Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][C:18]1[C:22]([C:23]2[CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:26]3[NH:30][C:29](=[O:31])[NH:28][C:27]=3[CH:32]=2)=[C:21]([CH3:42])[O:20][N:19]=1.N12CCCN=C1CCCCC2.CS(C)=O>O>[CH3:17][C:18]1[C:22]([C:23]2[CH:24]=[C:25]([C:2]3[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[C:26]3[NH:30][C:29](=[O:31])[NH:28][C:27]=3[CH:32]=2)=[C:21]([CH3:42])[O:20][N:19]=1
Reactant: FC(F)(F)Oc1ccc2ncccc2c1Br
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2c(OC(F)(F)F)ccc3ncccc23)c2[nH]c(=O)[nH]c2c1

Procedure:
A solution of 5-bromo-6-(trifluoromethoxy)quinoline (obtained by bromination of 6-trifluoromethoxyquinoline) (50 mg, 0.17 mmol), 6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (91 mg, 0.26 mmol), dichloro 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (12.7 mg, 0.02 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL, 1.37 mmol), DMSO (0.2 mL) and water (0.2 mL) under nitrogen was heated at 120° C. for 1 h. The reaction mixture was filtered and purified by reverse-phase HPLC to give 6-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethoxy)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].CC(C[AlH]CC(C)C)C>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH2:7][OH:8])[CH:12]=1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc(Br)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-bromo-2-chlorobenzoate (1 eq.) in THF (0.03 M) was added, at −78° C., DIBAL (2.5 eq). The reaction was stirred at −78° C. for 1 h and then warmed slowly to RT over 1 h. The reaction mixture was then diluted with ether and carefully quenched with aq. 6 M HCl. The organic layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a white semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:23][CH:24]1[C:33]2[C:28](=[C:29]([O:34][CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([CH:5]3[CH2:4][CH2:3][CH2:2][N:23]3[CH:24]3[C:33]4[C:28](=[C:29]([O:34][CH3:35])[CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2c1CCCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc2c1CCCC2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-5-methoxy-1,2,3,4-tetrahydronaphthalene (0.9 g) in CH2Cl2 (20 ml) was added SOCl2 (3 ml). After being stirred for 4 hours, the solvent was removed. The residue was dissolved in CH3CN (20 ml) and K2CO3 (5 g) was added to the solution. After being stirred for 4 hours under reflux, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-methoxy-1,2,3,4-tetrahydronaphthalene (0.57 g). MS (m/z): 451 (M+ +1) IR (Neat): 1580 cm-1NMR (CDCl3, δ): 1.5-2.3 (8H, m), 2.4-3.2 (4H, m), 3.69 and 3.76 (3H, each s), 4.0-4.2 (2H, m), 6.4-6.72 (3H, m), 7.3-7.7 (10H, m)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16])[CH3:13]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:18]([NH:17][C:15](=[O:16])[O:14][CH2:12][CH3:13])=[S:19])[N:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1cc(OC)nc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
2-Amino-4,6-dimethoxypyrimidine (5.0 g, 36 mmol) was dissolved in dry tetrahydrofuran (THF, 35 mL), ethoxycarbonylisothiocyanate (6.4 mL, 54 mmol) was added and the solution was allowed to stir at room temperature. After 24 hours, the solvent is removed in vacuo and the residue was mixed with ether to form a crystalline solid. The solids were removed by vacuum filtration and dried to afford ethyl [(4,6-dimethoxypyrimidin-2-yl)amino]carbono thioylcarbamate as a tan solid (8.9 g, 87%). mp 196-197° C. 1H NMR (CDCl3): δ 13.2 (bs, 1H); 8.8 (bs, 1H); 5.80 (s, 1H); 4.32-4.25 (q, 2H, J=7.2); 3.93 (s, 3H); 1.30 (t, 3H, J=7.2).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:4][C:3]=1B(O)O.[Br:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>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>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:7]([F:8])[C:2]=2[F:1])=[CH:25][CH:24]=1
Reactant: CCCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Yield: 87.5 %

Procedure:
