Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14](Br)[CH:15]=[C:16]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:17]=2)[N:12]=[C:11]([CH3:24])[C:10]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:31](OC)=[O:32].O>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH:31]=[O:32])[CH:15]=[C:16]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:17]=2)[N:12]=[C:11]([CH3:24])[C:10]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=O
Reactant: CCC(C)c1cc(Br)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Reaction time: 0.17 h

Procedure:
5 Grams of 4-hydroxy-6-s-butyl-8-bromo-2,3-dimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 20 ml of dimethylformamide, to which 700 mg of 60% sodium hydride was added under cooling with ice and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise 3 g of benzyl bromide under cooling with ice and the mixture was allowed to react at room temperature overnight. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane to obtain 2.5 g of 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline. 2.5 Grams of the thus-obtained 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline was dissolved in 25 ml of anhydrous tetrahydrofuran and cooled to −78° C., to which 2.8 ml of a 2.5 M solution of n-butyl lithium in n-hexane was added dropwise and the mixture was stirred for 10 minutes. One ml of methyl formate dissolved in 2 ml of anhydrous tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at 0° C. for 30 minutes. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and a saturated brine and then dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 800 mg of 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline.
Reaction SMILES: O.O.O.O.O.[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Cu+2:11].[Na].[O:13]=[C:14]1[O:20][C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17]([OH:18])=[C:15]1[OH:16].Br[C:26]1[CH:27]=[C:28]([C@:32]23[CH2:41][CH2:40][O:39][CH2:38][CH:37]2[CH2:36][S:35][C:34]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:33]3)[CH:29]=[CH:30][CH:31]=1.[N-:50]=[N+:51]=[N-:52].[Na+].C1(N)CCCCC1N>O.C(O)C>[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Cu+2:11].[O:13]=[C:14]1[O:20][C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17]([OH:18])=[C:15]1[OH:16].[N:50]([C:26]1[CH:27]=[C:28]([C@:32]23[CH2:41][CH2:40][O:39][CH2:38][CH:37]2[CH2:36][S:35][C:34]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:33]3)[CH:29]=[CH:30][CH:31]=1)=[N+:51]=[N-:52]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(Br)c3)CCOCC2CS1
Agent: [Cu+2]
Agent: NC1CCCCC1N
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N=[N+]=[N-])c3)CCOCC2CS1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
A 0.33 M solution of copper sulfate is prepared by dissolving copper (II) sulfate pentahydrate (1.0 g, 2.0 mmol) in water (12 mL). A 0.66 M solution of L-ascorbic acid is prepared by dissolving L-ascorbic acid sodium salt (1.58 g, 4.0 mmol) in water (12 mL). To a solution of tert-butyl (8aS)-8a-(3-bromophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (0.500 g, 1.20 mmol) in ethanol (3.6 mL) is added sodium azide (0.228 g, 3.50 mmol), 1,2-cyclohexanediamine, N,N′-dimethyl-, trans (+/−) (0.0549 g, 0.386 mmol), 0.66 M aqueous L-ascorbic acid sodium salt (0.772 mL, 0.509 mmol), and water (0.71 mL) and the mixture is purged with nitrogen. A 0.33 M aqueous solution of copper (II) sulfate pentahydrate (0.773 mL, 0.255 mmol) is added and the reaction is heated to 80° C. for 12 min. The reaction is poured into cold water to afford a blue mixture that is extracted three times with EtOAc. The organic layer is dried over Na2SO4 to afford crude material which is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (0.400 g, 88%). ES/MS m/e: 390 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][S:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCSc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1cc(CSc2ccccc2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-phenylsulfanyl-but-2-ynoic acid ethyl ester employing the procedure described in Example 94. [α]D25 −19.40 (c 0.5, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:20]([O-])=O)[N:3]=1>[Pd].CCOC(C)=O.CO>[NH2:20][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)Nc1cc(Oc2ccc(N)nc2C)ccn1
