Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23](O)=[O:24])=[CH:18][CH:17]=[CH:16]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:33][C:23]([C:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:24]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Product: Nc1ccccc1NC(=O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Yield: 75.5 %

Procedure:
The title compound (33.2 mg, 83% yield) was prepared as a brown solid from 6-(7-chloroquinolin-4-yloxy)-1-naphthoic acid (35.0 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.97 (s, 2H, benzene-NH2), 6.65 (t, J=7.4 Hz, Ar—H), 6.77 (d, J=5.5 Hz, 1H, Ar—H), 6.82 (d, J=7.2 Hz, 1H, Ar—H), 7.00 (t, J=7.0 Hz, 1H, Ar—H), 7.38 (d, J=7.2 Hz, 1H, Ar—H), 7.60 (dd, J=2.6 and 9.2 Hz, 1H, Ar—H), 7.67-7.74 (m, 2H, Ar—H), 7.89 (d, J=7.4 Hz, 1H, Ar—H), 7.94 (d, J=2.4 Hz, 1H, Ar—H), 8.09 (d, J=8.2 Hz, 1H, Ar—H), 8.13 (d, J=2.1 Hz, 1H, Ar—H), 8.41 (d, J=9.0 Hz, 1H, Ar—H), 8.46 (d, J=9.6 Hz, 1H, Ar—H), 8.76 (d, J=5.2 Hz, 1H, Ar—H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 440 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:20][C@@H:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[CH:6]=1.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@@H:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(C(=O)OCc2ccccc2)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[4-bromo-2-((S)-indan-1-ylaminomethyl)-phenoxy]-phenyl}-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[Cl-].[CH:32]1([Zn+])[CH2:34][CH2:33]1>C(Cl)Cl.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>[CH:32]1([C:2]2[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]3[NH:6][C:7]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=5)[CH:15]=4)=[N:8][C:9]=3[N:10]=2)[CH2:34][CH2:33]1
Reactant: [Zn+]C1CC1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CCCn1c(C2CC2)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 100 °C
Yield: 23 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (prepared using same procedure as given in Example 2) (0.1 g, 0.23 mmol), Pd(PPh3)4 (0.319 g, 0.28 mmol) and cyclopropyl zinc chloride solution (10 ml, 0.5 M solution) were heated at 100° C. for 30 minutes. Reaction mixture was cooled, diluted with DCM (10 ml). Organic layer washed with brine (2×10 ml), dried over Na2SO4, evaporated and purified by preparative TLC to obtain pure 2-Cyclopropyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as white solid (23 mg, 23%)
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:36]([CH3:38])[CH3:37])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N4CCCC4)CC3)ccc21
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a white solid (66%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:31])[N:11]3[C:12]=2[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:31])[N:11]3[C:12]=2[C:13]([OH:15])=[O:14])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(Cc3ccc(F)cc3)CS[C@H]12

