Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:25])C(=O)C(F)(F)F)[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:44]>>[F:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:29]2[CH:28]=[CH:27][C:26]([C:4]3[C:3]([C:1]([NH2:2])=[O:44])=[C:7]4[NH:8][CH2:9][CH2:10][CH:11]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[NH:18][CH3:25])[N:6]4[N:5]=3)=[CH:31][CH:30]=2)=[CH:38][CH:37]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: CNc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21

Procedure:
The desired product was prepared form N-(2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, CD3OD-d4) δ 7.39 (d, J=8.8 Hz, 2H), 7.09-6.90 (m, 7H), 6.58 (d, J=8.0 Hz, 1H), 6.51 (t, J=7.2 Hz, 1H), 6.30 (d, J=7.2 Hz, 1H), 5.52-5.48 (m, 1H), 3.27-3.24 (m, 1H), 3.11-3.02 (m, 1H), 2.76 (s, 3H), 2.32-2.10 (m, 2H). MS (ESI) m/e [M+1]+ 457.9.
Reaction SMILES: [CH3:1]N(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]3[N:19]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=[C:15]([C:37]#[N:38])[N:14]=2)[CH:10]=[N:11][CH:12]=1.CI.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]3[N:19]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:20]([N:22]([CH3:1])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=[C:15]([C:37]#[N:38])[N:14]=2)[CH:10]=[N:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 60 °C

Procedure:
DMF (4 mL) was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(phenylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (200 mg, 0.438 mmol), followed by methyl iodide (68 mg, 0.481 mmol) and potassium carbonate (121 mg, 0.877 mmol), and the vial was sealed and heated to 60° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 15% ethyl acetate/petroleum ether as eluent to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calc'd. for C27H27ClN6 [M+H]+ 471. found 471.
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([OH:18])=O)=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:22])=O>CCCCCC>[C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([Cl:22])=[O:18])=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)OCC(=O)OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: CCCCCCCC(=O)OCC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.6 g (0.022 mole) octanoyl-oxyacetyl-oxyacetic acid, 50 ml hexane were placed in a 250 ml round bottom flask. 2.9 ml (0.03 mole) oxalyl chloride was added in one portion and the reaction stirred at room temperature for 6 hours. The reaction was then heated to 80° C., a distillation head attached with condenser and receiver, and the excess oxalyl chloride and solvent removed at reduced pressure. There remained 4.5 g of light yellow oil. IR spectrum reveals no free --OH and a broad V--C=O absorbance, with maxima at 1815, 1780 and 1755 cm-1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19])=[O:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=[O:19])=[O:6]
Reactant: Cc1cc(C)c(C(C)(C)CCO)c(OC(=O)CCCBr)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C)c(C(C)(C)CC=O)c(OC(=O)CCCBr)c1
Temperature: 24 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
2.5 g of 3-[2-(4-bromobutyryloxy)-4,6-dimethylphenyl)-3,3-dimethylpropan-1-ol in solution in 160 cm3 of dichloromethane are added dropwise, at 24° C., to 3.1 g of pyridinium chlorochromate in suspension in 900 cm3 of dichloromethane. After stirring for 2 hours at 24° C., the reaction mixture is filtered on 630 g of silica (particle size 0.063–0.2 mm), eluting successively with pure dichloromethane, and then a mixture of dichloromethane and ethyl acetate (80/20 by volume). 2.4 g of 3-[2-(4-bromobutyryloxy)4,6-dimethylphenyl]-3,3-dimethylpropanal are thus obtained in the form of a colorless viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([P:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)(=[O:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[CH:5]=[C:6]([P:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)(=[O:11])[OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(P(=O)(O)c2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Nc1cccc(P(=O)(O)c2cccc(N)c2)c1