Yield: 84.6 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)propionamide (0.42 g, 1.389 mmol) in 2:1 EtOAc/MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.165 g, 0.139 mmol) and hydrogenated (1 atm) for 2 days. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)propionamide (320 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.12 (d, J=5.7 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 6.56 (dd, J=5.7, 2.4 Hz, 1H), 6.34 (d, J=8.7 Hz, 1H), 5.93 (s, 2H), 2.33 (q, J=7.5 Hz, 2H), 2.04 (s, 3H), 1.00 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 273.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:43](Cl)(=[O:46])[CH2:44][CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:43](=[O:46])[CH2:44][CH3:45])[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)c(Cl)c3)[C@@H](N(C)C(=O)Oc3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (200 mg, 0.41 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (208 μl, 1.21 mmol). After stirring for a period of 5 min propionyl chloride (53 μl, 0.61 mmol) was added. After stirring for 3 h at ambient temperature the reaction mixture was treated with an aqueous solution of sodium carbonate (1 M, 10 mL). The organic layer was separated and washed with brine (10 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 80:20) afforded the title compound (88 mg, 40%) as a white solid. MS m/e: 550.3 [M]+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=2)[OH:23])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.[Cr]([O-])([O-])(=O)=O>ClCCl.CCOCC>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([C:22]([C:16]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:23])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=1
Reactant: COc1cc(OC)cc(C(O)c2cc(OC)cc(OC)c2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Cr](=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2cc(OC)cc(OC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
Pyridinium chlorochromate (PCC) (12.9 g, 30 mmol) was suspended in 30 mL dichloromethane in a 200 mL round bottom flask. Crude bis(3,5-dimethoxyphenyl)methanol from above (compound A) was suspended in 30 mL dichloromethane then added to the chromate suspension. The dark solution was allowed to stir at ambient temperature for 18 hours then diluted with ether. After decantation, the organic solution was washed twice with 1N NaOH, twice with 10% HCl, saturated NaHCO3, and then with brine. It was dried over anhydrous MgSO4, filtered and concentrated to give a brownish yellow solid. The brownish yellow solid was purified by column chromatography using 50% acetone/hexane as eluent giving the product as a yellow solid in 63% yield over 2 steps: IR (cm−1): 2960, 2938, 2834, 1660, 1592, 1456, 1425, 1349, 1304, 1205, 1157, 1066, 744; 1H NMR (250 MHz, C6D6): δ 3.21 (s, 12H), 6.67 (t, J=2.2 Hz, 2H), 7.21 (d, J=2.5 Hz, 4H); 13C NMR (63 MHz, C6D6): 54.9 (4C), 105.3 (2C), 108.0 (4C), 140.2 (2C), 161.1 (4C), 195.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[C:14]([CH3:39])=[C:15]([N:19]([CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:27]([CH3:38])[CH:26]=2)[CH2:20][CH2:21][O:22][CH3:23])[CH:16]=[CH:17][CH:18]=1>>[CH3:23][O:22][CH2:21][CH2:20][N:19]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:15]1[C:14]([CH3:39])=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(Br)c2C)cc1C
Reactant: COc1ccc(B(O)O)cc1
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(OC)cc2)c1C

Procedure:
Prepared from 4-methoxyphenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]([CH3:19])=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1.[OH-].[Na+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:27][CH2:26][CH2:25][CH2:24][N:9]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=2[N:7]([C:11]([CH3:19])=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]1=[O:10]
Reactant: CC(=Cc1ccccc1)n1c(=O)[nH]c2ccc(F)cc21
Reactant: ClCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccccc1)n1c(=O)n(CCCCl)c2ccc(F)cc21