Procedure:
t-Butyl 3-p-fluorobenzyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (X) (36 mg) was treated with trifluoroacetic acid (5 ml) at room temperature for 40 minutes. The excess trifluoroacetic acid was distilled off azeotropically with dry benzene to give the free acid (XII) as a foam νmax (CHCl3) 1770, 1705, 1680 cm-1
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11][CH2:12][OH:13].CC(C)([O-])C.[Na+]>C1COCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([O:13][CH2:12][CH2:11][O:10][CH3:9])=[CH:7][N:6]=1
Reactant: COCCO
Reactant: Brc1cnc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 2,5-dibromopyrazine (22-1, 20.0 g, 84.1 mmol), 2-methoxyethanol (6.40 g, 84.1 mmol), and sodium tert-butoxide (11.3 g, 118 mmol) in 168 mL of THF was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with ethyl acetate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:hexanes=1:5 as eluant) to give 2-bromo-5-(2-methoxyethoxy)pyrazine (22-2, 17.2 g) as yellow oil in 88% yield: 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=1.0 Hz, 1 H), 8.07 (d, J=1.0 Hz, 1 H), 4.46 (t, J=5.0 Hz, 2 H), 3.74 (m, 2 H), 3.43 (s, 3 H).
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1)=O.Cl.[O:15]([NH2:17])[CH3:16]>CCO>[CH3:16][O:15][N:17]=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1)[CH2:3][Br:2]
Reactant: CCc1ccc(C(=O)CBr)nc1
Reactant: CON
Agent: Br
Agent: Cl
Solvent: CCO
Product: CCc1ccc(C(CBr)=NOC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-bromo-1-(5-ethylpyridin-2-yl)ethanone hydrobromide (1.024 g, 3.314 mmol; Supplier=Kalexsyn; Lot=1003-TTP-185) in EtOH (10 ml) was added methoxylamine hydrochloride (553.5 mg, 6.628 mmol). Left to stir at RT overnight. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM and an equal volume of saturated NaHCO3 was added and the biphasic mixture stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to afford a pale yellow oil which crystallized upon standing. 1H-NMR (CDCl3): δ 8.50 (s, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.59 (m, 1H), 4.79 (s, 1H), 4.64 (s, 1H), 4.13 (d, J=4.4 Hz, 3H), 2.70 (q, J=7.7 Hz, 2H), 1.28 (t, J=7.7 Hz, 3H). HPLC: 3.429 min., 30 area % and 3.621 min., 31 area % @ 210 nm; 3.414 min., 36 area % and 3.618 min., 36 area % @ 210 nm. MS (ESI—) for C10H13BrN2O m/z 258.2 (M+H)+.
Reaction SMILES: CON=[C:4]([CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][C:17]1[C:18]([NH:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1.O1CCCC1>C(O)(=O)C>[Cl:16][C:17]1[C:18]([N:23]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]([CH:12]([CH3:13])[CH3:14])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NNc1ncccc1Cl
Reactant: CCOC(=O)C(CC(=O)C(C)C)=NOC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(C)C)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.1 %

Procedure:
A mixture of 3.0 g of ethyl 2-methoxyimino-5-methyl-4-oxohexanoate, 2.4 g of 3-chloro-2-hydrazinopyridine, 50 ml of tetrahydrofuran and 100 ml of acetic acid was stirred at room temperature for 20 hours, and then heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. Water was poured into the residue, and the mixture was extracted with methyl t-butyl ether two times. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water and an aqueous saturated chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.07 g of ethyl 1-(3-chloro-2-pyridinyl)-3-isopropyl-1H-pyrazole-5-carboxylate of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.C(O)(C)C.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Yield: 95 %

Procedure:
206 parts of 3,5-dichloroanthranilic acid are introduced into 200 parts of isopropanol and 800 parts of 18 percent strength by weight hydrochloric acid. A solution of 100 parts of NaNO2 in 140 parts of water are run in at 80° C., resulting in the uniform evolution of nitrogen. The mixture is cooled, 500 parts of water are added and the product is filtered off. 182 parts (95% of theory) of 3,5-dichlorobenzoic acid of melting point 178°-180° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:38][C:39]([F:47])([F:46])[C:40]([C:42]([F:45])([F:44])[F:43])=[O:41]>C1(C)C=CC=CC=1.O>[F:38][C:39]([F:47])([F:46])[C:40]([C:18]1[CH:19]=[C:14]([CH2:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH:5]=3)[C:9]2=[O:12])[CH:15]=[N:16][CH:17]=1)([OH:41])[C:42]([F:45])([F:44])[F:43]
Reactant: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cccnc1)C2=O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 120 °C

Procedure:
To a stirred solution of 255 (0.05 g, 0.142 mmol) in toluene was added PTSA (0.054 g, 0.284 mmol) and kept stirring at 120° C. Hexafluoroacetone 244 (0.078 g, 0.356 mmol) was added to the reaction and kept at temperature and stirred for 16 h. Reaction was then cooled to RT, diluted with water, and extracted with ethyl acetate twice, The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel and eluting the compound at 30% ethyl acetate in hexane as thick sticky solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 256.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Reactant: OCCCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CCCO)CC4)n3)ccc21

