Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)[OH:2].[CH2:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([OH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:5]1(=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OB(O)O
Reactant: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
air oxidizing cyclohexane to KA oil in the presence of boric acid to provide a crude product stream comprising cyclohexanol, cyclohexanone, cyclohexane and boric esters;
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]#N)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].I[CH3:15].C[N:17]([CH:19]=O)C>>[CH3:15][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[C:19]#[N:17]
Reactant: CS(=O)(=O)CC#N
Reactant: CI
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of 2-(methylsulfonyl)acetonitrile (60 g, 504 mmol) in DMF (252 mL) at 0° C. was added potassium carbonate (209 g, 1511 mmol) portion-wise, followed by iodomethane (136 mL, 1511 mmol). After 15 minutes, the ice bath was removed and the reaction was stirred at RT for 48 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with ethyl acetate and ether. The combined filtrates were concentrated and partitioned between ether and water. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the titled intermediate (58 g, 78% yield) as an off-white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([O:11]CC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1csc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 4-isopropylthiazole-2-carboxylate (9.1 g, 46 mmol) in THF (100 ml) and MeOH (30 ml) was added a solution of lithium hydroxide (1.16 g, 48.5 mmol) and the mixture was stirred for two days at room temperature. The mixture was acidified with 2M hydrochloric acid and extracted four times with diethyl ether. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. Yield: 7.1 g, 90%.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([OH:21])[C:19]#[CH:20]>ClCCl.[Cu]I>[NH2:1][C:2]1[C:7]([C:20]#[C:19][C:18]([CH3:22])([OH:21])[CH3:17])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (10.0 g, 33.5 mmol), bis-(triphenyl-phosphine)-palladium(II)-dichloride (117 mg, 0.17 mmol), copper(I)iodide (79 mg, 0.41 mmol) and triethylamine (6.1 mL, 43.5 mmol) in dichloromethane (40 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (3.70 g, 44 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was diluted with dichloromethane (20 mL) and washed with water (2×50 mL). The organic phase was then treated with 1 M HCl (80 mL). The layers were separated and the organic layer was extracted with 1 M HCl (20 mL). The combined product containing aqueous layers were washed with dichloromethane (2×10 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water, 18 g). The resulting suspension was stirred at 20° C. for 2 hours and the crystals were then filtered off and washed with water (2×20 mL). The wet crystals were dried at 50° C./<30mbar affording 6.99 g (82%) of 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol as a melted mass with a purity of 99.5% (HPLC, area %). 1H NMR (400 MHz, CDCl3): δ ppm 1.63 (s, 6H); 4.0 (br., 3H); 7.59 (d, J=2.4, 1H); 8.03 (d, J=2.4, 1H).
Reaction SMILES: N(C(OC)=O)=NC([O-])=O.[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:38](O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[C:10]([O:18][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: COC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
