Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:37][C:34]1[CH:33]=[C:32]([Cl:38])[CH:31]=[CH:36][C:35]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][C@@H:10]([CH3:21])[C@H:9]([OH:8])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: CCO
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(-c2ccc(Cl)cc2Cl)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 1-bromo-2,4-dichlorobenzene (0.218 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g)in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 100° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was neutralised with sodium hydrogen carbonate solution (in water) and the aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a solid (0.064 g) from which the oxalate salt was prepared (0.054 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[BH-](O[C:24](=[O:26])[CH3:25])OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:7][C:6]3[O:26][C:24]4[C:25](=[N:4][CH:3]=[CH:2][CH:1]=4)[CH:5]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cccnc1N1CCN(Cc2cc3ncccc3o2)CC1

Procedure:
The product from Example 35B, 1-(3-methyl-2-pyridinyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) 62.68 (m, 4H), 3.29 (s, 3H), 3.58 (m, 4H), 3.79 (s, 2H), 6.41 (d, J=8.48 Hz, 1H), 6.49 (d, J=7.12 Hz, 1H), 6.85 (s, 1H), 7.18 dd, J=4.75, 8.14 Hz, 1H), 7.36 (dd, J=7.12, 8.14 Hz, 1H), 7.73 (dd, J=1.02, 8.14 Hz, 1H), 8.51 (dd, J=1.36, 4.75 Hz, 1H); MS (DCI/NH3) m/z 309.2 (M+H)+.
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1.[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:32]3[O:36][N:35]=[C:34]([CH3:37])[CH:33]=3)=[O:31])[CH:19]=2)[N:14]=1>C(Cl)Cl>[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:6]3[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=3)([C:32]3[O:36][N:35]=[C:34]([CH3:37])[CH:33]=3)[OH:31])[CH:19]=2)[N:14]=1
Reactant: Cn1cncc1Br
Reactant: Cc1cc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1cc(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)c2cncn2C)on1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethylmagnesium bromide (3 M in Et2O, 0.064 mL, 0.193 mmol) was added dropwise to a solution of 5-bromo-1-methyl-1H-imidazole (31.0 mg, 0.193 mmol) in DCM (1 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, then was cooled to 0° C. A solution of (2,4-dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanone (49.2 mg, 0.128 mmol, Intermediate 3: step b) in DCM (2 mL) was added via cannula. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA) to afford the title compound along with the intended product (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(3-methylisoxazol-5-yl)methanol. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.06 (d, J=9.05 Hz, 1H), 7.92 (d, J=8.80 Hz, 1H), 7.47-7.63 (m, 3H), 7.36-7.47 (m, 2H), 6.53 (br. s., 1H), 6.34 (s, 1H), 2.23-2.38 (m, 2H), 2.20 (s, 3H), 0.76 (t, J=7.21 Hz, 3H); MS m/e 413.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH2:32]([O:34][C:35](=[O:48])[C@@H:36]([O:45][CH2:46][CH3:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:48])[C@@H:36]([O:45][CH2:46][CH3:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:11][CH2:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:40][CH:39]=1)[CH3:33]
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1)OCC
Yield: 75.5 %

Procedure:
Reaction of 3,3-bis-(4-bromophenyl)-prop-2-en-1-ol (2.60 g, 7.0 mmol), tributylphosphine (2.52 g, 10.0 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.50 g, 6.3 mmol) and azodicarboxylic dipiperidide (2.02 g, 10.0 mmol) in an identical manner to example 3 gave the title compound (2.8 g, 75%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To an ice-cold mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (4.00 g, 3.43 mmol), and triethylamine (4.43 g, 43.8 mmol) in tetrahydrofuran (70 mL) was added 2,2,2-trichloroethyl chloroformate (3.06 g, 14.4 mmol) and the mixture was stirred at room temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was filtered through a pad of silica gel eluted with ethyl acetate to afford a white solid. The solid was triturated with hexane to give the title compound (2.54 g, 47%) as a white solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:23]([C:24](OC)=[O:25])=[CH:22][C:21]3[CH:28]=[CH:29][S:30][C:20]=3[S:19]2(=[O:32])=[O:31])=[CH:14][CH:13]=1>C1COCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:23]([CH2:24][OH:25])=[CH:22][C:21]3[CH:28]=[CH:29][S:30][C:20]=3[S:19]2(=[O:32])=[O:31])=[CH:14][CH:13]=1
Reactant: COC(=O)C1=Cc2ccsc2S(=O)(=O)N1c1ccc(OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2C(CO)=Cc3ccsc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
A 1M solution of DIBAL in THF (45 mL, 45 mmol) was added to a solution of the product from Step C (1.92 g) in anhydrous THF (100 mL) and this mixture was stirred at ambient temperature for 18 h. After cooling (ice bath) the reaction was quenched by the addition of 1N HCl (100 mL). This mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 50% ethyl acetate/hexane) to give a viscous oil (1.19 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:5].[CH3:23][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH3:23])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@H](O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-chloro-N-(4-formylcyclohexyl)-5-(trifluoromethyl)-benzamide (1.00 g, 3.00 mmol) in THF (50 mL) is added methylmagnesium bromide 2.5 mL of a 3M solution in THF, 7.49 mmol,) and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with water and partitioned between EtOAc and water. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo. The mixture is used directly in step 2 without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([Br:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
16.52 g (100 mmol) of 2-pyridylacetic acid ethyl ester is dissolved in 50 ml of carbon tetrachloride. It is cooled to 0° C. and 15.98 g (100 mmol) of bromine, dissolved in 15 ml of carbon tetrachloride, is then instilled in it within 30 minutes. Then, it is allowed to react for one more hour at 25° C. The bromine coloring fades away. It is concentrated by evaporation in a vacuum and the hydrobromide of the title compound is obtained. The free compound is obtained by extraction of ether from the aqueous solution after the addition of sodium bicarbonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Yield: 40.7 %

Procedure:
A solution of 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 28(B)(a), 94.5 mg, 0.23 mmol) in methanol (15 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 40 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (36.8 mg, 40.3%) as a white solid: mp 95–98° C.; EI-HRMS m/e calcd for C19H21ClN2O3S (M+) 392.0961, found 392.0989.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[NH:6][C:5]1=[O:30])[CH2:2][CH3:3].[F:31][CH:32]([F:37])C(OCl)=O.[Na].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[F:31][CH:32]([F:37])[O:30][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[N:6]=1
Reactant: O=C(OCl)C(F)F
Reactant: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(OC(F)F)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (100 mg, 0.24 mmol), Sodium chloro difluoroacetate (47 mg, 0.31 mmol), Cs2CO3 (117 mg, 0.36 mmol) and DMF (2 ml) were stirred at 60° C. for 18 hours. Reaction mixture was cooled and diluted with water (10 ml), solid materials were filtered off and it was purified by preparative HPLC to obtain 2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as off white solid (1 mg, 10%) and
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.[O:39]1CCOCC1>O>[CH:14]1([CH:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:39])[CH:11]=2)[OH:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OC(c1cc(Br)nc2ccccc12)C1CCCCC1
Reactant: C1COCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Product: Oc1cc(C(O)C2CCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of 2-bromo-α-cyclohexyl-4-quinolinemethanol (100 mg, 0.31 mmol) in dioxan (1 mL) was treated with 1-M HCl, stirred at room temperature for 16 h, refluxed for 24 h, cooled, diluted with water (5 mL), the resulting solid filtered and dried under vacuum to give the title compound (58 mg, 73%) as a white solid: mp>250° C.; IR νmax (Nujol)/cm−1 3451, 2956, 2924, 2854, 1649, 1546, 1437, 1103, 886 and 760; NMR δH (400 MHz, DMSO-d6) 1.07-1.29 (5H, m), 1.53-1.69 (6H, m), 4.77 (1H, t, J 4.5 Hz), 5.38 (1H, d, J 4.6 Hz), 6.50 (1H, s), 7.18 (1H, t, J 7.0 Hz), 7.34 (1H, d, J 7.6 Hz), 7.49 (1H, t, J 7.0 Hz), 7.84 (1H, d, J 7.6 Hz) and 11.64 (1H, s); M/Z 258 (M+H)+.
Reaction SMILES: Br[C:2]([CH3:11])([CH3:10])[C:3]([NH:5][C:6]([NH:8][CH3:9])=[O:7])=[O:4].[Na+].[C:13]([O:16][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:28]([NH:29][C:30](=[O:39])/[C:31](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:32]\[OH:33])[C:27](=[O:40])[N:22]2[C:23]=1[C:24]([O-:26])=[O:25])(=[O:15])[CH3:14].CCO>CS(C)=O>[C:13]([O:16][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:28]([NH:29][C:30](=[O:39])/[C:31](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:32]\[O:33][C:2]([C:3]([NH:5][C:6]([NH:8][CH3:9])=[O:7])=[O:4])([CH3:11])[CH3:10])[C:27](=[O:40])[N:22]2[C:23]=1[C:24]([OH:26])=[O:25])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Reactant: CNC(=O)NC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CNC(=O)NC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Yield: 76 %

Procedure:
This compound was prepared from 1-(2-bromo-2-methylpropionyl)-3-methylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. [α]D22 +84.6° (c 0.65, DMSO), λmax (EtOH) 274 nm (ε 16,900), νmax (Nujol) 3340 (NH), 3700-2100 (bonded OH), 1790 (β-lactam), 1740 (OCOCH3), 1700 (CO2H), 1690, 1540 cm-1 (--CONH--, --CONHCONH--), τ (DMSO d6) 2.25, 3.2, 3.35 (fur-2-yl), 8.51, 8.52 (C(Me)2), 0.5 (--CONHCO), 1.75 (CONHMe), 7.28 (CONHMe), 4.1 (7 H), 4.75 (6 H), 6.28, 6.50 (2 CH2), 4.97, 5.29 (3 CH2), 7.9 (OCOCH3). Yield: 76%.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:11]([CH3:14])([O-])=O.CN(C)C(=N)N(C)C>C(O)C>[CH:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][CH:1]([OH:10])[CH2:14][NH2:11])=[CH:5][CH:6]=1
Reactant: C[N+](=O)[O-]
Reactant: O=CCCc1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: CCO
Product: NCC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.70 g of dihydrocinnamaldehyde are dissolved in 20 ml of anhydrous ethanol, and 10 ml of nitromethane and 1 ml of tetramethylguanidine are added, and the mixture is stirred at RT for 1 h. It is concentrated in vacuo, the residue is taken up in 200 ml of ethanol and 5 ml of glacial acetic acid, 10 g of activated Raney nickel are added and the mixture is then hydrogenated at 50° C. and under 25 bar H2 pressure for 5 h. The catalyst is then filtered off, the filtrate is concentrated in vacuo, the residue is taken up in saturated aqueous sodium bicarbonate solution, and non-polar impurities are removed by extraction with diethyl ether. Extraction 3 times with tetrahydrofuran, drying over sodium sulfate, and concentration in vacuo provides 5.75 g of (D,L)-4-phenyl-2-hydroxy-1-butylamine as a colorless oil.
Reaction SMILES: COS([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)(=O)=O.[C-:22]#[N:23].[Na+]>CN(C=O)C>[N:13]1([C:9]2[CH:8]=[C:7]([CH2:6][C:22]#[N:23])[CH:12]=[CH:11][CH:10]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: [C-]#N
Reactant: COS(=O)(=O)Cc1cccc(N2CCc3ccccc32)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(N2CCc3ccccc32)c1
Yield: 80.7 %

Procedure:
A mixture of 10.2 g (ca. 33.8 mmole) of 3-(1-indolinyl)benzenemethanesulfonic acid methyl ester of Example 20c and 4.97 g (101.4 mmole, 3.0 equiv.) sodium cyanide in 200 ml sieve dried DMF was heated at 60°-70° C. for 50 minutes. The product was concentrated under high vacuum at 50°-60° C. and the residue was partitioned between chloroform (200 ml) and water (200 ml). The organic portion was washed twice with 200 ml water, 200 ml brine, dried over Na2SO4 and concentrated under vacuum to give 6.39 g (80.7%) of product. Kugelrohr distillation of a 0.8 g sample gave 0.6 g of an oil of 3-(1-indolinyl)benzeneacetonitrile, b.p. 189°-192° C./0.15 mm.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[C:36]1([CH2:42][C:43]([N:16]2[CH2:15][CH:14]([O:13][C:12]3[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17]2)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (5.8 g. 0.019 mole) and triethylamine (2.3 g, 0.023 mole) in chloroform (75 ml) was slowly dropped phenylacetyl chloride (3.5 g. 0.023 mole) in chloroform (10 ml). After stirring at ambient temperature overnight the reaction mixture was concentrated to an oil. The oil was dissolved in ether, then washed with water, dilute HCl (10%), again with water and dried (saturated NaCl, anhydrous (MgSO4). The solution was filtered, concentrated to an oil which was extracted with boiling hexanes and then concentrated to an oil (6.8 g, 84%). A sample was distilled to yield an oil of 3-phenylacetyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, 240°-250° C./0.1 mm.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[C:19](=O)(O)[O-:20].[Na+]>CN(C)C=O>[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([CH:19]=[O:20])=[CH:10][CH:11]=1
Reactant: Cc1ccc(-n2cccc2Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2c(Cl)ccc2C=O)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (747 μl) was added dropwise to N,N-dimethylformamide (7 ml) at 5° C. The mixture was stirred at 5° C. for 15 minutes and at ambient temperature for 15 minutes. To the mixture was added a solution of 2-chloro-1-(4-methylphenyl)pyrrole (1.2 g) in N,N-dimethylformamide (7 ml) at ambient temperature. The mixture was stirred at the same temperature for one hour and at 50° C. for 2.5 hours. After cooled to ambient temperature, the mixture was treated with saturated aqueous sodium bicarbonate solution. The separated oil was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was column chromatographed on silica gel to yield 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde (377 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7](Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>>[C:7]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: COCC(C)O
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)OC(C)COC

Procedure:
In the forgoing reaction, 1-methoxy-2-propanol is reacted with methacryloyl chloride to yield 1-methyl-2-methoxyethyl methacrylate. 1-methoxy-2-propanol and methacryloyl chloride are commercially available compounds (e.g., 1-methoxy-2-propanol is available from the Dow Chemical Company under the product name of “Dowanol PM”).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:17][O:18][CH2:19]Cl.O>CN(C)C=O>[Cl:3][C:4]1[C:14]([O:15][CH2:17][O:18][CH3:19])=[CH:13][CH:12]=[C:11]([Cl:16])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COCCl
Reactant: CCOC(=O)c1c(Cl)ccc(O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cl)ccc(OCOC)c1Cl
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in oil, 474 mg) in N,N-dimethylformamide (2 ml) was added a solution of ethyl 2,6-dichloro-3-hydroxybenzoate (2.42 g) in N,N-dimethylformamide (10 ml) under nitrogen at ambient temperature and the mixture was stirred for 1 hour at the same temperature. Chloromethyl methyl ether (1.15 ml) was added thereto and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:8, V/V) to give ethyl 2,6-dichloro-3-(methoxymethoxy)benzoate (2.58 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[C:26]([CH2:28][NH2:29])[CH:25]=[CH:24][C:21]=43)[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1.[O-:31][C:32]#[N:33].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[C:21]4[CH:24]=[CH:25][C:26]([CH2:28][NH:29][C:32]([NH2:33])=[O:31])=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1
Reactant: N#C[O-]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(CN)cc2OCC3)n(-c2ccc(F)cc2F)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CNC(N)=O)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
C-{2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-methylamine in acetic acid and water was reacted with potassium cyanate in water to give 354. MS(ESI+) 452.1. 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.68 (td, J=8.7, 6.2 Hz, 1H), 7.62-7.54 (m, 2H), 7.32-7.25 (m, 1H), 6.87-6.80 (m, 2H), 6.44 (t, J=6.1 Hz, 1H), 5.57 (br, 2H), 4.49-4.38 (m, 4H), 4.12 (d, J=6.1 Hz, 2H), 2.35 (s, 3H)