Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.ClCCl>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: CCCCCC(=O)c1cc(Br)cc2c1OCC2(C)C
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCc1cc(Br)cc2c1OCC2(C)C

Procedure:
Following General Procedure J and using 5-bromo-3,3-dimethyl-7-hexanoyl-2,3-dihydrobenzofuran (Intermediate 52, 0.325 g, 1.0 mmol), trifluoroacetic acid (0.31 mL, 4 mmol), triethyl silane (0.64 mL, 4 mmol) and dichloromethane (5 mL) followed by flash column chromatography using 2% ethyl acetate in hexane as the eluent, the title compound was obtained (0.20 g, 64% for 2 steps).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C:14]2[C:15]([C:21]([O:23]C)=O)=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=O)[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][C:12]1[C:14]2[C:15](=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])[C:21](=[O:23])[NH:2][N:3]=1
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1cccc(Br)c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(Br)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
Hydrazine hydrate (0.110 mL, 1.48 mmol) was added to methyl 4-(2-(3-bromophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (49) (0.470 g, 1.34 mmol) in acetic acid (20 mL). The resulting solution was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with 2M NaOH (100 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a beige solid (0.253 g, 56.7% yield); 1H NMR (400.132 MHz, MeOD) δ 2.18 (3H, s), 2.50 (3H, s), 4.03 (2H, s), 7.04-7.11 (2H, m), 7.25 (2H, m); m/z (LC-MS, ESI+), RT=1.84 min (M+H=333.97).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(O)(=O)C.C([O-])(=O)C.[Na+].[Br:42]Br>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[C:32]([Br:42])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) in THF (6 ml) were added acetic acid (3 ml) and sodium acetate (100 mg) at room temperature, and bromine (0.04 ml) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr., sodium acetate (100 mg) was added, and bromine (0.04 ml) was added dropwise at room temperature. The reaction mixture was further stirred at room temperature for 1 hr., and bromine (0.04 ml) was added dropwise. The mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue and crystals were collected by filtration. The crystals were further washed with ethyl acetate to give the title compound (250 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13](Cl)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[SH:13]
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]cc(S)c2cc(Br)ccc12
Reaction time: 0.08 h
Yield: 25.2 %

Procedure:
To a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 1 g) in THF (12 mL) was added triphenylphosphine (2.85 g). After 5 min, water (0.48 mL) was added followed by DMF (0.6 mL) and the reaction stirred for 1 h. Ethyl acetate and 2M HCl (aq) were added and the mixture shaken vigorously. The solid was filtered off and washed with further water and ethyl acetate before drying in vacuo at room temperature is for 2 h to afford the subtitle compound (0.2 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([Br:10])[CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Br)cc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (0.308 g, 1.0 mmol), benzylamine (0.218 mL, 2.0 mmol), and K2CO3 (0.553 g, 4.0 mmol) in toluene (6 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-bromo-2,3-dihydro-isoindol-1-one (0.150 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.76 (s, 2H), 7.21-7.38 (m, 5H), 7.52 (s, 1H), 7.61 (d, 1H), 7.76 (d, 1H). GC-MS: m/z 302 (M)+, 226 (M−76)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:46]1[CH:51]=[CH:50][C:49]([CH:52]([NH2:55])[CH2:53][OH:54])=[CH:48][CH:47]=1>ClCCl.CCCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([O:20][CH2:21][CH3:22])[C:17]([NH:55][C@H:52]([C:49]2[CH:50]=[CH:51][CH:46]=[CH:47][CH:48]=2)[CH2:53][OH:54])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccccc1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 30.6 %

