Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.C([O-])([O-])=[O:13].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C([O-])(O[O-])=O.[Na+].[Na+].O>C(O)(C(F)(F)F)=O>[CH2:6]1[C@@H:5]2[CH2:10][CH:1]3[O:13][C:2](=[O:11])[CH:3]([CH2:4]2)[CH2:9][C@@H:7]1[CH2:8]3
Reactant: O=C([O-])[O-]
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=C([O-])O[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1OC2C[C@@H]3CC1C[C@H](C2)C3
Temperature: 20 °C
Yield: 106.6 %

Procedure:
Commercially available 2-adamantanone (×1) (1000 g, 6.66 mol, Sigma-Aldrich) was dissolved in TFA (3 L, Sigma-Aldrich). To this mechanically stirred mixture surrounded by a cooling bath with a temperature maintained at 20° C. was added sodium percarbonate (1254.8 g, 7.99 mol, Sigma-Aldrich) (or sodium peroxocarbonate) portion-wise over 1 h; the temperature of the reaction mixture increased to 60° C. during the addition. After 2 h additional stirring, deionized water (4 L) was added followed by four extractions with DCM (2 L for each extraction). The organic portions were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to provide 1180 g of (1R,3r,6s,8S)-4-oxatricyclo[4.3.1.13,8]undecan-5-one (×2) as a white crystalline solid (yield 97%).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](=[O:29])SC2C=CC=CN=2)=[CH:3]1.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:29])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following a procedure similar to that described in Example 2(b), but using 9.77 g of S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared as described in Example 2(a)] and 14 ml of t-butylamine, 8.9 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[CH3:47][NH:48][CH2:49][C:50]([NH2:52])=[O:51].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[CH3:47][N:48]([CH2:49][C:50](=[O:51])[NH2:52])[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Reactant: CNCC(N)=O
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N(C)CC(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.9 %

Procedure:
Subsequently, to a suspension of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.51 mmol) (obtained as described in Reference Example 41(7)) and 2-methylamino-acetamide hydrochloride (282 mg, 2.26 mmol) (obtained as described above) in dimethylformamide (30 ml) were added diethylphosphoryl cyanide (0.37 ml, 2.26 mmol) and triethylamine (0.95 ml, 6.80 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 3.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (10:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[N-methyl-N-(carbamoyl)methyl-carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (932 mg, yield 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]Br.Cl>CN(C)C=O.O>[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Sc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
36 g of 3-bromothiophenol were dissolved in 400 ml of dimethylformamide. After the addition of 27 g of finely powdered potassium carbonate and 29 g of 3,3-dimethylallyl bromide, the mixture was stirred at room temperature for 1 hour, diluted with 500 ml of water, acidified with 3N hydrochloric acid while cooling and extracted with ether. The yellow-brown oil obtained after evaporation was distilled in a high vacuum. There were obtained 48 g of m-bromophenyl 3-methyl-2-butenyl sulfide as a colorless liquid, boiling point 85° C./13.3 Pa.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][S:10][C:11]2[NH:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH:1]1([NH:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][S:10]([C:11]2[NH:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(NC2CCCC2)c(CSc2nc3ncccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1NC1CCCC1)c1nc2ncccc2[nH]1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-cyclopentylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution to obtain 2-[2-(N-cyclopentylamino)benzylthio]-imidazo[4,5-b]pyridine in the same manner as in Example 9-(2). The obtained 2-[2-(N-cyclopentylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner as in Example 9-(3) to give 2-[2-(N-cyclopentylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 134° C. (decompn.)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[CH2:25])=CN=1.[OH-].[K+].[CH3:30][N:31]1C(=O)CCC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:22]=[N:23][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:30][N:31]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCCC1=O
