Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(NC)=O>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][CH3:17])[CH:18]=2)[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to compound 1B replacing Compound 1C with 2-amino-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylbenzamide (Compound 4C, 330 mg, 1.2 mmol) to give the title compound as a light-yellow solid. MS (ESI): m/z=692.59 [M+H]+. UPLC: tR=1.11 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13](O)=[O:14]>C1COCC1>[OH:14][CH2:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH3:16]
Reactant: Cc1c(C(C)C(=O)O)ccc2c1COC2=O
Solvent: C1CCOC1
Product: Cc1c(C(C)CO)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid (300 mg, 1.4 mmol) in 18 mL of anhydrous THF was added BH3. THF (2 mL, 2 mmol) dropwise at 0° C. Then the mixture was warmed to room temperature slowly and then stirred for 3 hours. Then the mixture was quenched with MeOH and the solvent was removed under vacuum. The residue was the purified via prep-TLC to give 5-(2-hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:12]([OH:14])=[O:13])[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[OH-].[Na+:16]>>[CH:1]1[CH:2]=[C:3]([C:12]([O-:14])=[O:13])[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[Na+:16]
Reactant: O=C(O)c1ccc2ccccn2c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1ccc2ccccn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4H-quinolizin-4-one-3-carboxylic acid (196.7 mg) in 0.1N-aqueous sodium hydroxide solution (9.9 ml) was stirred for one hour at room temperature. The resulting reaction mixture was filtered and then the filtrate was lyophilized to give sodium 4H-quinolizin-4-one-3-carboxylate (201 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C1C=CN=CC=1)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]2[CH:5]=[C:4]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[N:3]=[C:2]([NH:1][C:23](=[O:25])[CH3:24])[N:7]=2)=[CH:9][C:10]=1[F:16])#[N:13]
Reactant: N#Cc1ccc(-c2cc(N3CCCCC3)nc(N)n2)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
In a 25 mL sealable tube under argon were combined 4-[2-amino-6-(1-piperidinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (0.18 g, 0.44 mmol) and acetic anhydride (5 mL). The vial was sealed and the reaction mixture was stirred at 95° C. After 16 hours, LCMS indicated a mixture of 2:1 bis:mono acetylated products. The reaction mixture was cooled to room temperature and concentrated. To the resulting crude mixture (192 mg) was added CH3OH (10 mL) followed by DMAP (0.046 g, 0.38 mmol) and the reaction mixture was stirred overnight at 30° C. Additional DMAP (30 mg) was added and the reaction mixture was stirred for an additional 24 hours. The reaction was concentrated, and the resulting oil was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (150 mg, some DMAP is present) as a light yellow solid. LC-MS (ES) m/z=340 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH2:32]([CH:34]([CH2:38][CH3:39])[C:35](Cl)=[O:36])[CH3:33].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:35](=[O:36])[CH:34]([CH2:38][CH3:39])[CH2:32][CH3:33])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: CCC(CC)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)C(CC)CC)cc1OC

Procedure:
0.5 g of the compound obtained in Example 5 step B) in 20 ml of DCM was mixed with 0.5 g of 2-ethylbutyroyl chloride and 0.5 g of pyridine. The mixture was concentrated under vacuum, extracted with ethyl ether and then washed with water, with 1N hydrochloric acid and then with water. The residue was chromatographed on silica using DCM as the eluent to give the expected product, which crystallized from isopropyl ether. m=0.17 g. M.p.=168° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([NH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)C=C.C(Cl)(=O)C(Cl)=O.O>N1C=CC=CC=1.ClC(Cl)C>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)=[O:5]
Reactant: C=CCNc1nnnn1C
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC(CC#N)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2nnnn2C)c(Cl)c1C1=NOC(CC#N)C1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
178 mg (0.5 mmol) of 2-chloro-3-[5-(cyanomethyl)-4,5-dihydro-1,2-oxazol-3-yl]-4-(ethylsulfonyl)benzoic acid and 90 mg (0.65 mmol) of N-allyl-1-methyl-1H-tetrazol-5-amine are stirred in 3 ml of pyridine at room temperature (RT) for 1 h, and then a solution of 86 mg (0.675 mmol) of oxalyl chloride in 2 ml of dichloroethane is added. Subsequently, the mixture is stirred at 75° C. for 4 h. After cooling to RT, 0.5 ml of water is added. Then the mixture is stirred at RT for 30 min. The reaction solution is filtered and concentrated. The residue is purified by means of preparative HPLC (acetonitrile/water). Yield: 19 mg (8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].[Na]>S(=O)(=O)(O)O>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CC(=O)Oc1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
3-Chlorophenol (100 g, 0.78 mol) was dissolved in acetic anhydride (75 mL, 0.8 mol). Upon addition of 1 drop of concentrated sulfuric acid, the temperature raised to 120° C. After 45 minutes, the mixture was cooled and poured into a solution of sodium hydrogenocarbonate (8 g in 1 L of water) and extracted with diethylether. The organic layer was washed with a saturated sodium hydrogenocarbonate solution, dried over magnesium sulfate and evaporated under reduced pressure. The resulting oil was used directly in the next step (84%). IR (KBr): υ: 3072 (C—H aromatic), 2939 (C—H aliphatic), 1773 (C═O), 1196 (C—O) cm−1.
