Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[NH:6][C:7](=[O:21])[CH2:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl.Cl>[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:25][CH2:24]1)[NH:6][C:7](=[O:21])[CH2:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: COC(=O)C(CC1CCNCC1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CC1CCN(C(=O)c2ccccc2)CC1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
N-(Toluene4-sulfonyl)sarcosyl-β-(piperidin-4-yl)-D,L-alanine methyl ester hydrochloride (see Preparative Example C (109)) (65 mg, 0.15 mmol) was dissolved in CHCl3 (3 mL) and cooled in an ice bath. Triethylamine (61 μL) and benzoyl chloride (21 mg, 0.15 mmol) were added and the mixture was stirred for 1 hr. The mixture was diluted with 1N HCl (20 mL) and extracted with EtOAc (2×25 mL). The extracts were dried (Na2SO4), filtered and evaporated in vacuo to give a residue which was purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to yield N-(toluene4-sulfonyl)sarcosyl-β-(N-benzoylpiperidin-4-yl)-D,L-alanine methyl ester (67 mg, 89%). The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water (71 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[NH:26][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), 1-isocyanato-4-(trifluoromethyl)benzene (58 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (130 mg, 71%) as a colorless powder.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[CH3:33][S-:34].[Na+]>CN(C)C(=O)C>[CH2:1]([C@@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([S:34][CH3:33])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(SC)cc3)cc12

Procedure:
(3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.240 g, 0.538 mmol), sodium methanethiolate (0.188 g, 2.69 mmol) and N,N-dimethylacetamide (12 mL) were heated via microwave at about 90° C. for about 1 h. The reaction mixture was purified without manipulation in two portions by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 μm particle size) with a gradient of 50-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then basified with sat. NaHCO3 then extracted with EtOAc. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to yield (3R,4aR,12bR)-12b-ethyl-9-(4-(methylthio)phenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-(Methylthio)phenyl, R2=Ethyl, R3=Trifluoromethyl) (0.230 g, 90%); LC/MS, method 3, Rt=2.90 min, MS m/z 475 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=1.3 Hz, 1H), 7.83 (s, 1H), 7.75-7.68 (m, 2H), 7.57 (s, 1H), 7.48-7.42 (m, 2H), 5.84 (s, 1H), 3.23-3.19 (m, 1H), 2.95-2.90 (m, 1H), 2.54 (s, 3H), 2.27-2.18 (m, 1H), 2.15-1.95 (m, 4H), 1.91-1.76 (m, 2H), 1.70-1.57 (m, 5H), 1.38-1.29 (m, 1H), 0.43 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[C:8]([NH2:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:9][C:8]([NH:16][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:10])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
2-Chloro-1-ethane sulfonyl chloride (51.3 mL, 0.49 mol) in dichloromethane (400 mL) was added dropwise over 2 hours to a solution of tert-octylamine (236.3 mL, 1.47 mol) and triethylamine (68.3 mL, 0.49 mol) in dichloromethane (400 mL) at −18° C. The mixture temperature was maintained between −18° C. and −9° C. during the addition. The mixture was allowed to warm to ambient temperature over 1 hour then washed with 1N HCl (400 mL) and distilled water (2×200 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The oil was dried under vacuum at 50° C. to give ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide, 96.0 g (90% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([C@H:5]1[CH2:14][CH2:13][C@H:12]2[C@@:15]3([CH:36]=[CH2:37])[C@H:24]([C@@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:26][C@:6]12[CH2:7][O:8][SiH:9]([CH3:11])[CH3:10])[C:23]1[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=1[CH2:17][CH2:16]3)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H]2[C@@]3(C=C)[C@H]([C@@H](CCCCCO)C[C@]12CO[SiH](C)C)C1C=CC(OC)=CC=1CC3)(C)(C)C.[Br:74]CCCCC[C@H]1C[C@@]2(CO[SiH](C)C)[C@@H](CC[C@@H]2C(C)(C)C)[C@@]2(C=C)[C@H]1C1C=CC(OC)=CC=1CC2>>[Br:74][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C@H:25]1[CH2:26][C@@:6]2([CH2:7][O:8][SiH:9]([CH3:11])[CH3:10])[C@@H:12]([CH2:13][CH2:14][C@@H:5]2[C:1]([CH3:4])([CH3:2])[CH3:3])[C@@:15]2([CH:36]=[CH2:37])[C@H:24]1[C:23]1[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=1[CH2:17][CH2:16]2
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCBr)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCO)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Agent: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCO)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCBr)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21

