Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:17](OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O)[CH:18]1[O:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:17][CH:18]3[CH2:19][O:20]3)[CH:3]=2)[NH:7][C:6]=1[CH3:11])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(O)cc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)[nH]c2ccc(OCC3CO3)cc12
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 2.19 g (10 mmol) of ethyl 5-hydroxy-2-methyl-indole-3-carboxylate, 2.6 g (10 mmol) of 2S(+) glycidyl-3-nitrobenzenesulfonate and 1.5 g (11 mmol) of potassium carbonate in 25 mL reagent grade acetone was refluxed overnight. The mixture was then allowed to cool to room temperature and the solids were removed by vacuum filtration. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organics were washed once with water, twice with brine, dried over sodium sulfate and concentrated in vacuo. Then the solid was dried under vacuum to give 2.65 g of the title compound as a dull tan solid; mp 93-94° C.; 1H NMR (300 MHz, CDCl3) δ 1.44 (t, J=5.3 Hz, 3H), 2.71 (s, 3H), 2.74-2.80 (m, 1H), 2.92 (t, J=4.7 Hz, 1H), 3.37-3.43 (m, 1H), 4.00-4.06 (m, 1H), 4.27-4.31 (m, 1H), 4.37 (q, J=5.3Hz, 2H), 6.86 (dd, J=5.5, 3.0Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.67 (d, J=3.0 Hz, 1H), 8.32 (s, 1H); MS (ES) m/z: 275.9 (MH+); HRMS Calcd. for C15H18NO4 (MH+): 276.1236. Found: 276.1228.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[BrH:10]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Br:10]
Reactant: OCc1ccccc1Cl
Reactant: Br
Product: Clc1ccccc1CBr
Temperature: 25 °C
Yield: 85 %

Procedure:
100 ml of HBr (48%) were heated to 90° and treated portionwise with 1.43 g (0.01 mol) of 2-chlorobenzyl alcohol. The mixture was stirred for 1/4 hr. and then cooled to room temperature. The mixture was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate. 1.75g (85%) of 2-chlorobenzyl bromide were obtained as a slightly turbid, colorless oil; b.p. 130°/30 mmHg.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].[OH-:16].[Na+]>[N+]([O-])([O-])=O.[Ag+]>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=[O:15]
Reactant: [OH-]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccc2oc3ccccc3c2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To dibenzofuran-2-carboxaldehyde (17) (200 mg, 1.02 mmol) was added solid NaOH (49 mg, 1.22 mmol) then 10% NaOH solution (1.8 mL). Silver nitrate (173 mg, 1.02 mmol) was then added, the reaction mixture heated to 60° C. for 1.5 hours and then stirred overnight at ambient temperature. The reaction mixture was then filtered and washed with water. The filtrate was acidified to pH 2 using concentrated HCl and the precipitated product filtered and dried to give the title compound as an off-white solid. Yield: 83 mg, 38%; LC-MS tr 1.31 min; HPLC Purity: 100%; MS (ES+) m/z not detectable (M+H)
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[OH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:24]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH2:35][OH:36])=[CH:27][CH:26]=2)=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(CO)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(hydroxymethyl)-1-naphthalenecarboxylic acid (194 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (365 mg, 77%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1
Yield: 48.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (13 mg, 0.033 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 6 mg of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C2C=CC(S(C)(=O)=O)=CC=2)[CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:3]1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)C(F)(F)F)cc2)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 26, but starting from 1-chloro-4-(trifluoromethanesulfonyl)benzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a pale yellow solid. M+(ESI): 309.2. HPLC (Condition A), Rt: 2.3 min (HPLC purity: 99.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:7]([NH:9][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:38][CH:37]=2)[CH:8]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(CCc2ccc(OC)cc2N)cc1
Agent: Cl
Product: COc1ccc(CCc2ccc(OC)cc2NCc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 73.2 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenylamine (643 mg) and 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (989 mg) according to an analogous synthetic method to Example 152, the title compound (868 mg) was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23].N1CCCCC1.O>C(O)C>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:25]([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)(=[O:24])=[O:23])[C:26]#[N:27])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccccn1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(C=C(C#N)S(=O)(=O)c2ccccn2)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 450 mg (2.2 mmole) of 3,5-diisopropy-4-hydroxylbenzaldehyde and 400 mg (2.2 mmole) of 2-pyridinesulfonlyacetonitrile (Lancaster catalog number 7114) in 10 ml of ethanol was refluxed with few drop of piperidine for 3 hours. The reaction was then cooled to room temperature and added with about 5 ml of water until crystallization began. After standing at 0° C. for 2 hours, all the solid was collected and dried by suction filtration to provide 350 mg M26 (0.95 mmole, 43% yield) as an orange solid. The purity of this material is over 95% by HPLC and the structure confirmed by NMR, MS and IR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>CN(C=O)C>[N:13]1([CH2:12][CH2:11][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ClCCN1CCCC1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(OCCN2CCCC2)cc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 4-aminophenol (4.0 g, 37.4 mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride (7.6 g, 44.9 mmol, 1.2 equiv), NaOH (3.7 g, 93.5 mmol, 2.5 equiv) in DMF (64 mL) is stirred for 2 h at 75° C., under an argon atmosphere. The mixture is allowed to cool to RT and then filtered through a glass sintered funnel. The filtrate is diluted with CH2Cl2 (200 mL), washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel (260 g) column chromatography (CH2Cl2/MeOH, 70/30→50/50) to afford the title compound as a dark brown oil: ES-MS: 207.1 [M+H]+; Rf=0.18 (CH2Cl2/MeOH, 50/50).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C@@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C@@H:30]([C:32](=[O:49])NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])C>>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:32](=[O:49])[CH2:30][O:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][C@H:18]([O:17][CH3:15])[C:19]([OH:21])=[O:20])=[CH:28][CH:27]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: Fc1ccc(CN2CCNCC2)cc1
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(Cc3ccc(F)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-ropionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-fluoro-benzyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27FN2O5 [M+H]+: 431.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1.I[CH3:23]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[CH:20][C:15]3[N:16]([CH3:23])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1
Reactant: CI
Reactant: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
135 mg (3.10 mmol) sodium hydride (55%, suspension in mineral oil) were added to 800 mg (2.90 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one in 10 mL DMF and the mixture was stirred for 30 min at RT. Then 0.368 mL (5.80 mmol) iodomethane were added and the mixture was stirred for a further hour at RT. The mixture was mixed with ice water and extracted twice with EtOAc. The organic phases were combined, washed with water, dried and evaporated down. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Cl:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13]>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([Cl:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: COc1ccc(Cl)cc1OC
Reactant: O=[N+]([O-])O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OC
Reaction time: 1.5 h