Procedure:
88 mg (0.25 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazine are irradiated in the microwave at 140° C. for 2 h with 42 μl (0.50 mmol) of 3-chloropropan-1-ol in 2 ml of ethanol and 70 μl (0.50 mmol) of triethylamine. The reaction mixture is evaporated and purified by means of preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC(C)(O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(C(=O)c2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid (0.12 g) was reacted with 2-(piperidin-4-yl)propan-2-ol (1.2 eq), HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq) and DIPEA (3 eq) in DMF (3.2 mL) for 1 hour. The reaction was then extracted with EtOAc and bicarbonate solution and the organic layer was dried with Magnesium sulfate, filtered and concentrated to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone in quantitative yield.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:19](#[N:21])[CH3:20].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C:4]([CH3:16])([CH3:17])[C:3](=[O:18])[CH2:20][C:19]#[N:21])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)COCc1ccc(OC)cc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COCC(C)(C)C(=O)CC#N)cc1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of 3.66 g (14.5 mmol) of 2,2-dimethyl-3-(4-methoxybenzyl-oxy)-propionic acid methyl ester and 1.07 mL (20.5 mmol) of acetonitrile in anhydrous toluene (10 mL) is added dropwise to a refluxing suspension of 0.83 g (20.5 mmol) of sodium hydride (60% dispersion in mineral oil) in toluene (20 mL). After the addition is complete, the mixture is stirred at reflux for 3 h, then allowed to cool to room temperature. The reaction mixture is then diluted with 1M aqueous HCl solution to neutral pH, and extracted with ethyl acetate (3×40 mL). The combined organic extracts are washed with water and brine, then dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 3.95 g of 5-(4-methoxy-benzyloxy)-4,4-dimethyl-3-oxo-pentanenitrile, which is used in the next step without further purification. Yield: assumed quantitative, no spectroscpic analysis performed.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:20][C:15]1[CH:14]=[C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
To a solution of 6-{(S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile-48 mg (0.11 mmol) dissolved in toluene (1 mL) were added 47 mg (0.33 mmol) of 1-chloroethyl chloroformate and 43 mg (0.33 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 28 mg (72%) of the title compound as a light yellow oil. ES-MS m/e: 346.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH3:48])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:43]([CH3:48])[CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (S)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][C:25]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([O:28][C:29](=[O:30])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCNC1CCCc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.4 %

Procedure:
To a solution of N-(5,6,7,8-tetrahydro-quinolin-8yl)-butane-1,4-diamine (6.77 g, 30.9 mmol) in tetrahydrofuran (155 ml) was added slowly triethylamine (4.30 ml, 30.9 mmol) and Boc-ON (7.60 g, 30.9 mmol). The mixture was stirred for 72 hours at room temperature under a N2 atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v). A second purification by column chromatography on silica gel (ethyl acetate) afforded the product as a brown oil (8.03 g, 80%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.60 (s, 4H), 1.78 (m, 2H), 1.99 (m, 2H), 2.78 (m, 5H), 3.15 (m, 2H), 3.77 (t, 1H), 4.87 (s, 1H), 7.07 (dd, 1H, J=7.45, 4.82 Hz), 7.83 (d, 1H, J=7.89 Hz), 8.38 (d, 1H, J=4.38 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][OH:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)=[O:11]
Reactant: OCc1ccccn1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(=O)OCc1ccccn1)C(C)C
Yield: 54.1 %

Procedure:
A solution of 0.78 g (5.0 mmol) of α-isocyanato-valine methyl ester and 0.55 ml (5.7 mmol) of pyridine-2-methanol in 30 mL of toluene was heated at reflux under N2 atmosphere for 4 h. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to give 0.72 g (54%) of the desired compound as an oil. 1H NMR (CDCl3) δ 0.91 (d, J=7 Hz, 3 H), 0.98 (d, J=7 Hz, 3 H), 2.19 (m, 1 H), 3.75 (s, 3 H), 4.32 (dd, J=9, 5 Hz, 1 H), 5.24 (s, 2 H), 5.39 (br d, 1 H), 7.23 (ddd, J=8, 4, 1 Hz, 1 H), 7.37 (d, J=8 Hz, 1 H), 7.70 (td, J=8, 2 Hz, 1 H), 8.60 (br d, 1 H). Mass spectrum: (M+H)+ =267.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Yield: 81.9 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.), conc.hydrochloric acid (1.84 g.), methanol (36 ml.) and tetrahydrofuran (30 ml.) was stirred at 30° C. for 2 hours. The resultant solution was concentrated in vacuo. Water (60 ml.) was added to the residue and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.86 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:36]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:43])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3cccnc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, nicotinoyl chloride hydrochloride.