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred and hot (50° C.) mixture of 15 parts of 6-fluoro-1,3-dihydro-1-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one, 3 parts of N,N,N-triethylbenzenemethanaminium chloride and 75 parts of a sodium hydroxide solution 60% are added dropwise 11.1 parts of 1-bromo-3-chloropropane (slightly exothermic reaction). Upon completion, stirring is continued for 4 hours at 60° C. The reaction mixture is cooled, water is added and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 20 parts (100%) of 1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:16][CH2:15][CH2:14][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].ON1C2C=CC=CC=2N=N1.S1CCNC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(OCC)(=O)C>[NH:1]1[CH2:16][CH2:15][CH2:14][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CSCN1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 8 h
Yield: 80 %

Procedure:
6.5 mM Boc-Pro-Ile-OH (one equivalent=1 eq.) is suspended, together with N-hydroxybenzotriazole (1 eq.) and thiazolidine (1 eq.), in 30 ml of dichloromethane (DCM). The equivalent amount of 1M dicyclohexylcarbodiimide solution is added dropwise, at −10° C., with stirring. Stirring is carried out at −10° C. and overnight at room temperature. For the purpose of working-up, the solution is thoroughly filtered off from the dicyclohexylurea that is precipitated out, DCM is drawn off in vacuo and the residue obtained is taken up in ethyl acetate. The ethyl acetate solution is washed at least three times with saturated bicarbonate solution, once with saturated NaC1 solution, three times with dilute KHSO4 solution and again with NaC1 solution. The ethyl acetate phase is dried over Na2SO4 and concentrated using a rotary evaporator, and the remaining crude product is recrystallised using ethyl acetate/pentane. Boc-Pro-Ile-Thia crystallises after 1–2 days at 4° C. (yield 80%). 1.1N HC1/glacial acetic acid solution is added to Boc-Pro-Ile-Thia (3 ml per mmol of peptide). Stirring is carried out for two hours at RT, absolute ether is added and excess removal solution is evaporated off using a rotary evaporator. The hydrochloride crystallises quantitatively under absolute ether overnight at 4° C. The crystals are quickly separated off by suction filtration, washed several times with absolute ether, and the product is stored in a desiccator over KOH or phosphorus pentoxide.
Reaction SMILES: N#N.[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:13]/[CH:14]=[CH:15]\[CH2:16]Cl.[OH-].[K+]>C(Cl)Cl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[C:10]([C:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:16][CH:15]=[CH:14][CH2:13]1)#[N:11]
Reactant: ClC/C=C\CCl
Reactant: N#CCc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: N#CC1(c2ccccc2)CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a N2 covered, mechanically stirred solution of 4.93 ml (42.6 mmol) of phenylacetonitrile in 85 ml of CH2Cl2 was added 4.94 ml (46.9 mmol) of cis-1,4 dichloro-2-butene followed by 0.86 g (2.1 mmol) of Aliquat 336. There was then added 5.3 g (85.3 mmol) of powdered KOH in portions over 2.25 hours. A cold water bath was used to control a slight exotherm and keep the reaction temperature at about 25° C. during the addition. The reaction was stirred at room temperature for 1 hour and then heated in an oil bath at 55°-60° C. (reflux) for 1 hour. After allowing the reaction to cool, there was added 42 ml of H2O dropwise over 6 minutes. The mixture was transferred to a separatory funnel and mixed well. The aqueous fraction was separated and washed with Et2O. The combined organic fractions were dried over MgSO4 and concentrated in vacuo. The residue was distilled under reduced pressure and a single fraction was collected, 5.39 g, b.p. 62°-86° C. (0.05 mm Hg). This fraction was combined with 4.77 g of material from a previous run and heated neat under N2 in an oil bath at 200° C. for 30 minutes and then allowed to cool. The residue was chromatographed in two portions over silica gel (1% EtOAc: hexane) to yield 6.0 g of 4-Cyano-4-phenylcyclopentene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([O:24][CH3:29])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(O)c3ccccc3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 6-(hydroxy-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.15 g, 0.42 mmol) in THF (5 mL) was added sodium hydride (60%, 0.02 g, 0.50 mmol) and the mixture was stirred for 1 h. Methyl iodide (52 μL, 0.84 mmol) was added and the reaction mixture was stirred for 18 h at ambient temperature. Water (10 mL) was added and the product was extracted with EtOAc (2×10 mL). The combined organic phase was dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-70% EtOAc in 40-60 petroleum ether) gave the title compound (0.11 g, 70%) as an oil. MS: [M+H]+=369.