Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:11][CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][CH:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH3:11]
Reactant: NCCc1ccccc1Br
Reactant: CCCC(=O)CCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCC(CCC)NCCc1ccccc1Br
Reaction time: 20 h

Procedure:
10 g of 2-bromophenethylamine and 5.71 g of 4-heptanone are dissolved in 250 cm3 of 1,2-dichloroethane at a temperature close to 20° C. 14.84 g of sodium triacetoxyborohydride and 2.9 cm3 of glacial acetic acid are added to the reaction medium. Stirring is continued for 20 h. 300 cm3 of 1M sodium hydroxide are added to the reaction medium. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined and washed with 4 lots of 100 cm3 of water then 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated using a rotary evaporator under reduced pressure (5 kPa). The yellow liquid obtained is purified by flash chromatography over silica (column: 400 g; particle size: 20-40 μm, spherical; flow rate: 30 cm3/min; eluent: 100% heptane to 70% ethyl acetate/30% heptane gradient). After concentrating the fractions under reduced pressure, 17.33 g of N-[2-(2-bromophenyl)ethyl]heptan-4-amine are obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:41]1([C:47](Cl)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:41]1([C:47]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CN(C(=O)C3CCCCC3)c3ccc(OCCN4CCCC4)cc3)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of toluene-4-sulfonic acid 4-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methyl}-phenyl ester (0.120 g, 0.26 mmol) and triethylamine (0.18 mL, 1.36 mmol) in 2 mL methylene chloride was added cyclohexanecarbonyl chloride (0.138 mL, 1.03 mmol). The reaction mixture was stirred for 3 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Flash filter chromatography afforded the title compound of Step A. MS 577.1 (M+1)+
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])=[O:10]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: NCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1F)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
In a flask were placed 4 grams (g) (0.01326 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride, dissolved in methylene chloride. There was then added 1.7 g (0.01326 mole) of 2-fluorobenzylamine, very slowly, with vigorous stirring. After about 15 minutes, 1.34 g (0.01326 mole) of triethylamine was added dropwise. The reaction mixture was stirred for a short time, then heated intensely for about 5 minutes and allowed to return to room temperature. After approximately 1/2 hour, 5% aqueous sodium carbonate solution was added with stirring continued. The aqueous and organic phases were separated; the aqueous phase was decanted off and the organic phase washed twice with 5% sodium carbonate solution and twice with water. The organic phase was then dried over sodium sulfate; solvent was stripped off, and an oil-like mixture was recovered, which crystallized in a short time. The solid was then washed with pentane to remove any remaining amine. There was obtained 3.5 g (67% of theoretical yield) which was identified as the desired compounds by infrared, nuclear magnetic resonance, and mass spectroscopic analysis.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:65]1[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:71][CH:68]5[CH2:69][CH2:70][NH:65][CH2:66][CH2:67]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc 4-amino piperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.27 (m, 1 H) 1.30-1.51 (m, 4 H) 1.52-1.69 (m, 3 H) 1.69-1.90 (m, 6 H) 2.41-2.59 (m, 2 H) 2.97 (d, J=12.38 Hz, 2 H) 3.31 (s, 3 H) 3.73-3.89 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.52 Hz, 2 H) 4.38-4.52 (m, 1 H) 7.48 (dd, J=8.34, 1.77 Hz, 1 H) 7.51 (d, J=1.77 Hz, 1 H) 7.90 (s, 1 H) 8.14 (d, J=7.83 Hz, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C27H35F2N7O3 544; found 544.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[C:32]1[NH:36][C:35](=[O:37])[O:34][N:33]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23]OS(C)(=O)=O.C(N(C(C)C)CC)(C)C.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>CN(C)C=O>[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][N:54]([CH2:23][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH2:7][O:6][C:5]2[CH:29]=[CH:30][C:31]([C:32]3[NH:36][C:35](=[O:37])[O:34][N:33]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:53][CH2:52]1)(=[O:50])=[O:49]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCN(S(C)(=O)=O)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
To a solution of 50 mg of methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester in 2 mL of dimethylformamide was added 80 μL of diisopropylethyl amine and 19.2 mg of 1-methylsulfonylpiperazine. The resulting mixture was heated in a sealed tube to 90° C. under microwave irradiation for 5 minutes and then concentrated under reduced pressure. The residue was purified by chromatography on a SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH followed by recrystallization in dichloromethane 9/methanol 1 to give 6.7 mg of 3-{4-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([OH:17])=O)=[CH:4][C:5]2[O:10][CH:9](COC)[CH2:8][O:7][C:6]=2[CH:14]=1.[N:18]1[CH:23]=CC=NN=1.N1CCCCC1.[CH3:30][OH:31]>>[CH3:30][O:31][CH:9]1[O:10][C:5]2[CH:4]=[C:3]3[C:2](=[CH:14][C:6]=2[O:7][CH2:8]1)[N:1]=[CH:23][N:18]=[C:15]3[OH:17]
Reactant: c1cnnnc1
Reactant: COCC1COc2cc(N)c(C(=O)O)cc2O1
Reactant: CO
Solvent: C1CCNCC1
Product: COC1COc2cc3ncnc(O)c3cc2O1
Temperature: 25 °C

