Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:5][C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][S:9]C(=O)C.C(SCC(CC1C=CC=CC=1)C(O)=O)(=O)C>>[CH2:13]([CH:7]([CH2:8][SH:9])[C:6]([NH:5][C@H:4]([C:3]([OH:25])=[O:2])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: CC(=O)SCC(Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)C(CS)Cc1ccccc1)C(=O)O
Yield: 81 %

Procedure:
N-[S-Acetyl-2'-benzyl-3'-mercaptopropionyl]leucine methyl ester Prepared by Method B of Example 19 but on a 1:1 mixture of D and L-leucine methyl ester hydrochlorides (113 mg, 0.5 mmol, L isomer from Aldrich) and using S-acetyl-2-benzyl-3-mercaptopropionic acid (0.5 mmol). This gave the title compound as a clear oil in 81% yield, an approximately equimolar mixture of diastereoisomers. These were partially separated.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[CH:12]1[C:13]2[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]([CH:33]3[CH2:35][CH2:34]3)[C:14]=2[CH:15]=[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]=1[F:18].[Na]>C1COCC1>[NH2:9][C:10](=[S:11])[N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[C:14]3[C:13]([C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]3[CH:33]3[CH2:34][CH2:35]3)=[CH:12][C:17]=2[F:18])[CH2:24][CH2:23]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na]
Solvent: C1CCOC1
Product: NC(=S)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
[6R-[6a,7b]]-3-[[[(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1-quinolinyl)-4-piperazinyl]iminomethyl]thio methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt, of the following formula ##STR330## according to this invention, is made as follows. A solution of benzoyl isothiocyanate 10.92 g) in THF (20 ml) is added to a mixture of ciprofloxacin sodium salt (2.0 g) in THF (300 ml), and the reaction is stirred for 20 hours. The reaction is concentrated to dryness and the residue is triturated with acetone. The resultant benzoylurea is added to a preheated at approximately 80° C. (176° F.) solution of 5% aqueous NaOH and the reaction is stirred for 30 minutes. The mixture is cooled to approximately 5° C. (41° F.) and acidified with 1N HCl. The solid is collected by filtration and recrystallized from DMF to yield 7-[4-(aminothioxomethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[CH:15]=[CH:16][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn(C3CCCCO3)n2)cc1
Yield: 92.6 %

Procedure:
A solution of the 5-[(1R,2S)-2-(benzyloxy)cyclopentyl]-1H-pyrazole (322 mg, 1.33 mmol) prepared in Example 148c, 3,4-dihydro-2H-pyran (0.728 mL, 7.98 mmol) and p-toluenesulfonic acid hydrate (50 mg, 0.266 mmol) in dichloromethane (5.0 mL) was stirred for 3 hours under reflux. After allowing to cool, the reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (402 mg, 93%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.9 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexane/acetone) affording 23.9 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis are consistent with the desired structure).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:37])[CH2:11][CH:12]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=[C:15]2[C:14]1=[O:25])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[CH2:35]([O:34][C:28]1[CH:27]=[C:26]([CH:12]([N:13]2[C:17](=[O:18])[C:16]3=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=[C:15]3[C:14]2=[O:25])[CH2:11][C:10]([NH:9][OH:8])=[O:37])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH3:36]
Reactant: [H][H]
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc(C)c(C)c3C2=O)ccc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C)c(C)c3C2=O)ccc1OC
Yield: 83.4 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3,4-dimethylphthalimido)propionamide was prepared by the procedure of Example 16 N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3,4-dimethylphthalimido)propanamide (0.63 g, 1.25 mmol), Pd(OH)2/C (100 mg) and hydrogen (50 psi) in ethyl acetate and methanol (30 mL each) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3,4-dimethylphthalimido)propionamide as a white solid (430 mg, 84% yield): mp, 197.0-202.5° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.56 (s, 3H, CH3), 3.09 (d, J=7.09 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.65 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.00 (br s, 1H, Ar), 7.59 (br s, 2H, Ar), 8.78 (br s, 1H, OH), 10.56 (br s, 1H, NH); 13C NMR (DMSO-d6) δ13.22, 14.65, 19.33, 34.21, 49.88, 55.43, 63.72, 111.75, 112.40, 119.62, 120.39, 127.76, 129.33, 131.36, 134.71, 136.50, 145.13, 147.62, 148.48, 166.02, 167.32, 168.65; Anal Calcd for C22H24N2O6+0.3 H2O: C, 63.24; H, 5.93; N 6.70. Found: C, 63.11;H, 5.88; N, 6.67.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([S:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[S:9])=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-]>C(OCC)C>[CH3:21][O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][S:10][C:8](=[S:9])[NH:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CCCSC(=S)NCc1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
1.5 G. of 4-{[(p-chlorobenzyl)thiocarbamoyl]thio}-butyric acid were dissolved in 30 ml. of diethyl ether and treated with an excess of an ethereal diazomethane solution. The resulting solution was evaporated. The residue was recrystallized from cyclohexane, and 1.2 g. of 4-{[(p-chlorobenzyl)thiocarbamoyl]thio}-butyric acid methyl ester having a melting point of 60°-62° C. were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:17][CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH3:6]>C1C=CC=CC=1>[CH2:5]([N:7]([CH2:17][CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:3])=[O:13])=[CH:10][CH:9]=1)[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: CCN(CC)c1ccc(C(=O)Cl)cc1
Yield: 93 %