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:13]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]([O:24][NH:25]/[C:26](=[N:28]\[H])/[CH3:27])=O)=[N:20][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]3[O:24][N:25]=[C:26]([CH3:27])[N:28]=3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: [H]/N=C(/C)NOC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 13.9 %

Procedure:
A solution of crude (Z)-N-[[[5-[[2(R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-1-oxopropyl]amino]-2-pyrazinyl]carbonyl]oxy]ethanimidamide (0.331 mmol) in toluene (3.6 mL) was treated with 4 Å molecular sieves and warmed to 80° C. where it stirred for 48 h. The reaction was then partitioned between ethyl acetate (25 mL) and water (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (50 mL). The combined aqueous layers were then back-extracted with ethyl acetate (50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 ethyl acetate/hexanes) afforded impure 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrazin-2-yl]-propionamide as a light yellow foam (22.5 mg, 13%). The impure product was re-purified by reverse phase high-performance liquid chromatography (Waters symmetry packing, acetonitrile/water with 0.05% trifluoroacetic acid, 2% to 45% acetonitrile gradient). The fractions containing product were concentrated in vacuo and lyophilized to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrazin-2-yl]-propionamide (12 mg, 7%) as a white lyophilized solid: mp 101–105° C. (foam to gel); (ES)+-HRMS m/e calcd for C22H24ClN5O4S (M+H)+ 490.1311, found 490.1315.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]([C:25]([OH:28])([CH3:27])[CH3:26])[CH:22]=[N:23][CH:24]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[CH:10][C:2]=1[C:19]1[CH:20]=[C:21]([C:25]([OH:28])([CH3:27])[CH3:26])[CH:22]=[N:23][CH:24]=1
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1cc2ccccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(-c2cc3ccccn3n2)c1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-pyrazolo[1,5-a]pyridine (0.200 g, 1.31 mmol) and the title compound from Example 1 Step D (0.414 g, 1.573 mmol) in tetrahydrofuran (6.55 mL) were added palladium acetate (0.029 g, 0.131 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.108 g, 0.262 mmol), and potassium phosphate tribasic (0.835 g, 3.93 mmol). The resulting mixture was heated at 100° C. for 18 hours, then diluted with ethyl acetate, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound: LCMS m/z 254.02 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.05 (s, 1 H), 8.74 (s, 1 H), 8.49 (d, J=6.9 Hz, 2 H), 8.40 (s, 1 H), 7.55 (d, J=6.9 Hz, 2 H), 7.15 (dd, J=7.6, 7.9 Hz, 1 H), 6.86 (s, 1 H), 6.79 (dd, J=7.1, 6.6 Hz, 1 H), 1.68 (s, 6 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: Cc1cccc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1ccc2c(c1)CCC2=O
Yield: 54.3 %

Procedure:
A mixture of 5-bromoindan-1-one (1.20 g, 5.69 mmol), 2,6-dimethylphenylboronic acid (1.02 g, 6.82 mmol), tetrakis(triphenylphosphine)palladium(0) (328 mg, 0.285 mmol), sodium carbonate (1.81 g, 17.1 mmol), methanol (8 mL), water (8 mL) and toluene (25 mL) was heated under reflux overnight under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-50% ethyl acetate/hexane) to give the title compound (0.73 g, yield 54%) as a colorless oil.
Reaction SMILES: C(O[C:6]([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C>O1CCCC1.CNC>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][S:17]4(=[O:21])=[O:22])=[CH:15][C:10]=3[C:9]([N:8]([CH3:40])[CH3:6])=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C)C)CC2)c(C)c1
Yield: 45.9 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (115 mg) described in Example 808 and 2 mol/L dimethylamine tetrahydrofuran solution (105 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (39 mg) was obtained.