Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][CH2:13][CH:14]([OH:16])[CH3:15].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24](F)[CH:25]=1)[C:21]#[N:22].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:16][CH:14]([CH3:15])[CH2:13][O:12][CH3:11])[CH:25]=1)[C:21]#[N:22]
Reactant: COCC(C)O
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
NaHMDS (148 mmol; 27.2 g) was charged to a 1000 ml round-bottomed flask (4 necks, thermometer, pressure-equalising dropping funnel, stopper, nitrogen inlet, magnetically stirred, oven dried, nitrogen purged), followed by DMF (300 ml). The mixture was stirred for 5 minutes then 1-methoxy-2-propanol (1.50 equiv; 148 mmol; 14.3 ml; 13.4 g) was added dropwise over a 10-minute period. The reaction temperature increased to 25° C. The mixture was cooled using a cold-water bath to 23° C., then 3-bromo-5-fluorobenzonitrile (1.00 equiv; 99.0 mmol; 20.0 g) in DMF (90 ml) was added over a 5 minutes period (cold water bath still present). The mixture warmed to 27° C. during addition, turning from yellow to brown. A line wash of DMF (10 ml) was added. The mixture was stirred at ambient temperature for 30 minutes, then quenched by addition of HCl solution (2M, aqueous, 200 ml), the dark brown reaction mixture turning pale yellow. The mixture was poured into water (400 ml) and extracted with EtOAc (3×400 ml). The combined organic extracts were washed with water (3×400 ml) and dried over MgSO4, filtered and the solvent removed in vacuo affording 3-bromo-5-(2-methoxy-1-methylethoxy)benzonitrile as an orange oil (25.38 g, 95%). 1H NMR (400 MHz, CDCl3) δ: 7.32 (s, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 4.58-4.55 (m, 1H), 3.59-3.48 (m, 2H), 3.41 (s, 3H), 1.33-1.31 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.C1CNC(=O)C1.[Br:26][Br-]Br>CO.C(Cl)Cl>[Br:26][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C1CCCN1
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethanone (2.92 g) was dissolved in methanol:DCM (2:1, 75 mL) and pyrrolidinone hydrotribromide (7.5 g) was added and stirred at room temperature for 2.5 h. After completion of the reaction, the mixture was concentrated in vacuo and poured into saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were combined and concentrated in vacuo. Then this residue was dissolved in DCM (10 ml) and methanol (10 mL) was slowly added to this solution to precipitate the product. The colored solution was filtered through to give clear white powder product 2-bromo-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone with quantitative yield (3.75 g). 1H NMR (400 MHz, CDCl3): 7.98 (d, 2H), 7.54 (s, 1H), 7.47 (d, 1H), 7.25 (m, 1H), 7.01 (d, 2H), 5.09 (s, 2H), and 4.40 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[OH-].[Na+].[F:17][CH:18]([F:20])Cl>O1CCOCC1>[F:17][CH:18]([F:20])[O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)c1ccc2ccccc2c1OC(F)F

Procedure:
10 g of 1-hydroxy-2-acetylnaphthalene are dissolved in 60 ml of dioxane, and 30 ml of 30% sodium hydroxide solution are added. At a temperature of from 70° C. to 80° C., difluorochloromethane (Freon 22) is introduced until no further absorption is observed. The dioxane phase is then decanted, the NaOH phase is washed with dioxane, the dioxane phase is decanted, and the combined dioxane solutions are largely concentrated in vacuo using a rotary evaporator. Water is added to the residue, the mixture is extracted several times with diethyl ether, and the diethyl ether solution is dried over Na2SO4, filtered and concentrated by evaporation. The residue is recrystallised from diethyl ether/hexane. Yield: 4 g, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[O:11]1CCOCC1>O>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH:1]=[O:11])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
4-Hydroxyacetophenone (15 g., 0.11 mol) was dissolved in 70 ml. dioxane and 8.3 ml. H2O. SeO2 (12.2 g., 0.11 mol) was added and the mixture heated at 80° for 18 hours, then filtered over diatomaceous earth. The filtrate was stripped, taken up in 150 ml. H2O, heated on a steam bath, decolorized with activated carbon, cooled to refrigerator temperature, and hydrate of title product recovered by filtration, 5.72 g. Anhydrous title product was obtained by Kugelrohr distillation; 1H-nmr 5.97 (s, 1H), 6.97 (d, 2H, J=6 Hz), 8.22 (d, 2H, J=6 Hz), 9.68 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH:16]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH:16]=[N:19][OH:20])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1onc(-c2ccccc2)c1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 80 °C