Procedure:
First, thionyl chloride was added dropwise to a benzene solution (20 mL) containing 0.96 g (5 mmol) of 4-(diethylamino)benzoic acid (a compound (10-2) in the following reaction formula) and was allowed to react at room temperature in a nitrogen atmosphere, yielding 4-(diethylamino)benzoic acid chloride (a compound (10-3) in the following reaction formula, 4.65 mmol, yield 93%).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:24][CH2:25][Cl:26]>>[Cl:26][CH2:25][CH2:24][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: ClCCBr
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCCl
Temperature: 55 °C
Yield: 67.3 %

Procedure:
(1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (525 mg, 2.65 mmol) and potassium phosphate (1686 mg, 7.94 mmol) were combined in a 75 mL medium pressure flask and purged in a 50° C. vacuum oven for 10 mins and placed under N2 (g) atmosphere. THF (30 mL) was added, followed by 1-bromo-2-chloroethane (1.124 mL, 13.24 mmol) and the mixture was heated to 55° C. for 18 h. The reaction mixture was cooled to rt, treated with more 1-bromo-2-chloroethane (0.043 mL, 0.517 mmol) and heated back up to 55° C. for 68 h. The reaction was filtered and washed with DCM. The liquid filtrate was concentrated to viscous brown oil which was purified by column chromatography (SiO2, 40 g cartridge, eluted with 95:5 DCM:MeOH), dried under vacuum with stirring to give (1S,4S)-tert-butyl 5-(2-chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (465 mg, 1.783 mmol, 67.3% yield) as viscous light brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.37 (s, 1H), 4.36 (br. s., 1H), 4.24 (br. s., 1H), 3.44 (d, J=9.5 Hz, 1H), 3.17 (t, J=8.8 Hz, 1H), 3.08-2.94 (m, 1H), 2.93-2.85 (m, 2H), 2.67 (d, J=9.5 Hz, 1H), 2.53 (d, J=9.5 Hz, 1H), 1.82 (d, J=6.4 Hz, 1H), 1.71 (dd, J=15.9, 9.8 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: Nc1ccccc1F
Product: O=C(O)c1nnn(-c2ccccc2F)n1

Procedure:
This intermediate was prepared from 2-fluoro-phenylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH2:10])[CH:7]([CH3:9])[CH3:8]>CCOCC>[CH2:6]([NH:10][C:3](=[O:4])[CH2:2][Cl:1])[CH:7]([CH3:9])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CN
Solvent: CCOCC
Product: CC(C)CNC(=O)CCl

Procedure:
Chloroacetyl chloride (ex. Aldrich) (50 g) was added dropwise, with stirring to isobutylamine (ex. Aldrich) (70 ml) in dry ether (250 ml) at 0° C. When the mixture had reached room temperature it was worked up in conventional fashion to give N-isobutyl 2-chloroacetamide. The latter (20 g) was heated for 3 hours at 120° C. with triethylphosphite (23 g). The mixture was subjected to distillation in vacuo to give N-isobutyl diethylphosphono acetamide (22.5 g, bp. 140-142.5° C. at 0.1 mm).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][C:24]2([CH2:32][O:33][CH3:34])[CH3:31])#[CH:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:34][O:33][CH2:32][C:24]1([CH3:31])[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]#[C:20][C:2]3[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[CH:22]=2)[O:27][CH2:26][CH2:25]1
Reactant: C#Cc1ccc2c(c1)C(C)(COC)CCO2
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1(C)CCOc2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reaction time: 0.25 h