Reaction SMILES: C([O:3][C:4](=[O:57])[C@H:5]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:48][CH:47]=1)[NH:6][C:7]([C:9]1([CH2:14][CH:15]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(C)=O>[CH3:24][S:21]([NH:20][C@H:19]([C:18]([NH:17][CH2:16][CH:15]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:14][C:9]1([C:7]([NH:6][C@H:5]([C:4]([OH:57])=[O:3])[CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[CH:50][CH:51]=2)=[O:8])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CC(CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NS(C)(=O)=O)C(=O)NCC(CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)CCCC1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
N-{1-[3-(N2 -Methanesulphonyl-N6 -t-butyloxycarbonyl-(S)-lysyl-amino)-2(R,S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t- butyl-(S)-tyrosine ethyl ester (2.21 g, 2.68 mmol) was dissolved in acetone (5.5 ml) and then a 1N aqueous solution of sodium hydroxide (5.36 ml, 5.38 mmol) was added. After stirring for 10 minutes at room temeprature the solution was acidified to pH4 with aqueous citric acid (10%). The acetone was then removed on a rotary evaporator and the residue extracted with ethyl acetate (50 ml). The organic phase was separated, washed with saturated brine, dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a white foam (1.89 g, 88%). Found: C,58.49; H,8.01; N,6.64. C19H64N4O11S requires C,58.77; H,8.09; N,7.03%.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].C(N(CC)CC)C>ClCCl>[C:21]([CH2:23][C:24]([NH:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:10])=[O:6])[CH3:4])=[O:25])#[N:22]
Reactant: N#CCC(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)CC#N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
1.7 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 50 ml of dichloromethane at 0° C. 0.42 g (0.005 mol) of cyanoacetic acid, 0.7 ml (0.005 mol) of triethylamine and 1.1 g of N,N-dicyclohexylcarbodiimide were added and the mixture was stirred at 0° C. overnight. The solvent was removed by evaporation, the residue suspended in 50 ml of ethyl acetate, the suspension filtered and the filtrate washed with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated to give a white solid. Recrystallisation of this solid from ethyl acetate yielded 0.6 g (37%) of N-cyanoacetyl-L-alanyl-L-proline anilide of melting point 183°-184° C.; [α]D20 =-204.6° (c=0.78% in methanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+](CC)([O-])=O.[Cl:15][S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17]>>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([Cl:15])(=[O:18])=[O:17])=[O:21])[N:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1nc(C)nc(N)n1
Solvent: CC[N+](=O)[O-]
Product: Cc1nc(C)nc(NC(=O)NS(=O)(=O)Cl)n1
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-amino-4,6-dimethyl-1,3,5-triazine in 10 parts by volume of nitroethane at -10° to 0° is added dropwise an equivalent amount of chlorosulfonyl isocyanate. The mixture is stirred for one hour at -10° allowing for completion of the reaction to form [(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonylsulfamoyl chloride. The additional reagent such as pyrrole is then added and the preparation of the stable herbicidal compound is continued as described in Example 2 or for Equations 3 and 3A.