Yield: 86.7 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde (Intermediate I-12B, 0.38 g, 1.576 mmol) in ethanol (5 mL) were sequentially added hydroxylamine hydrochloride (0.131 g, 1.891 mmol) and sodium acetate (0.155 g, 1.891 mmol) at room temperature. The reaction mixture was heated at 80° C. for 20 min. The reaction mixture was concentrated and water (10 ml) was added. A pale yellow solid separated out from solution, and was filtered, washed with water (2×5 mL) and dried overnight to yield 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde oxime (0.35 g, 1.366 mmol, 87% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (br. s., 1H) 8.32 (s, 1H) 7.62-7.67 (m, 2H) 7.47-7.57 (m, 3H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:38])/[C:7](/[NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:21][C:20]=1[Cl:36])=[CH:8]/[C:9]1[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=1[CH3:16].Cl>O.O1CCCC1.CO>[Cl:36][C:20]1[CH:21]=[C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17]/[C:7](=[CH:8]\[C:9]1[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=1[CH3:16])/[C:6]([OH:38])=[O:5])=[O:37]
Reactant: CCc1nc(C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)OC)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A solution of lithium hydroxide monohydrate (100 mg, 2.4 mmol) in water (3 mL) was added to a solution of (Z)-3-(2-ethyl-4-methylthiazole-5-yl)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]amino]propenoic acid methyl ester (Example 216; 120 mg, 0.2 mmol) in tetrahydrofuran/methanol (3:1; 12 mL) and the reaction was allowed to stir at room temperature overnight. Water (50 mL) and 1N hydrochloric acid solution (3 mL) were added and the mixture was extracted with ethyl acetate (2×50 mL). The ethyl acetate layers were concentrated and purified by HPLC to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-ethyl-4-methylthiazole-5-yl)propenoic acid (105 mg, 90% yield) as a colorless solid, mp>200° C.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C)C=O>[CH:1]1([CH2:6][O:7][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OCC1CC=CC1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC2CC=CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of cyclopent-3-en-1-ylmethanol (3.50 g, 35.66 mmol) in anhydrous dimethylformamide (100 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.71 g, 42.79 mmol) portionwise under nitrogen. The mixture was stirred at 0° C. for 1 hour and then stirred at ambient temperature for 1 hour. para-Methoxybenzyl chloride (5.80 mL, 42.79 mmol) was added to the reaction mixture and the resulting mixture was stirred for 2 hours. The reaction mixture was quenched with methanol (10 mL) and then water (200 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with saturated ammonium chloride (2×200 mL) and brine (200 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3:1 hexanes:ethyl acetate) to provide the title compound (6.15 g, 79%): 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.67-5.60 (m, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.34 (d, J=7.2 Hz, 2H), 2.66-2.40 (m, 3H), 2.16-2.03 (m, 2H); MS (ES+) m/z 241.2 (M+23).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br.O>C(=S)=S>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][C:8]=1[Br:12]
Reactant: BrBr
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: S=C=S
Product: Oc1ccc(Br)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 59.2 %

Procedure:
3-Trifluoromethylphenol (compound I) (5.0 g) was dissolved in carbon disulfide (3.0 ml) and then to the solution was added a solution of bromine (5.0 g) in carbon disulfide (2.0 ml) over a period of about 15 minutes at 25° C. or less, followed by allowing the reaction to proceed for 2 hours at 25° C. The resulting reaction mixture was added to water (10 ml) and then subjected to repeated extraction with methylene chloride. The methylene chloride layer was washed with aqueous sodium hydrogen-carbonate solution and then with water and dehydration-dried by adding anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3-trifluoromethyl-4-bromophenol (compound II, 4.4 g).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2].[I:10][C:11]1[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([NH2:20])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[I:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:1]([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(I)cc1C(=O)O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
