Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])[CH:2]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:19][C:2]1[C:3]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:15]
Reactant: CCOC(=O)CC(=O)c1cccc(C)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1cccc(C)c1Cl
Yield: 103.9 %

Procedure:
To a cold (5° C.) mixture of 137.5 g (1.05 mole) of ethyl acetoacetate, 175 ml. of benzene, 325 ml. of water, and 45.8 ml. of 33% sodium hydroxide was added simultaneously 221.05 g (1.430 mole) of m-toluoyl chloride and 190 ml. of 33% sodium hydroxide as described in Example 4. The aqueous solution of sodium salt of ethyl m-toluoylacetoacetate was stirred with 56.3 g of ammonium chloride overnight and worked up as described in Example 4 to give 38.0 g (17%) of crude ethyl m-toluoylacetate after a Kugelrohr distillation (95°-98° C. at 0.05 mm Hg). A mixture of 20.6 g (0.1 mole) of crude ethyl m-toluoylacetate, 13.6 g (0.105 mole) of sulfuryl chloride, and 30 ml. of chloroform was held at reflux for 6 hours and worked up as described in Example 4 to give 25.0 g of ethyl 2-chloro-m-toluoylacetate, which was used directly as described below. A mixture of 22.5 g (0.1 mole) of ethyl 2-chloro-m-toluoylacetate, 7.6 g (0.1 mole) of thiourea and 100 ml. of ethanal was held at reflux for 2 hours and worked up as described in Example 4 to give 23.0 g of solid, which was recrystallized from ethanol to give 11.6 g (44%) of ethyl 2-amino-4-(m-tolyl)-5-thiazolecarboxylate, m.p. 185°-187° C. An additional 4.5 g (17%) of less pure ethyl 2-amino-4-(m-tolyl)-5-thiazolecarboxylate, m.p. 183°-184° C. was obtained by concentration of the mother liquor. To a cold (-5° C.) mixture of 10.5 g (0.04 mole) of ethyl 2-amino-4-(m-tolyl)-5-thiazolecarb and 80 ml. of 85% phosphoric acid was added 40 ml. of 70% nitric acid. To the vigorously stirred above mixture was added 3.0 g (0.0434 mole) of sodium nitrite in 20 minutes. The reaction mixture was stirred for 10 minutes and poured into a mixture of 4.0 g (0.04 mole) of cuprous chloride, 20 ml. of concentrated hydrochloric acid and 20 ml. of water. After the gas evolution had subsided the reaction mixture was extracted with ether, dried (MgSO4) and concentrated under reduced pressure to give 10 g of oil which was Kugelrohr distilled (135°-140° C. at 0.05 mm) to give 6.5 g of oil, which was crystallized from ethanol to give 3.9 g (34%) of the desired product as a white solid, m.p. 41°-42° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]([OH:29])([CH3:28])[CH2:22]OS(C)(=O)=O)=[CH:15][C:14]=1[C:31]([F:34])([F:33])[F:32])#[N:12].Cl.C>O.C(O)(C)C>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]([OH:29])([CH3:28])[CH2:22][S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:14]=1[C:31]([F:32])([F:34])[F:33])#[N:12]
Reactant: CC(O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(O)(CSc1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, to a solution of 25.6 g (0.20 mol) of 4-fluorthiophenol in 500 ml of isopropanol 8.4 g (0.20 mol) of sodium hydroxide in 400 ml of water was added. The mixture was stirred at 25° C. for 2 h, then 58.6 g (16 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2-hydroxy-3-(methanesulfonyloxy)-2-methyl-propionamide in 500 ml of isopropanol was added. Then the mixture was stirred at 25° C. for 5 h, then the pH was adjusted to neutral with concentrated hydrochloric acid and treated with charcoal at reflux temperature. Most of the isopropanol was evaporated in vacuum and 250 ml of 2% aqueous sodium hydroxide solution was added to the residue under vigorous stirring, then the crystalline mixture was left for 1 h, then filtered and washed with water. The dried crystals were recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:22][C@@H:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride (CAN 63038-27-7) as starting materials. MS (EI): m/e=412.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:24][C:20]1[CH:19]=[C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([N:26]([CH3:54])[CH3:25])=[O:53])=[CH:33][CH:32]=4)=[CH:43][CH:42]=2)[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Oc1cccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4cccc(-c5cccc(O)c5)c4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a 50 mL round bottom flask, 3-(2-chloro-4-morpholin-4-ylquinazolin-8-yl)-phenol (80 mg, 0.000234 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (114 mg, 0.00028 mol), cesium carbonate (153 mg, 0.00047 mol), DMF (7 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (8 mg, 0.0000011 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2-5% MeOH in chloroform) to yield the title compound [15 mg, 6%]. 1H NMR: (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.00 (s, 1H), 8.97 (s, 1H), 8.31 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.50-7.59 (m, 5H), 7.29-7.35 (m, 3H), 7.16-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 3.83 (m, 8H), 2.97 (s, 6H); LC-MS (ESI): Calculated mass: 588.2; Observed mass: 588.8 [M+H]+ (RT: 0.64 min).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl>O.C(Cl)Cl>[S:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:16][CH:15]([OH:18])[CH2:14][Cl:13])[C:7]=2[CH:8]=[N:9]1
Reactant: Oc1cccc2sncc12
Reactant: OC(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OC(CCl)COc1cccc2sncc12
Reaction time: 4 h

Procedure:
30.0 g of 4-hydroxy-1,2-benzisothiazole are suspended in 26.0 g of 1,3-dichloro-propan-2-ol and a solution of 8.5 g of sodium hydroxide in 60 ml of water is added in the course of 4 hours at 60°-80° C. After reacting for a further four hours at the same temperature, the organic phase is taken up in methylene chloride, dried over magnesium sulfate and evaporated to dryness. The residue left (35 g) is recrystallized from methanol. The 1-(1,2-benzisothiazol-4-yloxy)-3-chloropropan-2-ol thus obtained is identical with the sample prepared as described in (a). Preparation of compounds according to the invention
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](I)[N:7]([CH3:11])[C:6]=2[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:34]=2)[CH:32]=[O:33])O1>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.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:34]=3)[CH:32]=[O:33])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: Cn1c(I)nc2ccc(Cl)cc21
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: CN(C)C=O
Product: Cn1c(-c2cncc(C=O)c2)nc2ccc(Cl)cc21
Temperature: 160 °C

Procedure:
A flask was charged with 6-chloro-2-iodo-1-methyl-1H-benzo[d]imidazole (627 mg, 2.145 mmol), DMF (10 mL), 2M aqueous sodium carbonate (2.145 mL, 4.29 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1 g, 4.29 mmol). Nitrogen was bubbled through the mixture for 10 min and polymer bound Pd(PPh3)4 (1.19 g, 0.107 mmol) was added. The mixture was heated to 160° C. under micro-wave irradiation for 30 min. The mixture was filtered through a thin pad of celite, which was washed with EtOAc (100 mL). The filtrate was poured into water (200 mL) and extracted with EtOAc (500 mL). The organic phase was washed with water (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica chromatography eluting with 20 to 100% EtOAc in heptane to give 5-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)nicotinaldehyde. ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@@H:8]1[CH2:12][CH2:11][O:10][CH2:9]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].Cl>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:7][C@@H:8]4[CH2:12][CH2:11][O:10][CH2:9]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O[C@@H]1CCOC1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Reaction time: 1 h

Procedure:
13.80 g of potassium tert-butoxide are added batchwise to a solution of 10.80 g of (R)-3-hydroxytetrahydrofuran in 100 ml of N,N-dimethylformamide while cooling with an ice bath. The reaction mixture is stirred for about one hour, then 10.40 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline are added batchwise. The cooling bath is then removed and the deep red reaction mixture is stirred for two hours at ambient temperature. For working up the reaction mixture is poured onto about 500 ml of water and neutralized with 2 N hydrochloric acid. The yellowish precipitate formed is suction filtered and dried at 70° C. in a circulating air drier. Yield: 12.80 g; melting point: 244° C.; mass spectrum (ESI−): m/z=403, 405 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[OH:32])(=[O:40])=[O:41])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1O
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccccc3O)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-hydroxybenzenesulfonamide [Synth. Commun., 1994, 24, 671]: 1H-NMR (CDCl3) δ 7.74-7.70 (1H, m), 7.48-7.24 (9H, m), 7.15 (2H, d, J=8.2 Hz), 7.02 (1H, d, J=7.7 Hz), 6.93 (1H, t, J=7.6 Hz), 6.16 (1H, br.s), 3.47-3.40 (2H, m), 2.81 (2H, t, J=6.5 Hz), 2.32 (3H, s), 2.23 (3H, s).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[CH:41]1([S:44]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[C:10]([CH:14]4[N:18]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])[CH2:15]4)[CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6]2)(=[O:46])=[O:45])[CH2:43][CH2:42]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
5-[3-(Piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1 of Example 96, triethylamine (143.0 uL, 1.02 mmol) and cyclopropanesulfonyl chloride (43.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 80.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+].C(O)C.[C:18](=S)=[S:19]>O>[SH:19][C:18]1[N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1ccccc1NCCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCn1c(S)nc2ccccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 93 parts of 3-(2-aminophenyl) amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of an ethanol solution 85% in water are added dropwise 60.8 parts of carbon disulfide. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in 1500 parts of water. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The oily product solidifies on scratching. It is filtered off, washed with water and dried, yielding 2-mercapto-1H-benzimidazole-1-propanol; mp. 110° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH:19]=[C:18]2[O:37][S:39]([CH3:38])(=[O:41])=[O:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 50.6 g (98 mmols) of 7β-phenoxyacetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 500 ml of methylene chloride is cooled to -20° C. and, after adding 14 ml of methanesulphonyl chloride (142 mmols), 22.3 ml (142 mmols) of triethylamine are added slowly. After a reaction period of 1 hour at -15° C. to -20° C. under nitrogen, the solution is washed with water, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, concentrated in a rotary evaporator and dried under a high vacuum. A mixture consisting of 7β-phenoxyacetylamino-3-methanesulphonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 7β-phenoxyacetylamino-3-methanesulphonyloxy-2-cephem-4-carboxylic acid diphenylmethyl ester is obtained; thin layer chromatogram (silica gel; toluene/ethyl acetate, 2:1), 3-cephem derivative Rf=0.39; 2-cephem derivative Rf=0.32.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1I>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:4]#[C:3][CH2:2][CH2:1][OH:5]
Reactant: C#CCCO
Reactant: Clc1ccc(I)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(Cl)cc1Cl

Procedure:
Synthesis of an intermediate in which m is 3 is detailed in Example 4. This route starts with the reaction of 3-butyn-1-ol with 2,4-dichloroiodobenzene in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in acetonitrile and triethylamine, producing 4-(2,4-dichlorophenyl)-3-butyn-1-ol. Hydrogenation of this acetyleneic alcohol over platinum oxide produces 4-(2,4-dichlorophenyl)-1-butanol which is then oxidized with chromium trioxide and sulfuric acid to the corresponding carboxylic acid. The remaining steps are the same as those detailed in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH2:18][N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH:18]([N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:27])([F:26])[F:28])=[N:20]4)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)cc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
To a mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone (0.150 g, 0.37 mmol) in THF (4 ml) at −78° C. was added LDA (0.247 mL, 0.50 mmol, 2 M in THF). After stirring for 10 min at −78° C., ethyl bromoacetate (0.061 mL, 0.55 mmol) was added. The mixture was then warmed to rt for 10 min and quenched with sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography (SiO2 with a gradient elution of 0-60% EtOAc/hexanes) to afford ethyl 4-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-4-oxo-butanoate (0.120 g, 83%).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[N:32]=[C:33]=[O:34])([CH3:24])[CH3:23]>O1CCCC1>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:34])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:24])[CH3:23]
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: Cc1cccc(C(C)C)c1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3c(C)cccc3C(C)C)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-isopropyl-6-methylphenyl isocyanate (558 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 30 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:19) to afford 10d as solid. Yield: 520 mg, 67.16%.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.O>CN(C)C=O>[CH3:17][O:18][CH2:19][CH2:20][N:14]1[CH2:15][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][CH2:12][C:13]1=[O:16]
Reactant: COCCBr
Reactant: O=C1CCCC(c2ccccc2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CC(c2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.32 g, 8.03 mmol) was added to a solution of 6-phenylazepan-2-one (0.76 g, 4.02 mmol) in N,N-dimethylformamide (15 mL) at 0° C., followed by the addition of 2-bromoethyl methyl ether (0.837 g, 6.03 mmol), and the mixture was allowed to warm to ambient temperature. After 21 h, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. MS 248 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])[CH3:2].[NH2:17][OH:18]>CO>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=1[C:6]([NH:17][OH:18])=[O:7])[CH3:2]
Reactant: NO
Reactant: CCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Solvent: CO
Product: CCOc1ccc([N+](=O)[O-])cc1C(=O)NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-ethoxy-5-nitrobenzoate (6.099 g, 26.99 mmol) and 50% wt/v aqueous hydroxylamine (40 ml) were taken up in MeOH (100 ml) and stirred at RT overnight. The resulting precipitated yellow solid was collected by filtration, washed with IPA and dried in vacuo The filtrate was evaporated in vacuo and the residue was triturated with IPA (25 ml). The solid that didn't dissolve was filtered off, washed with a minimum quantity of IPA and dried in vacuo. The two crops of solid were suspended in H2O (300 ml) and the pH was lowered to 2 by careful addition of concentrated HCl. The solid was filtered off, washed with MTBE and dried in vacuo to give 3.9 g of crude 2-ethoxy-5-nitro-N-hydroxybenzamide. The IPA mother liquors from above were combined with the crude 2-ethoxy-5-nitro-N-hydroxybenzamide and evaporated in vacuo. The residue was triturated with CH2Cl2 (25 ml) and the solid was filtered off and dried in vacuo to give 2-ethoxy-5-nitro-N-hydroxybenzamide (2.39 g, 39%) as a yellow solid.