Procedure:
Into a triple-necked flask of one liter, provided with a magnetic stirring system, with a thermometer and a dropping funnel, were introduced successively 143.9 g (0.83 mole) of 3,4-dimethoxy chlorobenzene, then drop by drop 166 cm3 of nitric acid (d=1.38), without the temperature exceeding 25° C. When the addition was ended, the reaction mixture was allowed to stand 1.5 h and then filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14]COC)[C:6]([CH3:13])=[C:7]([O:9]COC)[CH:8]=1.Cl.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6]([CH3:13])=[C:7]([OH:9])[CH:8]=1
Reactant: COCOc1cc(OC)cc(OCOC)c1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(O)c(C)c(O)c1
Yield: 88.3 %

Procedure:
A solution of 9 (314 mg, 1.30 mmol) in MeOH (10.8 mL) at room temperature was treated dropwise with 3 M HCl (3.46 mL, 10.3 mmol), then heated to reflux for one hour. Water (11 mL) was added and the solution was extracted with EtOAc (3×15 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 10 as a red amorphous solid (177 mg, 99%): 1H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 6.09 (d, J=1.6 Hz, 1H), 6.04 (s, 1H), 3.67 (d, J=9.9 Hz, 3H), 2.08 (d, J=4.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 160.3, 157.8, 155.4, 108.4, 93.9, 93.8, 55.0, 7.0; IR (film) νmax 3445, 2924, 2853, 2359, 2332, 1653, 1636, 1456, 1080, 1022, 798, 669 cm−1; HRMS (ESI+) m/z: [2M+H]+ calcd for C8H10O3, 309.1338 found, 309.1332.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:16][CH:17]=O>CCO>[N:1]1[CH:16]=[CH:17][N:3]2[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[CH:7][C:2]=12
Reactant: Nc1cc(CO)ccn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCc1ccn2ccnc2c1
Yield: 81.8 %

Procedure:
To a solution of a (2-Amino-pyridin-4-yl)-methanol (0.40 g, 3.3 mmol) in EtOH was added NaHCO3 (0.56 g, 6.67 mmol) followed by chloroacetaldehyde (0.81 ml, 5.0 mmol). The mixture was refluxed for 2 h. Solvents were removed in vacuo and the crude mixture was partitioned between water and EtOAc. The aqueous was further extracted with EtOAc, the organics combined, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified using silica column chromatography (0-50% MeOH/Et2O) to afford 0.40 g of product MS: [M+H]+=149.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[Cl:30][CH2:31][C:32](Cl)=[O:33]>>[Cl:30][CH2:31][C:32]([N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:23])=[CH:19][CH:18]=1)[CH3:22])=[O:33]
Reactant: O=C(Cl)CCl
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CCl)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and chloroacetyl chloride, the title compound was prepared as yellow foam (51% yield). MS: m/e=489 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][NH2:35].C(N(C(C)C)CC)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][NH:35][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=1)=[O:23]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Yield: 99.7 %

Procedure:
To a stirred suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 113 μmol) and O-methylhydroxylamine hydrochloride (11.3 mg, 136 μmol) and diisopropylethylamine (79 μL, 453 μmol) in DMF (2 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate (58.6 mg, 136 μmol) at 20° C. for overnight. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl solution. The organic layer was then washed with saturated sodium bicarbonate and brine then dried (sodium sulfate), filtered and concentrated in vacuo to give the crude 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid methoxy-amide (53 mg) as a white solid. This was used directly in the next step without further purification. MS (M+H)+=471.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(CCl)cs1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Temperature: 35 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
4-(Chloromethyl)-2-methyl-thiazole (0.590 g, 3.18 mmol, 1 eq) was suspended in DCM (5 mL). DIPEA (1.39 mL, 7.95 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (1.300 g, 7.0 mmol, 2.2. eq). The mixture was stirred at 35° C. for 5 h, then diluted with EtOAc, and washed with H2O and brine. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (0.940 g, 99%); 1H-NMR (500 MHz, CDCl3): δ 1.47 (s, 9H, C(CH3)3), 2.47 (t, 4H, J=4.5 Hz, piperazine N(CH2)2), 2.73 (s, 3H, Me), 3.48 (t, 4H, J=4.5 Hz, piperazine N(CH2)2), 3.64 (s, 2H, NCH2), 6.96 (s, 1H, thiazole 5-H); LC (Method B)-MS (ESI, m/z): Rt=1.96 min—298 [(M+H)+, 100%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].CC(C)([O-])C.[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1S
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1SCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 25.0 g (178 mmol) of 2-methoxythiophenol in 50 mL of dry tetrahydrofuran was added dropwise to a mixture of 22.0 g (196 mmol) of potassium t-butoxide and 100 mL of tetrahydrofuran at 0° C. with stirring. A solution of 25 mL (214 mmol) of benzyl chloride in 50 mL of tetrahydrofuran was added to this with stirring and cooling and the mixture was then allowed to warm to ambient temperature and was stirred for 18 hours. The resulting mixture was concentrated by evaporation under reduced pressure and the residue was diluted with 300 mL of dichloromethane. The solution obtained was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was the title compound, a white solid melting at 69-70° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:4]4[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 75 mg (0.75 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 127 mg (55% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[I-].[K+].Br[CH:22]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24]>CO.C1C=CC=CC=1.CC(C)=O.CCCCCC.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:22]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(OCc2ccccc2)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 5.0 g of p-benzyloxyphenol and 1.19 g of sodium methoxide in 40 ml of methanol is added 50 mg of potassium iodide and 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed for 22 hours and poured into ice and water. The mixture is extracted with ether and the ether extracts washed with 10% potassium carbonate and with water. The extracts are dried (MgSO4) and the solvent removed under vacuum to give an oily solid. Trituration with hexane plus a small amount of acetone and chilling gives crystals. Filtration gives the product as off-white crystals, mp 91°-96° C. Recrystallization by dissolving in hot acetone, diluting with petroleum ether, chilling and filtering gives the product as white crystals, mp 88°-90° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: OC1CCOC1
Product: Cc1cc(OC2CCOC2)ncc1Br

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-4-methylpyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): colorless liquid.