Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]1[O:45][CH:46]=[CH:47][N:48]=1)CCC.[F-].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:44]4[O:45][CH:46]=[CH:47][N:48]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.34 mmol, 0.2 g), 2-(tri-n-butylstannyl)oxazole (0.68 mmol, 0.24 g), tetrakis(triphenylphosphine)palladium (0.034 mmol, 0.04 g) in dioxane (5.0 mL) were degassed with nitrogen for 10 min and heated at 90° C. over night under nitrogen. Cooled, KF solution (2.0 M, 10 mL) was added, stirred at room temperature for 30 min. extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 25% ethyl acetate in hexanes to get 4-[6-butyl-5-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.1 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:40][NH2:41].CO>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[N:16]=2)[CH2:11][C:12]([NH:41][OH:40])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1)NO
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1H-imidazol-2-ylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 103) (200 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 ml) was treated with 1,1′-carbonyidiimidazole (77 mg, 0.48 mmol) and stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (160 μl, 1.30 mmol) was added and the mixture was stirred for 18 hours. The mixture was then treated with methanol (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 90:10:1 (dichloromethane:methanol:ammonia) to afford a colourless oil which began to crystallise once a little methanol and dichloromethane were added. The solid was triturated with dichloromethane and dried under reduced pressure to afford the title compound as a solid (49 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:5](=[O:32])[NH:6][C@@H:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].CO>O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:1][CH2:2][CH2:3][N:4]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:5](=[O:32])[NH:6][C@@H:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)=[O:9]
Reactant: CN1CCN(C(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)N(CCO)CCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)N(CCO)CCc2ccccc2)CC1
Reaction time: 72 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, 20% palladium hydroxide on carbon (200 mg) is added to a solution of 1-[(2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-3-[4-(benzyloxy)phenyl]propionyl]-4-methylpiperazine (Compound No. 18-40, 1.09 g) in tetrahydrofuran (2 ml)-methanol (2 ml). The mixture is stirred under a hydrogen atmosphere for three days. Palladium hydroxide on carbon is filtered out with Celite, and the filtrate is concentrated under reduced pressure to give 685 mg (75%) of the titled compound (Compound No. 23-1) as noncrystalline powder.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>O1CCOCC1.C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:10][C:9](=[O:11])[C@@H:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:46]2
Reactant: O=C(O)C(Cc1ccccc1)Nc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@H](Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3-phenyl-2-(phenylamino)propanoic acid (I21) (1.21 g, 5.01 mmol) in dioxane, a 4M solution of HCl in dioxane (5 mL) is added and the reaction is allowed to stir at RT for 1 hour; the solvent is evaporated under reduced pressure to obtain a white solid which is dissolved in dry THF (70 mL). DCC (1.22 g, 6.01 mmol), HOBt (0.8 g, 6.0 mmol) and 3(R)-quinuclidinol (1.31 g, 10.1 mmol) are added to the resulting solution and the mixture stirred for 24 hours at RT under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated. 1N HCl (20 mL) is added to the resulting crude and the aqueous layer is washed with EtOAc (2×50 mL); NaHCO3 is added to the aqueous layer (pH=7-8) and the product is extracted with DCM and dried over Na2SO4, to obtain 530 mg (35% yield) of diastereoisomer 1 of C22, which is further purified by preparative LC-MS to get the titled product as a brown oil (mixture of diastereoisomers that contains 20% of diastereoisomer 2 of C22, TFA salt).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[N:7]2.Br[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][S:28]([OH:31])(=[O:30])=[O:29])[CH:23]=[CH:24][CH:25]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.CO>[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][S:28]([OH:31])(=[O:30])=[O:29])[CH:23]=[CH:24][CH:25]=1)=[N:7]2
Reactant: O=S(=O)(O)CCc1cccc(Br)c1
Reactant: Cc1nc(-c2ccccc2)n2nc(N)ncc12
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3cccc(CCS(=O)(=O)O)c3)ncc12
Temperature: 160 °C
Yield: 66.2 %