Quantities: tetrakis(triphenylphosphine)palladium(0) (0.87 g, 0.75 mmol), compound from Example 47 (9 g, 30 mmol) and 1-bromo-4-iodobenzene (7.07 g, 25 mmol). The experimental procedure was as described in Example 48 except that the reaction was carried out under conditions of reflux (5 h). The crude product was purified by flash column chromatography (light petrol/dichloro methane, 5:1) to give a colourless solid (9 g) which was recrystallised from light petrol to yield colourless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1>CN(C=O)C>[CH3:1][C:2]1([C:18]([NH:60][C:59]2[CH:61]=[CH:62][C:56]([CH3:55])=[CH:57][CH:58]=2)=[O:19])[CH2:3][CH2:4][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(C)CCN(c3ncnc4[nH]cc(C)c34)CC2)cc1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from example 6, step B, (0.020 g, 0.073 mmol) in DMF (1 mL) were added BOP reagent (0.065 g, 0.15 mmol), triethylamine (0.019 mL, 0.15 mmol), and 4-methylaniline (0.012 mL, 0.11 mmol). The reaction was stirred overnight and concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.0133 g, 50%).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH2:31]([OH:34])[C:32]#[CH:33].C(N(CC)CC)C>C1COCC1.[Cu]I.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:33]#[C:32][CH2:31][OH:34])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2c(C#CCO)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (195 mg, 0.372 mmol), propargyl alcohol (0.033 mL, 0.558 mmol), copper(I) iodide (7.09 mg, 0.037 mmol), bis(triphenylphosphine)palladium(II) chloride (10.45 mg, 0.015 mmol) and triethylamine (0.156 mL, 1.117 mmol) in THF (1.7 mL) was stirred under an atmosphere of nitrogen at 70° C. for 3 h. The mixture was allowed to cool to RT, with stirring, over the weekend. The mixture was then partitioned between a saturated aqueous solution of NaHCO3 (25 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with additional ethyl acetate (25 mL). The organic extracts were combined, washed with brine (25 mL), dried with anhydrous MgSO4, filtered and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-100% cyclohexane in ethyl acetate. Further purification on silica, eluting with 0-50% cyclohexane in ethyl acetate, afforded the title compound (14 mg) LCMS (A) m/z: 499 [M+1]+, Rt 1.24 min (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH2:33])[S:25][C:26]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[NH:33][C:24]1[S:25][C:26]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:23]=1)([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-2-methyl-propionic acid (1.5 eq) and 4-(4-Fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-ylamine (1 eq)) in DMF (50 mL) were added HATU (1.5 eq) and TEA (2 eq). Reaction was stirred at 60 C over night. Aqueous work up followed by silica gel chromatography afforded the title compound. LCMS Method A Rt=1.51 (M+1=465.1, M−1=463.1). 1H NMR (400 MHz, DMSO-D6) 1.21 (s, 1H) 1.28-1.40 (m, 14H) 2.80-2.87 (m, 4H) 3.70-3.77 (m, 4H) 7.21-7.27 (m, 2H) 8.10-8.16 (m, 2H) 11.59 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)c1

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 3-methoxybenzyl chloride (0.6 g; 3.85 mmol) and K2CO3 (1.5 g; 10.9 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (10 ml) and hydrochloric acid (6 N; 30 ml). Pure 5-amino-1-(3-methoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.06 g) precipitates by pouring the reaction mixture into ice-water.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:19](COCC[Si](C)(C)C)[C:18]4[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:17]=4[N:16]=3)[C:11](=[O:36])[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)(C(F)(F)F)=O.ClCCl>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[CH:28][C:18]2[NH:19][C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[C:3]([C:2]([F:1])([F:37])[F:38])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:10][C:11]3=[O:36])=[N:16][C:17]=2[CH:31]=1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2=O)nc2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A solution of 4-(3-trifluoromethyl-pyridin-2-yl)-1-[5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-piperazin-2-one from step (c) above (114 mg, 0.2 mmol) in 30% TFA in dichloromethane (3 mL) was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 430 (M+1).
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][C:5]1[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CCOCC>[CH3:4][C:5]1[C:10]([C:11]([OH:13])([CH3:1])[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)c1cccnc1C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: Cc1ncccc1C(C)(C)O
Temperature: 25 °C
Yield: 61.9 %

Procedure:
MeMgBr (3.0 M in Et2O, 4.63 ml, 13.9 mmol) was added dropwise via syringe to a solution of 1-(2-methyl-pyridin-3-yl)-ethanone (1.88 g, 13.9 mmol) (Sanders et al. J. Org. Chem. 1978, 43, 324) in Et2O (60 mL) to give a white slurry. The mixture was refluxed for 16 h, cooled to room temperature, quenched with water (50 mL) and extracted with CH2Cl2 (7×60 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) afforded 2-(2-methyl-pyridin-3-yl)-propan-2-ol as a white crystalline solid (1.30 g, 62%). 1H NMR (CDCl3) δ 1.67 (s, 6H), 2.79 (s, 3H), 7.08 (m, 1H), 7.75 (d, 1H, J=7.5 Hz), 8.36 (d, 1H, J=3.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:11]([CH3:13])([CH3:12])[CH2:10][Cl:9])[CH:3]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(CCl)c1cc(Cl)ccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chlorophenol (12.6 g, 0.1 mol) and 3-chloro-2-methyl-propene (10.8 g, 0.12 mol) was added concentrated sulfuric acid (5 g, 0.05 mol) and stirred at 0° C. for 1 hour. The mixture was diluted with cold water and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford 4-chloro-2-(1-chloro-2-methylpropan-2-yl)phenol (721).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:12]([O:11][CH:8]([CH3:9])[CH2:7][C:1]1[CH:6]=[CH:5][C:4]2[C:3](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:2]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)Cc1ccc2ccccc2c1
Reaction time: 4 h

Procedure:
In a four-necked flask equipped with a thermometer and stirrer, were placed 15.1 g (0.08 mole) of the compound (XII-1) obtained in Preparation Example 1, 50 ml of toluene and 20 ml of pyridine, thereafter 10.2 g (0.1 mole) of acetic anhydride and 0.1 g of 4-dimethylaminopyridine was added thereto, and the resulting mixture was stirred at 40°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of 4N hydrochloric acid to conduct extraction and layer separation. The organic layer obtained was washed successively with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water. The organic layer was then concentrated under reduced pressure to obtain 18.2 g of 2-(2-acetoxypropyl)naphthalene (XIII-1). Yield: 99 0%, nD20 1,5413
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].C(NC1C=C([C:43]2[C:48]([C:49]([C:51]3[C:52]([C:57]4C=CC=[C:59]([NH:63][C:64](=[O:66])[CH3:65])[CH:58]=4)=NC=C[CH:56]=3)=O)=[CH:47][CH:46]=[CH:45][N:44]=2)C=CC=1)(=O)C>O1CCCC1>[C:64]([NH:63][C:59]1[CH:56]=[C:51](/[C:49](/[C:48]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:7]\[CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH:52]=[CH:57][CH:58]=1)(=[O:66])[CH3:65]
Reactant: CC(=O)Nc1cccc(-c2ncccc2C(=O)c2cccnc2-c2cccc(NC(C)=O)c2)c1
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(/C(=C\CCCC#N)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 25.5 g of 4-cyanobutyl-triphenylphosphonium bromide and 14 g of potassium tert.butoxide in 200 ml of tetrahydrofuran are added, at -40° C., 12 g of 3-acetylaminophenyl-3-pyridylketone. The mixture is stirred for 3 hours at ambient temperature and the reaction mixture is decomposed by the addition of 50 ml of ice water. The mixture is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue is purified over a silica gel column with dichloromethane/ethanol=40:1. The product fraction is evaporated down and the residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:24]1[N:25]=[C:26]([NH:29][CH:30]=[O:31])[S:27][CH:28]=1)[C:21]([OH:23])=O)=[O:16].C[Si](CC(N)=O)(C)C.[NH2:40][CH:41]1[C:59](=[O:60])[N:43]2[C:44]([C:56]([OH:58])=[O:57])=[C:45]([CH2:48][S:49][C:50]3[N:54]([CH3:55])[N:53]=[N:52][N:51]=3)[CH2:46][S:47][C@H:42]12.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(C)=O.C(OCC)(=O)C.O.CN(C)C=O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:24]1[N:25]=[C:26]([NH:29][CH:30]=[O:31])[S:27][CH:28]=1)[C:21]([NH:40][CH:41]1[C:59](=[O:60])[N:43]2[C:44]([C:56]([OH:58])=[O:57])=[C:45]([CH2:48][S:49][C:50]3[N:54]([CH3:55])[N:53]=[N:52][N:51]=3)[CH2:46][S:47][C@H:42]12)=[O:23])=[O:16]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCC(=O)Nc2cc(Cl)ccc2O)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cc(Cl)ccc3O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 40 °C
Reaction time: 0.83 h
Yield: 35.4 %

Procedure:
A mixture of N,N-dimethylformamide (10 ml.) and phosphorus oxychloride (0.507 g.) was warmed at 40° C. for 30 minutes and subsequently cooled to -10° C. and thereto was added 2-[N-(2-hydroxy-5-chlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.00 g.). The resulting mixture was stirred at -10° to -5° C. for 50 minutes. On the other hand, to a solution of trimethylsilylacetamide (3.60 g.) in methylene chloride (15 ml.) was added 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.003 g.). To this solution was added the stirred mixture obtained above at -25° C. followed by stirring at -20° to -10° C. for 2 hours. After concentration of the reaction mixture, to the residue were added a saturated aqueous solution of sodium bicarbonate (25 ml.) and water (50 ml.). The resulting mixture was washed with ethyl acetate and thereto was added ethyl acetate (100 ml.). The mixture was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated. The residue was triturated with diethyl ether and the precipitates were collected by filtration and then washed with diethyl ether to give a powder (1.0 g.), which was dissolved in a small amount of a mixture of acetone and ethyl acetate. This solution was washed with water twice, dried over magnesium sulfate and then concentrate to a small volume. To the concentrate was added diethyl ether followed by stirring at room temperature overnight. The precipitates were collected by filtration, washed with diethyl ether and dried to give the title compound (0.63 g.).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[O:12]1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:12][C@H:13]([CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C@@H:14]([OH:17])[C@H:15]2[OH:16])=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1n1cnc2c(Nc3ccc(F)cc3)ncnc21
Temperature: 22 °C
Yield: 46.6 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(2,2,2-trifluoroethoxymethyl)-tetrahydro-furan-3,4-diol (125 mg) in isopropanol (5 ml) under nitrogen was treated with 4-fluoroaniline (0.08 ml, 90 mg) and diisopropylethylamine (0.28 ml, 210 mg), and the mixture was heated under reflux for 24 h. After cooling to 22° C. the mixture was filtered, the filter cake washed with isopropanol (2 ml) and ether (15 ml) and the solid dried in vacuo to give the title compound as a white solid (70 mg), m.p. 214-5°.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=1[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(#N)C>[Cl:13][C:14]1[C:15]2[CH2:21][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:6](=[O:7])[NH:20][C:16]=2[N:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CNCc2c(Cl)ccnc2N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (583 mg, 3.56 mmol) was added to a solution of 4-chloro-3-((4-methoxybenzylamino)methyl) pyridin-2-amine (100 mg, 1.19 mmol) in acetonitrile (5 mL), and stirred for 1 h at room temperature. The resulting precipitate was filtered, and washed with H2O and MeOH, to provide 1 as a solid. LC-MS (M+H=303, obsd.=303. 1H NMR: (DMSO-D6) δ 3.74 (s, 3H); 4.34 (s, 2H); 4.52(s, 2H); 6.92 (d, 2H); 7.03 (d, 1H); 7.26 (d, 2H); 8.03 (d, 1H); 10.08 (s, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O=O.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[CH:10]1.[OH-].[Na+]>O.C1COCC1>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:10]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: O=O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiAlH4 (1.14 g, 30 mmol) was initially introduced into dry THF (100 ml) with exclusion of oxygen. 4-(1H-Indol-3-yl)butanoic acid (2.03 g, 10 mmol, dissolved in 80 ml of dry THF) was added dropwise to the suspension in the course of 30 min. Thereafter, the mixture was heated under reflux at the boiling point for 3 h. The reaction mixture was stirred at room temperature overnight. Water (30 ml) was then cautiously added to the mixture. The mixture was stirred for 20 min and 2N NaOH (10 ml) was added. The organic phase was separated off and the aqueous solution which remained was extracted with diethyl ether (3×40 ml). The ethereal solution was dried over Na2SO4 and concentrated to dryness on a rotary evaporator. Ind-57 was obtained in this way in a yield of 1.8 g