Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClC(Cl)C.O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH:19]([C:20]([CH:19]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reaction time: 1 h
Yield: 82 %

Procedure:
120 kg (1.09 kmole) of resorcinol were suspended in 660 l of dichlorethane and 150 kg (1.12 kmole) of anhydrous aluminum chloride were added to the suspension while the temperature raised from 15° C. to 25° C. The complex obtained dissolved in the reaction medium. 171 kg (1.10 kmole) of phenyl-acetyl chloride were added over a period of one hour while the temperature raised to 35°-40° C. The mixture was stirred for one hour thereafter it was admixed with diluted hydrogen chloride (the mixture of 300 l of hydrogen chloride and 600 l of water), and it was treated as described in the preceding Examples. The solvent was removed by distillation, the residue was recrytallized from toluene, the product obtained was centrifuged and dried at 45°-50° C. 205-210 kg of 2,4-dihydroxy-phenyl-benzyl-ketone were obtained, yield 82-84.5%. Calculated amount: 248.5 kg. The physical data are identical with the data given in Example 1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)COc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
In 20 ml of methanol is dissolved 4.1 g of methyl 2-isobutoxybenzoate. After adding 6 ml of 5 mol/L solution of sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 2 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 3.9 g of 2-isobutoxybenzoic acid is obtained as a colorless crystalline product.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C@H:16]([OH:25])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30].CCOCC.[ClH:37]>C1COCC1.CCOCC>[ClH:37].[CH2:30]([O:25][C@H:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][CH2:20][C@@H:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: O[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Reaction time: 0.5 h

Procedure:
0.2 g (0.596 mmol) of (±)-cis-7-[(4-phenylpiperdin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol dissolved in 5 ML THF were added dropwise to a suspension of 0.029 g (0.715 mmol) of NaH (60% dispersion in mineral oil) in 10 mL THF. After 30 min at room temperature, 0.12 mL of allyl bromide were added and the reaction mixture was refluxed 8 h. After cooling, the reaction mixture was quenched by addition of MeOH and the solvent was removed in vacuo. The residue was taken up in 1 N NaOH and extracted with CH2Cl2; the organic phase was dried and the solvent was removed in vacuo. The resulting crude product was purified by chromatography, eluting with a mixture CH2Cl2/MeOH 100:2 respectively, yielding an oil which was dissolved in Et2O; the solution was brought to acidic pH with Et2O/HCl and the solvent was removed in vacuo. The resulting solid was triturated with Et2O, yielding 65 mg of the title product. m.p. 126-128° C.
Reaction SMILES: O1CCCC1.[CH2:6]([NH2:8])[CH3:7].[CH2:9]([C:11]1[CH:12]=[C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)[CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:23][N:24]=1)=[CH:16]2)[CH3:10].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:6]([NH:8][C:26](=[O:27])[CH2:25][CH:22]1[S:21][C:20]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[CH:12][C:11]=3[CH2:9][CH3:10])=[N:24][CH2:23]1)[CH3:7]
Reactant: CCN
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(CC)c3[nH]2)S1
Reaction time: 15 h
Yield: 44 %

Procedure:
To a mixed solution of 2.0M-ethylamine tetrahydrofuran solution (0.33 mL), [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), and N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (89 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio), and the obtained pale-yellow oil was recrystallized from ethyl acetate-hexane to give the title compound (92 mg, yield 44%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[NH:25][C:26](=[N:29][C:30]([O:32][C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:31])[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1.[OH-].[Na+].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:23])[C:24]4[N:25]=[C:26]([NH:29][C:30]([O:32][C:33]([CH2:36][CH3:37])([CH3:34])[CH3:35])=[O:31])[S:27][CH:28]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Reaction time: 0.17 h

Procedure:
To a solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.36 g.) in methanol (35 ml.) was added 1N sodium hydroxide aqueous solution (5.5 ml.) under ice-cooling, and to the mixture was dropwise added an aqueous solution of sodium borohydride (91 mg.) in water (2.5 ml.) over 2 minutes at 10° to 15° C. The mixture was stirred for 10 minutes at the same temperature, and the methanol was distilled off from the mixture below 40° C. under reduced pressure. The remaining aqueous solution was washed with a small amount of ethyl acetate, adjusted to pH 5 to 6, with 10% hydrochloric acid, further washed with a small amount of ethyl acetate. The solution was adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then treated with an activated charcoal. The solvent was distilled off from the extract till the volume of the extract became a smaller amount. The precipitates were collected by filtration, washed with a small amount of ethyl acetate, and then dried to give 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (1.69 g.). On the other hand, the mother liquor and the ethyl acetate washing were combined together and concentrated under reduced pressure, and then the precipitates were similarly treated as aforementioned to give the same object compound (0.80 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COc1ccc(Br)c([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
1.0 g (4.3 mmol) 4-bromo-3-nitroanisole is nitrated by dropwise addition of 1.0 ml of a mixture of 0.4 ml nitric acid (100%) and 0.6 ml concentrated sulfuric acid. Stirring is continued for 1 h. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine (2×), dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 630 mg of the title compound as yellow crystals.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15].C(OCC)(=O)C.[ClH:22]>O.[Cu]Cl>[Cl:22][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A saturated solution of sodium nitrite (1.8 g, 26.0 mmol) in water (12 mL) was added dropwise to a suspension of 2-amino-5-nitro-phenol (2.0 g, 13.0 mmol) in concentrated hydrochloric acid (10 mL) at 0° C. and stirred for 30 min. In another flask, copper (I) chloride (5.15 g, 52.0 mmol) and concentrated hydrochloric acid (20 mL) were heated to between 60 and 70° C. and the diazonium salt solution was added dropwise to this over a period of 30 min. The reaction mixture was heated to 80° C. and stirred for 15 min. It was then cooled to room temperature and ethyl acetate (50 mL) was added and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with water (4×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent to afford 2-chloro-5-nitro-phenol (2.08 g, 92%) as a crystalline yellow solid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH:38]C=O)[S:36][CH:37]=1)[C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH2:2][CH3:3].Cl>>[CH2:1]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH2:2][CH3:3]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(N)n1
Yield: 52.4 %

