Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NN>CN1CCOCC1.CN(C=O)C.CN1CCOCC1.CN(C=O)C>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:44]([O:43][CH3:42])=[O:45]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71e) i)) and 34 mg (0.196 mmol) of N-methoxycarbonyl-(L)-valine (Example 73b) are dissolved in 1.75 ml of a 0.3M solution of NMM in DMF, 74 mg (0.196 mmol) of HBTU are added and the mixture is stirred at RT. Since, after 3 days, there is still unreacted hydrazine present, a further 0.3 equivalents in each case of N-methoxycarbonyl-(L)-valine and HBTU in 0.48 ml of 0.3M NMM/DMF is added. After 18 h the reaction mixture is concentrated by evaporation under HV, the residue is dissolved in methylene chloride and washed with saturated NaHCO3 solution, water and brine, the aqueous phases are extracted twice with methylene chloride, and the organic phases are dried with Na2SO4 and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/methanol 15:1) and digestion from DIPE yields the title compound: TLC Rf (A')=0.17; tRet (V)=14.6 min; FAB-MS (M+H)+ =718.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)[CH:14]=[CH:13][C:12]=2[O:25][CH3:26])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:24][C@H:19]1[NH:20][C@@H:21]([CH3:23])[CH2:22][N:17]([C:15]2[CH:14]=[CH:13][C:12]([O:25][CH3:26])=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:29][O:28][CH3:27])[CH:35]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=2)[CH2:18]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Reactant: COCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COCc1cccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OC)s2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-thiophenesulfonamide (E122) (100 mg, 0.22 mmol) and {3-[(methyloxy)methyl]phenyl}boronic acid (83 mg, 0.5 mmol) in DME (3 ml) was added potassium tert-butoxide (210 mg, 1.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then concentrated in Genevac and residues passed over SCX. Basic fractions were re-concentrated in Genevac and the residue purified using mass directed autoprep HPLC to afford the title compound (E123). MS (ES+) m/e 502 [M+H]+.
Reaction SMILES: [CH3:1][O:2][Na].[CH3:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH2:25]Br)[N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7]>CO.CCOC(C)=O.O>[CH3:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][O:2][CH3:1])[N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1cccc2cc(Oc3ccnc(CBr)n3)ccc12
Reactant: CO[Na]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1nccc(Oc2ccc3c(C(=O)OC)cccc3c2)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
760 μl (4.12 mMol) of a 5.4 M solution of MeONa in MeOH are added to a solution of 1.28 g (3.43 mMol) 6-(2-bromomethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester in 70 ml MeOH. After 22 h stirring at rt, the mixture is diluted with EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 19: 1→1:3) gives the title compound: MS: [M+1]+=325; 1H NMR (CDCl3): δ ppm 9.06 (d, 1H), 8.66 (d, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.70 (s, 1H), 7.59 (t, 1H), 7.46 (d, 1H), 6.82 (d, 1H), 4.58 (s, H2C), 4.06 (s, H3C), 3.53 (s, H3C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([OH:24])=O)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1.O.OC1C2N=N[NH:32]C=2C=CC=1.N.O1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([NH2:32])=[O:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1
Reactant: COc1ccc(-c2nc(-c3c(F)cccc3F)oc2C(=O)O)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)oc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylic acid (0.026 g, 0.08 mmol) and hydroxybenzotriazole monohydrate (0.012 g, 0.08 mmol) in DMF (3 mL) was added 0.5M ammonia in dioxane (0.471 mL, 0.24 mmol) and the reaction mixture stirred at room temperature for 10 minutes. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.015 g, 0.08 mmol) was then added and the resulting reaction mixture stirred at room temperature overnight. After a further addition of hydroxybenzotriazole monohydrate (0.008 g, 0.05 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.010 g, 0.05 mmol) and 0.5M ammonia in dioxane (0.315 mL, 0.1116 mmol) the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo, and the residue was partitioned between DCM (10 mL) and water (10 mL). The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxamide (0.018 g, 0.05 mmol, 69%) as a white solid. 1H NMR (CD3OD) δ 3.88 (3H, s), 7.03 (2H, d), 7.25 (2H, t), 7.68 (1H, m), 8.21 (2H, d). LCMS (2) Rt: 2.80; m/z (ES+) 331.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([CH3:17])[C:8]([CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:10])[N:4]2[N:3]=1.C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[Br:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([CH3:17])[C:8]([CH:11]([O:16][C:8]([CH3:11])([CH3:9])[CH3:7])[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:10])[N:4]2[N:3]=1
Reactant: COC(=O)C(O)c1c(C)nc2cc(Br)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(Br)nn2c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 120 %

