Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38]([O:41][CH2:42]Br)(=[O:40])[CH3:39].[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[C:38]([O:41][CH2:42][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18])(=[O:40])[CH3:39]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Reactant: CC(=O)OCBr
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added bromomethyl acetate (76 mg, 503 μmol), NaI (101 mg, 670 μmol), and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1) to yield the title compound as a white solid (15 mg). LC-MS: 597.7 [M+H]+. 1H NMR (CDCl3, 400 MHz,) δ 2.02 (s, 3H), 3.37 (br, 2H), 4.22 (br, 2H), 4.38 (br, 1H), 5.78-6.02 (m, 2H), 7.15-7.20 (m, 1H), 7.40-7.45 (m, 2H), 7.50-7.91 (m, 7H), 8.15-8.17 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[NH:3]1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:26]([NH2:28])=[O:27]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][C:2](=[O:1])[NH:3]4)=[CH:8][CH:7]=3)[CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:26]([NH2:28])=[O:27]
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Reactant: O=C1Cc2cc(B(O)O)ccc2N1
Product: NC(=O)c1nnc2c(-c3ccc4c(c3)NC(=O)C4)cccc2c1N

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-oxoindolin-5-ylboronic acid and 4-amino-8-bromocinnoline-3-carboxamide. ESI-MS m/z [M+H]+ 320.2.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)C=CC=CC=1>C(#N)C>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:32]([N:14]2[CH2:15][CH2:16][CH:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:1])([F:17])[O:3][C:4]=4[CH:10]=3)[CH2:13]2)=[O:31])[CH:35]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CC3CCNC3)cc2O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 35 °C
Yield: 38.8 %

Procedure:
To a solution consisting of 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-pyrrolidine (111 mg, 0.399 mmol), triethylamine (0.1 mL, 0.72 mmol) and acetonitrile (2 mL) was added pyridin-3-yl-carbamic acid phenyl ester (90.1 mg, 0.421 mmol). The mixture was heated at 35° C. for 18 h, cooled to rt and then concentrated. The crude residue was purified (FCC) to give the title compound (56 mg, 39%). MS (ESI): mass calcd. For C18H17F2N3O3, 361.12. m/z found, 362.2 [M+H]+. 1H NMR (CD3OD): 8.63-8.59 (m, 1H), 8.16-8.13 (m, 1H), 7.97-7.92 (m, 1H), 7.35-7.30 (m, 1H), 7.16-7.09 (m, 2H), 7.06-7.02 (m, 1H), 3.66-3.53 (m, 2H), 3.48-3.38 (m, 1H), 3.19-3.11 (m, 1H), 2.85-2.72 (m, 2H), 2.62-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.78-1.66 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)I
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To 2,6-dichloro-9H-purine (a) (998 g, 5.28 mol) dissolved in anhydrous DMF (5.0 L) was added sodium hydride (60% dispersion, 254 g, 6.35 mol) with stirring at 10° C. over 1 hr. 2-iodopropane (1595 g) was added and the mixture was stirred at rt for 24 hr. Water (5.0 L) was added, and the resulting solid precipitate was collected and washed with water (500 ml) and heptane (2×2.5 L). The crude solid was crystallized from isopropyl acetate (2.1 L) to provide the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=1.[ClH:27].CCOCC>CCO>[Cl-:27].[CH3:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)=[NH+:6][CH:7]=1
Reactant: Cl
Reactant: Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Solvent: CCO
Solvent: CCOCC
Product: Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)[nH+]c1
Product: [Cl-]