Procedure:
To a solution of 5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (28 mg, 0.107 mmol) in 1,4-dioxane (0.8 mL) was added 2-(3-bromophenyl)ethanesulfonic acid (28.25 mg, 0.107 mmol), 2-(dit-butylphosphino)biphenyl (9.6 mg, 0.032 mmol), Tris(dibenzylidineacetone)-dipalladium (0) (9.8 mg, 0.011 mmol) and sodium t-butoxide (23.65 mg, 0.246 mmol). In a sealed reaction vessel, the mixture was heated with microwave radiation at 160° C. for 13 minutes. After cooling to room temperature, methanol (5 mL) and silica gel (1.0 g) were added to the reaction mixture, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to isocratic elution using ethyl acetate:hexanes (50:50) followed by ethyl acetate:methanol (80:20) using a Biotage silica gel cartridge (8.0 g). The appropriate fractions were combined and concentrated under reduced pressure to give 2-{3-[(5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-yl)amino]phenyl}-ethanesulfonic acid (0.029 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.73 (s, 1H), 9.23 (s, 1H), 8.42 (d, J=7.5 Hz, 2H), 7.74 (s, 1H), 7.63 (dd, J=7.70 Hz, 2H), 7.49-7.07 (m, 3H), 6.86 (d, J=7.3 Hz, 1H), 2.94-2.82 (m, 2H), 2.71-2.62 (m, 2H), 2.52 (s, 3H). MS m/z 410 (M+1).
Reaction SMILES: [IH:1].C1O[C:5]2([CH2:10][CH2:9][C:8]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]2)[O:4]C1.I.C1OC2(CCC(C3C=CC=CC=3C)(N(C)C)CC2)OC1>>[IH:1].[C:16]1([CH3:20])[CH:17]=[CH:18][CH:19]=[C:14]([C:8]2([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: Cc1cccc(C2(N(C)C)CCC3(CC2)OCCO3)c1
Agent: Cc1ccccc1C1(N(C)C)CCC2(CC1)OCCO2
Agent: I
Product: Cc1cccc(C2(N(C)C)CCC(=O)CC2)c1
Yield: 75 %

Procedure:
Following the procedure of Example 16, but substituting 4-(m-tolyl)-4-dimethylaminocyclohexanone ethylene ketal hydroiodide for the 4-(o-tolyl)-4-dimethylaminocyclohexanone ethylene ketal hydroiodide there is obtained the 4-(m-tolyl)-4-dimethylaminocyclohexanone hydroiodide salt in 75% yield after recrystallization from methylene chloride:ethyl acetate: m.p. 172°-174.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Trifluorobenzoic acid (0.176 g, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3,4,5-trifluorobenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH:16]3[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][S:17]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(O)C>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[O:27]1[CH:31]=[CH:30][C:29]([C:2]2[CH:26]=[CH:25][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([S:13]([CH:16]4[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][S:17]4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)=[CH:4][CH:3]=2)=[CH:28]1
Reactant: OB(O)c1ccoc1
Reactant: O=C(O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Temperature: 80 °C
Yield: 67 %

Procedure:
A mixture of 0.45 g (1.0 mmol) of 3(S)-4-(4-(4-bromophenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid and 0.11 g (1.0 mmol) of 3-furan boronic acid (J. Org. Chem. 1984, 49, 5237-5243) in 2 mL of benzene, 2 mL of 2M aq. sodium carbonate, and 1.5 mL of ethanol was deoxygenated with a stream of argon for 15 minutes, and then 115 mg (0.1 mmol) of tetrakis(triphenylphosphine)palladium was added and the mixture was heated at 80° C. for six days. After cooling to room temperature, the mixture was partitioned between ethyl acetate and pH 4 citrate buffer. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane, to provide 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid (0.317 g, 67%) as a sticky solid foam. FAB+MS Calcd for M+Cs+=606.0021. Obs 606.0036; 1H NMR (CDCl3) δ 7.72-7.43 (m, 6H), 7.04 (d, 2H, J=8.46 Hz), 7.00 (d, 2H, J=8.82 Hz), 6.67 (s, 1H), 4.51 (s, 1H), 4.1-3.9 (bm, 1H), 3.7-3.6 (bm, 1H), 3.2-3.1 (bm, 1H), 2.42 (bd, 1H, J=12.87 Hz), 1.61 (s, 3H), 1.38 (s, 3H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C>C(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: CCOC(=O)COC1CCNCC1
Yield: 74.2 %