Procedure:
7-[2-n-Propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.20 g.) was treated with conc. hydrochloric acid (0.56 g.) according to a similar manner to that of Example 12 to give 7-[2-n-propoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.10 g.).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
A mixture of 0.15 g (0.33 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246), 0.133 g (1.32 mmole) of triethylamine, 0.186 g (0.49 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.056 g (0.49 mmole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.140 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-247).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=2)[CH2:23]Cl)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:9]([O:8][P:1]([CH2:23][C:22]1[CH:25]=[C:18]([CH2:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:11][CH3:12])=[CH:28][CH:27]=2)[CH:19]=[CH:20][C:21]=1[F:26])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCc1ccc(Cc2ccc(F)c(CCl)c2)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1F)OCC
Temperature: 155 °C
Reaction time: 16 h

Procedure:
Triethyl phosphite (0.8 mL) was added to [5-(4-ethylbenzyl)-2-fluorobenzyl chloride (0.65 g), and the mixture was stirred for 16 hr at 150-160° C. The mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to give the title compound (0.70 g) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:7])[CH2:4][CH2:5][Br:6].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:6][CH2:5][CH2:4][C@@H:3]([CH2:2][Br:1])[O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O[C@H](CBr)CCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H](CBr)CCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of (S)-1,4-dibromo-2-butanol (5.0 g) in N,N-dimethylformamide (30 mL) were added imidazole (1.91 g) and tert-butylchlorodiphenylsilane (7.1 mL) under ice-cooling, followed by stirring the mixture at room temperature for 13 hours. To the reaction mixture were further added imidazole (0.59 g) and tert-butylchlorodiphenylsilane (1.77 mL), followed by stirring the mixture at room temperature for 7 hours To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:50) to give ((S)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane (8.56 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[CH:6]=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
1.5 g of 2-imidazole carboxaldehyde was dissolved in 20 ml of dimethylformamide, 2.18 ml of triethylamine and 4.3 g of triphenylmethyl chloride were added to the above solution, and then the resulting mixture was stirred at room temperature for 24 hours. A saturated sodium bicarbonate aqueous solution and chloroform were added to the reaction solution, and the resulting organic layer was collected, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to silica gel chromatography eluted with dichloromethane-methanol (50:1) to obtain 4.717 g of 1-triphenylmethyl-2-imidazole carboxaldehyde.
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:2])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3ncc(Cl)cc32)CC1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1Cc2ncc(Cl)cc2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (195 ml) of tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (13.0 g) was added dropwise at −78° C. a tetrahydrofuran solution (1 M, 39.1 ml) of lithium hexamethyldisilazide. After stirring at the same temperature for 30 minutes, a tetrahydrofuran solution (65 ml) of methyl iodide (2.65 ml) was added dropwise. After stirring at the same temperature for 10 minutes and under ice cooling for 1 hour, ethyl acetate and water were added to the reaction solution, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3-methyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (12.2 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:9][CH2:10][C:11]#[N:12]>>[C:1]([NH:12][CH2:11][C:10]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#CCN
Agent: Cl
Product: CC(C)(C)C(=O)NCC#N

Procedure:
The compound was prepared according to Example 1 a) from 36.17 g pivaloylchloride and 27.76 g aminoacetonitrile hydrochloride
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[S:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:25])[CH2:19][C:20](=O)[CH:21](Br)[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:16][O:17][C:18](=[O:25])[CH2:19][C:20]1[N:13]=[C:11]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[S:12][C:21]=1[CH3:22]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=S)c1ccc(-c2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)Cc1nc(-c2ccc(-c3ccccc3)nc2)sc1C
Yield: 56.6 %

Procedure:
A mixture of 6-phenyl-thionicotinamide (7.0 g) and 4-bromo-3-oxo-pentanoic acid methyl ester (9.15 g, 35 mmol) in 1,4-dioxane (30 mL) was heated at reflux for 4 h. The reaction mixture was cooled, poured into aqueous saturated NaHCO3, and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc, 2/1) to afford the title compound (6.0 g, 56%). MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CCOCC>[CH2:30]([O:29][C:27]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:9])[CH2:7][CH3:8])=[O:28])[CH3:31]
Reactant: CCC(O)(NCc1ccccc1N)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccccc1CNC(O)(CC)c1ccccc1

Procedure:
2.6 g (0.01 mole) of N-2-amino-benzyl-1-phenyl-2-methyl-amino-1-ethanol are dissolved in 30 ml of ether. To the solution 0.79 g (0.01 mole) of anhydrous pyridine are added, whereupon 1.3 g (0.012 mole) of ethyl chloroformate are added under vigorous stirring and cooling and the reaction is carried out at 15° C. The reaction mixture which contains a white precipitate is stirred at room temperature for 330 minutes, poured into 30 ml of icecold water, the aqueous phase is extracted three times with 100 ml of ether each, the united ether extracts are dried over anhydrous sodium sulfate and evaporated in vacuo. Thus 2.8 g of N-[2-ethoxycarbonylamino-benzyl]-1-phenyl-2-methyl-amino-1-ethanol are obtained in the form of a yellowish-white oil which can be subjected to further reaction without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 49 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.