Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:9][N:8]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32].O>ClCCl>[Cl:13][C:12]1[C:7]([C:4](=[N:3][O:2][CH3:1])[CH2:5][NH:6][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[C:28]([F:27])([F:38])[F:39])=[N:8][CH:9]=[C:10]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[CH:11]=1
Reactant: CON=C(CN)c1ncc(OCC(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(OCC(F)(F)F)cc1Cl
Yield: 69.5 %

Procedure:
To a solution of 227 mg of 2-amino-1-[3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanone-O-methyloxime and 92 mg of triethylamine in 5 ml of dichloromethane, 175 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with chloroform (10 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 249 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1.C(OCC)(=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@H:26]([CH2:28][O:29][NH:30][C:19]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:16]=[N:17][CH:18]=3)[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:25][O:24]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CONC(=O)c2ccc3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (326 mg, 0.82 mmol) in THF (4.1 ml) was added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (362 mg, 2.46 mmol), DIPEA (1.26 ml, 7.4 mmol), HOBt (327 mg, 2.46 mmol) and EDCI (471 mg, 2.46 mmol), the mixture stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate followed by water and then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) afforded the title compound as a pale yellow solid (364 mg, 84%). LCMS (method B): RT=2.58 min, [M+H]+=527.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=CC=C[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH4:21]>CO.[Pd]>[CH3:21][C:15]([CH3:16])([CH3:20])[CH:14]=[N:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: c1ccc(CNC2CCN(Cc3ccccc3)C2)cc1
Reactant: C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C=NC1CCNC1
Yield: 58 %

Procedure:
36.8 g (0.138 mol) of 1-benzyl-3-benzylaminopyrrolidine are hydrogenated in 160 ml of methanol over 5 g of 5% strength palladium on active charcoal at 130° C. under a hydrogen pressure of 100 bar for 10 hours. The catalyst is filtered off and 16.6 g (0.138 mol ) of 71% strength pivalaldehyde are added to the filtrate, while stirring, after which the temperature rises from 20° C. to 28° C. The mixture is subsequently stirred for 30 minutes, the methanol is removed on a rotary evaporator and the residue is distilled. 12.7 g of 3-(2,2-dimethyl-propylidene-amino)-pyrrolidine of boiling point: 61° C./10 mbar are obtained with a purity, determined by gas chromatography, of 97%, corresponding to a yield of 58% of theory.
Reaction SMILES: Br[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[OH-].[Na+]>C(OC)(C)(C)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C@H:3]2[CH2:2][O:4]2)=[CH:6][CH:7]=1
Reactant: O[C@H](CBr)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: Fc1ccc([C@H]2CO2)cc1
Temperature: 21 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Dissolve (1S)-2-bromo-1-(4-fluorophenyl)ethanol (1650 g, 7.53 mol) in 6.8 L of methyl tert-butyl ether. Add NaOH (2M, in H2O; 4.93 L) while the mixture is at 20° C. Stir the mixture for 3 h while maintaining it at 20-22° C. Separate the layers and extract the aqueous layer with methyl tert-butyl ether (1×2 L). Combine the organic phases; wash the organic phases with brine (1×2 L); dry over Na2SO4; and filter; concentrate the filtrate to give a residue. Purify via silica gel flash column chromatography using a 50:1 mixture of petroleum ether:EtOAce to elute the product. Concentrate the product fractions to give the title compound as a pale yellow oil (880 g, 84%). 1H NMR (300 MHz, CDCl3): 7.27-7.21 (m, 2H), 7.06-7.01 (m, 2H), 3.86 (dd, J=2.6, 4.0 Hz, 1H), 3.16 (dd, J=4.1, 5.5 Hz, 1H), 2.79 (dd, J=2.6, 5.4 Hz, 1H); ee value: 97.5% (AD-H 250 mm×4.6 mm×5 μm column using 99:5 hexanes:ethyl alcohol at 25° C. with a flow rate of 1.0 mL/min).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][C:37]1=[O:45].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CO.ClCCl>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:33][CH2:34][CH2:35][N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][C:37]3=[O:45])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:30][CH:31]=1