Procedure:
The titled compound of Example 5 (0.367 g, 1.53 mmol), triazine (0.19 g, 2.3 mmol) and piperidine (0.015 ml, 0.153 mmol) was dissolved in 10 ml of methanol, followed by refluxing for 4 hours to obtain a white solid, which was then cooled down to a room temperature. The solid compound was filtered, washed with methanol and dried under vacuum to prepare the titled compound (0.240 g, 63%, m.p. 246-251° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ncc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cn1
Yield: 40 %

Procedure:
A solution of 2,2,2-trichloroethyl [2-(acetylamino)pyrimidin-5-yl]carbamate (60.0 mg, 0.187 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (44.9 mg, 0.183 mmol), diisopropylethylamine (0.0319 ml, 0.183 mmol) and dimethylsulfoxide (2 ml) was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (31.0 mg, 40.0%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Cl:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Cl)cc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-Chloroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation G, 3.3 g, 9.8214 mmol) and triethylamine (1.34 g, 12.74 mmol) in CH2Cl2 (120 mL) was added over 40 min to a solution of triphosgene (3.5 g, 11.7852 mmol) in 80 mL of CH2Cl2 at 0° C. with an ice-bath. The reaction mixture was stirred for 20 min at this temperature then quenched with saturated aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to obtain the title compound. Yield: 1.2 g (34%); 1H NMR (DMSO-d6, 300 MHz): δ 12.190 (s, 1H), 8.921 (s, 1H), 8.069-8.100 (d, 1H, J=8.7 Hz), 7.807-7.835 (d, 2H, J=8.4 Hz), 7.641-7.694 (m, 3H), 6.808-6.815 (d, 1H, J=2.1 Hz), 1.766 (s, 6H); MS: m/z 363 (M+).
Reaction SMILES: [N+](C1C=CC(COC(=O)/[C:11](/[N:22]2[CH:25]([S:26]S(C3C=CC(C)=CC=3)(=O)=O)[CH:24](NC(=O)COC3C=CC=CC=3)[C:23]2=[O:48])=[C:12](\OCC2C=CC=CC=2)/[CH3:13])=CC=1)([O-])=O.[N+](C1C=CC(COC(=O)/C=C\C)=CC=1)([O-])=O.N12CCCCC1C=NCCC2.C(Cl)Cl>O1CCCC1>[S:26]1[C@@H:25]2[CH2:24][C:23](=[O:48])[N:22]2[CH:11]=[CH:12][CH2:13]1
Reactant: C/C(OCc1ccccc1)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C/C=C\C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@H]2SCC=CN12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 731 mg (1 mmol) of a 1:1 mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid p-nitrobenzyl ester in a mixture of 0.185 ml (1.2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene in 20 ml of dry tetrahydrofurane is stirred for precisely 35 minutes at room temperature. 50 ml of methylene chloride are added to the mixture and the whole is washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 25 mg of acid-washed silica gel, using toluene/ethyl acetate (3:1). A mixture consisting of the ceph-2-em compound and the ceph-3-em compound in the ratio of about 3:1 is obtained; this mixture can be separated by repeated chromatography into the pure isomers, giving 7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester of melting point 160° C.-162° C. (diethyl ether/pentane); IR spectrum (methylene chloride): characteristic bands at 5.6, 5.7, 5.9 and 7.4μ, and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colourless foam, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.8 sh, 5.9, 7.9 and 8.4μ.
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH2:64])[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.[CH3:65][C:66]1[C:78]([CH3:79])=[CH:77][C:69]2[N:70]([CH2:73][C:74](O)=[O:75])[CH:71]=[N:72][C:68]=2[CH:67]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH:64][C:74](=[O:75])[CH2:73][N:70]3[C:69]4[CH:77]=[C:78]([CH3:79])[C:66]([CH3:65])=[CH:67][C:68]=4[N:72]=[CH:71]3)[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Reactant: Cc1cc2ncn(CC(=O)O)c2cc1C
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: Cc1cc2ncn(CC(=O)NC(Cc3cc(F)cc(F)c3)c3cnc(-c4ccc(Cl)cc4)o3)c2cc1C