A solution of Troc-Cl (2.88 mL, 20.9 mmol) in dry dichloromethane (20 mL) was added drop wise to a solution of 5-iodoanthranilic acid 131 (5 g, 19 mmol) and pyridine (3.1 mL, 38 mmol) in dry dichloromethane (30 mL) at 0° C. The solution was stirred for 5 hours at room temperature and then washed with 1N HCl (2×25 mL), water (1×25 mL) and brine (1×25 mL). The organic phase was dried over MgSO4 and evaporated, residue was recrystallized from ethyl acetate to afford the title compound as a yellow solid (6.2 g, 75%): m.p. 248 C (ethyl acetate). 1H NMR (CDCl3, DMSO-d6) δ4.83 (s, 2H); 7.78-7.82 (dd, J=9.2, J=2.2 Hz, 1H); 8.18 (d, J=9 Hz, 1H); 8.38 (d, J=2.2 Hz, 1H); 9.0-10.5 (bs, 1H); 11.04 (s, 1H). 13C NMR (CDCl3, DMSO-d6) δ74.4, 84.6, 95.2, 117.7, 120.7, 140, 140.8, 142.8, 151.5, 169. MS: m/e (relative intensity) 437 (M−1, 60), 289 (55), 272 (37), 245 (100), 218 (27). HRMS Calculated for C10H7Cl3INO4: 436.8485. Found: 436.8485.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[CH:53]=[C:52]([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([NH:60][CH:61]([CH3:65])[CH2:62][O:63][CH3:64])[CH:55]=2)[CH:51]=[CH:50][N:49]=1.[Cl:66][C:67]1[CH:68]=[C:69]([CH:71]=[CH:72][CH:73]=1)[NH2:70].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:66][C:67]1[CH:68]=[C:69]([NH:70][C:48]2[CH:53]=[C:52]([C:54]3[CH:59]=[CH:58][N:57]=[C:56]([NH:60][CH:61]([CH3:65])[CH2:62][O:63][CH3:64])[CH:55]=3)[CH:51]=[CH:50][N:49]=2)[CH:71]=[CH:72][CH:73]=1
Reactant: COCC(C)Nc1cc(-c2ccnc(Cl)c2)ccn1
Reactant: Nc1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCC(C)Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)c2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Pd(OAc)2 (8 mg) and BINAP (16 mg) were suspended in toluene (10 ml) and stirred under argon for 10 mins, then (2′-Chloro-[4,4′]bipyridinyl-2-yl)-(2-methoxy-1-methyl-ethyl)-amine (90 mg), 3-chloroaniline (124 mg) and potassium carbonate (890 mg) were added. The mixture was stirred at 110° C. for 5 hours then cooled to room temp, poured onto water and extracted with ethyl acetate, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by passing the crude mixture down Kieselgel using 1:99 THF:CH2Cl2 as the eluent.
Reaction SMILES: [CH3:1]C1C=NC2CCCCC=2C=1.C[Li].[Li]C1C2N=CC(C)=CC=2CCC1.C(=O)=O.[Li+].[CH3:30][C:31]1[CH:32]=[N:33][C:34]2[CH:35]([C:41]([O-:43])=[O:42])[CH2:36][CH2:37][CH2:38][C:39]=2[CH:40]=1>CCOCC>[CH3:1][O:42][C:41]([CH:35]1[C:34]2[N:33]=[CH:32][C:31]([CH3:30])=[CH:40][C:39]=2[CH2:38][CH2:37][CH2:36]1)=[O:43]
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: Cc1cnc2c(c1)CCCC2C(=O)[O-]
Agent: O=C=O
Agent: [Li+]
Agent: [Li]C
Solvent: CCOCC
Product: COC(=O)C1CCCc2cc(C)cnc21
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (10 g) in anhydrous ether (50 ml) was added dropwise with stirring under nitrogen a 1.67 molar solution of methyllithium (40 ml.). The stirring was continued for 1/2 hour then the dark red solution of 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline was treated with a brisk stream of CO2 gas until the suspension became pale yellow. The resulting 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylic acid lithium salt was processed in the manner described in copending application U.S. Ser. No. 460,265 to give methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[C:18]([F:20])[C:14]([C:15](O)=[O:16])=[C:13]([F:21])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:24](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[C:18]([F:20])[C:14]([C:15]([NH2:24])=[O:16])=[C:13]([F:21])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(C(=O)O)c(F)c1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(C(N)=O)c(F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirred solution of the above benzoic cid intermediate (1.23 g, 4.08 mmol) and triethylamine (0.63 mL, 4.5 mmol) in THF (20 mL) at −25° C. was added ethyl chloroformate (0.43 mL, 4.5 mmol). The reaction was warmed to 0° C. in 1 h and an ammonia solution (0.5 N in dioxane, 20 mL, 10 mmol) was then added. The reaction was stirred at room temperature overnight, concentrated, diluted with dichloromethane, washed with 1N HCl and brine, dried with sodium sulfate, concentrated, and dried in vacuo to give 4-(N-boc-2-aminoethyl)-2,6-difluorobenzamide (0.8 