Reactant: O=C1Cc2ccccc2N1CCCCl
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)Cc5ccccc54)CC3)C2=O)cc1
Yield: 25 %

Procedure:
tert-Butyl 4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-(3-chloropropyl)indolin-2-one (0.12 g, 0.593 mmol), sodium iodide (0.026 g, 0.18 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.088 g, 25%); MS for C36H42N4O4 m/z 595 (M+H)+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)([F:9])[F:8]>Cl.C(O)C>[F:6][C:7]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([F:9])[F:8]
Reactant: O=[N+]([O-])c1ccccc1SC(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1SC(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
A solution of 25.53 g of tin(II) chloride dihydrate in 40 ml of concentrated hydrochloric acid was added dropwise to a stirred solution of 5.05 g of 2-nitrophenyl trifluoromethyl sulfide, obtained according to Example 1, in 30 ml of ethanol. After the addition had ended, the mixture was heated to 100° C. and stirred at this temperature for 1.5 hours. The mixture was cooled, ethanol was evaporated off under reduced pressure, and the residue was poured into a mixture of 150 g of ice and 150 ml of 40% strength by weight aqueous sodium hydroxide solution. The product was extracted with ether. The combined ether extracts were dried over magnesium sulfate and concentrated under reduced pressure. Vacuum distillation of the residue gave 3.31 g (75.7% of theory) of 2-aminophenyl trifluoromethyl sulfide (boiling point 102-104° C. at 50 mbar, melting point: 30-31° C.).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:8])=[O:5])C.[Li+].[OH-].OS([O-])(=O)=O.[Na+]>CO.O>[C:4]([CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)CC(=O)Nc1ccc2ccccc2c1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of 2-((ethoxycarbonyl)methylcarbonylamino)naphthalene (2.3 g, 8.9 mmol) in MeOH (40 mL) was added a solution of LiOH (1.18 g, 27 mmol) in water (40 mL). The reaction mixture was stirred at ambient temperature. After 3 hours, the reaction mixture was acidified to pH 2–3 by 2N NaHSO4, then extracted with ethyl acetate (3×50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 2-((carboxy)methylcarbonylamino)naphthalene (2.0 g, 8.7 mmol) as a solid that was used in further preparations without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[F:14][C:15]([F:23])([F:22])[C:16]([C:18]([F:21])([F:20])[F:19])=[O:17].[NH4+].[Cl-]>CCOCC>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]([OH:17])([C:18]([F:21])([F:20])[F:19])[C:15]([F:23])([F:22])[F:14])=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
n-Butyllithium (2.4M solution in hexane; 92.7 mL, 0.222 mol) was added dropwise (20 min) to a solution of p-dibromobenzene (50.0 g, 0.212 mol) in Et2O (1.2 L) at -60° C. After completion of the addition, the reaction was left at -50° C. for 30 min and hexafluoroacetone (42.2 g, 0.254 mol) was bubbled through the heterogeneous mixture, at the same temperature. The resulting solution was allowed to warm to -30° C. over 30 min before saturated aqueous NH4Cl was added. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were successively washed with 25% aqueous NH4OAc buffer, water and brine, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure (bp 85°-90° C./12 mmHg) to afford the title compound as colorless crystals (53.5 g, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22](=[O:24])[CH3:23]>CC(=O)CC>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[O:1][C:21]([C:22](=[O:24])[CH3:23])=[CH:4][C:3]=2[CH:6]=1
Reactant: CC(=O)CBr