Procedure:
The reaction of 930 mg of alcohol 12 is carried out analogously to the test instructions for the conversion of alcohol 8 into bromide 10. In this way, 975 mg of bromide 13 is obtained as a colorless, viscous oil (GC-MS: m/z theor.: 588, pract.: 588).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH3:27][C@@H:28]1[CH2:33][NH:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1>>[OH:34][C@H:30]1[CH2:29][C@H:28]([CH3:27])[CH2:33][N:32]([CH2:6][CH2:5][C@H:4]([N:8]2[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[CH2:10][CH2:9]2)[CH2:3][O:2][CH3:1])[CH2:31]1
Reactant: C[C@@H]1CNC[C@@H](O)C1
Reactant: COC[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Product: COC[C@H](CCN1C[C@@H](C)C[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 63 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-methoxy-3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyraldehyde (example 23D) and (3S,5S)-5-methyl-piperidin-3-ol hydrochloride (intermediate 4) gave the title compound in 63% yield as light yellow gum. MS: 458.3 (MH+).
Reaction SMILES: [CH3:1][N-:2]C.[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].C(N)=O>O>[F:14][C:12]1[CH:13]=[C:5]2[C:6]([C:7](=[O:8])[NH:2][CH:1]=[N:4]2)=[CH:10][CH:11]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: C[N-]C
Solvent: NC=O
Solvent: O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 180 °C
Yield: 78 %

Procedure:
A catalytic amount (1 ml) of N,N-dimethylamide was added to 2-amino-4-fluorobenzoic acid (50 g, 322 mmol) and formamide (77 ml, 1934 mmol), and the resulting solution was stirred. The solution was heated to 180° C. and stirred for 14 hours. The temperature of the solution was cooled to room temperature, and 300 ml of distilled water was added thereto. The resulting solid was stirred about 30 min, and filtered to obtain the title compound 41.3 g (yield: 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][O:12][CH3:13].C([Mg]Br)(C)C.C([O:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:22](=[O:21])[C:23]([F:26])([F:25])[F:24])=[C:3]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:4]=1
Reactant: COCCOc1cc(Cl)ccc1Br
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COCCOc1cc(Cl)ccc1C(=O)C(F)(F)F
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-4-chloro-2-(2-methoxy-ethoxy)-benzene (CAS#1245563-20-5) (5.00 g, 18.8 mmol) was dissolved in THF (30 mL) and cooled to 0° C. i-Propylmagnesium bromide (11.3 mL, 2.0 M in THF, 22.6 mmol) was added dropwise, and the reaction was stirred at 10° C. for 30 min, then warmed to RT for 16 h. The reaction was then cooled to −15° C. and trifluoroacetic acid ethyl ester (3.37 mL, 28.2 mmol) was added. The reaction was stirred at 10° C. for 1 h. The reaction was quenched with HCl (2 N, 38 mL) at 0° C. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuric chloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C. for 1 hour. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in pet-ether as an eluent to give 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([Cl:21])[CH:15]=1)(=[O:13])[NH2:12]>>[C:11]([C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)=[C:16]([Cl:21])[CH:15]=1)(=[O:13])[NH2:12]
Reactant: OC1CNCc2ccoc21
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: NC(=O)c1ccc(OC2CNCc3ccoc32)c(Cl)c1

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COCCCCN
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.7 %

Procedure:
2-Chloro-3-nitropyridine (3.54 g) and 4-methoxybutan-1-amine hydrochloride (3.12 g) were suspended in 2-propanol (100 ml), diisopropylethylamine (11.6 μl) was added and the mixture was heated under reflux with stirring for 4 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (4.26 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:29]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[C:36]([F:47])([F:46])[F:35])[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]([OH:15])=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:13]([C:5]3[O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH2:3][O:2][CH3:1])=[O:15])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COCc1c(C(=O)O)oc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Product: COCc1c(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)oc2ccccc12