Procedure:
A solution of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid (2.92 g, 9.74 mmole) in dry dichloromethane (30 ml) was cooled on an ice-bath and EDC (2.03g; 10.61 mmole), diisopropylethylamine (1.84 ml, 10.61 mmole) and HOBt x H2O (1.43 g; 10.61 mmole) were added. After 30 minutes the ice-bath was removed and (R)-phenylglycinol (1.46 g, 10.61 mmole) was added. After stirring at room temperature over night ethyl acetate (100 ml) was added and the mixture was washed with potassium hydrogensulfate (1 M), saturated sodium bicarbonate solution, sodium carbonate solution and brine. The organic phase was dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using ethyl acetate:heptan to give 1.5 g (yield 37%) of 3-(4-benzyloxyphenyl)(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoic amide and 1.25 g (yield 31%) of 3-(4-benzyloxyphenyl)-(R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoic amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[N:34]1[N:38]2[CH2:39][CH2:40][NH:41][CH2:42][C:37]2=[CH:36][C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:41]2[CH2:40][CH2:39][N:38]3[N:34]=[C:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:36]=[C:37]3[CH2:42]2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(n1)CCN(C(=O)c1ccc(OC)cc1)C2
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of 4-methoxybenzoic acid (0.187 g, 1.23 mmol) dissolved in N,N-dimethylformamide (5 mL) and triethylamine (0.428 mL, 3.07 mmol) was added tetramethylfluoroformamidinium hexafluorophosphate (0.406 g, 1.54 mmol) and the reaction mixture was stirred for 15 minutes. Ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.2 g, 1.02 mmol) was added and the reaction continued to stir at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via silica gel chromatography (0-90% EtOAc/hexane) to afford ethyl 5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Intermediate 27 (0.359 g, 100%). LC-MS: (FA) ES+330.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=2[CH3:15])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[Cu](C#N)[C:17]#[N:18].O.C(OCC)(=O)C>CN(C)C=O>[N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:17]#[N:18])=[CH:10][C:9]=2[CH3:15])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)ccc1C(=O)N1CC=CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1C(=O)N1CC=CC1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
31.6 g (0.11 mol) of 4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbromobenzene is dissolved in 125 mL of dimethylformamide and combined with 20.2 g (0.23 mol) of copper cyanide and 3.2 g (2.7 mmol) of tetrakis-triphenylphosphinepalladium(0). The suspension is stirred for 20 hours at 140° C. Then it is cooled to 80° C., combined with 150 mL of water, 150 mL of ethyl acetate, and 25 g of CELITE® filter aid and filtered through CELITE® filter aid. The organic phase is separated off, washed with sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/ethanol (50:1 and 19:1). The corresponding fractions are combined and concentrated by evaporation. Yield: 11.7 g (49% of theory); Rf value: 0.55 (silica gel; ethyl acetate/ethanol=9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:23][CH2:22][C:21](=[O:24])[C:20]4=[CH:25][N:26]([CH3:28])[CH:27]=[C:19]4[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:23][CH2:22][CH:21]([OH:24])[C:20]4=[CH:25][N:26]([CH3:28])[CH:27]=[C:19]4[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2O
Yield: 86.5 %

Procedure:
To a suspension of 174 mg (0.4 mmol) of Compound 24 in 8 ml of ethanol, 151 mg (4 mmol) of sodium borohydride were added gradually under ice-cooled stirring. The resulting mixture was stirred under ice cooling for 1 hour and further at room temperature for 13 hours. Water (80 ml) was added to the reaction mixture. The thus-obtained mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Post treatment and purification were conducted as in Example 15, whereby 151 mg of the title compound were obtained (yield: 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]2([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:42]=1.O>O1CCCC1.ClCCl.CO>[F:20][C:15]1[CH:14]=[C:13]([C:10]2([CH2:21][CH2:22][N:50]3[CH2:49][CH2:48][C:47]([C:43]4[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=4)([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reaction time: 64 h

