Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.C[NH:13][NH2:14]>CCOCC>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1/[CH:4]=[N:13]/[NH2:14]
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: CNN
Solvent: CCOCC
Product: N/N=C/c1c(F)cc(F)cc1F
Reaction time: 8 h

Procedure:
2,4,6-Trifluoro-benzaldehyde (x) (4.5 g, 27.3 mmol) was dissolved in Et2O, methylhydrazine was added (1.43 mL, 27.3 mmol) and the RM was stirred overnight. The solvent was evaporated and the solid residue was suspended in a mixture of pentane and EtOAc to afford after filtration the title compound as a bright yellow crystalline solid (tR 4.95 min (conditions 3), MH+=198.1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24].[Cl:25]/[CH:26]=[CH:27]\[CH2:28]I.[Cl-].[NH4+]>O1CCCC1>[Cl:25][CH:26]=[CH:27][CH2:28][C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24]
Reactant: Cl/C=C\CI
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1CC=CCl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5 M in hexane, 3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained at -70° C. After 30 minutes, copper (I) bromide - dimethyl sulphide complex (1.54 g) was added in one portion and the reaction temperature allowed to warm to 0° C., for a period of 15 minutes. After cooling to -70° C., a solution of Z-1-chloro-3-iodoprop-1-ene (2.03 g) in dry tetrahydrofuran (3 cm3) was added portionwise, and the reaction mixture stirred for a further hour at -70° C. After warming to the ambient temperature, (ca. 25° C.), aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure to give an orange oil. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 40°-60° C.) containing diethyl ether (5% by volume) to give 2-[4-(3-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran, as a mixture consisting predominantly of the Z isomer.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].[OH-].[Na+].Cl>ClCCl.C(O)(=O)C>[N+:19]([C:8]1[O:9][C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:24])=[O:20]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc2c(-c3ccccc3)coc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Reaction time: 70 h

Procedure:
A solution of 2 g of 3-phenyl-6-benzofurancarboxylic acid in 100 ml of dichloromethane and 20 drops of acetic acid is treated with 3.0 g of dinitrogen tetroxide. The mixture is stirred for about 70 hours then evaporated to provide a residue. The residue is treated with cold 5% sodium hydroxide solution until solution occurs. The solution is acidified with 6N hydrochloric acid and the yellow solid is collected and recrystallized from ethanol to provide 2-nitro-3-phenyl-6-benzofurancarboxylic acid, m.p. 244°-247° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:46][O:45][CH2:44]7)[CH2:39][C@@H:38]6[CH3:47])=[CH:33][N:32]=5)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:44][O:45][CH2:46]7)[CH2:39][C@@H:38]6[CH3:47])=[CH:33][N:32]=5)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A 25 mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 136a (100 mg, 1.0 eq., 0.15 mmol), NaBH4(17 mg, 3.0 eq., 0.45 mmol), and MeOH (10 mL). The mixture was stirred at room temperature for 1 h. The residue was purified by reverse-phase prep-HPLC to afford 136 (64 mg, 64%). LCMS: [M+H]+ 669.3. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=2.0, 1H), 8.48 (d, J=5.0, 1H), 7.96 (d, J=2.5, 1H), 7.83-7.82 (m, 2H), 7.36 (d, J=5.0, 1H), 7.30 (dd, J=2.5, 9.0, 1H), 6.81 (d, J=8.5, 1H), 4.99-4.96 (m, 1H), 4.71-4.61 (m, 5H), 4.45-3.83 (m, 5H), 3.71 (s, 3H), 3.54-3.45 (m, 2H), 3.08-3.06 (m, 2H), 2.56-2.47 (m, 7H), 2.21-2.17 (m, 1H), 1.89-1.76 (m, 4H), 0.98 (d, J=6.5, 3H)
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23]
Reactant: CCOP(=O)(CCCCc1ccc2ccccc2c1OC)OCC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(CCCCc1ccc2ccccc2c1O)OCC
Reaction time: 2 h
Yield: 39 %

Procedure:
A solution of diethyl 4-(1-methoxy-2-naphthyl)butylphosphonate (5.50 g, 0.016 mole) in methylene chloride (80 mL) was stirred at -78°, and treated with boron tribromide (1.0M in methylene chloride; 24.0 mL, 0.024 mole) over 20 minutes. Stirring was continued for 2 hours at this temperature, then at room temperature for 16 hours. Water (80 mL) was added, and the mixture was extracted with ether. The organic layer was extracted with 1.0N aqueous sodium hydroxide, the aqueous layer was acidified with concentrated hydrochloric acid, and the crude product was isolated from this by extraction with ether. The residue was recrystallized (hexane) to provide the title compound (2.10 g, 40%) as a white solid, mp 90°-91°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C(O)C>[Pd].O1CCCC1>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:19])=[CH:15][CH:14]=1
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Yield: 57.4 %

Procedure:
A solution of 4.34 g (0.0165 mole) of N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide, 0.50 g of 10% palladium on carbon catalyst, 200 mL of ethanol and 30 mL of tetrahydrofuran was stirred under an atmosphere of hydrogen for 4 hours. The mixture was then filtered through Celite and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 2.21 g of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([OH:9])[C:7]=1[Cl:8].[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([Cl:8])[C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7 mmol) and tin (II) chloride (5.8 g, 26.1 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.4 mg, 90%). 1H NMR (CD3OD): δ 6.71 (d, 1H), 6.45 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:19][CH:20]1[C:28]2[C:23](=[C:24]([CH3:31])[CH:25]=[C:26]([CH3:30])[C:27]=2[OH:29])[CH2:22][C:21]1([CH3:33])[CH3:32].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([CH3:31])[CH:25]=[C:26]([CH3:30])[C:27]=4[OH:29])[CH2:22][C:21]3([CH3:33])[CH3:32])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c2c(c1O)C(N)C(C)(C)C2
Reactant: Clc1cccc(N2CCN(CC3CO3)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(c1O)C(NCC(O)CN1CCN(c3cccc(Cl)c3)CC1)C(C)(C)C2

Procedure:
0.21 Gram of 4-(3-chlorophenyl)-1-(2,3-epoxypropyl)piperazine was added to a solution containing 0.21 g of 1-amino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene hydrochloride in 10 ml of ethanol solution, and the mixture was refluxed for 5 hours. After the reaction was completed, the reaction mixture was concentrated by removing the solvent under a reduced pressure, the residue thus obtained was alkalified with 10%-sodium bicarbonate aqueous solution, then extracted with 100 ml of methylene chloride. The extract was washed three times with 100 ml of water each time, then dried with anhydrous magnesium sulfate. The methylene chloride extract was concentrated by removing the solvent under a reduced pressure, and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 0.21 g of 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]-2-hydroxypropylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[O:14])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>>[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[C:13](=[O:14])[CH3:1])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Product: CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
25 ml (75 mmol) 3 M methylmagnesium chloride (diethyl ether) and 8.25 g (41.4 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of the crude product 9.19 g. The product was purified with a silica column using 33% ethyl acetate in petroleum ether as eluent. Yield 7.54 g (35.0 mmol 85%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 6.91 g. The product was purified with a silica column using 20–25% ethyl acetate in petroleum ether as eluent. Yield 5.61 g (26.3 mmol, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[N:15]=[C:14](Cl)[C:13]=2[CH2:12][CH2:11]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[N:15]=[C:14]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])[C:13]=2[CH2:12][CH2:11]1
Reactant: COc1ccc(N2CCc3c(Cl)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Reactant: NCCCO
Product: COc1ccc(N2CCc3c(NCCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(550 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, and reacted at the same condition of Step 3 in the Example 23 to obtain 400 mg of desired compound as solid in 67% of yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH2:27]Cl)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:29])=[N:6][CH:7]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[C:3]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH2:27][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:29])=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCCl)CC4)cc3C)ncc2Cl)n[nH]1
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCN5CCOCC5)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
The product from Step 1 was stirred in neat morpholine (0.5 mL) at 100° C. in a sealed vial for one hour. The reaction was purified by RP-HPLC to give 5-Chloro-N2-(2,5-dimethyl-4-(1-(3-morpholinopropylsulfonyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white powder; ESMS m/z 603.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@@H:3]1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH3:19]I>CN(C=O)C.O>[CH3:19][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@H:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:2]1=[O:1]
Reactant: COC(=O)C[C@H]1Nc2ccccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1Nc2ccccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 650 mg, 2.95 mmol) in DMF (5 mL) at 0° C. was added NaH (142 mg, 3.54 mmol). After stirring at 0° C. for 20 minutes, MeI (220 uL, 3.54 mmol) was added and the reaction mixture was stirred for an additional 15 minutes at 0° C. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (1×50 mL), dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate, which was used without further purification. LCMS (ES) 235.1 m/z (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:3]1=[O:18].CN1C2C(=CC=CC=2)C(C2[C:30](=[O:35])NCCN=2)=C1.[H-].[Na+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:30]=[O:35])[CH:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:3]1=[O:18]
Reactant: Cn1cc(C2=NCCNC2=O)c2ccccc21
Reactant: CN1CCN=C(c2cn(C)c3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CN1CCN(C=O)C(c2cn(C)c3ccccc23)C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The 1-methyl-3-(1-methylindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone required as the starting material is prepared as follows: 45.5 g (0.2 mol) of 3-(1-methylindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, prepared in accordance with Example 33, are dissolved in 400 ml of dimethylformamide, 5.3 g (0.22 mol) of sodium hydride are introduced, the mixture is stirred for 4 hours at 60° C., 27.8 g (0.22 mol) of dimethyl sulphate are added dropwise and the mixture is stirred for 20 hours at 60° C. The compound which is precipitated by dilution with water is recrystallised from methanol.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:20])[CH2:15][CH2:16][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=2)=[O:18])=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: CCCOC(=O)c1ccc(O)cc1
Product: CCCOC(=O)c1ccc(OC(=O)CCC(=O)Oc2ccc(C(=O)OCCC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 7.8 g of propyl p-hydroxybenzoate and 18 g of succinic acid dichloride to yield di(p-propyloxycarbonylphenyl)succinate, m.p 122°-123.5° C., as white crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH3:29]>CN1C(=O)CCC1>[C:27]([C:25]1[N:26]=[C:21]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:22]([CH3:29])=[CH:23][CH:24]=1)#[N:28]
Reactant: Cc1ccc(C#N)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C#N)nc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 140 °C