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3=[N:18][NH:19][C:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[C:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[C:35](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:19]=[C:20]([NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(Nc1[nH]nc2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-2,2,2-trifluoro-acetamide (43.76 g, 106.65 mmol) and triethylamine (44.6 mL, 319.95 mmol) in dichloromethane (1 L), at room temperature, trityl chloride (31.22 g, 111.98 mmol) was added. The reaction was stirred at room temperature for 1 hour. The organic phase was washed with NaHCO3 satured solution, water and brine, dried over sodium sulfate filtered and evaporated to dryness affording the crude title compound as white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:34]4[CH:35]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:33]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(Cc2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(Cc2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-benzyl)-4-methyl-piperazine (77.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.036 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.24 (d, J=8.5 Hz, 2H), 8.09 (d, J=8.5 Hz, 2H), 7.66 (dd, J=7.4, 0.9 Hz, 1H), 7.58 (dd, J=7.8, 1.9 Hz, 1H), 7.46 (s, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H), 6.90 (s, 1H), 3.54 (s, 2H), 3.10 (s, 3H), 2.70-2.32 (m, 8H), 2.29 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[N:15]=3)[NH:10][C:9]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(C2C=CC(CC(OC)=O)=CC=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:22]=4)[N:15]=3)[NH:10][C:9]2=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Temperature: 100 °C

Procedure:
Methyl 2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetate. Bromo-1-(cyclohexylmethyl)-4-imidazolino[4,5-b]pyrazin-2-one (200 mg, 0.64 mmol), methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (213 mg, 0.77 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (53 mg, 0.06 mmol) and potassium phosphate (543 mg, 2.56 mmol) in DMF (20 mL) and water (5 mL) were reacted according to General Procedure B. The product was purified by reverse-phase semi-preparatory HPLC (30-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated, and the residue was taken up in DMSO (2 mL) and heated at 100° C. until completely dissolved. Water was added upon cooling and the desired product precipitated out of solution. The precipitate was collected by vacuum filtration, washed with water and dried under high vacuum to provide the title compound (95 mg, 39 yield) as a tan solid. MS (ESI) m/z 381.4 [M+1]+.
Reaction SMILES: C([N:11]=[C:12]=[O:13])CCCCCCCCC.Cl.C(O[NH:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])C1C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][NH:23][C:12](=[O:13])[NH2:11])=[O:28])[CH3:31]
Reactant: CCCCCCCCCCN=C=O
Reactant: CCOC(=O)CCCNOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCNC(N)=O
Reaction time: 1 h
Yield: 180.7 %

Procedure:
Using the method of Example 2 above, but using ethyl 4-bromobutyrate, t-butyl N-[3-(ethoxycarbonyl)propyl]-N-benzyloxy carbamate was obtained as a colorless oil. This carbamate (6.17 g, 18.8 mmol) was dissolved in 3.3M HCl in ethyl acetate (50 ml) at room temperature under nitrogen. After one hour, the turbid solution was evaporated, and the residue was triturated with hexane. Filtration gave ethyl 4-(benzyloxyamino)butyrate hydrochloride as a white solid (4.59 g, 93% yield). To a solution of decyl isocyanate (0.92 g) in toluene (50 ml) was added this hydrochloride (1.40 g) in DMF (5 ml). Triethylamine (0.75 ml) was added, and the solution was stirred for one hour. The mixture was washed with 10% aqueous citric acid, and the organic solution was dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave N'-decyl-N-benzyloxy-N-[3-(ethoxycarbonylpropyl]urea as a colorless oil (1.58 g, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[N:6][CH:7]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO.O1CCCC1>[Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of methyl 3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propionate (200 mg, 0.400 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added a 1N aqueous sodium hydroxide solution (2 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was made weakly acidic by the addition of 1N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (161 mg, 0.331 mmol, 83%) as a white powder.