Procedure:
Combine 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (prepared from (-)-2-[3-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (R,R)-di-p-anisoyltartaric acid salt)(0.6 g, 1.2 mmol), potassium carbonate (0.46 g, 3.4 mmol), and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide in tetrahydrofuran (6 mL)/ water (2 mL). Heat to reflux. After 64 hours, evaporate the reaction mixture in vacuo to remove most of the tetrahydrofuran and combine with dichloromethane. Extract with a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1% methanol/dichloromethane, 3% methanol/dichloromethane, 5% methanol/dichloromethane, dichloromethane/methanol/concentrated ammonia (464/35/2.5) and then, dichloromethane/methanol/concentrated ammonia (450/50/2.5) to give the title compound: Rf =0.17 (silica gel, dichloromethane/methanol/concentrated ammonia 9/1/0.05).
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.C1(CBr)CC1.CN(C)C=O>O1CCCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:1][CH:2]2[CH2:4][CH2:3]2)[CH:13]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1ccc(Br)cn1CC1CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
KOtBu (0.68 g) was added to a solution of 5-bromo-1H-pyridin-2-one (1.00 g) in tetrahydrofuran (20 mL) at room temperature. After stirring for 30 min, cyclopropylmethyl bromide (0.77 mL) and dimethylformamide (3 mL) were added to the suspension and the resulting mixture was warmed to 70° C. After stirring the mixture at 70° C. for 2 h, the reaction was complete. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2×20 mL) and brine (20 mL). Then, the solution was dried (MgSO4) and the solvent was removed to give the title compound as a colorless oil. Yield: 1.18 g (90% of theory). Mass spectrum (ESI+): m/z=228/230 (Br) [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][CH:6]=[C:7]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13](=[O:21])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude compound from Step 1 was dissolved in tetrahydrofuran (0.3 M), the solution was cooled to 0° C., and sodium hydride (as a 60% dispersion in oil, 1.3 eq) was added in portions. After stirring at 0° C. for 1 hour, the mixture was allowed to warm up to room temperature. After 2 hours, water was added to the suspension and and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether at room temperature for 24 hours and filtered to afford the title compound as a cream-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[N:14]1.[H-].[Na+].[CH3:22]I.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][O:19][CH3:22])[CH:15]=[N:14]1
Reactant: CI
Reactant: OCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]methanol (1.5 g), sodium hydride (0.15 g) and methyl iodide (0.7 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 2 hours and left over the weekend. The mixture was added to water and extracted with ether. The extract was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methoxymethyl-2H-1,2,3-triazole, m.p. 32°-33°. (Compound 20)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([NH:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)=[O:10])#[N:2]
Reactant: N#Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: N#Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-cyano-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 14; 160 mg, 0.63 mmol), 3-pyridinamine (65.4 mg, 0.70 mmol), HOBT (116 mg, 0.76 mmol) and EDC (145 mg, 0.76 mmol) in DMF (10 ml) was stirred at room temperature overnight. Water (30 ml) was added and the mixture was then filtered. The residue was dried to yield the title compound as a white solid. 90 mg.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][O:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:28]/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: COc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 2-methoxyaniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(F)c2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(F)c3)cc2=O)n1
Yield: 53 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(3-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 42) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(3-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.74 g, 53%); ES+-HRMS m/e calcd for C25H30N5O4F [M+H+] 484.2355 found 484.2356. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.27-1.75 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48 (dd, J=4.3, J=10.9 Hz, 1H), 5.88 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.17 (dd, Jm=2.3 Hz, Jo=8.3 Hz, 1H), 7.22 (td, Jm=2.3 Hz, Jo=8.3 Hz, 3JF=8.3 Hz, 1H), 7.31 (dt, Jm=2.3 Hz, 3JF=9.9 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.57 (dt, Jo=8.3 Hz, 4JF=6.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=O)OC(C)(C)C)[CH:13]=2)[CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].ClC1[S:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=1>Cl.O1CCOCC1.O.C([O-])(O)=O.[Na+]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[S:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=3)[CH:13]=2)[CH3:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(C)c2ccnc(NC(=O)OC(C)(C)C)c2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(C(C)c2ccnc(Nc3ncc(C#N)s3)c2)CC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[1-(4-acetylpiperazin-1-yl)ethyl]pyridin-2-ylcarbamate (16-4, 137 mg, 0.39 mmole) was taken up in 4 M HCl in dioxane (10 mL) at RT. After 60 hr the mixture was diluted with H2O and neutralized with solid NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in dry THF (2 mL). To this was added NaH (40 mg, 60% dispersion in mineral oil, 0.98 mmole). After gas evolution had ceased 2-chloro-5-cyano-1,3-thiazole (85 mg, 0.59 mmole) was added and the mixture heated to reflux. After 3 hr the mixture was cooled to RT and quenched with saturated NH4Cl. The layers were separated and the aqueous layer extracted with EtOAc (4×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-15% EtOH/EtOAc) gave the titled compound as a tan solid. 1H-NMR (500 MHz, d6-DMSO) δ 12.18 (s, 1 H), 8.34 (d, 1 H, J=5.13 Hz), 8.26 (s, 1 H), 7.12 (s, 1 H), 7.05 (d, 1 H, J=5.13 Hz), 3.52-3.41 (m, 5 H), 2.44-2.03 (m, 4 H), 1.96 (m, 3 H), 1.28 (d, 3 H, J=6.59 Hz); MS (ES) (M+H)+ 357.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH2:31][NH:32][C:16]([C:13]([CH3:14])([O:12][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=1)[CH3:15])=[O:18]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil.