Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:13]=1.[OH-].[Na+]>CO>[O:23]=[C:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:24])=[O:2])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1

Procedure:
700 mg (2.15 mmol) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester is mixed in 15 ml of methanol with 2.7 ml of 1N sodium hydroxide solution and refluxed for 1 hour. After the methanol is distilled off in a vacuum, it is diluted with water and shaken once with ethyl acetate. The aqueous phase is mixed with 5 ml of 1-molar citric acid solution and stirred overnight. The solid precipitation is suctioned off and quickly dried. 600 mg of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid, which is used as a crude product in the next stage, is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]([CH3:27])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>>[CH3:27][N:9]1[C:8]2[CH:28]=[CH:29][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:25])([F:24])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 95.7 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (185 mg) was prepared by following General Procedure E starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (200 mg) and lithium hydroxide (80 mg). LC/MS: m/z 409.9. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (s, 1H), 7.95 (s, 1H), 7.86 (d, 1H), 7.78-7.61 (m, 2H), 7.51 (d, 1H), 7.37 (d, 1H), 3.67 (s, 3H), —COOH proton signal was not observed.
Reaction SMILES: [H-].[Na+].[C:3]12([OH:13])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:14]([N:18]1[CH2:22][CH2:21][O:20][P:19]1Cl)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:3]12([O:13][P:19]3[N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:22][CH2:21][O:20]3)[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)N1CCOP1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCOP1OC12CC3CC(CC(C3)C1)C2
Temperature: 40 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A 500 ml, three neck flask equipped with a thermometer, an additional funnel and a condenser topped with a nitrogen sweep is charged with 2.62 g (0.06 mol) of sodium hydride. The sodium hydride is washed with two 20 ml portions of hexane and finally suspended in 30 ml of tetrahydrofuran. To the resultant suspension is added dropwise a solution of 9.12 g (0.06 mol) of 1-adamantanol in 75 ml of THF at such rate to keep the reaction temperature between 20°-30° C. The resulting yellow solution is warmed to approximately 40° C. for 1 hour and then cooled in an ice bath. A solution of 10.9 g (0.06 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 75 ml of THF is added and stirring continued for 16 hours at room temperature. The resulting cloudy mixture is filtered and the solvent evaporated under reduced pressure. The residue is treated with 200 ml of toluene and the resultant suspension is filtered. The filtrate is concentrated in vacuo to yield a thick syrup. Triturating with methanol gives 6.0 g (33.6%) of a white solid: m.p. 48°-50° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: CC(C)N(CCOc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1)C(C)C
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: CC(C)N(CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1)C(C)C

Procedure:
was prepared from (2-{[5-(2-Morpholin-4-yl-ethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (9) in an analogous manner to that described for the preparation of (1), example 1, step 5; yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:3]=1[O:4][C:5]1[O:9][C:8]([C:10]([O:12]C)=[O:11])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][C:3]=1[O:4][C:5]1[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2cc([Si](C)(C)C)ccc2C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc([Si](C)(C)C)cc1Oc1ccc(C(=O)O)o1
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of methyl 5-[2-methyl-5-(trimethylsilyl)phenoxy]furan-2-carboxylate (Intermediate 4; 217 mg, 0.71 mmol) in methyl alcohol (3 mL) at room temperature was added a solution of sodium hydroxide (126 mg) in water (1 mL) and the reaction stirred for 18 hours. The resulting mixture was concentrated under reduced pressure, the residue taken up in water and extracted into diethyl ether (1×20 mL). The aqueous layer was acidified with hydrochloric acid (1 M) and extracted with ethyl acetate (2×25 mL). The organic extracts were dried (magnesium sulphate) and concentrated under reduced pressure to give the title compound as a colourless powder (181 mg, 87%). Rf=0.21 (9:1, dichloromethane-methyl alcohol). LCMS Rt=4.33 minutes, m/z=291 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:32]>>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH:8]1[C:7]2[S:6][C:5]([C:3](=[O:2])[NH2:32])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:22])[CH3:23])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(=O)OC)sc21
Reactant: N
Solvent: CO
Product: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21