Methyl azodicarboxylate resin (6.55 g of 0.61 meq/g ~4.0 meq) was suspended in dry THF (100 ml) and allowed to swell for ~15 minutes. Benzoic acid (0.366 g, 3.0 mmol) was dissolved in THF (10 ml) and added to the resin. To the stirred mixture at 25° C. was added dropwise a solution of Ph3P (0.786 g, 3.0 mmol) and benzyl alcohol (0.361 ml, 3.5 mmol) in THF (5 ml). This mixture was left to stir at 25° C. for 16 hours. Resin was then filtered and washed with CH2Cl2 (4×150 mL) and Et2O. The filtrate and washings were concentrated in vacuo at 30° C. and flash chromatographed (3.5% EtOAC/hexane) to yield benzyl benzoate (0.417 g, 65%): IR (film) 1720 (vs), 1451 (m), 1272 (vs), 1110 (m), 710 (s), 697 (m) cm-1 ; 1H NMR (80 MHz, CDCl3) δ8.25-8.05 (m, 2H, o-PhCOO), 7.65-7.25 (m, 8H, m-, p-PhCOO, OCH2PH), 5.32 (s, 2H, OCH2Ph); EI-MS: 212.0839 (M+, 212.0837 calcd. for C14H12O2), 105.0343 (Base Peak, phC=O).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O.S(=O)=O.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Product: Cc1cc(C)cc(C(=O)Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Into the same apparatus as used in the method A, were charged 300 g (2 mol) of 3,5-dimethylbenzoic acid and 357.2 g (3 mol) of thionyl chloride. The temperature was raised to 80° C. while stirring in a nitrogen atmosphere to allow the reaction to proceed for 3 h under reflux. During the reaction, sulfur dioxide and hydrogen chloride generated were washed away and captured by an aqueous alkali solution, The result of analysis of the reaction product solution showed the production of 310 g (1.84 mol) of the aimed 3,5-dimethylbenzoyl chloride (yield: 92%). By vacuum distillation, 287-(1.7 mol) of 3,5-dimethylbenzoyl chloride was isolated (yield: 85%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](Cl)=[O:14].O>C1COCC1>[CH3:10][C:11]([CH3:16])=[CH:12][C:13]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14]
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
In a 100 mL round bottom flask was placed NaH (1.93 g, 0.05 mol). After washing with dry hexane (2×10 mL dry THF (15 mL) was added), to this tan solid. Then, the resulting suspension was added to a solution of aniline (Compound 36, 4.89 mL, 0.054 mol) in dry THF (7 mL) at 0° C. After stirring for 30 min, 3,3-dimethylacryloyl chloride (Compound 35, 6.56 mL, 0.059 mol) was added dropwise to the above solution. The reaction mixture was stirred under N2 for overnight followed by a slow addition of water. The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with NH4Cl (sat.) and NaCl (sat.), dried over MgSO4 and concentrated to give the title compound as a tan solid (4.45 g, 51%). 1H NMR d 1.87 (s, 3H), 2.21 (s, 3H), 5.72 (s, 1H), 7.29-7.56 (m, 5H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1>O1CCCC1>[Br:1][C:13]1[C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][C:10]([NH2:9])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(Br)cn1
Temperature: -5 °C
Yield: 75.9 %

Procedure:
Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 112.14 g (0.63 mol) of N-bromosuccinimide (NBS) and 645 g (725 mL) of tetrahydrofuran. Stir and cool the slurry to −5±3° C. Charge a nitrogen-flushed 1 L round bottom 4-neck flask that equipped with a thermocouple, mechanical stirrer and nitrogen inlet/outlet with 97.26 g (0.6 mol) of 2-amino-4-(trifluoromethyl)pyridine, 4b and 511 g (575 mL) of tetrahydrofuran. Stir to dissolve the 4b. Transfer the 4b solution to the addition funnel on the reactor and add the solution to the NBS slurry over 2 h maintaining an internal temperature of 0±3° C. throughout the addition. Rinse the 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran and add the wash to the reaction mixture. Warm the solution to 20±3° C. over 30 minutes. Check for completeness of the reaction. Quench by charging a solution of 24.6 g of sodium thiosulfate pentahydrate dissolved in 475 mL of water over 10 minutes, maintaining a batch temperature