Reactant: COc1cc(O)c(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc2cc(C(C)=O)oc2cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a solution of 2-hydroxy 4,5-dimethoxybenzaldehyde (2 g, 10.98 mmol) in butane-2-one (15 ml) added K2CO3 (6.07 g, 43.95 mmol) and then stirred at 0° C. for 10 min added bromoacetone (2.24 g, 16.47 mmol) and refluxed at 90° C. for 4 hr. After completion of the reaction butane-2-one was distilled off and water was added and extracted by ethylacetate twice. The EtOAc phase was dried over Na2SO4, Chromatography of the residue on silica gel (3:7 EtOAc/hexane) afforded the ketone A2 (1.69 g) in 70% yield pale yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.29 (s, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 2.30 (s, 3H) ppm. Mass: ESI [M+Na]+: 243.07; Elemental anal. calcd. for C12H12O4; C, 65.45; H, 5.49. found C, 65.20; H, 5.25.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 4.2 g. portion of 3-(4-cyanophenylaminomethyl)pyridine was dissolved in 25 ml. of dichloromethane, and 4.1 g. of potassium carbonate and 2.4 ml. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for 4 days, and was then diluted with 30 ml. of dichloromethane. It was then extracted with 20 ml. of water, dried over magnesium sulfate, and evaporated to an oily residue. The residue was applied to a silica gel column and eluted with dichloromethane. The product-containing fractions were combined and evaporated, and the residue was triturated with diethyl ether to obtain 1 g. of the desired product, m.p. 73°-75°.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].F[C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1>>[CH:1]([C:4]1[N:5]([C:10]2[CH:20]=[CH:19][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)c1ncc[nH]1
Product: CC(C)c1nccn1-c1ccc(CO)cc1

Procedure:
Prepared from 2-isopropylimidazol and ethyl 4-fluorobenzoate.
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCl.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH2:5])[CH:2]=[CH2:3]
Reactant: C=CCNN
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCN(N)CC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To the solution of 70%-allylhydrazine 7.73 g (75 mmol) and triethylamine 8.38 ml (60 mmol), ethyl 2-bromoacetate in dichloromethane 25 ml was added and stirred at room temperature for 24 hours and reflux for additional 1 hour. The reaction mixture was diluted with ethyl acetate 150 ml and washed with brine 100 ml. The organic phase was dried with magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 6.90 g (87%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(Cl)(Cl)Cl.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:36](O)=[O:37])[CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:36](=[O:37])[C@H:30]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
L-Histidine methyl ester dihydrochloride (1.21 g) is suspended into chloroform (20 ml), and therto are added triethylamine (1.40 ml) and further N-benzyloxycarbonyl-L-glutamine (1.40 g) and triethylamine (0.70 ml). After stirring for a while, to the mixture is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.07 g) and the mixture is stirred for 1 hour. After allowing to stand overnight, the solvent is distilled off. To the residue are added water and 1 N aqueous sodium hydrogen carbonate and the mixture is cooled. The precipitated gelling product is separated by filtration and washed with water. The product is heated together with a small amount of water and cooled. The precipitated by filtration to give N-(N-benzyloxycarbonyl-L-glutaminyl)-L-histidine methyl ester (1.25 g), melting point: 186°-188° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:23])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1cc2ncccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cc3ncccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a suspension of 50 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, 36 mg 1-isopropyl-piperidin-4-ylamine hydrochloride and 35 mg bis(2-oxo-3-oxazolidinyl)phosphinic chloride in 1 mL dichloromethane, 77 μl triethylamine were added at room temperature and the mixture was stirred for 16 hours. After removing of the solvent under reduced pressure, the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). The fractions containing the product were evaporated and lyophilized to yield a white residue which was partitioned between 5 mL aqueous 0.1 N sodium hydroxide solution and 5 mL ethyl acetate. The organic layer was washed with additional water and then dried over sodium sulphate. After filtration and removal of the solvent under reduced pressure, a white solid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:24]1[S:25][C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][C:24]3[S:25][C:26]4[C:27]([N:32]=3)=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: Clc1nc2ncccc2s1