Procedure:
The compound bis(3-nitrophenyl)phosphinic acid (14.0 g, 45.4 mmol) from Example 1 was suspended in methanol (200 ml). Platinum (5 wt. %, on activated carbon, 1.4 g) was added. The mixture was shaken on a hydrogenation apparatus (50 psi) until no further hydrogen consumption was observed. The mixture was filtered through celite and then evaporated to dryness. The solid obtained (9.87 g, 88%) was used without purification. The structure of bis(3-aminophenyl)phosphinic acid is:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[BH4-].[Na+].C(O)(=O)C>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[OH:10]
Reactant: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OC(CCCCCCCBr)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-1-(4-chlorophenyl)octan-1-one (0.95 g) in industrial methylated spirit (10 ml) was added sodium borohydride (0.115 g) at −10° C. After stirring for 1 h, glacial acetic acid (0.2 g) was added and the mixture was poured into water (60 ml) and extracted with diethyl ether. The diethyl ether layer was washed with brine and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave an oil that was chromatographed on silica gel using dichloromethane as eluent. This gave 8-bromo-1-(4-chlorophenyl)-1-hydroxyoctane (0.70 g). 1H-NMR (CDCl3) δ 1.15-1.95 (12H, m), 3.40 (2H, t), 4.65 (1H, t) and 7.2-7.4 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][Mg]Cl.Cl.O>C1COCC1.[Pd]>[CH:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[OH:1])([CH3:11])[CH3:13]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: C[Mg]Cl
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone (10.0 g) in 80 mL of THF was gradually added 46.4 g of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25 degrees C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours. To the stirred solution was then added 10% palladium on carbon (1.02 g, 50% water wet) suspended in 4 mL of THF. The reaction mixture was placed under a hydrogen atmosphere at 5 psig and cooling was applied to maintain a temperature of approximately 25° C. To the cooled mixture was gradually added concentrated HCl (20 mL) while maintaining the reaction temperature at 25° C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 45 mL water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated under reduced pressure to give 10.4 g of 2-isopropyl-4-methoxy-phenol, MS (M+H)=167. This product was dissolved in 2-butanone (20.4 g) and the crude solution was employed directly in the next step.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH3:38])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([O:36][CH3:37])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:27]([C:29]2[O:30][CH:31]=[C:32]([O:36][CH3:37])[C:33](=[O:35])[CH:34]=2)=[O:28])[CH2:11][C@@H:10]([CH3:38])[C:9]([OH:39])=[O:8])=[CH:15][CH:16]=1
Reactant: COc1coc(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C[C@@H](C)C(=O)OCc2ccccc2)cc1=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1coc(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C[C@@H](C)C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, To a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester in methylene chloride (1 mL) is added BCl3 (0.12 mL of a 1M solution in methylene chloride) and the mixture is stirred at room temperature for 18 hours. An additional 0.12 mL of the BCl3 solution is added and stirring is continued for 5 hours. An additional 0.12 mL of the BCl3 solution is added and stirring is continued for 18 hours. The mixture is quenched with water (2 drops) and DMF (1 mL) is added. The solution is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to elute the title compound; HPLC Retention time 1.28 minutes (condition C): MS 436.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]\[C:13]([CH3:16])([CH3:15])[CH3:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[N:25][C:26]([O:28][Si](C)(C)C)=[CH2:27])[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[C:13]([CH:12]1[CH2:27][C:26](=[O:28])[NH:25][CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[C:6]21[C:5]1[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[NH:8][C:7]2=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CC(C)(C)/C=C1/C(=O)Nc2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 1c, E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one (0.23 g, 1 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.63 g, 2.5 mmol) prepared in example 1b, in toluene to give racemic (2′SR,3S,4′R)-4′-(tert-butyl)-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a mixture of two sets of diastereomers (Yield 0.21 g, 50%).
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13].[H][H]>[Pd].O>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[CH:12]=[O:13]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(F)c(Br)c1
Temperature: 85 °C
Yield: 88.6 %

Procedure:
2 g of palladium/activated carbon (5% by weight of Pd) and 350 g of toluene are heated for 1 hour at 75° C. in a three-necked flask equipped with a gas inlet tube, a reflux condenser and a stirrer while water gas (CO:H2 =1) is being passed through. 70.0 g of 3-bromo-4-fluorobenzoyl chloride prepared as in Example 3 were then added and hydrogen was passed in instead of water gas. The temperature was increased to 85° C. After 4 hours 95% of the amount of hydrogen chloride expected had been split off. After cooling down, the reaction mixture was filtered and the filtrate was distilled off. 53 g of 3-bromo-4-fluorobenzaldehyde, boiling point 112° C./20 mbars, nD30 1.5685 and melting point: 30° C., were obtained.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[Na+].[CH:14]1([N:20]=[N:21][C:22]2(Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[CH:22]1([N:21]=[N:20][C:14]2([N:5]3[C:1](=[O:11])[C:2]4=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]4[C:4]3=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC1(N=NC2CCCCC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1(N=NC2CCCCC2)CCCCC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 10.45 grams (.071 moles) phthalimide in 80 mls of N,N-dimethylformamide in a 250 ml 4-neck flask equipped with a magnetic stirrer, thermometer and addition funnel was added 4.0 grams (.05 moles) of 50% sodium hydroxide and the solution stirred for 15 minutes at 40° C. To this solution was added dropwise 11.45 grams (.05 moles) of 1-cyclohexylazo-1chlorocyclohexane (from Example 3-11) over 20 minutes at 40° to 45° C. After the addition was complete, the reaction was stirred an additional 60 minutes at 40° C, poured into 250 ml cold water and the white solid that formed was filtered off and dissolved in 100 ml of pentane. The insolubles were filtered off and the pentane filtrate washed with water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a white solid and weighed 11.5 grams (68% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-cyclohexylazo-1-phthalimidocyclohexane (absence of NH and OH bands and a strong carbonyl band at 1700-1730 cm-1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C-:20]#[N:21].[Na+].[Na+].[I-].Cl>O.CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])#[N:21]
Reactant: [C-]#N
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCCCCCCCCCC(=O)O
Temperature: 120 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
A mixture of 16-bromohexadecanoic acid (16.61 g, 49.5 mmol), DMSO (150 ml), NaCN (12.5 g, 255 mmol), and NaI (1.92 g, 12.8 mmol) was stirred at 120° C. for 20 h. The mixture was allowed to cool to room temperature, and was then poured into a stirred mixture of water (1.7 l) and concentrated HCl (30 ml). Rinsing with water (100 ml). The resulting suspension was stirred at room temperature overnight. The product was filtered and washed with water (2×100 ml), and the solid was recrystallized twice from MeCN (90 ml and 50 ml). 10.1 g (72%) of 16-cyanohexadecanoic acid was obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([C:10]#[N:11])[CH2:7][NH:6]1)=O.[NH3:12]>CO>[C:10]([C@H:8]1[CH2:7][NH:6][C@H:5]([C:3]([NH2:12])=[O:2])[CH2:9]1)#[N:11]
Reactant: COC(=O)[C@@H]1C[C@@H](C#N)CN1
Reactant: N
Solvent: CO
Product: N#C[C@H]1CN[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2S,4R)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester (22 mg) and 7M ammonia in methanol (0.24 ml) is stirred at room temperature for 1 hour. The reaction mixture is then evaporated to give the title compound which is used without further purification. MS (Method D) M+H 140.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Product: Cc1cc(F)c(C(=O)Cl)cc1F