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 9.06-8.94 (m, 2H), 8.10 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.50 (s, 1H), 7.17 (s, 1H), 6.97 (m, 3H), 5.17-4.95 (m, 3H), 3.24-3.07 (m, 1H), 3.04 (dd, J=13.7, 9.7 Hz, 1H), 2.29 (s, 1H), 2.22 (s, 1H). MS (m/z) 520.9 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2](/[C:29](/[CH3:37])=[CH:30]/[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3][C@@H:4]1[O:28][C@:5]1([CH3:27])[CH2:6][CH2:7][C:8](=[O:26])[C@H:9]([CH3:25])[C@H:10]([OH:24])[C@@H:11]([CH3:23])[C:12](=[O:22])[C:13]([CH3:21])([CH3:20])[C@@H:14]([OH:19])[CH2:15][C:16]([OH:18])=[O:17].N([C@H](/C(/C)=C/C1N=C(C)SC=1)C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(O)=O)=[N+]=[N-].CP(C)C>C1COCC1.O.C1(C)C=CC=CC=1>[NH2:1][C@H:2](/[C:29](/[CH3:37])=[CH:30]/[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3][C@@H:4]1[O:28][CH:15]([C:16]([OH:18])=[O:17])[C@@H:14]([OH:19])[C:13]([CH3:21])([CH3:20])[C:12](=[O:22])[C@H:11]([CH3:23])[C@@H:10]([OH:24])[C@@H:9]([CH3:25])[C:8](=[O:26])[CH2:7][CH2:6][C@H:5]1[CH3:27]
Reactant: C/C(=C\c1csc(C)n1)[C@@H](N)C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O
Agent: C/C(=C\c1csc(C)n1)[C@H](C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O)N=[N+]=[N-]
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@@H](N)C[C@@H]1OC(C(=O)O)[C@@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)C(=O)CC[C@H]1C

