Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([N:16]3[CH:20]=[N:19][N:18]=[CH:17]3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:21][C@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:23])[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:44]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:44].[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:24]([C@@H:22]([O:21][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:15][C@H:14]3[N:16]2[CH:17]=[N:18][N:19]=[CH:20]2)[CH3:23])[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=1
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](n3cnnc3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: C[C@H](O[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2n1cnnc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1.5 h

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-6-(1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (Example 133; 185 mg, 0.31 mmol) was dissolved in methanol (5 ml) and 2N hydrochloric acid (0.5 ml) and 10% palladium hydroxide (50 mg) added. The mixture was hydrogenated at 45 psi for 1.5 hours. The reaction mixture was filtered then concentrated in vacuo. The residue was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics removed, dried (MgSO4) and concentrated in vacuo. The oil was purified by flash column chromatography [5% methanol in dichloromethane] and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60° C. (27 mg, 16%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:25](C(C)C)C(C)C)C.ClC(OCC(C)C)=O.N>O1CCCC1>[C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:14])[NH2:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Temperature: -9 °C
Reaction time: 0.5 h

Procedure:
A suspension of (S)-2-benzyloxycarbonylamino-3-(pyridin-3-yl)propionic acid (2.60 kg, 8.65 mol) in tetrahydrofuran (60 l) was cooled to −9° C. At this temperature, N-ethyldiisopropylamine (1.33 kg, 10.29 mol) was added over a period of 5 min. At −9° C., isobutyl chloroformate (1.36 kg, 9.96 mol) was then added within 20 min, the internal temperature in the end increasing to −6° C. After 10 min of vigorous stirring, ammonia gas (2.1 kg, about 123 mol) was introduced at a constant temperature of (−5)–(−6)° C. into the resulting thin suspension in the course of 3 h. The reaction was initially strongly exothermic (requires initially slow introduction), later on less exothermic. Over a period of 30 min, the reaction mixture was warmed to 16° C., which gave a thick but still stirrable crystal slurry. At a jacket temperature of 30° C., the solvent was removed under reduced pressure. The white, greasy residue was suspended in ethyl acetate (125 l). A solution of sodium hydrogen carbonate (3.0 kg) in water (50 l) was added and the mixture was stirred vigorously for 30 min, after which all of the solid had dissolved. The organic phase was separated off and dried over sodium sulfate (1.0 kg), the drying agent was filtered off and the filtrate was concentrated under reduced pressure at a bath temperature of 30° C. to a volume of about 6 l. The resulting precipitate was filtered off with suction, washed with ethyl acetate (1.5 l) and dried at 30° C. under reduced pressure. Yield: 2.26 kg (7.55 mol, 87.3% of theory). The chemical purity was 99.9% (HPLC: 125×4.0 mm RP18 Purospher, 40° C., detection 210 nm); the enantiomeric purity was 100% ee (HPLC: 250×4.6 mm CSP Chiralpak AD Daicel, 40° C.; detection 248 nm; mobile phase: n-hexane/isopropanol/ethanol 84/12/4+0.1% diethylamine; tret [(S)-isomer] 14.93 min). M.p.: 152.8° C. (by DSC); MS (ESI+): m/z (%): 300 ([M+H+], 100); 1H-NMR (200 MHz, DMSO-d6): δ=2.77 (dd, J=9.5 and 7.0 Hz, 1H), 3.02 (dd, J=9.5 and 3.5 Hz, 1H), 4.19 (m, 1H), 4.96 (s, 3H), 7.00–7.40 (m, 7H), 7.40–7.60 (m, 2H), 7.60–7.76 (m, 1H), 8.36–8.53 (m, 2H); IR (KBr): ν=3306.8, 1674.9, 1537.7, 1424.0, 1271.6, 1251.3 cm−1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[F-].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccccc3)n2)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 2 g (5.84 mmol) of tert.butyl 4-(6-bromo-pyridin-2-yl)-piperazine-1-carboxylate, 0.75 g (6.15 mmol) of phenylboric acid, 2.66 g (17.52 mmol) of caesium fluoride, 0.045 g (0.15 mmol) of 2-(di-t-butylphosphino)-biphenyl and 0.013 g (0.06 mmol) of palladium acetate in 20 ml of dioxane is stirred for six hours at 50° C. under nitrogen. Then it is diluted with water and the reaction mixture is extracted with ethyl acetate. The organic phase is separated off and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=4:1).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](Cl)=[N:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C>[CH2:1]([N:4]1[C:12]2[C:11]3=[N:20][N:21]=[N:22][N:10]3[C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCn1cnc2c1c(Cl)nc(=O)n2CCCCC
Agent: [Na+]
Solvent: CCO
Product: C=CCn1cnc2c1c1nnnn1c(=O)n2CCCCC
Yield: 3.5 %