Reaction SMILES: [O:1]1[C@@H:5]2[O:6][CH2:7][C:8](=[O:10])[CH2:9][C@@H:4]2[CH2:3][CH2:2]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C(Cl)Cl>[O:1]1[C@@H:5]2[O:6][CH2:7][C@H:8]([OH:10])[CH2:9][C@@H:4]2[CH2:3][CH2:2]1
Reactant: O=C1CO[C@H]2OCC[C@H]2C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: ClCCl
Product: O[C@H]1CO[C@H]2OCC[C@H]2C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of the ketone 29 (25 mg, 0.173 mmol) dissolved in CH2Cl2 (5 mL) was cooled to −78° C. under argon. L-Selectride (1M in THF, 200 μL, 0.2 mmol) was added dropwise. The solution was stirred at this temperature for 3 h and quenched by addition of sat. aq. NH4Cl solution. The aqueous phase was extracted with EtOAc, the combined organic extract was dried (Na2SO4), filtered, and evaporated. The crude was purified by column chromatography on silica gel using hexanes/EtOAc (2:1, 1:1, then 1:2) to yield alcohol 30 as a 5:1 mixture of diastereoisomers (18 mg, cis major). The stereoisomers were separated in the subsequent synthesis of the mixed activated carbonate 31g. TLC: Rf=0.25 (hexanes/EtOAc=1:2); 1H NMR (CDCl3, 300 MHz) δ 5.08 (d, J=3.8 Hz, 0.2H), 5.05 (d, J=3.3 Hz, 1H), 4.16-4.11 (m, 1.2H), 3.95-3.84 (m, 1.6H), 3.81-3.70 (m, 2H), 3.63 (m, 1H), 3.27 (dd, J=7.9, 11.2 Hz, 0.2H), 2.35-1.70 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.O[C:12]([C:15](O)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cccc(Br)c1
Product: CC1(C)OB(c2cccc(Br)c2)OC1(C)C
Yield: 77 %

Procedure:
The title compound (77%, oil) was prepared from 3-bromophenylboronic acid and pinacol.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH:39]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2cccnc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2cccnc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-pyridin-3-ylmethyl-benzenesulfonamide (example B.5) according to general procedure II. Yellow solid. MS (ISP) 603.2 [(M+H+]; mp 256° C.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@@H:4]([NH:23][C:24]([C:26]1[CH:45]=[CH:44][C:29]2[N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:31]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[N:32][C:28]=2[CH:27]=1)=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]([C:19]([OH:21])=[O:20])([CH3:18])[CH3:17])[CH:13]=2)[N:8]([CH3:22])[CH:7]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CS(C)=O>[C:19]([C:16]([CH3:18])([O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[CH:7]=[C:6]2[CH2:5][C@H:4]([NH:23][C:24]([C:26]1[CH:45]=[CH:44][C:29]2[N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:31]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[N:32][C:28]=2[CH:27]=1)=[O:25])[C:3]([OH:46])=[O:2])[CH3:17])([OH:21])=[O:20]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccc(OC(C)(C)C(=O)O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)c2cc(OC(C)(C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound of example 115 (6 mg) was dissolved in DMSO (0.4 mL) and 2.5N NaOH (0.2 mL) was added. After stirring for 30 min at room temperature, the reaction mixture was acidified with TFA (0.1 mL) and the product of example 116 isolated directly by preparative C18 reversed-phase HPLC.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.C(I)C.[C-:12]#[N:13].[Na+]>ClCCl.O>[CH3:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:12]#[N:13]
Reactant: Cc1ccc[n+]([O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCI
Product: Cc1cnccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
To a solution of 3-picoline N-oxide (60 g, 0.55 mol) in dichloromethane (1000 mL) was added ethyl iodide (132 mL, 1.65 mol) and the mixture stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with diethyl ether (200 mL) to give a white solid. The solid was dissolved in water (600 mL) and warmed to 50° C. Sodium cyanide (50 g, 1.02 mol) was added as a solution in water (180 mL) over 1 hour, keeping the internal temperature below 60° C. and the resulting dark brown solution was stirred at 55° C. for a further 1 hour. The reaction mixture was extracted with diethyl ether (3×600 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown oil. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of n-pentane:dichloromethane (40:60 to 0:100). The product was co-evaporated with dichloromethane (2×300 mL) to give the title compound as a colourless oil (30.5 g, 47%).