of 20±3° C. throughout the addition. Stir for 1 h after the quench. Concentrate (internal temp=25° C., 50 mbar) to remove tetrahydrofuran. Add 379 g (500 mL) of tert-butyl methyl ether. Stir and warm the resulting solution/suspension to 30±3° C. and stir for 15 minutes. Separate the phases. Wash the extract four times with a solution of 32 g of sodium chloride dissolved in 768 g (768 mL) of water (4×200 mL per wash), separating the phases after each wash. Finally, wash the extract with 150 g (150 mL) of water. Separate the phases. Charge 152 g (200 mL) of tert-butyl methyl ether. Partially concentrate (57±3° C.) to a volume of 350 mL. Cool to 50° C. and add 265 g (350 mL) of tert-butyl methyl ether. Resume the concentration (57±3° C.) until a batch volume of 350 mL is reached. Cool to 50° C. and add 265 g (350 mL) of tert-butyl methyl ether. Again, resume the concentration (57±3° C.) until a batch volume of 350 mL is reached. Cool to 50° C. and add 103 g (150 mL) of tert-butyl methyl ether to raise the batch volume to 500 mL. Charge 1026 g (1500 mL) of heptane over 15 minutes maintaining 45±3° C. throughout the addition. Slowly increase the vacuum and concentrate (internal temp=40° C. to 50° C.) to a batch volume of 1000 mL. Release the vacuum and seed the batch. Resume the distillation, further increase the vacuum (slowly) and concentrate (internal temp=25° C. to 40° C.) to a batch volume of 500 mL. Stir the resulting suspension at 0° C. for 30 min. Filter the solids. Wash the filter cake with 68 g (100 mL) of cold (0° C.) heptane (containing 30 ppm Octastat). Dry the solids (40° C., 50 mbar) for 16 h to afford 109.8 g (78.0% yield) 4a as an orange solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Yield: 72 %

Procedure:
Reaction of tert-butyl 4-hydroxypiperidine-1-carboxylate with N-hydroxyphthalimide following the procedure described for the preparation of Reference Example 9 gave tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidine-1-carboxylate (3.0 g, 72%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.46 (9H, s), 1.82-1.85 (2H, m), 1.92-1.96 (2H, m), 3.20-3.25 (2H, m), 3.86-3.90 (2H, m), 4.41-4.44 (1H, m), 7.74-7.78 (2H, m), 7.82-7.86 (2H, m).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:18][N:19]([O:20][CH3:21])[C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CNOC
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 22 h
Yield: 87.7 %

Procedure:
A mixture of N-Boc-L-leucine (2.47 g), N,O-dimethylhydroxylamine hydrochloride (1.09 g), 1-hydroxybenzotriazole monohydrate (1.51 g), and N-methylmorpholine (1.21 mL) was dissolved in DMF (40 mL), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.14 g) was added at 0° C. and the mixture was stirred at 0° C. for 2h, then at room temperature for 22 h. The reaction was quenched with water (100 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with aqueous 10% HCl, saturated NaHCO3, and brine, then dried over anhydrous MgSO4, filtered, and evaporated to afford the product (2.57 g) as an oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 1.07 g (5.24 mmol) of 2,6-dichlorobenzothiazole in dry DMF (25 mL) was added 2.4 g of potassium carbonate (15.7 mmol) and 0.5 g of piperazine (5.8 mmol). The mixture was stirred at room temperature for 4 h. When the reaction was complete it was partitioned between EtOAc (150 mL) and water (50 mL) and separated. The aqueous layer was extracted with EtOAC (2×100 mL). The combined organic layers were then washed with water (2×25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give 1.33 g (100%) of desired product as a white solid. MS (electrospray): exact mass calculated for C11H12CIN3S, 253.04; m/z found, 254.0 [M+H]+.