Reactant: CCOC(=O)c1cc2ccc(O)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 6-hydroxy-benzofuran-2-carboxylic acid ethyl ester (2.0 g, 10 mmol) in MeCN (100 mL) added Cs2CO3 (6.3 g, 19 mmol) followed by 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (2.0 g, 10 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was treated with H2O (50 mL) and the solid was filtered to afford the title compound as a beige solid (2.3 g, 69%). MS (ESI): mass calcd. for C17H12N2O4S, 340.1; m/z found, 341.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.58 (dd, J=4.8, 1.6, 1H), 8.04 (dd, J=7.9, 1.6, 1H), 7.75-7.69 (m, 2H), 7.55 (d, J=0.8, 1H), 7.42 (dd, J=8.6, 2.1, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 4.46 (q, J=7.1, 2H), 1.44 (t, J=7.1, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1.[N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1CN[C@@H](C(O)=O)C1.[BH4-].[Na+]>CC#N.C(O)C>[OH:10][CH2:9][C@@H:8]([N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCC1CCCOC1
Agent: O=C(O)[C@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: O=C(NN(C(=O)OCc1ccccc1)[C@H](CO)CC1CCCOC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 0.058 mol) and dibenzyl azodicarboxylate (94%, 12.3 g, 0.041 mol) in MeCN (250 mL) at 0° C. was added (R-proline) (0.47 g, 0.0041 mol). After stirring the mixture at 0° C. for 15 hr, ethanol (100 mL) and NaBH4 (1.56 g, 0.041 mol) was added, and the mixture was stirred at 0° C. for 40 min. The reaction was quenched by slow addition of 10% aqueous citric acid (15 ml), and the whole solution was concentrated in vacuo. This residue was diluted with EtOAc (200 ml), washed with saturated brine (1×50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give dibenzyl 1-((2S)-1-hydroxy-3-(tetrahydro-2H-pyran-3-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (14.68 g, 81%).
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[C:4]([NH:14]C(=O)C)=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[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[C:4]([NH2:14])=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1cccc2c1oc1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1cccc2c1oc1ccccc12
Temperature: 25 °C
Yield: 91.4 %

Procedure:
N-(dibenzo[b,d]furan-4-yl)acetamide (90 g, 400 mmol) was suspended in the mixture of concentrated HCl (240 mL) and methanol (240 mL). The reaction was refluxed for 2 h and then cooled to room temperature. Saturated sodium carbonate was used to neutralize the solution. The residue was collected by filtration and redissolved in DCM. After dried over sodium sulfate, the solution was concentrated to give dibenzo[b,d]furan-4-amine (67 g, 92% yield) as brown solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:29]=CC(C(OC)=O)=C[CH:21]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB(C2C=[N:41][C:42]([NH2:45])=[N:43]C=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[NH2:45][C:42]1[N:43]=[CH:21][C:20]([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([N:8]3[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:13][C:14]=2[F:30])=[CH:29][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COC(=O)c1ccc(C#Cc2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C#Cc3cnc(N)nc3)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A solution of Example 1F (41 mg) in degassed DME (1.3 mL) was treated with 5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-pyrimidin-2-ylamine (41.5mg, prepared according to the procedure described in Tetrahedron Letters, 1997, 38, 3447-3450), tetrakis(triphenylphosphine)palladium (12 mg) and a degassed 2 N solution of potassium carbonate in water (0.2 mL). The tube was sealed, heated to 70° C., and stirred for 20 hours. The reaction mixture was then cooled to room temperature, concentrated, and diluted with dichloromethane (4 mL). The precipitate was removed by filtration and washed with water (10 mL) and then cold acetone (3 mL) to provide the desired product. MS (ESI(+)) m/e 370 (M+H)+; 1H NMR (300 MHz, MeOH) δ 8.49 (s, 2H), 7.61 (dd, J=2.1, 12 Hz, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.32 (dd, J=2.1, 8.7 Hz, 1H), 4.8 (m, 1H), 4.16 (t, J=9 Hz, 1H), 3.83 (dd, J=6.3, 9.6 Hz, 1H), 3.56(d, J=5.4 Hz, 2H), 1.96 (s, 3H).