Procedure:
A mixture of 7-allyl-6-chloro-3-pentyl-3,7-dihydro-2H-purin-2-one (0.65 g, 2.3 mol) and sodium azide (0.98 g, 15 mmol) in ethanol (20 mL) was refluxed overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with water and EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative LCMS to provide the desired product as a white powder (0.15 g, 22.6%). LCMS calculated for C13H18N7O (M+H): 288.2; found: 288.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)c2cncn2C)ccc1N
Temperature: 25 °C

Procedure:
A mixture of (1-methyl-1H-imidazol-5-yl)(3-methyl-4-nitrophenyl)methanone (3.3 g, 13.456 mmol, Intermediate 40: step b) and tin(II)chloride dihydrate (15.6 g, 67.282 mmol) in EtOH (80 mL) was stirred at reflux for 1 hour, cooled to room temperature overnight and evaporated in vacuo to remove most of the EtOH. The residue was poured into a 3M aqueous NaOH/ice solution rinsing with EtOAc. The mixture was stirred at room temperature for 15 minutes and layers were separated. The aqueous layer was again extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to provide crude product. The tan solid title compound was precipitated from Et2O, collected by filtration and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:31])([CH2:12][CH2:13][C:14]1[O:15][C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:31])([CH2:12][CH2:13][C:14]1[O:15][C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(C(=O)CCCCc2ccccc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@](C)(C=O)CCc1ccc(C(=O)CCCCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of (2R)-2-t-butoxycarbonylamino-2-methyl-4-[5-(5-phenylpentanoyl)furan-2-yl]butan-1-ol (110.2 mg, 0.26 mmol) obtained in Example (29a) in dichloromethane (2.6 ml) was added Dess-Martin reagent (165.0 mg, 2.28 mmol), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After stirring, the reaction mixture was evaporated in vacuo, and to the residue was added a 10% aqueous sodium thiosulfate solution to decompose the excess reagent. The resulting mixture was extracted with dichloromethane, and the extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:1) as the eluent to afford the title compound (105.9 mg, yield: 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].II.[I:14]([O-])(=O)=O.[Na+].O>C(O)(=O)C.S(=O)(=O)(O)O>[I:14][C:7]1[C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-3-nitro-2-pyridone (2.00 g, 13 mmol) in acetic acid (12 mL) and concentrated sulfuric acid (1.6 mL) was added iodine (1.32 g) and sodium iodate (0.55 g). The mixture was heated at 75° C. for 2.5 hours and then stirred at rt overnight. Water (100 mL) was added, and the precipitated 5-iodo-4-methyl-3-nitro-2-pyridone was collected by filtration (2.97 g, 82%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[N:31]=[CH:30][NH:29][N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1nc[nH]n1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCSc1nc[nH]n1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 56 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 3-mercapto-1,2,4-triazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 87°-89° C., in a 56% yield.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[CH:14]=2)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4].[N+:22]([C:25]1C=C(C=[CH:30][CH:31]=1)N)([O-])=O.C(CC(=O)CCC=C)#N.CC([O-])=O.[Na+]>>[CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=[C:15]3[C:16](=[CH:17][CH:18]=2)[N:22]=[CH:25][CH:31]=[CH:30]3)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1=NN=C(N)C1=NNc1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: C=CCCC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCCC1=NN=C(N)C1=NNc1ccc2ncccc2c1
Yield: 61 %