Procedure:
With a procedure similar to the example above, 4-{4-[(3-methoxymethyl-benzofuran-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-methoxymethyl-benzofuran-2-carboxylic acid and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C26H31N3O5 (m/e) 465, obsd 466 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:17][CH2:18][CH2:19][CH2:20][OH:21]>C(#N)C>[Br:1][C:2]1[C:3]([S:17][CH2:18][CH2:19][CH2:20][OH:21])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: OCCCS
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCSc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.47 g (10.8 mmol) of 5-Bromo-2,4-dichloropyrimidine in 30 ml of acetonitrile at −20° C. is mixed with 1.5 ml (10.8 mmol) of triethylamine and 1.00 g (10.8 mmol) of 3-Mercapto-propan-1-ol. The batch is slowly warmed to room temperature and stirred for 16 hours. The batch is filtrated to remove the solid precipitate. The filtrate is concentrated by evaporation. 2-Methoxy-2-methyl-propane is added to the remaining residue and the batch is stirred for 15 minutes. The batch is filtrated and the solid precipitate is dried. 3.03 g (10.6 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]4[CH2:55][CH2:54][CH2:53][C@@H:52]4[C:56]([O:58][CH3:59])=[O:57])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:60][C:61]([F:72])([F:71])[C:62]1[CH:70]=[CH:69][C:65]([C:66](Cl)=[O:67])=[CH:64][CH:63]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:66](=[O:67])[C:65]4[CH:69]=[CH:70][C:62]([C:61]([F:60])([F:71])[F:72])=[CH:63][CH:64]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C@@H:51]1[CH2:55][CH2:54][CH2:53][C@@H:52]1[C:56]([O:58][CH3:59])=[O:57]
Reactant: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Yield: 86 %

Procedure:
The compound of example 597 was prepared analogous to compound of example 97 by reaction of compound of example 592 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC[N:17](CC)CC.ClC(OCC)=O.N.O>C1COCC1>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of 4-bromo-5-chloro-2-nitrobenzoic acid (1.3 g, 4.63 mmol), Et3N (1.4 g, 13.9 mmol) in THF (20 mL) at 0° C., ethyl chloroformate (1.5 g, 13.9 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. Then NH3.H2O (4 mL) was added and stirred for 0.5 h. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (900 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCOC(C)=O.C1COCC1>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1

Procedure:
To a solution of tert-butyl [2-[(4-nitrobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (598 mg, 1.36 mmol) in 1:1 EtOAc/THF was added 10 mol % Pd/C (136 mg, 1.36 mmol). The reaction mixture was evacuated and refilled with hydrogen (2×). The black reaction mixture was stirred in a parr shaker under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite (with EtOAc then CH2Cl2 washes) and concentrated to provide tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate which was confirmed by MS: cal'd 410.1 (MH+), exp 410.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:51][CH2:52][CH2:53][OH:54]>O1CCCC1.C(#N)C>[OH:54][CH2:53][CH2:52][NH:51][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(CC(=O)NCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol (150 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) in tetrahydrofuran (3 mL) and acetonitrile (3 mL) was added 2-aminoethanol (100 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (124 mg, yield 56%) as white crystals from a fraction eluted with ethyl acetate:hexane=50:50. melting point 214° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:16][O:17][CH3:18])[C:13](Cl)=[O:14])[N:8]=1.Cl.[NH2:20][CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:25]([CH2:28][Cl:29])[CH2:26][S:27][C@H:22]12.C(=O)([O-])O.[Na+]>O>[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:16][O:17][CH3:18])[C:13]([NH:20][CH:21]2[C:46](=[O:47])[N:23]3[C:24]([C:30]([O:32][CH:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:31])=[C:25]([CH2:28][Cl:29])[CH2:26][S:27][C@H:22]23)=[O:14])[N:8]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CON=C(C(=O)Cl)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixed solution of dichlorometahne (1000 ml) and tetrahydrofuran (200 ml) were added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride (syn isomer) (64 g) and benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (100 g) at -15° C. The mixture was stirred at -15° C. for one hour. The reaction mixture was poured into ice-cooled water, and neutralized with sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (130.5 g)