Procedure:
To a suspension of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (80 mg, 0.239 mmol) in tert-butyl acetate (2 mL) at room temperature was added CH2Cl2 (2 mL) followed by perchloric acid (0.022 mL, 0.359 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (56 mg, 59.9%). 1H NMR (500 MHz, MeOD) δ ppm 1.27 (9H, s), 2.62 (3H, s), 3.74 (3H, s), 5.75 (1H, s), 6.75 (1H, s).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([CH:51]=[CH2:52])=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO.C1COCC1.[Pd]>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([CH2:51][CH3:52])[CH:33]=2
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3C[C@H](C)[C@H](n4ccnn4)[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnccc3N3C[C@@H](N)[C@@H](n4ccnn4)[C@@H](C)C3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of benzyl {2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-vinylquinolin-3-yl}carbamate (5.2 mg, 0.007 mmol) in MeOH (0.29 mL) and THF (0.29 mL) was added a mixture of palladium (2.9 mg) (10% Pd on carbon). The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under vacuum to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.074 mL, 0.30 mmol) and stirred at room temperature for 30 min. The solution was then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the desired product as yellow powder (2.3 mg, 66%). LCMS calc. for C25H30N9O (M+H)+: m/z=472.3. Found: 472.3.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 4.5 h

Procedure:
Preparation (3R,3aR,6R,6aS)— tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (35b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and anti-(33b) (100 mg, 0.25 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 4.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2×3 mL) to obtain (3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [NH3:1].F[B-](F)(F)F.C(O[C:10](=[N+:18]1[CH2:26][CH:25]2[CH:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:1]=[C:10]([N:18]1[CH2:26][CH:25]2[CH:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N
Reactant: CCOC(Cc1ccccc1)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N=C(Cc1ccccc1)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 5 h

Procedure:
A 0.8N solution (8.8 cc) of ammonia in dichloromethane is added to a stirred suspension, cooled to -20° C., of (3aRS,7aRS)-2-(1-ethoxy-2-phenylethylidene)-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (3.75 g) in anhydrous dichloromethane (30 cc). The reaction mixture is allowed to return to room temperature and stirring is continued for 5 hours. The reaction mixture is treated with 10% strength aqueous potassium carbonate solution (30 cc). The precipitate present is removed by filtration and the organic phase is then washed with distilled water (15 cc) and with saturated aqueous sodium chloride solution (15 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in acetonitrile (22 cc). The crystals obtained are drained and dried. (3aRS,7aRS)-2-(α-Iminophenethyl)-7,7-diphenylperhydro-4-isoindolone (1.3 g), m.p. 202° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[N:18]=1)[C:5]([NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14]OCC1)=[O:6].[N:20]1([CH2:26]CCN)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.ClC1C=C(C=C(Cl)N=1)C(O)=[O:35]>>[Cl:19][C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([Cl:1])[N:18]=1)[C:5]([NH:7][C:8](=[O:35])[C@@H:9]1[CH:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:14][CH2:15][NH:10]1)=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: O=C(NCCN1CCOCC1)c1cc(Cl)nc(Cl)c1
Reactant: NCCCN1CCOCC1
Product: O=C(NC(=O)[C@H]1NCCC1N1CCOCC1)c1cc(Cl)nc(Cl)c1

Procedure:
The title compound was prepared by the procedure of Intermediate 40 from 3-morpholin-4-yl-propan-1-amine and 2,6-dichloroisonicotinic acid (both commercially available).
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.[CH3:51][N:52]([CH2:54][CH2:55]Cl)[CH3:53]>>[CH3:51][N:52]([CH3:53])[CH:54]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:55]
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: CN(C)CCCl
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C

Procedure:
that N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl-ammonium salt as starting material is reacted with dimethylaminoethylchloride to form N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester,
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[S:15][C:16]([CH3:24])=[C:17]([CH3:23])[C:18]=1[C:19](=[O:22])[CH2:20][CH3:21].CC[N:27](C(C)C)C(C)C.N>ClCCl>[CH3:23][C:17]1[C:18]([C:19](=[O:22])[CH2:20][CH3:21])=[C:14]([NH:13][C:5]([NH2:27])=[O:11])[S:15][C:16]=1[CH3:24]
Reactant: CCC(=O)c1c(N)sc(C)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Product: CCC(=O)c1c(NC(N)=O)sc(C)c1C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
To a solution of triphosgene (68 mg, 0.224 mmol) in dry dichloromethane (2 mL) was added dropwise a mixture of 1-(2-amino-4,5-dimethylthiophen-3-yl)propan-1-one (Example 51b) (111 mg, 0.605 mmol) and DIEA (0.24 mL, 1.344 mmol) in dry dichloromethane (3.5 mL) over a period of 20 minutes. After the reaction mixture was stirred for 5 minutes, a mixture of ammonia (7 M in MeOH, 0.086 mL, 0.605 mmol) and DIEA (0.24 mL, 1.344 mmol) in dry dichloromethane (2 mL) was added in one portion. The reaction mixture was then stirred at room temperature for 1 h under nitrogen. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (50 mL) and then washed with 10% NaHSO4, 5% NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The yellow residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (15.4 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.18 (t, 3H, J=7.2 Hz), 2.25 (s, 3H), 2.30 (s, 3H), 2.87 (q, 2H, J=7.2 Hz), 4.77 (s, 2H), 11.99 (s, 1H). MS 227 (MH+).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[OH-].[K+].O.CO>C(OCC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C=CCCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 43.3 %