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (491 mg, 2.62 mmol) in NMP (4 mL) was added Cs2CO3 (1025 mg, 3.15 mmol). The mixture was stirred at 0° C. for 1 hour at which time 6-chloro-5-methylpicolinonitrile (400 mg, 2.62 mmol) was added. The reaction mixture was heated at 140° C. for 1 hour in a microwave reactor to give the title compound in a crude reaction mixture that was used directly in the next step.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:19][C:20]([NH2:22])=[S:21].O>C(O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([C:4](=[N:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=1
Reactant: CCOC(=O)C(=NOC1CCCCC1)C(=O)CCl
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOC1CCCCC1)c1csc(N)n1
Yield: 12 %

Procedure:
Ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), thiourea (7.7 g.), sodium acetate 3-hydrate (13.7 g.), water (70 ml.) and ethanol (140 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.6 g.), mp. 125° to 126° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:25]([CH3:24])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:22])([F:23])[F:1])=[N:4]2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNC
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CCCCN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylbutylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-66% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[NH:16])[NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]([SH:21])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[C:18]([Cl:17])[S:21][N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: SC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(N2CCN(Cc3ccccc3)CC2)ns1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
To a solution of 4-benzylpiperazine-1-carboximidamide (2.50 g, 11.5 mmol) and perchloromethyl mercaptan (1.24 ml, mmol) in methylene chloride (12 ml) was added dropwise a solution of sodium hydroxide (1.84 g, 46.0 mmol) in water (5 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The reaction mixture was poured to water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.00 g (29.6%) of the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH:32](=O)[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31])[CH3:33]
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Reaction time: 1 h

Procedure:
cis-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.177 mmol) was suspended in 1,2-dichloroethane (6 mL). A solution of acetaldehyde (12 mg, 0.266 mmol) in 1,2-dichloroethane (0.300 mL) and acetic acid (42 mg, 0.708 mmol) was added and the mixture was stirred for 1 hour. Sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. After 16 hours, more sodium triacetoxyborohydride (37 mg, 0.175 mmol) was added and the reaction continued for another 3 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL) then washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (80 mg) was collected as a colorless oil.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37](Cl)=[O:38]>C1C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:38]
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)ccc1OC)c1ccccc1-c1ccccc1
Yield: 94 %

Procedure:
Analogously to Example 47, 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 7.3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml of benzene to obtain, as reaction product, 15.0 g (94.1% of theory) of ethyl 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]butyrate as a viscous non-distillable oil. The saponification of this ester yields 12.4 g (88% of theory) of 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido-9 butyric acid, MP 160° to 162°.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1.CN(C=O)C>O>[Br:1][C:2]1[N:6]=[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: CC(C)COC(=O)NC1CCNCC1
Reactant: Clc1nc(Br)ns1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC(=O)NC1CCN(c2nc(Br)ns2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (0.21 g, 1.1 mmol), isobutyl piperidin-4-ylcarbamate (0.23 g, 1.2 mmol), and DMF (2 mL) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for two minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 365.0 (M+H)+ at 3.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).