Procedure:
(35,6R,7S,8R,12R, 13S,15S,16E)-15-amino-3,7-dihydroxy-5,9-dioxo-12,13-epoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-16-heptadecenoic acid. A solution of (3S,6R,7S,8R,12R,13S,15S,16E)-15-azido-3,7-dihydroxy-5,9-dioxo-12,13-epoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-16-heptadecenoic acid (565 mg) in 15 mL of THF/water (10:1 v/v) is treated with a 1.0 M solution of trimethylphosphine in toluene (3 mL) under argon for 2 hours at ambient temperature. The mixture is concentrated, and the product is purified by flash chromatography on SiO2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:33])[CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[C:5]([C:36]#[N:37])=[C:4]([S:38][CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[S:43][CH:44]=2)[N:3]=1.[OH-].[Na+:53]>C(#N)C.O>[Na+:53].[Na+:53].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:33])[CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([O-:24])=[O:23])=[CH:34][CH:35]=2)[C:5]([C:36]#[N:37])=[C:4]([S:38][CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[S:43][CH:44]=2)[N:3]=1.[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:33])[CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([O-:24])=[O:23])=[CH:34][CH:35]=2)[C:5]([C:36]#[N:37])=[C:4]([S:38][CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[S:43][CH:44]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCOC(=O)CC[C@H](NC(=O)CCC(=O)O)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCOC(=O)CC[C@H](NC(=O)CCC(=O)O)C(=O)[O-])cc1

Procedure:
0.5 g (0.667 mmol) of the compound from example 9 is dissolved in 12.5 ml of acetonitrile and 62.5 ml of water, and 13 ml of 0.1N sodium hydroxide solution are added. After brief stirring, the mixture is lyophilized. After drying under high vacuum, 0.53 g (quant.) of the title compound remain.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([C:19]2[C:26]([Cl:27])=[CH:25][C:22]([CH2:23]Br)=[CH:21][C:20]=2[Cl:28])=[O:18])=[CH:15][CH:14]=1.O>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:23][C:22]2[CH:21]=[C:20]([Cl:28])[C:19]([C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:30][CH:29]=3)=[C:26]([Cl:27])[CH:25]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1nn[nH]c1N
Reactant: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Reaction time: 1 h
Yield: 17 %

Procedure:
A stirred ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (630 mg, 4.96 mmol) in dry dimethylformamide (20 ml) was treated in one portion with sodium hydride (230 mg of a 50% suspension in mineral oil, 115 mg NaH, 4.79 mmol). After 15 min. solid 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide was added in one portion. The mixture was stirred 1 hour, poured into water (20 ml), acidified to pH 6 with glacial acetic acid, and filtered. The solid was washed three times with water and dissolved in dichloromethane. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and evaporated under vacuum. The residue was chromatographed on a column of silica gel (200 g) eluted with 97:3 (v/v) dichloromethane-methanol to provide 351 mg (17%) 5-amino-1-(4-[4-chlorobenzoyl]-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OC(C)C
Yield: 90.8 %

Procedure:
A mixture of 3.0 g (0.007 mol) of product of Example 12, 0.72 g (0.007 mol) of triethylamine and 0.36 g of Pd/C (10%) in 30 ml of ethanol was hydrogenated with 501 kPa hydrogen pressure at 50° C. for 1 hour and filtered. The filtrate was concentrated, the residue dissolved in ether, washed with 3.7% aqueous HCl, dried (MgSO4) and concentrated in vacuo to 2.74 g of a brown oil. This oil was kugelrohr distilled at 67 Pa, pot temperature 90° C., to give 2.45 g (90.8%) of product as a yellow solid; mp 29-31° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28]C1C=CC(CC=O)=CC=1>C(Cl)Cl.CO>[CH3:27][O:28][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Reactant: COc1ccc(CC=O)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using (4-methoxy-phenyl)-acetaldehyde. Title compound: ES-MS: 396.0 [M+H]+; single peak at tR=6.36 min (System 1); R4=0.28 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23]([F:28])[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34]C1C=C(C2C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=2)C=CC=1F.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:34])=[C:23]([F:28])[CH:22]=3)[C:19]=2[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(-c2ccc(F)c(F)c2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85.5 %

Procedure:
Following the procedure of Example 1 (10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 85.5%).