Procedure:
In a similar manner, 5-but-3-enyl-4-[(3-nitrophenyl)hydrazono]4H-pyrazol-3-ylamine was prepared from 3-nitroaniline (166 mg, 1.2 mmole) and 1-cyano-5-hexen-2-one (123 mg, 1 mmole) with NaOAc (979 mg, 7.2 mmole) according to a procedure similar to Example 2. The crude material was purified by a prepreparative TLC (CH2Cl2:MeOH=21:1) to yield 175 mg (61%) of the title compound as an orange powder. MS (m/z, ES+): 287 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6-CDCl3) δ 11.60 (br s, 1H), 8.38 (s, 1H), 7.99 (m, 1H), 7.57 (t, 1H), 6.64 (br s, 2H), 5.84 (m, 1H), 5.03 (d, 1H), 4.92 (d, 1H), 2.88 (m, 2H), 2.48 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:19]2[C@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:21]([CH3:33])[CH2:20]2)[C:12]2[CH2:18][NH:17][CH2:16][CH2:15][C:13]=2[N:14]=1.FC(F)(F)S(O[C:40]1[CH:45]=[C:44]([CH:46]([CH3:48])[CH3:47])[CH:43]=[CH:42][C:41]=1[CH3:49])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:19]2[C@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C@@H:21]([CH3:33])[CH2:20]2)[C:12]2[CH2:18][N:17]([C:40]3[CH:45]=[C:44]([CH:46]([CH3:48])[CH3:47])[CH:43]=[CH:42][C:41]=3[CH3:49])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(C)c1-c1nc2c(c(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)n1)CNCC2
Reactant: Cc1ccc(C(C)C)cc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)c2C1
Temperature: 130 °C

Procedure:
To a solution of racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.187 g, 0.414 mmol) in THF (4 mL) was added 5-isopropyl-2-methylphenyl trifluoromethanesulfonate (0.175 g, 0.620 mmol) prepared as described in Example 15, Cs2CO3 (0.404 g, 1.24 mmol) and chloro(2-dicyclohexylphosphino-2′-4′-6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butylether adduct (0.046 mg, 0.062 mmol). The reaction was purged with argon and was heated at 130° C. for 3 h in a microwave reactor. The mixture was then concentrated and the residue was purified via FCC (10-35% EtOAc/heptane) to give racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate. MS (ESI+) m/z 584.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[C:32]([F:33])=[CH:31][C:30](B(O)O)=[C:29]([O:37][CH3:38])[CH:28]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:30]3[CH:31]=[C:32]([F:33])[C:27]([F:26])=[CH:28][C:29]=3[O:37][CH3:38])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Yield: 95.5 %

Procedure:
Bis(tricyclohexylphosphine)palladium (236 mg, 0.35 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (6.5 g, 17.73 mmol), potassium carbonate (3.67 g, 26.6 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (5 g, 26.6 mmol) in 156 ml, dioxane were reacted as above and purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to give 6.51 g (95.6%) of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])(=[O:3])N.C(=O)([O-])[O-:21].[Na+].[Na+]>Cl>[C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:21])=[O:3]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
15.16 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (i) above] were dissolved in 170 ml of 2N aqueous hydrochloric acid, and the solution was stirred in a bath kept at 110° C. for 3.5 hours. At the end of this time, the reaction mixture was cooled to room temperature, and its pH was adjusted to a value of 8.5 by the addition of sodium carbonate. The mixture was then concentrated by evaporation under reduced pressure, after which it was allowed to stand in a refrigerator to precipitate crystals. The precipitated crystals were collected by filtration and washed with a small amount of cold water. They were then dried, to give 10.4 g of the title compound. The mother liquor was then concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through CHP20P (75-150μ, Mitsubishi Chemical Industries, Ltd.), using 50% v/v aqueous methanol as the eluent, to afford a further 3.7 g of the title compound, as crystals melting at 185°-187.5° C.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)[Cl:5].[CH2:9]([O:16][NH:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[S:35][N:34]=[CH:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([O:16][N:17]([C:4]([Cl:5])=[O:3])[C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[S:35][N:34]=[CH:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncns1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1ncns1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diphosgene (360 mg, 1.8 mmol) was added to a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (468 mg, 1.2 mmol) in dry DCM (20 mL) at 0° C. followed by addition of TEA (360 mg, 3.6 mmol). The mixture was stirred at 0° C. for 2 hrs and then quenched with saturated NaHCO3 (20 mL). The reaction mixture was then extracted with DCM (3×) and the combined organic layer was dried over Na2SO4 and concentrated to afford (2S,5R)-tert-butyl 5-(benzyloxy(chlorocarbonyl)amino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate, which was directly used in the next step. ESI-MS (EI+, m/z): 445 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:25][C:26]#[CH:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CO.C(Cl)Cl.O>[CH3:23][C:19]1[C:18]([O:24][CH2:25][C:26]#[CH:27])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28]
Reactant: C#CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C#CCOc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 108 h
Yield: 108 %