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc(C(F)(F)F)cn2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4](=[CH2:28])[CH2:5][C@H:6]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:28])[CH2:5][CH:6]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid methyl ester (2-a, R1=Boc, R2=H, R3=CO2Me) is added to ethanol (5 ml) at ambient temperature. Triethylamine (176 μl) is then added to the mixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford 2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-b, R1=Boc, R2=H, R3=CO2Me). Spectroscopic data as in Example 60. Ratio of diastereomers 66:34 (1-a, R1=Boc, R2=H, R3=CO2Me: 1-b, R1=Boc, R2=H, R3=CO2Me) by integration of signals at 1.76-1.85 (1-b, R1=Boc, R2=H, R3=CO2Me) and 1.92-1.99 (1-a, R1=Boc, R2=H, R3=CO2Me).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24](=[O:44])[NH:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28])([CH3:22])([CH3:21])[CH3:20]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:32]1[CH:31]=[CH:30][C:29]([C@H:27]([CH3:28])[CH2:26][NH:25][C:24](=[O:44])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:34][CH:33]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 63.6 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with (S)-tert-butyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (251 mg, 0.69 mmol) to afford the desired product (140 mg, 62%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[N:26][CH3:27])SC)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]([NH:26][CH3:27])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)SC
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 59.1 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.33 g.) and N-(4-chlorobenzenesulphonyl)-N',S-dimethylisothiourea (5.40 g.) in acetonitrile was heated under reflux for 24 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded N-(4-chlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (4.6 g.), m.p. 153°-154°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: C=CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1ccccc1OCC(=O)OCC
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A mixture of 2-allyl-phenol (10 g, 74.5 mmol), ethyl 2-bromoacetate (12.4 mL, 112 mmol) and cesium carbonate (36.5 g, 112 mmol) in DMF (180 mL) was heated at 60° C. overnight. The mixture was cooled and filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel to give 14.5 g of title compound. 1H NMR (400 MHz, CDCl3) • 7.19˜7.14 (m, 2H), 6.97˜6.92 (m, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.09˜5.95 (m, 1H), 5.11˜5.02 (m, 2H), 4.54 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.46 (d, J=6.8 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[Cl:10].[F:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[CH:19][CH:18]=1.O>CN(C=O)C.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:20]3[CH:30]=[CH:31][C:17]([F:16])=[CH:18][CH:19]=3)[CH:23]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(CO)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(COCc1cccc(Oc2ccc(F)cc2)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 ml of toluene was added 0.63 g of sodium hydride (60% in oil) and the mixture was refluxed, and a solution of 2.3 g of 2-(3,4-dichlorophenyl)-2-methylpropyl alcohol in 10 ml of 25% DMF/toluene was added dropwise to the mixture over a period of 15 minutes. The mixture was stirred for 15 minutes, and a solution of 3.5 g of 3-(4-fluorophenoxy)benzyl bromide in 10 ml of toluene was added dropwise to the mixture over a period of 20 minutes. Then, the mixture was refluxed for 1 hour and cooled to room temperature, and poured into water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][C:20](=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
To a solution of methyl (E)-7-[3-(4-fluorophenyl)bicyclo [3.2.1]oct-2-en-2-yl]-5-hydroxy-3-oxohept-6-enoate (2.85 g, 7.65 mmoles) in 12 ml anhydrous THF was added triethylborane (11.5 ml of a 1M THF solution, 11.5 mmoles). The mixture was stirred for 5 minutes and cooled to -78° C. Sodium borohydride (0.333 g, 8.8 mmoles) was added followed by the dropwise addition of 5 ml methanol. The mixture was stirred for 60 minutes and quenched with the dropwise addition of aqueous H2O2 (12 ml of 30% H2O2 in 27 ml H2O). The mixture was warmed to 25° C. during 90 minutes and poured into a mixture of ethyl acetate and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 60% hexanes in ethyl acetate. The product rich fractions were concentrated in vacuo and provided 1.32 g of the oily product.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)[C:6](=[O:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:33]1([O:42][P+](N(C)C)(N(C)C)N(C)C)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.[CH3:53][C:54]1([CH3:66])[O:58][C@H:57]([CH2:59][N:60]2[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]2)[CH2:56][O:55]1>CN(C)C=O.C(OCC)(=O)C>[CH3:53][C:54]1([CH3:66])[O:58][C@H:57]([CH2:59][N:60]2[CH:64]=[CH:63][C:62]([NH:65][C:10](=[O:12])[CH:9]([N:5]3[C:6](=[O:8])[CH:7]=[C:2]([O:42][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[N:35]=[N:34]4)[CH:3]=[N:4]3)[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:61]2)[CH2:56][O:55]1