Procedure:
A solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (70 mg, 0.117 mmol) in methanol-ammonia (40 mL) was stirred at room temperature for 2 h. Then the mixture was concentrated to afford crude compound which was purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid methyl ester as light yellow oil. LC-MS (ESI & APCI): 401.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Reaction time: 16 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.4 g, 2.32 mmol) was diluted with THF (12 mL), treated with 4-methoxy-benzoyl chloride (0.353 g, 2.23 mmol) and stirred for 16 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.5 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])[O:6][CH2:7][CH3:8].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])=[O:19]
Reactant: CCOC(=N)c1ccccc1OC
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccccc1OC

Procedure:
starting from ethyl o-methoxybenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-o-methoxybenzimidate and therefrom with methylhydrazine there is obtained 3-(o-anisyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 74°-78° C.;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:18][CH:15]2[CH2:17][CH2:16]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: NC1CC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethyl-amino)-pyrimidine-5-carbonitrile was treated with cyclopropylamine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=254.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].C([Li])CCC.CN(C)[CH:28]=[O:29].Cl.[Na+].[Cl-]>O1CCCC1>[Cl:20][C:18]1[CH:17]=[C:4]([CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:8]([CH3:9])[CH3:10])[CH:11]([CH3:12])[CH3:13])[CH:3]=[C:2]([Cl:1])[C:19]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: CC(C)[Si](OCc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cc(Cl)c(C=O)c(Cl)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
[(3,5-Dichlorobenzyl)oxy](triisopropyl)silane (14.8 g, 44.4 mmol) was stirred in tetrahydrofuran (30 mL) and cooled to −78° C. A solution of n-butyllithium (30.5 mL, 1.6 M in hexane, 48.8 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 hour. N,N-dimethylformamide (4.47 mL, 57.7 mmol) was added and the mixture was allowed to warm to room temperature. A solution of 1 N HCl saturated with NaCl (15 mL) was added. The organic layer was separated and concentrated. The crude product was purified by chromatography on silica gel eluting with hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired product as a white solid (13.0 g, 81%). 1H NMR (CDCl3) δ 10.43 (s, 1H), 7.39 (s, 2H), 4.80 (s, 2H), 1.18 (m, 3H), 1.03 (s, 18H). LC/MS: 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O.C1C=CC=CC=1>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[C:7]([F:13])=[CH:8][C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(F)cc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
2,3,4,6-Tetrafluorobenzoic acid (4.8 g, 24.7 mmol) in dichloromethane (80 mL) is cooled to 0° C. under a nitrogen atmosphere and treated with oxalyl chloride (11.2 mL, 128 mmol) followed by anhydrous N,N-dimethylformamide (2 drops). The mixture is warmed to room temperature and stirred for 2 hours. The solution is co-evaporated with benzene to yield an oil that is taken up in dichloromethane (80 mL), cooled to 0° C. under an inert atmosphere, and treated with anhydrous ethanol (15 mL, 258 mmol). After 5 hours at room temperature, the solution is poured into saturated NaHCO3 and extracted with chloroform. The organic phase is washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (3.3 g). This material is used without further purification. 1H NMR (CDCl3): δ 6.93-6.75 (m, 1H), 4.42 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].CS(O[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.12 g, 21.2 mmol, Aldrich, Cat. 525057) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.78 g, 44.5 mmol) at 0° C. The resulting solution was stirred at r.t. for one hour, and then tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (6.3 g, 22 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 90° C. overnight. Then the reaction mixture was cooled to r.t., quenched with water, and extracted with ethyl acetate. The organic layer was washed with NaHCO3 aqueous solution and brine successively, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 30% ethyl acetate in hexane as eluent to afford the desired compound (2.30 g, 28.74%). LCMS (M+H)+: m/z=378.4.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:37](OCC)[CH2:38][N:39]=[C:40]=[N:41][Si](C)(C)C)C>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:40]3[NH:39][CH:38]=[CH:37][N:41]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CCOC(CN=C=N[Si](C)(C)C)OCC
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a stirred solution of t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate (164 mg.) in anhydrous CH2Cl2 at room temperature was added a molar solution of anhydrous toluene-p-sulphonic acid in CH2Cl2 (0.5 ml.) and then 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (125 μl.). Stirring was continued for 10 minutes and the solvent was evaporated. The residue, t-butyl 3-acetoxymethyl-7-[2-(2,2-diethoxyethyl)-3-trimethylsilyl]guanidinoceph-3-em-4-carboxylate, was dissolved in acetonitrile and 12N aqueous HCl (42 μl.) added. The mixture was stirred for 1.5 hours at room temperature, and the solvent evaporated. To the residue, t-butyl 3-acetoxymethyl-7-(imidazol-2 -yl)aminoceph-3-em-4-carboxylate, was added trifluoracetic acid and the mixture was stirred for 15 minutes. The solvent was evaporated and the residue was precipitated from a solution in the minimum of CH2Cl2 with ether. The precipitate was dissolved in CH2Cl2 /MeOH and the solvent evaporated to give 3-acetoxymethyl- 7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (262 mg. of 42% strength), identical with the product obtained in Example 2 (yield from 7-amino derivative 65%).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Mg].[C:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:1]([O:35][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Octadecyloxytriphenylmethane (C18 Tr-OH) was prepared in a Grignard procedure starting from octadecyloxyphenyl bromide and magnesium in dry THF. Benzophenone was added to the metalorganic compound and the product was hydrolyzed with 2 M HCl. The worked-up reaction mixture was dried, evaporated, and the pure product crystallized from toluene. The trityl alcohol was converted to the trityl chloride by treatment with an excess of acetylchloride.
Reaction SMILES: O[C:2]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:5]2[CH2:4][CH:3]=[C:2]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH2:7][CH2:6]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)CCCN2CCC(O)(Cc3ccc(C)cc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(CC2=CCN(CCCC(=O)c3ccc(O)cc3)CC2)cc1
Temperature: 182.5 °C
Reaction time: 6.5 h
Yield: 26.5 %