Procedure:
A 50 mL flask containing the 2-(3-methyl-2-prop-2-ynyloxy-benzoylamino)-indan-2-carboxylic acid ethyl ester (0.20 g, 0.53 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH (56 mg, 1.35 mmol). After 108 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜10 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to constant weight to give 0.2 g of off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:29])[CH2:27][CH3:28])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCCCC(CNc2ccccc2)C1
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCCN(C(=O)OCc2ccccc2)C1)c1ccccc1
Temperature: 0 °C
Yield: 72 %

Procedure:
Et(iPr)2N (0.24 mL, 1.38 mmol) was added to a stirring solution of crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148) in CH2Cl2 (2.3 mL) under N2. The reaction was cooled to 0° C. in an ice bath, then propionyl chloride (0.22 mL, 2.53 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was then judged complete by TLC. It was concentrated in vacuo and EtOAc and 10% NaOH (aq) were added. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, and purified by automated silica gel chromatography with 96:2:2 Hexanes:CH2Cl2:2N NH, in EtOH to obtain 3-[(phenyl-propionyl-amino)-methyl]-azepane-1-carboxylic acid benzyl ester (149) (0.3266 g) in 72% yield for two steps.
Reaction SMILES: [C:1]([CH:4]1[S:8][CH:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25]3)C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[N:6]=[C:5]1[O:35]C)(=[O:3])[NH2:2].B(Br)(Br)Br>C(Cl)Cl.CO>[F:34][C:33]1[C:28]([C:24]2([CH2:23][NH:15][C:12]3[N:13]=[N:14][C:9]([CH:7]4[N:6]=[C:5]([OH:35])[CH:4]([C:1]([NH2:2])=[O:3])[S:8]4)=[CH:10][CH:11]=3)[CH2:25][CH2:26][CH2:27]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC1=NC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)SC1C(N)=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C1SC(c2ccc(NCC3(c4ncccc4F)CCC3)nn2)N=C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31060.1 %

Procedure:
To a stirring mixture of t-butyl 6-(5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (60 mg, 0.12 μmol) in CH2Cl2 (2 mL) was added BBr3 (140 μL, 1.2 mmol). The reaction was stirred at rt for 2 h and then at 60° C. for 15 min. The reaction was cooled to rt and carefully diluted with methanol (2 mL). The reaction was concentrated, diluted with ethyl acetate (20 mL), and saturated sodium bicarbonate (10 mL) was added. The mixture was agitated and then filtered. The subsequent crude solid was then purified using reverse phase chromatography to give 15 mg of 2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxamide as a yellow solid (M+H=401.3)
Reaction SMILES: [CH2:1](OC(C1OC2C=CC(O)=CC=2N=1)=O)[CH2:2][CH3:3].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]([O-:28])=[O:27])=[N:23][C:22]=2[C:29]=1[OH:30]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]([O:28][CH2:1][CH2:2][CH3:3])=[O:27])=[N:23][C:22]=2[C:29]=1[OH:30]
Reactant: O=C([O-])c1nc2c(O)c(Cl)ccc2o1
Reactant: CCCOC(=O)c1nc2cc(O)ccc2o1
Product: CCCOC(=O)c1nc2c(O)c(Cl)ccc2o1

Procedure:
When the carboxylic acid of Example 29 is replaced by 5-chloro-4-hydroxybenzoxazole-2-carboxylate, n-propyl 5-chloro-4-hydroxybenzoxazole-2-carboxylate is obtained.