Reaction SMILES: C(O)[C@@H](O)C(O)=[O:4].NC=CC1C=CC=CC=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:4])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)[C@H](O)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC=Cc1ccccc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To a solution (cooled to 0° C) of 5.3 g (0.05 mole) D-glyceric acid in 150 ml of acetonitrile, there was added 8.9 g (0,075 mole) β - aminostyrene and 10.3 g (0.05 mole) N.N' - dicyclohexylcarbodiimide. A precipitate of N.N' - dicyclohexylurea is formed immediately, but the reaction was allowed to proceed for 15 hours at room temperature. After filtration and removal of the acetonitrile by distillation under reduced pressure, the residue was taken up in ethyl acetate and extracted with HCl, bicarbonate and water. After drying and removal of the solvent the residue was crystallized from chloroform, yielding 7.5 g (73%), m.p. 135°-136° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3=[N:18][CH2:19][CH2:20][N:10]23)=[CH:5][CH:4]=1>CCOCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[NH:18][CH2:19][CH2:20][N:10]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCN21
Agent: Cl
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1ccccc1C1=NCCN1
Reaction time: 0.5 h

Procedure:
The hydrochloride was prepared by adding a solution of hydrogen chloride in ether to a suspension of 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole. After stirring for 30 minutes a crystalline crop was collected and recrystallized from a mixture of chloroform and ether to give white prisms melting at 168°-171° dec. Ultraviolet inflexion (2-propanol) at 220 μ (ε = 22,000), maxima at 252 μ (ε = 12,900), 266 μ (ε = 13,000); infrared absorption (KBr) at 1670 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (Z)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (1.200 g, 3.6 mmol), dimethyl-prop-2-ynyl-amine (0.9 ml, 10.88 mmol), bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.144 mmol), copper(I) iodide (2.06 mg, 0.0108 mmol) in dry triethylamine (10 ml) were heated to 100° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The resulting residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]([CH2:15]O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2].O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:15][C:14]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:17][CH3:18])=[CH:9][CH:8]=2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nc(NC(C)C)c(CO)cc2c1
Solvent: ClCCl
Product: COc1ccc2nc(NC(C)C)c(CCl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of (2-(isopropylamino)-6-methoxyquinolin-3-yl)methanol SLA 28188 (1.41 g, 5.72 mmol) in dry CH2Cl2 (115 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (8.30 mL, 114 mmol). The mixture was stirred for 1 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-N-isopropyl-6-methoxyquinolin-2-amine hydrochloride SLA 28190 as a yellow solid (1.79 g, >100% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([C:9](OCC)=[O:10])=[CH:5][N:4]=1.CC(C[AlH]CC(C)C)C>ClCCl>[F:15][C:2]([F:1])([F:14])[C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1cnc(C(F)(F)F)nc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 138.1 %

Procedure:
To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (25.5 g, 116.0 mmol) in dichloromethane (580 mL) at −78° C. was slowly added DIBAL-H (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at −78° C. After 2 h, the mixture was quenched via slow addition of HCl (2.0 M in water). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3×). The combined organic extracts was dried over Na2SO4, filtered and concentrated to give the title compound (28.2 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
NaH (60%, 36.8 g, 921 mmol) was added portionwise to a stirring solution of 5-bromoindole (152.0 g, 768 mmol) in DMF (1.4 L) at 0° C. under a nitrogen atmosphere over a period of one hour. The mixture was stirred at 0° C. for one hour and at room temperature for 2.5 hours. 4-(tert-Butyl)benzyl bromide (180.0 g, 768 mmol) was added over a period of one hour. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride (5%, 1.4 L). The precipitated solid was isolated by filtration, washed with water (5×0.5 L), then with petroleum ether (0.3 L). The solid was dried in the air and then under vacuum at 60° C. for 18 hours to afford the title compound as a white solid (257 g, 97%), m.p. 108–109° C. Mass spectrum (ESI, [M+H]+) m/z 342. 1HNMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), δ 7.55 (s, 1H), δ 7.44 (d, 1H, J=8.71 Hz), 7.30 (d, 2H, J=7.96 Hz), 7.19 (d, 1H, J=8.71 Hz), 7.10 (d, 2H, J=7.63 Hz), 6.46 (s, 1H), 5.36 (s, 2H), and 1.21 ppm (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1)(0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0)(16 mg), then heated under reflux for 4 hours. The mixture was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([CH2:16][C:17](O)=[O:18])[CH2:15][CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[CH2:16][CH:13]3[CH2:15][CH2:14]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)CC1CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC1CC1)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 42 h
Yield: 75.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-cyclopropylacetic acid (218 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP—Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 42 hours. Then 2M LiOH.H2O (3 mL) was added, and the mixture was stirred for 18 hours. The mixture was then diluted with CH2Cl2 (50 mL). The layers were separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (204 mg, 75% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 9.40 (s, 1H), 8.34 (d, 1H), 7.61 (s, 1H), 2.24 (d, 2H), 1.10-1.03 (m, 1H), 0.52-0.47 (m, 2H), 0.24-0.20 (m, 1H); LCMS (APCI+) m/z (M+H)+, Retention time=2.92 minutes (Method 2).