Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][S:25]([C:22]1[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To 1 g (3.9 mmol) of D-tryptophan methyl ester hydrochloride in 12 mL of pyridine at ambient temperature is added 1 g (3.9 mmol) of 4-bromobenzene sulfonyl chloride. The yellow mixture is allowed to stir overnight. It is then poured into aqueous 10% HCl and extracted with several portions of ethyl acetate. The combined organic phases are washed with aqueous 10% HCl, water, and brine, and dried over sodium sulfate. The solution is decolorized with activated charcoal, and concentrated to 1.1 g (65%) of a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Temperature: 25 °C

Procedure:
A 250 mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-chloromethyl-3-nitrobenzene (10.0 g, 58.3 mmol), morpholine (15.0 g, 175 mmol) and toluene (75 mL), and the solution was heated at reflux for 2.5 h. The reaction mixture was allowed to cool to ambient temperature then washed with 1N aqueous sodium hydroxide (2×50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure to afford compound 9 as an off-white solid. 1H NMR (CDCl3) δ (ppm) 8.22 (s, 1H), 8.12 (d, 1H, J=8.2 Hz), 7.68 (d, 1H, J=7.6 Hz), 7.49 (t, 1H, J=7.9 Hz), 3.73 (m, 4H), 3.59 (s, 2H), 2.46 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[C:18]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:17]=[CH:16][C:15]=3[CH3:26])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.I[CH3:28]>>[CH:1]1([CH2:4][N:5]([CH3:28])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[C:18]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:17]=[CH:16][C:15]=3[CH3:26])=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)CC4CC4)cc3)c2)o1

Procedure:
N-(Cyclopropylmethyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method H.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:44]([O:46][C:47]([C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55](Br)[CH:56]=2)[N:51]([CH3:59])[CH:50]=1)=[O:48])[CH3:45]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:44]([O:46][C:47]([C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([CH:1]3[CH2:3][CH2:2]3)[CH:56]=2)[N:51]([CH3:59])[CH:50]=1)=[O:48])[CH3:45]
Reactant: CCOC(=O)c1cn(C)c2ccc(Br)cc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C)c2ccc(C3CC3)cc12
Temperature: 75 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
Cyclopropylboronic acid (457 mg), palladium (II) acetate (79.5 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (290 mg) and tripotassium phosphate (1.88 g) were added at room temperature to a solution of 5-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester (1.0 g) described in Reference Example 52(2) in tetrahydrofuran (14 ml), and the mixture was stirred at 75° C. for five hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added and filtered through Celite. The filtrate was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-cyclopropyl-1-methyl-1H-indole-3-carboxylic acid ethyl ester (802 mg) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:17]=[C:16]([C:35]#[C:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:44])C.[OH-].[Na+].Cl>C(O)C>[Cl:44][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:26][CH:27]=3)[CH:17]=[C:16]([C:35]#[C:36][C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:45])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCc3ccc(CN4CCOCC4)cc3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCc3ccc(CN4CCOCC4)cc3)c2)cc1Cl
Reaction time: 16 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (250 mg; 0.38 mmol) was dissolved in ethanol (10 mL), and aqueous 1N sodium hydroxide (5 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method A). Yield: 32 mg. HPLC-MS: m/z: 634.5 (M+); Rt: 2.21 min.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=3)[C:28]#[N:29])[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([S:2][CH3:1])=[C:27]([CH:30]=3)[C:28]#[N:29])[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium thiomethoxide (0.21 g, 3 mmol) and potassium carbonate (0.28 g, 2 mmol) in 4 mL of N,N-dimethylformamide was added a solution of 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-fluorobenzonitrile (prepared by a method similar to Example 2, Step A and Step B; 1.00 g, 2.48 mmol) in N,N-dimethylformamide (6 mL). This mixture was stirred at ambient temperature for 1 h. Then an additional portion of sodium thiomethoxide (0.21 g, 3 mmol) was added. After an additional 15 minutes, water was added, and the mixture was successively extracted with diethyl ether and ethyl acetate. The organic extracts were combined and washed several times with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate, and concentrated to leave an off-white solid. The solid was triturated with a mixture of diethyl ether and hexanes, collected on a glass frit, and dried in air to afford the title compound, a compound of the present invention, as a white solid (1.04 g).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][NH2:54])[CH:48]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:53]([C:49]3[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=3)[N:54]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
600 mg (1.39 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 303 mg (2.08 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 355 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.O=[C:28]([CH3:42])[CH2:29][CH2:30][N:31]1C(=O)C2C(=CC=CC=2)C1=O>>[F:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]([CH:19]3[CH2:20][CH2:21][N:22]([CH:28]([CH3:42])[CH2:29][CH2:30][NH2:31])[CH2:23][CH2:24]3)([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Fc1ccc2c(c1)OC(c1ccc(C(F)(F)F)cc1)(C1CCNCC1)O2
Product: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Oc3ccc(F)cc3O2)CC1