Procedure:
A mixture of 17 g of methyl 4-(9-decenyloxy)benzoate. 17 g of potassium hydroxide, 20 ml of water and 200 ml of methanol was heated to 75° C. on an oil bath for 4 hours. The cooled mixture was treated with 100 ml of ice-cold 3N hydrochloric acid and the liberated acid was taken up in 150 ml of diethyl ether. The separated aqueous phase was back-extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the crude product obtained from ethanol gave 7 g of 4-(9-decenyloxy)benzoic acid, m.p. (C-SC) 77° C., phase transition (SC -N) 116° C., cl.p. (N-I) 137° C.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li+].[OH-].[ClH:30]>C1COCC1.O>[Cl:30][CH2:25][C:21]1[CH:20]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:27])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][CH:22]=1
Reactant: Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CO)c4)ccnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CCl)c4)ccnc32)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of compound G″ in THF, water was added LiOH (3.68 g, 0.087 mol) at rt and stirred for 4 h at same temperature. The reaction mixture was concentrated to obtain residue which was diluted with water (50 ml), acidified with 2N aq. HCl solution, adjusted to pH=5-6, the precipitated solid was filtered, washed with water and dried (traces water were removed by co-evaporating with toluene) to obtain compound H″. The compound H″ was washed with diethyl ether to obtain desired purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:10]=1)[C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)cc(OC(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Cl)cc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
3-Chloro-5-difluoromethoxybenzoic acid (1.8 g, 8 mmol; see step (iii) above) and oxalyl chloride (1.5 g, 11.8 mmol) were dissolved in methylene chloride (50 mL). DMF (2 drops) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. Then, N,O-dimethylhydroxylamine (1 g, 10.2 mmol) and triethylamine (3 g, 30 mmol) were added and after another 10 minutes stirring at ambient temperature, the reaction mixture was concentrated at reduced pressure. The residue was taken up in ether (100 mL) and water (50 mL). After separation, the organic phase washed with brine, dried over sodium sulphate, filtered and concentrated. This residue was chromatographed on silica (hexane/ethyl acetate 2:1) which gave 2 g, 7.5 mmol (93%) of the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[C:23](=[O:28])[N:24]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc[nH]c1=O
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 11A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.74 Hz, 1H) 7.89 (d, J=1.87 Hz, 1H) 7.42 (dd, J=8.73, 2.18 Hz, 1H) 7.25-7.31 (m, 2H) 6.18 (t, J=6.86 Hz, 1H) 3.57-3.68 (m, 1H) 3.15-3.25 (m, 1H) 3.02-3.10 (m, 1H) 2.72-2.85 (m, 1H) 2.59-2.68 (m, 1H) 2.44-2.53 (m, 2H) 2.31-2.43 (m, 1H) 2.20 (s, 3H) 1.91-2.02 (m, 1H) 1.79-1.88 (m, 1H) 1.65-1.76 (m, 1H) 1.44-1.64 (m, 2H) 1.15 (s, 3H). MS: (M+H)+=380.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[C:19]1(C)C=CC=CC=1>>[CH3:19][CH:8]([CH3:18])[CH2:13][CH2:12][C:11]1[C:5](=[O:7])[CH2:6][CH2:9][CH:10]=1
Reactant: Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)CCC1=CCCC1=O
Temperature: 125 °C

Procedure:
2-(3-Methyl-butyllidene)-cyclopentanone (1.093 Kg, 7.19 mol, obtained as detailed above), acetic anhydride (300 mL, 3.17 mol), p-toluenesulfonic acid (PTSA, 10 g), and toluene (500 mL) were charged into a flask and heated to 120-130° C. When gas chromatography analysis indicated the completion of the reaction, the reaction mixture was cooled to room temperature and quenched with Na2CO3 solution (100 mL). The resulting mixture was washed twice with brine (1 L). A rushover process provided the crude product 2-(3-methyl-butyl)-cyclopent-2-enone.