Procedure:
A solution of 36.4 g (0.131 mole) of ethyl 2-(1-benzyl-4-piperidyloxy)-acetate in 200 ml of absolute ethanol was reacted with hydrogen at 50° C in the presence of 3.5 g of 5% palladized charcoal until the theoretical amount of hydrogen was absorbed and the catalyst was filtered off. The ethanol was evaporated off and the residue was distilled to obtain 18.2 g (74% yield) of ethyl 2-(4-piperidyloxy)-acetate as a clear oil boiling at 102° C at 0.1 mm Hg and having a refractive index nD20 = 1.4665.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18])=[CH:12][CH:11]=1.[CH3:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:40](=[O:41])[NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:42])=[CH:38][CH:37]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)OCCO)cc1
Reactant: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCOc1ccc(NC(=O)OCCOC(=O)Nc2ccc(OCCCCCC(=O)OC)cc2)cc1
Temperature: 60 °C
Yield: 95 %

Procedure:
To a mixture of 6-[4-(2-Hydroxyethoxycarbonylamino)phenoxy]hexanoic acid methyl ester 37 (5 g, 15.38 mmol) in toluene (50 ml) was added 6-(4-Isocyanatophenoxy) hexanoic acid methyl ester 36 (4 g, 15.2 mmol) at room temperature and heated to 60° C. for 2 hours. Toluene was distilled off and water (50 ml) was added. The solid was filtered and dried to give crude 38, which was purified by column chromatography on silica gel using chloroform as eluant to get pure 38 (8.5 g, 94%) as a white powder. M.p: 118-120.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:21][C:20]([F:23])([F:22])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:31][C:28]2[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][C:27]=2[C:32]([F:35])([F:33])[F:34])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:19][C:20]([F:22])([F:23])[CH2:21]1)=[O:17])=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CC(F)(F)C1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared in analogy to Example 68/69, step 8, using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester and 4-Bromo-2-trifluoromethyl-benzenethiol (Example 58, intermediate 1). Light yellow oil. MS (EI): 518.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH:11][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH3:13])=[N:4][C:3]=1[NH:21][C:22]1[CH:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[NH:24][N:23]=1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1[N+](=O)[O-])c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (S)-3-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-(1-(4-fluorophenyl)ethyl)-5-nitropyridin-2,6-diamine (Example 36; 0.57 g, 1.37 mmol) and zinc dust (0.447 g, 6.84 mmol) in MeOH:THF (1:1, 24 ml) was slowly added saturated ammonium chloride solution (3.5 ml). The reaction mixture was stirred at 25° C. for 2 hours, followed by addition of saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 minutes. Zn dust was removed by filtration and washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), dried over Na2SO4 and the solvent removed to give the title compound. MS: Calcd.: 386. Found: [M+H]+ 387.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:13]>>[OH:13][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: NC(=O)Cc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Product: O=C(Cc1ccc(O)cc1)NO