Procedure:
A mixture of 1.40 g of compound (3) and 7.29 g of pyridine hydrochloride was stirred at 180 to 185° C. for 6.5 hours. After cooled to room temperature, the mixture was made basic with aqueous NaHCO3 and then extracted with ethyl acetate. The organic layer was successively washed with water and brine and dried over MgSO4. After the solvent was removed, the obtained oily residue was purified by silica gel chromatography (chloroform:methanol=50/1 to 20/1) to obtain 0.34 g of the oily compound (4). Thus-obtained free compound was crystallized in form of an oxalate and recrystallized from MeOH/Et2O.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[NH2:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:27][CH:28]=O.O>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]3[CH:27]=[CH:28][N:25]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1nc(N)n2-c1ccc(OCc2ccccc2)cc1
Reactant: O=CCCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3-[4-(benzyloxy)phenyl]-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine (4.96 g) and 6.1 M aqueous chloroacetoaldehyde solution (4.92 ml) in DMA (50 ml) was stirred at 100° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from hexane/THF to give the title compound (1.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([NH2:12])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:12][C:5]1[C:6](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 1.3 g of methyl 5-chloroanthranilate and 1.8 g of 3,4,5-trimethoxybenzoylchloride in 30 ml of tetrahydrofuran is added 1.5 g of triethylamine under cooling, and the mixture is stirred at room temperature for 2 hours and then heated under reflux for 1 hour. The reaction mixture is concentrated under reduced pressure and to the residue is added water. The precipitated crystals are collected by filtration and recrystallized from a mixture of chloroform and ether to obtain 1.4 g of methyl N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilate as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][O:51]1.CCOC(/N=N/C(OCC)=O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:56][CH:53]([CH2:54][OH:55])[CH2:52][OH:51])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.8 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (75 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution. Triphenylphosphine (102 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (34 mg), and diethylazodicarboxylate (0.07 ml) were added to the solution, and the mixture was stirred at room temperature for 7 hr. Further, 1N-sulfuric acid (4 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (56 mg, yield 62%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2cc(C#Cc3ccccc3)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2cc(CCc3ccccc3)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared following the procedure described in Example 3d using N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]-6-(phenylethynyl)pyrimidin-4-amine and Pd(OH)2 on carbon (20% dry weight). LC/MS: Rt=2.30 min, ES+ 542 (FA standard).