Procedure:
250 ml of thionyl chloride are taken and 120 g of 2,5-difluoro-4-methyl-benzoic acid are introduced in portions at room temperature, with brisk evolution of gas. When the evolution of gas has subsided, the mixture is heated slowly to the reflux temperature and stirred until the evolution of gas has ended. The excess thionyl chloride is distilled off, the reaction product is coarsely distilled over and the distillate is fractionated on a small column. Yield: 97 g (72.9% of theory) of 2,5-difluoro-4-methylbenzoyl chloride of boiling point b.p.: 103°/20 mbar, nD20 : 1.5232.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1ncc(-c2ccc(F)cc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 5-bromopyrimidine-2-carboxylic acid and 4-fluorophenylboronic acid, the title compound was obtained as white solid.
Reaction SMILES: Cl.Cl.[CH3:3][S:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[OH:22]O>>[CH3:3][S:4]([C:5]1[CH:6]=[C:7]([C:13]2[NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])=[O:22]
Reactant: OO
Reactant: COc1ccc(-c2nc3cnccc3[nH]2)cc1SC
Agent: Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)cc1S(C)=O

Procedure:
The compound obtained in Example 34, was oxidised using hydrogen peroxide (2 eq) in a manner analogous to that described in Example 21. The title compound was obtained as a white solid, m.p. 227°-229° C.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:28]1([C:21]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([CH2:34][C:35]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.579 g, 2.84 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.762 g, 2.58 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.594 g, 3.10 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 30% ethyl acetate/hexanes over 30 minutes (flow=40 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.09-8.15 (m, 2H), 7.71-7.76 (m, 2H), 7.23-7.43 (m, 10H), 4.91 (s, 2H), 3.58 (t, J=6.5 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 462 (M−H)−.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:10]([C:18](O)=[O:19])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOCC>[NH:9]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:10]([C:18]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1
Yield: 97.9 %

Procedure:
Benzylamine (0.270 g, 2.52 mmol) was coupled to Fmoc-Thr(tBu)-OH(S29, 1.00 g, 2.52 mmol) using the standard HATU coupling procedure. The reaction was diluted with Et2O (150 mL), and washed with 10% citric acid solution (60 mL), water (3×60 mL), and brine (60 mL). The organic layer was dried (MgSO4), filtered, and concentrated by rotary evaporation. The crude product was purified using flash chromatography (15% EtOAc/hexanes) to afford S30 as a white solid (1.20 g, 98% yield). Rf 0.53 (1:1 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.61 (d, J=7.4 Hz, 2H), 7.44-7.27 (m, 9H), 6.06 (d, J=4.6 Hz, 2H), 4.50 (dd, J=7.8, 5.7 Hz, 2H), 4.44-4.37 (m, 2H), 4.27-4.14 (m, 3H), 1.24 (s, 9H), 1.04 (d, J=6.5 Hz, 3H); HRMS m/z calcd for C30H34N2NaO4 [MNa+] 509.2416. found 509.2226.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)cc1OC
Yield: 90.2 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-phenylpiperazine (5.9, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 26.55 hr and followed the same processes as in Example 1 to obtain 14.7 mg (100%) of the target compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][CH:44]([CH2:47][NH2:48])[O:43][C:42]=2[CH:49]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:48][CH2:47][CH:44]2[CH2:45][O:46][C:41]3[CH:40]=[CH:39][C:38]([OH:37])=[CH:49][C:42]=3[O:43]2)=[CH:2]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: NCC1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
3-Indolebutyric acid (1.0 g, 5.0 mmole), 1-hydroxybenzotriazole hydrate (0.8 g, 6.0 mmole) and 1,3-diisopropylcarbodiimide (1.9 ml, 12.0 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.1 g, 5.0 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Chromatography on silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants gave 0.3 g (16%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-methyl)-4-(1H-indol-3-yl)-butanamide, as an oil.