (2 H, m), 1.76-1.72 (1 H, m), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:45][CH3:46])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:35]=4[C:36]([NH:38][CH3:39])=[O:37])[C:17]4[CH:22]=[CH:21][N:20](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[O-].[Na+]>CO.C1COCC1.CCOC(C)=O.[Na+].[Cl-]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:45][CH3:46])=[C:10]([NH:13][C:14]3[NH:19][C:18]4=[N:20][CH:21]=[CH:22][C:17]4=[C:16]([NH:33][C:34]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:35]=4[C:36]([NH:38][CH3:39])=[O:37])[N:15]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(C)=O)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(C)=O)[nH]c2nccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A solution of 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (130 mg, 0.2 mmol) in MeOH (10 mL) and THF (20 mL) was treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The resulting mixture was stirred at rt overnight, then diluted with EtOAc (100 mL) and saturated NaCl solution. The organic layer was washed with a saturated NaHCO3 solution, concentrated onto Celite and purified by silica gel chromatography using 0-5% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a beige solid (73 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3H) 2.80 (d, J=4.4 Hz, 3H), 3.12 (t, J=8.42 Hz, 2H), 3.78 (s, 3H), 4.10 (t, J=8.42 Hz, 2H), 6.27 (d, J=1.28 Hz, 1H), 6.86-6.98 (m, 3H), 7.28-7.37 (m, 1H), 7.55 (s, 1H), 8.34 (d, J=8.61 Hz, 1H), 8.55 (br s, 1H), 8.63 (s, 1H), 10.14 (s, 1H), 11.27 (s, 1H); ESIMS (M+H)+=489.98.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Si:23]([O:4][CH2:3][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:1])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: NC(CO)c1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC(N)c1ccc(I)cc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a mixture of the compound (4.70 g) obtained in step (3) above, 4-dimethylaminopyridine (48.2 mg), triethylamine (4.40 mL) and chloroform (63.2 mL), a solution of tert-butyldimethylchlorosilane (2.38 g) in chloroform (31.6 mL) was added dropwise under cooling with ice and the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for three days. The reaction mixture was concentrated under reduced pressure and water and ethyl acetate were then added. Extraction was conducted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-98:2) to give the titled compound as a pale yellow oil (4.68 g).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: O=C(O)C(F)(F)C(F)(F)Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(F)(F)C(F)(F)Br

Procedure:
To a solution of 7.0 g (31 mmol) of 3-bromo-2,2,3,3-tetrafluoropropionic acid in 40 ml of ethanol was added 1.0 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 8 hours and then distilled under ordinary pressure to give an ethanolic solution of ethyl 3-bromo-2,2,3,3-tetrafluoropropionate. Ammonia gas was blown into the solution, which was left at room temperature overnight and then concentrated under reduced pressure to give 5.6 g of 3-bromo-2,2,3,3-tetrafluoropropionamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7]([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=O)[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[NH:22][N:23]=[C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)[CH:6]=1)=[O:20])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)n[nH]1
Yield: 91.1 %

Procedure:
Preparation C13, Step 2: 4-Adamantan-1-yl-2,4-dioxo-butyric acid ethyl ester 7.80 g, 28 mmol, 1 eq.), hydrazine hydrate (1.36 mL, 28 mmol, 1 eq.) and ethanol (20 mL) were refluxed until reaction was complete by LCMS. Stripped off the ethanol, and extracted (3×) with ethyl acetate (50 mL). The organic layers were combined, dried and stripped to give 7.00 g of 5-adamantan-1-yl-2H-pyrazole-3-carboxylic acid ethyl ester as a yellow solid. MS found: (M+H)+=275.