Procedure:
A 450 mg (1.007 mmol) portion of ′N-(tert-butoxy)-2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide was stirred in neat TFA at room temperature for 72 h. TFA was removed in vacuo. The residue was chromatographed on preparative TLC, eluting with 1% HOAc and 10% MeOH in dichloromethane to provide 33.8 mg (9%) of 2-{[4-(2-butynyloxy)phenyl]-sulfonyl}amino)-N-hydroxy-2-(4-hydroxyphenyl)acetamide as a white solid. Electrospray Mass Spec 391.4 (M+H)+
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[S:12][C:11](=S)[NH:10][C:8]=2[N:9]=1.OO.NC(N)=[O:18].Cl>O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[S:12][C:11](=[O:18])[NH:10][C:8]=2[N:9]=1
Reactant: Nc1ncc2sc(=S)[nH]c2n1
Reactant: NC(N)=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ncc2sc(=O)[nH]c2n1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To a solution of NaOH (0.6 g, 15 mmol, 3 eq) in water (20 ml) was added 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-thione (0.92 g, 5 mmol, 1.0 eq). The mixture was stirred to dissolve. Urea hydrogen peroxide (2.8 g, 30 mmol, 6 eq) was slowly added dropwise to the above solution, keeping the temperature below 50° C. The reaction was then cooled down to room temperature (about 25° C.). Concentrated HCl (37%, 6 ml) was added to the above solution until the pH is less than 1. The mixture is stirred at room temperature for 30 minutes. Celite (2 g) was added to the solution and the solution was filtered and washed with water (10 ml). To the filtrate was added 50% NaOH solution to adjust the pH to 5-5.5. The solution was heated up to 50-60° C. for 30 minutes. The resulting solution was cooled down to room temperature, filtered, and washed with water, dried at 50° C. under vacuum to give 0.56 g (67%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-one as a pale yellow solid. 1H NMR, HPLC and LCMS analyses of this product are identical to the product described from Procedure A in Step 2 of Example 1 above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[OH:18][C:19]1[CH:20]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:22]=[C:23]([CH:32]=1)[C:24]([NH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[O:25].O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:18][C:19]2[CH:32]=[C:23]([C:24](=[O:25])[NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:22]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:20]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2cc(OC(C)C)cc(C(=O)Nc3nccs3)c2)nc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
After adding 123 mg (0.72 mmol) of 6-chloronicotinic acid methyl ester and 199 mg (1.44 mmol) of potassium carbonate to a solution of 100 mg (0.36 mmol) of the obtained amide compound in N,N-dimethylfommamide (10.0 ml), the mixture was stirred at 80° C. for 18 hours under a nitrogen atmosphere. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound as a white solid. The analysis data for the compound obtained in Production Example 65 are shown below.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:10][CH2:11][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:6][C:7](O)=[O:8])([OH:3])=[O:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[C:17]([CH2:16][N:15]([CH2:14][CH2:13][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:11][CH2:10][N:5]([CH2:6][C:7](=[O:8])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:4][C:1]([OH:3])=[O:2])[CH2:20][C:21]([OH:23])=[O:22])([OH:19])=[O:18]
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Reactant: Nc1ccccc1
Solvent: CO
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)Nc1ccccc1

Procedure:
In a 1-liter autoclave, 42.1 g (0.1 mol) of N3,N6 -bis(carboxymethyl)-N9 -ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid is heated with 93.1 g (1 mol) of aniline for 30 hours to 110° C. After cooling, the content is dissolved in 800 ml of methanol and the solution concentrated to dryness under vacuum. The residue is combined with 800 ml of water and the excess aniline exhaustively extracted with methylene chloride. The aqueous phase is passed, after an initial distillation, over 100 ml of "Amberlite" IR 120. The acidic eluate is concentrated and the residue dried under vacuum at 50° C., thus obtaining 35.1 g (75% of theory) in the form of a white powder with a melting point of 125° C.
Reaction SMILES: Cl.Br.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:14])[C:11]=2[NH2:13])[CH2:6][CH2:5][NH:4]1.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[NH:13]1[C:11]2[C:12]3[CH2:3][NH:4][CH2:5][CH2:6][C:7]=3[CH:8]=[CH:9][C:10]=2[NH:14][C:16](=[O:17])[C:15]1=[O:19]
Reactant: Nc1ccc2c(c1N)CNCC2
Reactant: O=C(O)C(=O)O
Agent: Br
Agent: Cl
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Temperature: 90 °C
Yield: 81.5 %

Procedure:
A solution of Example 29 (01.27 g, 0.96 mmol) in 25 mL 3 N HCl, was treated with oxalic acid (0.15 g, 1.2 mmol) and heated at reflux for 4 h. The mixture was cooled in an ice bath and the precipitate collected by filtration and washed with 3 N HCl, water and then diethyl ether consecutively. After air drying, the solid was suspended in 10 mL water and heated at approximately 90° C., basifyed with ammonium hydroxide solution to pH 8, and filtered hot. The solid was washed first with water, then with diethyl ether and then dried in a vacuum oven to give an off-white solid (0.17 g, 81% yield) mp=294-297° C. MS (CI) M+1, 218; IR 1691, 1659cm−1.