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[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:50][C:51]1[CH:55]=[CH:54][N:53]([CH2:56][C:57]([CH3:60])([OH:59])[CH3:58])[N:52]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:50][C:51]2[CH:55]=[CH:54][N:53]([CH2:56][C:57]([OH:59])([CH3:58])[CH3:60])[N:52]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3c2CCCC3)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4c3CCCC4)cc2=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.8 %

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 39, 1.0 g, 2.61 mmol) in methylene chloride (26 mL, 0.10 M) at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (470 μL, 2.65 mmol) and 1-hydroxybenzotriazole (370 mg, 2.73 mmol). The solution was stirred at 25° C. for 2.5 h. After this time, the reaction was treated with a slurry of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 490 mg, 3.15 mmol) in methylene chloride at 25° C. The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with methylene chloride (250 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×250 mL), a saturated aqueous sodium bicarbonate solution (1×250 mL), water (1×250 mL), and a saturated aqueous sodium chloride solution (1×250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 115 g, 35-75% ethyl acetate/hexanes gradient) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionamide (730 mg, 54%) as a white solid; ES+-HRMS m/e calcd for C29H37N5O4 [M+H+] 520.2919, found 520.2920. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.27-1.78 (m, 12H), 1.91 (m, 1H), 2.27 (m, 1H), 2.50 (m, 2H), 2.78 (m, 2H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (dd, J=4.3, J=10.9 Hz, 1H), 5.57 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:31][C@H:32]([CH2:37][OH:38])[CH2:33][CH2:34][S:35][CH3:36].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:31][C@H:32]([CH:37]=[O:38])[CH2:33][CH2:34][S:35][CH3:36]
Reactant: CSCC[C@H](N)CO
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Product: CSCC[C@H](N)C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
CBZ-L-Leu-L-Phe-L-methioninol (sulfoxide) (1.38 g, 2.53 mmol) was dissolved in DMSO. o-Iodoxybenzoic acid (2.12 g, 7.59 mmol) was added, requiring a few minutes of stirring at room temperature to dissolve. After three hours, the DMSO was removed under reduced pressure. The residue was twice diluted with CH2Cl2, and the solvent was evaporated to remove any residual DMSO. The residue was diluted with a minimum of acetone, and the white precipitate was filtered off. The filtrate was concentrated to near dryness and dissolved in EtOAc, which produced more of the white precipitate, which was again filtered off. The filtrate was washed with a 10% Na2S2O3/10% NaHCO3 solution, water, and brine before drying over Na2SO4. Upon removal of the organic solvent, the residue was twice taken up in benzene and evaporated to remove any residual water, giving 0.98 g (71%) of a white glassy solid which was used immediately without further purification: 1H NMR (DMSO-d6) δ 6 0.81 (m, 6H), 1.30 (m, 2H), 1.50 (m, 1H), 1.97 (m, 1H), 2.48 (s, 3H), 2.55-3.27 (m, 5H), 3.70 (m, 1H), 4.47 (m, 1H), 4.71 (m, 1H), 5.00 (s, 2H), 7.20-7.40 (m, 10H), 7.93 (m, 1H), 8.08 (m, 1H), 8.51 (m, 1H), 9.22 (s, 1H); (M+H) 544.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20]([O:24][C:25](ON=C(C1C=CC=CC=1)C#N)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CC(C)=O.O>[C:20]([O:24][C:25]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
To a suspension of D-phenylalanine (33.0 g, 0.2 mol) in acetone (120 ml) and water (120 ml) was added triethylamine (41.8 ml, 1.5 eq) followed by 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (54.2 g, 1.1 eq). The resulting mixture was stirred overnight and then diluted with water (250 ml). The aqueous fraction was extracted twice with ether and the ether fractions were discarded. The aqueous fraction was acidified with 0.5M citric acid and extracted with ethyl acetate (2×500 ml). The ethyl acetate fractions were combined and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed to give the title compound as a viscous yellow oil: 52.2 g.