Procedure:
5-Methyl-2-{[(1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methyl]amino}-pyrimidine (6.81 g, 19.4 mmol) (EXAMPLE 145) was dissolved in EtOH (400 mL) and 1M HCl in ether (19.4 mL, 19.4 mmol) added. The solution was then concentrated and the residue was crystallized from 30% 2-propanol in ether (100 mL) to give the title compound. Melting Point 157.5° C.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:18])[CH:8]=1.C([Li])CCC.C(N1CCOCC1)=O>C(OCC)(=O)C.O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=1[F:18]
Reactant: C1CCOC1
Reactant: Fc1cc(Br)ccc1C1OCCO1
Agent: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(C2OCCO2)c(F)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a tetrahydrofuran (600 mL) solution of 2-(4-bromo-2-fluoro-phenyl)-[1,3]dioxolane (12.5 g, 50.7 mmol) described in Manufacturing Example 204-1-1 was added dropwise n-butyl lithium (28.5 mL, 2.67 M hexane solution, 76.1 mmol) over 15 minute. The system was stirred for 5 minutes at −78° C., after which a THF solution of N-formylmorpholine (5.61 mL, 55.8 mmol) was added to this reaction solution, which was stirred for another 2.5 hours at room temperature. Water and ethyl acetate were added to this mixture, which was partitioned. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (9.99 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[C:19]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:20]=1)[CH3:10]
Reactant: CCCCCC(=O)Cl
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCCCC(=O)c1cc(CCC(=O)OCC)ccc1OC
Temperature: 50 °C

Procedure:
98 ml (0.7 mol) of hexanoyl chloride are added dropwise to a solution of 70 g (0.336 mol) of ethyl3-(4-methoxyphenyl)propanoate in 280 ml of dichloromethane. 89 g (0.67 mol) of aluminium chloride are then added in small amounts, and the mixture is heated for one hour at 50° C. The mixture is poured into cold water and extracted with ether. The organic phase is washed with sodium bicarbonate solution. After drying (Na2SO4) and evaporating off the solvents, a yellow liquid is obtained, and then distilled: Bp0.4 mmHg=160° C. (74 g; 72%);
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>CN(C=O)C>[Br:8][C:21]1[C:22]([NH2:25])=[N:23][CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:11])=[O:12])=[CH:18][CH:17]=2)[N:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
NBS (1.807 g, 10.15 mmol) was added to a stirred solution of 5-(4-methylsulfonylphenyl)pyrazin-2-amine (2.53 g, 10.15 mmol) in DMF (40 mL) and the reaction stirred at ambient temperature for 15 hours. The reaction mixture was added slowly to rapidly stirring water and the resultant precipitate was isolated by filtration and dried in vacuo to give the sub-title compound as a beige solid that was used without further purification (2.8 g, 84% Yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.C(C1C=CC2OC(C)(C)[C@H](O)[C@@H](N(CC(OCC)=O)C3C=CC=CC=3)C=2C=1)#N.[NH2:44][C:45]1[S:46][CH:47]=[C:48]([CH3:50])[N:49]=1>>[OH:8][C@@H:7]1[C@@H:6]([NH:44][C:45]2[S:46][CH:47]=[C:48]([CH3:50])[N:49]=2)[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]1([CH3:15])[CH3:1]
Reactant: Cc1csc(N)n1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Agent: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Product: Cc1csc(N[C@H]2c3cc(C#N)ccc3OC(C)(C)[C@@H]2O)n1

Procedure:
The title compound was prepared from (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (the title A compound of Example 3) and 2-amino-4-methyl-thiazole by the procedure described for the title compound of Example 1. The residue was purified by a flash column to give a colorless solid (730 mg, 58%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Br[C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[NH:39][CH:40]=[CH:41][C:34]=12.C(=O)(O)[O-].[Na+].O>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.O1CCOCC1>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:39][CH:40]=[CH:41][C:34]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: Brc1ccnc2[nH]ccc12
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.28 g, 0.66 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (0.14 g, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol) and sodium bicarbonate (0.28 g, 3.3 mmol) in a solution of water (0.5 mL) and 1,4-dioxane (1 mL) was degassed for a while and sealed. The mixture was stirred at 85° C. for 3 h. After cooling the mixture was diluted with ethyl acetate. The organic solution was washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.15 g). LCMS (M+H)+: m/z=415.2.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]2[CH2:16][C:15](=[O:17])[NH:14][C:10]=2[N:11]=[CH:12][N:13]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[N:28]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31]3)[CH:29]=2)=[CH:21][C:20]=1[C:43]([F:46])([F:45])[F:44]>O>[ClH:7].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([CH:37]3[CH2:38][CH2:39][N:40]([C:8]4[C:9]5[CH2:16][C:15](=[O:17])[NH:14][C:10]=5[N:11]=[CH:12][N:13]=4)[CH2:41][CH2:42]3)[N:28]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31]3)[CH:29]=2)=[CH:21][C:20]=1[C:43]([F:46])([F:44])[F:45]
Reactant: CN1CCC[C@@H](n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CN1CCC[C@@H](n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc4c3CC(=O)N4)CC2)C1
Product: Cl

Procedure:
Combine potassium tert-butoxide (1.1 equiv; 321 μmol; 36.8 mg); IPrPd(acac)Cl (0.1 equiv; 29.2 μmol; 18.4 mg) and stir bar in 4 mL vial and purge with nitrogen for 10 min. Add anhydrous DME (2.5 mL) followed by 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 equiv; 292 μmol; 50 mg); (R)-3-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-1-methyl-piperidine (1.1 equiv; 321 μmol; 131.8 mg) and heat to 80° C. for 18 h. Dilute with 15 mL water, filter, and rinse with water. Dissolve purple solid in EA, wash with saturated sodium bicarbonate, brine, dry with anhydrous MgSO4, filter, evaporate and purify on 40 g silica gel with 2-10% MeOH/DCM to provide 99.6 mg (0.18 mmol; 63%) of the title compound as the free base. Dissolve in DCM, add 1 equiv 1M HCl in ether and evaporate to provide 101 mg of the title compound. MS (ES+): m/z=544 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[CH2:24](I)[CH3:25].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH2:24][CH3:25])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1
Reactant: CCI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in DMF (2.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (0.30 g (0.92 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, ethyl iodide (0.50 ml (6.25 mmol)) was added dropwise. After one hour's heating at 100° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, giving 0.24 g (74%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)N.[ClH:11].N([O-])=O.[Na+].[C:16](#[N:19])[CH:17]=[CH2:18]>[Cl-].[Na+].O.CC(C)=O.C(O)(=O)C>[Cl:11][CH:17]([C:16]#[N:19])[CH2:18][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: C=CC#N
Reactant: Nc1ccccc1C(=O)O
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: N#CC(Cl)Cc1ccccc1C(=O)O

Procedure:
274 parts of anthranilic acid are mixed with 650 parts of hydrochloric acid (density 1.15) and 560 parts of crystallizable acetic acid. The mixture is cooled externally to 0° C. by means of a brine, then diazotised by means of 138 parts of sodium nitrite. The solution of the diazo derivative is then poured, whilst being stirred, into a mixture of 190 parts of acetone and 370 parts of acrylonitrile, at the same time as a solution of 6 parts of cuprous chloride in 50 parts of hydrochloric acid (density 1.08). The reaction is exothermic. After the diazonium chloride has disappeared and after decantation and crystallization in water, 330 parts of a product are obtained which has a melting point of 116°-117° C. and which is recrystallized in xylene. 314 parts of 2-(2-chloro-2-cyanoethyl) benzoic acid are obtained. M.P.: 119°-120° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH:47]12[NH:53][CH:50]([CH2:51][CH2:52]1)[CH2:49][CH2:48]2>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:24])([CH3:25])[C:21]([N:53]3[CH:47]4[CH2:52][CH2:51][CH:50]3[CH2:49][CH2:48]4)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: C1CC2CCC1N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (856 mg in 8.0 mL methylene chloride) at 0° C. was added 310 mg of 1-hydroxybenzotriazole (HOBt)followed by 400 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture stirred at low temperature for 90 minutes. At this time, a solution of 7-aza-bicyclo[2.2.1]heptane hydrochloride (632 mg in a mixture of 2.0 mL methylene chloride and 0.66 mL triethylamine) was added and the mixture warmed to room temperature. The reaction was quenched after 24 hours by dilution with methylene chloride and washing with half-saturated brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (hexane:ethyl acetate, 70:30; then 60:40; then 50:50; then 40:60) to give the title compound (736 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[NH:14][C:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)=NN=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.[CH3:32][CH2:33][CH2:34]P(=O)=O.CCN(C(C)C)C(C)C>ClCCl.CO>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([N:29]3[CH2:30][C:27]([F:31])([F:26])[CH2:28]3)=[O:22])[CH:34]=[CH:33][CH:32]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: CCCP(=O)=O
Reactant: O=C(O)/C=C\c1nnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C/c1cccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(F)(F)C1
Yield: 104.2 %

Procedure:
In a 50-mL round-bottomed flask Intermediate 2 (0.4 g, 1.1 mmol) and 3,3-difluoroazetidine hydrochloride (0.17 g, 1.3 mmol) was dissolved in dichloromethane (20 mL). Propylphosphonic anhydride (0.42 g, 1.3 mmol), DIPEA (0.28 g, 2.2 mmol) was added at room temperature and stirred reaction mixture for 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 0.5% Methanol:dichloromethane as mobile phase and visualization with U.V light, reaction mixture was quenched into ice water slurry, filter it, compound was extracted in dichloromethane, dried over Na2SO4, filtered, and concentrated by rotary evaporation (28° C., 20 mmHg) to afford 0.5 g of a solid crude, The purification done by Flash chromatography and product elute at neat dichloromethane to afford pure compound 0.030 g yield (6.2%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:46]/[O:47][C:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:50])[CH3:49])/[C:27]([NH:29][CH:30]2[C:44](=[O:45])[N:32]3[C:33]([C:41]([O-:43])=[O:42])=[C:34](/[CH:37]=[CH:38]\[CH2:39]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:58].[Na+]>CC(C)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:46]/[O:47][C:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:50])[CH3:49])/[C:27]([NH:29][CH:30]2[C:44](=[O:45])[N:32]3[C:33]([C:41]([O:43][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:42])=[C:34](/[CH:37]=[CH:38]/[CH2:39][I:58])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 204.9 %

Procedure:
To a solution of 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (IXa) (1.23 g, 1.24 mmole) in acetone (5 ml) was added a solution of sodium iodide (560 mg, 3.72 mmol) in acetone (7 ml). The mixture was stirred at room temperature for 1.5 hour, and diluted with ethyl acetate (150 ml) and aqueous sodium thiosulfate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated to give 1.38 g of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-[(E)-3-iodo-1-propen-1-yl]-3-cephem-4-carboxylate (Xa) (see also Example 23 below) as an amorphous powder. Compound Xa was dissolved in ether (50 ml). The insoluble was filtered off and the filtrate was chilled in an ice-water bath, and was treated with a solution of 5,6-diacetoxy-2-methyl-2-isoindoline (600 mg, 2.4 mmol) in ether (50 ml). The mixture was stirred over 30 min, and the precipitate was collected by filtration to obtain 446 mg (27% yield) of the title iodide as a tan powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:22])=O>>[Cl:22][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C=CC(=O)c2ccccc2)cc1
Yield: 100.4 %

Procedure:
A 1-L reaction vessel was charged with 80.0 g (0.32 mole) of 4-carboxychalcone and 377.7 g (3.17 mole) of thionyl chloride, and heated under reflux for 1 hour. Thereafter, thionyl chloride was removed by distilling, and thus 87.0 g of 4-(chlorocarbonyl)-chalcone was obtained (101% yield). This reaction is shown by the reaction formula in FIG. 1(b).