Procedure:
Using general procedure B with the above amine (59 mg, 0.16 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (70 mg, 0.32 mmol) and then using general procedure D gave 3-{4-[5-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (35 mg, 51% over 2 steps).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48]CC(C)=CC=C)(=[O:41])=[O:40])([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.C(N1C2C(=CC(Cl)=CC=2)C(CCOC2C=CC(C(OC)=O)=CC=2)=C1CCNS(C1C=CC=CC=1OCC1C=CC=CC=1)(=O)=O)(C1C=CC=CC=1)C1C=CC=CC=1>CO.CCO.[Pd]>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[OH:48])(=[O:40])=[O:41])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC=C(C)COc1ccccc1S(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 104.9 %

Procedure:
4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-penta-2,4-dienyloxy)-benzensulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoic acid (0.55 g, 0.70 mmole), (Step 1, Example 183) Methyl 4-(2-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethy]-5-chloro-1H-indol-3yl}-ethoxy)benzoate, (0.55 g, 0.70 mmol), (Setp 1 , Example 184) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixture was filtered through Celite and concentrated. The residue was chromatographed with 35-40% EtOAC/hexane to give the desired product (0.50 g, 95%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].[CH2:12](O)CCO.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)C>[O:10]1[CH2:11][CH2:12][CH2:1][O:2][CH:3]1[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: OCCCO
Reactant: COC(CNC(=O)CCl)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Product: O=C(CCl)NCC1OCCCO1
Temperature: 120 °C

Procedure:
N-(2,2-Dimethoxyethyl)-2-chloroacetamide (18.2 grams; 0.1 mole), 1,3-propanediol (7.61 grams; 0.1 mole) and 10 drops of a solution of 1 gram of toluenesulfonic acid in 100 ml of diethyl ether were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distillation head and condenser. The mixture was stirred and heated at about 120° C. for a period of about 1 hour while byproduct methanol was distilled off. The mixture was cooled to room temperature, sodium carbonate (2 grams) was added, and the slurry stirred for a period of about 1 hour. The slurry was filtered and the filtrate was stripped of solvent by mild warming under reduced pressure to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2-chloracetamide as a residue.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[S:23][CH:24]=3)=[C:15]([CH3:34])[CH:14]=2)=[N:10][CH:11]=1.C(OC(=O)C)(=[O:37])C.OO>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([S:12]([C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[S:23][CH:24]=3)=[C:15]([CH3:34])[CH:14]=2)=[O:37])=[N:10][CH:11]=1
Reactant: COCCOc1cnc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: ClCCl
Product: COCCOc1cnc(S(=O)c2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A mixture of 27 (200.0 mg, 0.41 mmol, 1.0 equiv), acetic anhydride (0.040 mL, 0.45 mmol, 1.1 equiv), 30% hydrogen peroxide (201.1 mg, 5.94 mmol, 4.4 equiv), and silica gel (81.1 mg, 230-400 mesh) in dichloromethane (5.0 mL) was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (30 mL). The solution was washed with saturated aqueous NaHCO3 (20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (90% EtOAc in hexanes as eluant) to provide to provide N-(4-{4-(5-(2-methoxyethoxy)pyrazin-2-ylsulfinyl)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (32, 100.3 mg, 0.2 mmol) as yellow solids in 49% yield: 1H NMR (DMSO-d6, 500 MHz) δ 13.05 (s, 1 H), 8.81 (d, J=5.5 Hz, 2 H), 8.68 (s, 1 H), 8.40 (s, 1 H), 7.98 (d, J=5.5 Hz, 2 H), 7.50 (s, 2 H), 7.26 (s, 1 H), 4.47-4.48 (m, 2 H), 3.67-3.69 (m, 2 H), 3.29 (s, 3 H), 2.14 (s, 6 H); ESI-MS: m/z 510.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)ccc1OCCN1CCCC1
Temperature: 60 °C
Yield: 12.6 %

Procedure:
A suspension of 5-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6.0 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.2 g, 7.1 mmol) and cesium carbonate (5.0 g, 15 mmol) in DMF (40 mL) was heated at 60° C. for 17 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% MeOH/DCM) to afford the title compound (0.2 g, 13%) as a light brown solid. MS (ES+): m/z 265 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:28][CH:29]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: O=C(NCCN1CCOCC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0345 cm3 of N-(2-aminoethyl)morpholine. 62 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide are thus obtained in the form of an ochre-colored foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 2.30 to 2.45 (mt, 4H), 2.46 (t, J=7.5 Hz, 2H), 2.98 (s, 3H), 3.38 (mt, 2H), from 3.50 to 3.65 (mt, 4H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.85 (dd, J=8 and 2 Hz, 1H), 8.45 (t, J=6.5 Hz, 1H)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.[Na].[CH3:18][OH:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10]([O:19][CH3:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc(Cl)c(Cl)c(Cl)n2)cc1
Reactant: CO
Agent: [Na]
Solvent: C1CCOC1
Product: COc1nc(-c2ccc(Cl)cc2)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(4'-chlorophenyl)-4,5,6-trichloropyrimidine (1.85 g, 6.3 mmol) in methyl alcohol (30 mL) and THF (60 mL) is added a solution of sodium (0.145 g, 6.3 mmol) in methyl alcohol (10 mL) and the mixture is stirred at ambient temperature overnight. After removal of the solvents in vacuo dichloromethane is added to the residue and the resulting mixture is washed with water. After drying of the organic layer with anhydrous magnesium sulphate, the solvent is removed. Treating of the residue with pentane affords the title compound (1.75 g, 96%) as colorless crystals of melting point 157°-159° C.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:32]2[N:33]=[C:34]([NH:37]C(=O)C(F)(F)F)[S:35][CH:36]=2)[C:9]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH3:26])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+].O1CCCC1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH:1]1([O:6][N:7]=[C:8]([C:32]2[N:33]=[C:34]([NH2:37])[S:35][CH:36]=2)[C:9]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH3:26])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3CCCC3)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3CCCC3)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
7-[2-cyclopentyloxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.8 g) was added to a solution of sodium acetate trihydrate (5.8 g) in water (25 ml), and tetrahydrofuran (8.0 ml) was added thereto to give clear solution. The solution was stirred for 16 hours at ambient temperature. To the reaction mixture were added water and ethyl acetate and the mixture was adjusted to pH 6.2 with a saturated aqueous solution of sodium bicarbonate. The separated aqueous layer was washed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.63 g), mp 152° to 154° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A solution of 4-fluoro acetophenone (5.0 g, 3.6 mmol) and N-methyl piperazine (20 ml, 4 vol %) was heated in a sealed tube at 120° C. for 16 h. The reaction mixture was cooled to room temperature and poured into ice water. The precipitated solid was filtered and dried in vacuo to afford 7.50 g (94.5%) of 1-(4-(4-methylpiperazin-1-yl)phenyl)ethanone as solid.
Reaction SMILES: N[C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1.N(OCCCCC)=O>Cl.[Zn]>[OH:11][C:5]1[C:6]2[CH:7]=[N:8][S:9][C:10]=2[CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)c2cnsc12
Agent: CCCCCON=O
Agent: Cl
Agent: [Zn]
Product: Oc1cccc2sncc12
Temperature: 60 °C

Procedure:
15.1 g of 7-amino-4-hydroxy-1,2-benzisothiazole are slowly suspended in 30 ml of concentrated hydrochloric acid and diazotized with 15 ml of amyl nitrite at from 0° to 5° C. After slowly heating the mixture to 60° C., 18 g of zinc dust are added in 10 portions and the mixture is refluxed until the evolution of gas has ceased. When the mixture has cooled, it is filtered through Celite and the filtrate is partitioned between dilute sodium hydroxide solution and chloroform. After acidifying the aqueous phase and repeatedly extracting it with methylene chloride, the combined organic extracts are dried over magnesium sulfate and freed from the solvent. This gives from 2 to 3 g of 4-hydroxy-1,2-benzisothiazole, which is identical with the compound prepared as described in Example 9.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[CH:14][CH:13]=1.Cl>O1CCCC1.CCCCCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:3]([O:7][CH2:8][CH3:9])=[O:10])[C:19]2=[O:23])=[CH:14][CH:13]=1
Reactant: O=C1CCCN1c1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ccc(Cl)cc2)C1=O
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a suspension of 25 g of sodium hydride (60% oil dispersion) in 100 mL of tetrahydrofuran was added 37 g of diethyl carbonate. Under reflux, to the mixture was added dropwise a solution of 52.0 g of 1-(4-chlorophenyl)-2-pyrrolidinone in 150 mL of tetrahydrofuran over about 1.5 hours. After refluxing for 4.5 hours, the reaction mixture was cooled, and carefully poured into ice-water. The mixture was made to weakly alkaline with diluted hydrochloric acid and extracted with 300 mL of ethyl acetate. The organic layer was washed sequentially with water, aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and concentrated to give an oil. To the residue was added 200 mL of n-hexane, and the precipitated crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 60 g of the title compound.