Procedure:
In 11 ml of abs. DMF was successively dissolved 1.061 g (1.25 eq.) of methyl 4-iodo-benzoate, 114 mg (0.05 eq.) of bis (triphenylphosphine)palladium(II) chloride, 74.1 mg (0.12 eq.) of CuI, and 1.13 ml (2.5 eq.) of triethylamine. 701 mg (3.24 mmol) of the above prepared 6-ethynyl-4-methoxymethyl-4-methyl-chroman, dissolved in 2.7 ml of abs. DMF, was added within 1 h via dropping funnel. After 0.25 h, the reaction was quenched by pouring the reaction mixture onto crushed ice/ HCl. Extraction with diethylether, washing the organic phase twice with water, drying it over magnesium sulfate, filtration and evaporation of the solvent yielded after flash chromatography (SiO2, hexane/ ethylacetate 92/8) 630 mg of the title compound as yellowish oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:22])([F:23])[F:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (164.0 mg, 0.47 mmol) and triphenylphosphine (184.2 mg, 0.70 mmol) in methylene chloride (1.2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (141.6 mg, 0.80 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (140.6 mg, 1.40 mmol). The resulting reaction mixture was stirred at 25° C. for 22 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (47.9 mg, 24%) as a cream solid: mp 189-191° C.; EI-HRMS m/e calcd for C18H19F3N2O3S2 (M+) 432.0789, found 432.0791.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32](=[O:34])[NH:31][C:30]=2[CH:35]=1>>[CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:26]2[CH:27]=[CH:28][C:29]3[O:33][C:32](=[O:34])[NH:31][C:30]=3[CH:35]=2)[CH:8]=[N:7][CH:6]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3oc(=O)[nH]c3c2)c1)c1ccccc1
Yield: 40.5 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromo-2-benzoxazolinone (102 mg, 0.46 mmol) were reacted to give the title compound as light yellow solid (71 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9](Br)=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[CH:18]1(B(O)O)[CH2:20][CH2:19]1.[F-].[Cs+]>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[C:9]([CH:18]2[CH2:20][CH2:19]2)=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1
Reactant: COCc1c(Br)cccc1-n1nnn(C)c1=O
Reactant: OB(O)C1CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
A mixture of 1-(2-methoxymethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 8) 30.1 g, cyclopropylboronic acid 12.9 g, cesium fluoride 46.2 g, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct 8.2 g and dioxane 680 ml was stirred at 90° C. for four hours. After cooling the reaction mixture, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methoxymethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 26.0 g.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:14]([C:17]1[N:18]=[C:19]([C:22](O)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:4]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:10]([CH3:11])[C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)(=[O:5])[NH2:6]
Reactant: COc1ccc(C(N)=O)c(N)c1C
Reactant: CC(C)c1csc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred mixture of 2-amino-4-methoxy-3-methyl-benzamide (2.0 g, 11 mmol), 4-isopropyl-thiazole-2-carboxylic acid (2.4 g, 14 mmol) and Hobt-hydrate (2.2 g, 14 mmol) in dry DMF (80 ml) was added EDAC (2.88 g, 15 mmol) and TEA (2.1 ml, 15 mmol) and the mixture was stirred overnight. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution (two times) and brine, dried with sodium sulfate and evaporated under reduced pressure which gave the title compound (3.1 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][CH:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CC(O)c1ccccc1
Product: CC(Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1)c1ccccc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and DL-1-phenylethanol (63 mg; 0.515 mmol), example 68 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.[Cl:19]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Cl:19][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Yield: 97.5 %

Procedure:
4.07 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was suspended in 60 ml of ethyl acetate; 2.13 g of N-chlorosuccinimide was added, followed by thermal refluxing for 4 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and concentrated under reduced pressure to yield 4.48 g of the title compound.
Reaction SMILES: C1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])CC1.Br[C:18]1C=CC(C)=C(C=1)C(O)=O.BrC1C=C(C=CC=1C1CC1)C(O)=O>>[CH3:18][C:11]1[CH:12]=[CH:4][C:5]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Agent: O=C(O)c1ccc(C2CC2)c(Br)c1
Product: CCC(=O)c1ccc(C)c(C(=O)O)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 10.6, except 5-bromo-2-methylbenzoic acid was used in place of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (5.0 g, 21.8 mmol) in dichloromethane (80 mL) were added N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.1 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (9.95 g, 26.1 mmol), N-ethyl-N-isopropylpropan-2-amine (8.46 g, 65.42 mmol) and stirred at 30° C. for 16 hours. The reaction was quenched by adding water (100 ml) and extracted with ethyl acetate (200 ml*3). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated under vacuum to give tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (5.7 g, yield 97.6%). LRMS (M+H+) m/z: calcd 272.17. found 273.17.
Reaction SMILES: [CH2:1]([C:8]1[C:12]([C:13]2[CH:14]=[C:15](SC)[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[N:18]=2)=[CH:11][N:10]([CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[C:12]([C:13]2[CH:14]=[C:15]([Cl:29])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[N:18]=2)=[CH:11][N:10]([CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1cc(-c2cn(C)nc2Cc2ccccc2)nn2c(C)nnc12
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nnc2c(Cl)cc(-c3cn(C)nc3Cc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-benzyl-1-methyl-4-[3-methyl-8-(methylsulfanyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1H-pyrazole (32 mg; 0.09 mmol) was dissolved in 1 ml chloroform and was treated with sulfurylchlorid (44 μl; 0.54 mmol). The reaction mixture is stirred for 18 h at 25° C.