Reactant: CC(C)CC(C(=O)O)n1ncc(I)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid (Intermediate 86, 1.93 g, 5.74 mmol) in N,N-dimethylformamide (26 mL, 0.22M) at 25° C. was treated with N,N-diisopropylethylamine (2.8 mL, 16.94 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (3.81 g, 8.61 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4, 1.31 g, 6.64 mmol). The reaction was stirred at 25° C. over 2 nights. After this time, the reaction was diluted with ethyl acetate (150 mL) and was washed with a saturated aqueous ammonium chloride solution (150 mL), a saturated aqueous sodium bicarbonate solution (150 mL) and a saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 25-75% gradient ethyl acetate/hexanes) afforded 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (1.52 g, 51%) as a light yellow solid as a mixture of diastereomers.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1-n1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Product: Cc1ccncc1-n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 85 %

Procedure:
3-(2-(Diphenylmethylene)hydrazinyl)-4-methylpyridine (1.3 g, 4.52 mmol) in 3 mL THF was treated with 4,4-dimethyl-3-oxopentanenitrile (850 mg, 6.79 mmol) and 6N HCl (3.8 mL, 22.6 mmol). Stirred the mixture at 50° C. for 24 hours. Extracted using EtOAc/(sat.)NaHCO3 (3×100 mL (sat.)NaHCO3, 1×100 mL brine). Dried using MgSO4 and then purified by flash chromatography (silica, 5-100% EtOAc/Hexane) to afford 3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-amine (844 mg, 3.67 mmol, 81%). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, 1H), 8.40 (s, 1H), 7.38 (d, 1H), 5.32 (s, 1H), 5.03 (br s, 2H), 2.08 (s, 3H), 1.20 (s, 9H); LC-MS (ESI) m/z 231 (M+H)+. Example 303A Step 3: 3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-amine (844 mg, 3.66 mmol) was treated with phenyl chloroformate (1.90 mL, 15.0 mmol) according to the procedure in Example 118A to afford phenyl 3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (1.09 g, 3.11 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 10.09 (br s, 1H), 8.53 (d, 1H), 8.43 (s, 1H), 7.44 (d, 1H), 7.39-7.34 (m, 2H), 7.22 (t, 1H), 6.98 (br s, 2H), 6.35 (s, 1H), 2.09 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.C[O-].[Na+:41].CO>CO.C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:31][CH:32]=2)=[O:11])=[CH:5][CH:6]=1.[Na+:41]
Reactant: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Yield: 102 %

Procedure:
7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (42 mg, 0.07955 mmol) was dissolved in MeOH-THF (1 ml-1 ml). A 0.5 M solution of NaOMe in MeOH (159.1 μl, 0.0795 mmol) was added and the mixture was stirred for few minutes. The crude mixture was concentrated and chased with EtOAc and dichloromethane to provide 44.6 mg of the title compound as a white solid (102%). MS (apci) m/z=528.1 (M+2H-Na).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[CH2:24][N:23]([CH3:28])[C:22]3=[O:29])[C:14]1=[O:30])[C:6]([O:8]C(C)(C)C)=[O:7])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][C@H:5]([C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[CH2:24][N:23]([CH3:28])[C:22]3=[O:29])[C:14]1=[O:30])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of compound 70-3 (85 mg) in CH2Cl2 (2.5 mL) at 0° C. was added TFA (0.5 mL) dropwise. The mixture was stirred for 1 h at 0° C. and at rt for 30 min whereupon an additional portion of TFA (0.5 mL) was added. After an additional 1 h at rt, the mixture was diluted with CH2Cl2 and concentrated to dryness under reduced pressure. The crude mixture was redissolved in CH2Cl2 and concentrated and this protocol was repeated 5 times with to afford compound 70-4 (65 mg) as a light semisolid. LC-MS: M+H=363. This material was used without further purification.
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][O:6][CH2:7][C@H:8]([NH:16][CH2:17]C(OC(C)(C)C)=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[Li].[CH2:27]([OH:29])C.C(O)(=O)[CH2:31][C:32]([CH2:37]C(O)=O)([C:34](O)=O)[OH:33]>C1COCC1>[C:32]([O:33][C:27](=[O:29])[N:16]([C@@H:8]([CH2:7][O:6][CH2:5][CH2:4][OH:25])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17])([CH3:31])([CH3:34])[CH3:37]
Reactant: CCOC(=O)COC[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCO
Agent: [Li]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](COCCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
((2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropoxy)acetic acid ethyl ester (0.50 g, 1.42 mmol) was dissolved in THF (4 mL). Lithium boronhydride (1.56 mL of a 2.0 M solution in THF, 3.13 mmol) was added dropwise. Ethanol (8 mL) was added. The reaction mixture was stirred 16 h at room temp. The solution was acidified with 10% citric acid to pH=4. The solvent was removed in vacuo. The residue was dissolved in water (50 mL). This solution was extracted with dichloromethane (3×40 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g) with dichloromethane/ethyl acetate 1:1 as eluent to give 0.29 g of N-((1R)-1-(2-hydroxyethoxymethyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester