Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SiH:2]1[O:9][Si:8]([CH3:11])([CH3:10])[O:7][Si:6]([CH3:13])([CH3:12])[O:5][Si:4]([CH3:15])([CH3:14])[O:3]1.CCCCCCC.[Cl:23]Cl>>[Cl:23][Si:2]1([CH3:1])[O:3][Si:4]([CH3:14])([CH3:15])[O:5][Si:6]([CH3:13])([CH3:12])[O:7][Si:8]([CH3:11])([CH3:10])[O:9]1
Reactant: C[SiH]1O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1
Reactant: ClCl
Solvent: CCCCCCC
Product: C[Si]1(C)O[Si](C)(C)O[Si](C)(Cl)O[Si](C)(C)O1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a 1000 mL three-necked round bottom flask equipped with a magnetic stirring bar, a thermometer, an inlet for gases and an outlet fitted with a drying tube, was charged the following: 37.17 g (77.87 mmol) of heptamethylcyclotetrasiloxane (59.2% in octamethylcyclotetrasiloxane) and 521.9 g (5214 mmol) of heptane. The mixture was cooled in an ice bath to 0° C. Chlorine (Cl2) was bubbled through the stirred mixture at a rate such that the temperature did not rise above 10° C. The addition of the chlorine was continued until a persistent yellow color, accompanied by a drop in temperature, was observed. Nitrogen gas was bubbled through the solution to remove the HCl generated in the reaction and the excess Cl2. A yield of 100% under anhydrous conditions was determined by gas chromatographic analysis.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])(=[O:8])[CH3:7].[N+:18]([O-])([OH:20])=[O:19]>>[C:6]([NH:9][C:10]1[C:11]([F:17])=[CH:12][C:13]([Cl:16])=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=1)(=[O:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To 20 % ice-cooled fuming sulfuric acid (50 g), 4-(N-acetylamino)-1-chloro-3-fluorobenzene (9.4 g) was dissolved, followed by gradual addition of fuming nitric acid (3.5 g) while keeping the temperature at 0° to 5° C. The resultant mixture was stirred at the same temperature for 1 hour and poured into ice (50 g). The precipitated crystals were collected by filteration, and the filtrate was washed with water and dried to give 11.6 g of 4-(N-acetylamino)-1-chloro-5-fluoro-2-nitrobenzene. M.P., 124.7°-125.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.[Br:16][C:17]1[C:18]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:19][C:20](Cl)=[N:21][CH:22]=1>C(O)(C)C>[Br:16][C:17]1[C:18]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:19][C:20]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Br
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Br)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A microwave vessel was charged with 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (65.6 mg, 0.182 mmol) 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (47 mg, 46%) as a pale yellow powder that had the following properties: m.p: 231-232° C.; LC/MS (ESI+): 528/530 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.40 (s, 1H), 9.33 (s, 1H), 8.63 (m, 1H), 8.27 (s, 1H), 7.47 (d, J=7.0, 1H), 7.44 (s, 1H), 7.35-7.20 (m, 3H), 6.98 (d, J=8.2, 1H), 3.65 (br s, 2H), 2.75 (d, J=5.1, 3H), 2.50 (m, 2H), 2.10-1.85 (m, 4H), 0.93 (t, J=7.0, 3H).
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:40][CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:33]2[C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:39][CH:40]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 96.8 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (1.6 g, 4.08 mmol, 1 eq.) in 30% aqueous THF was treated with lithium hydroxide (0.29 g, 12.24 mmol, 3 eq.). When complete, the reaction was worked up as described and the resulting oil purified via silica gel flash chromatography using 50% EtOAc in hexane as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.44 g, 97% yield) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To a solution of 3,5-difluoro-4′-acetoxystilbene (0.69 g, 2.5 mmol) in MeOH (10 ml) was added 5 mL 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3,5-difluoro-4′-hydroxystilbene (0.51 g, 88%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.40 (m, 2H), 7.05-6.83 (m, 6H), 6.67 (tt, 1H), 4.88 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 164.49(d), 162.47, 156.01, 141.29, 130.90, 128.53, 124.74, 115.96, 109.03 (t), 102.53 (t); 19F NMR (CDCl3, 282 MHz) δ-31278.95 (t, J=1720.2 Hz); HRMS (EI+) found 232.0715 M+, calcd 232.0700 for C14H10F2O.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].S([O-])([O-])(=O)=S.[Na+].[Na+]>S(=O)(=O)(O)O>[I:1][C:8]1[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:17]=[CH:16][C:9]=1[CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12]
Reactant: II
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1I)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 250 mL round bottomed flask equipped with a magnetic stirrer was charged with 60 mL of fuming sulfuric acid (Aldrich) and 12.1 g of iodine (Aldrich). To the resulting dark red solution was added 10.0 g of 4-nitro-L-phenylalanine by slow addition. The flask was fitted with a CaCl2 drying tube and the reaction mixture was. stirred at RT for 18 h. The mixture was then poured onto 300 g of crushed ice. A yellow-brown emulsion resulted which was treated with 7.4 g of sodium thiosulfate and stirred. The resulting light brown suspension was basified to pH=9 by addition of solid NaCO3. This was followed by acidification to pH=5.5 by addition of conc. H2SO4. A brown solid precipitated which was collected by filtration and dried in vacuo. This afforded 6.54 g (41%) of 2-iodo-4-nitro-L-phenylalanine as a brown powder, m.p.>200° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:10])[CH3:9].[OH-].[Na+]>>[CH2:8]([NH:10][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH3:9]
Reactant: CCN
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1OCCO1
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (15 grams; 0.09 mole) and ethylamine (74 ml; 1.65 mole) were charged into a Parr Shaker. The shaker was sealed and was heated with an infra-red lamp to a pressure of about 50 p.s.i. Heating was stopped and the reaction mixture was shaken for a period of about 1/2 hour. After this time aqueous sodium hydroxide (12 ml; 50% concentration) was added to the reaction mixture with stirring. The organic phase was then separated from the aqueous phase, was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield the desired product N-ethyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([OH:12])[C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc2c(c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.97 Gram of 7,8-dihydro-3-methylquinolin-5(6H)-one was dissolved in 20 ml of methanol, then to this solution was added 0.23 g of sodium borohydride under ice-cooled condition, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, then methanol was removed by evaporation, next extracted with chloroform, and the chloroform extract was dried with anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain 0.98 g of 3-methyl-5-hydroxy-5,6,7,8-tetrahydroquinoline in the form of colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].[O:13]1[CH2:30][CH:14]1[CH2:15][O:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.O.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>ClC1C=CC=CC=1>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[CH:20]1[C:21]2[NH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[C:17]([O:16][CH2:15][CH:14]([OH:13])[CH2:30][NH:8][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[CH:18][CH:19]=1
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
174 g (1.04 moles, 2.5 mol equivalents) of 2-(2-methoxy phenoxy)ethylamine is dissolved in 500 ml of monochlorobenzene. The temperature is raised to 125° C. under stirring. 100 g (0.42 moles) of 4-(2,3-epoxy propoxy)carbazole is slowly added in five lots during 1 hr at reflux temperature. Refluxing is then carried on for two hrs. The reaction is monitored to completion by thin layer chromatography and then cooled to 90° C. 500 ml water is then charged followed by cooling to 70° C. The pH of reaction mass is adjusted to 2.5-2.7 with 10% oxalic acid solution at 60° C.-70° C. Stirring is done for one hr at 60° C.-70° C. The reaction mass is cooled to room temp and maintained for two hrs. The material is filtered and washed with water and dried at 50° C.-60° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[N:23]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[CH:26]=[C:25]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=3)[CH:24]=[N:23]2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(Br)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A slurry of 2.50 g (8.81 mmol) 3-bromo-5-iodo-pyridine, 3.66 g (9.7 mmol) 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidin-1-carboxylic acid tert.butyl ester (synthesis described in WO 2007/066187) and 3.74 g (17.6 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 618 mg (0.88 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 16 hours at 80° C. The reaction mixture was partitioned between THF and brine. The organic phase was dried over sodium sulfate and evaporated yielding 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS: 2.28 min, [M+H] 407/409.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([OH:19])[C:15]1=[O:20].[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([O:19][C:22](=[O:24])[CH3:23])[C:15]1=[O:20]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O

Procedure:
2.0 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide are heated to reflux for 3 hours in 60 ml of chloroform and 1.5 ml of acetyl chloride. After evaporation of the volatile constituents, the residue is treated three times with toluene and in each case again evaporated in vacuo. The residue is chromatographed over aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is extracted with chloroform has a melting point of 121°-122° after recrystallization from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: Sc1ccccc1Cl
Reactant: CI
Product: CSc1ccccc1Cl
Yield: 89 %

Procedure:
2-Chlorothioanisole was prepared in 89% yield from commercially available 2-chlorothiophenol (4.0 g, 27.6 mmol) using methyl iodide (4.66 g, 32.81 mmol) according to the procedure described in preparation 1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1.[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=1
Reactant: Cc1ccn2c(C)c(-c3ccc(O)c([N+](=O)[O-])c3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccn2c(C)c(-c3ccc(O)c(N)c3)nc2c1
Yield: 53.8 %

Procedure:
A solution of 3,7-dimethyl-2-(4-hydroxy-3-nitrophenyl)imidazo[1,2-a]pyridine (2.6 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium-carbon (wet. 2.0 g) under an atomospheric pressure of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 3,7-dimethyl-2-(3-amino-4-hydro-xyphenyl)imidazo[1,2-a]pyridine (1.25 g). mp. 251°-253° C.
Reaction SMILES: Cl[CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3]>C(N=C=O)C>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[CH2:2]([N:4]=[C:5]=[O:6])[CH3:3]
Reactant: CC(Cl)NC(=O)Cl
Agent: CCN=C=O
Product: C=CN=C=O
Yield: 50.5 %

Procedure:
57 parts of 1-chloroethylcarbamic acid chloride are dissolved in 520 parts of ethyl isocyanate at 22° C. and dry nitrogen is blown through the solution, a Raschig ring column being used to achieve a preliminary separation of the 3-component mixture (ethyl isocyanate, vinyl isocyanate and 1-chloroethyl isocyanate) in the column. The reaction mixture is subjected to fractional distillation for 3 hours. 14 parts (50.5% of theory) of vinyl isocyanate of boiling point 38.5° C./1013 mbar and 466 parts of ethyl isocyanate of boiling point 60° C./1013 mbar are obtained.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[N:10]=[C:6]2[C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1>>[C:18]([O:17][C:15]([N:13]1[CH2:14][CH:11]([C:9]2[N:10]=[C:6]3[C:5]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:4][CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)=[O:49])[CH2:44][CH2:43]5)=[N:40][CH:41]=4)[N:7]3[CH:8]=2)[CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3c(Br)cnc(N4CCOCC4)c3n2)C1
Reactant: CC1(C)OB(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)nc2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CC(c2cn3c(-c4ccc(N5CCN(C(=O)OCc6ccccc6)CC5)nc4)cnc(N4CCOCC4)c3n2)C1

Procedure:
Compound 29b was subjected to Suzuki coupling reaction conditions with benzyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the methods described in Example 1, Step G to obtain compound 29c. Mass Spectrum (LCMS, ESI pos.) Calcd. for C35H42N8O5: 655.3 (M+H). Found 655.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]([O:23]CC)=[O:22])=[C:12]2[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]([OH:23])=[O:22])=[C:12]2[Cl:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OCc3ccccc3)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2ncc(C(=O)O)c(Cl)c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 6-(Benzyloxy)-4-chloro-7-methoxy-3-quinolinecarboxylate (11.9 g, 32 mmol) was dissolved in a mixture of tetrahydrofurane (THF) and methanol (300 ml) in a ratio of 1:1. Aqueous sodium hydroxide (2.0 M, 65 ml, 130 mmol) was added and the mixture stirred at room temperature for 2 hours. The organic solvents were removed by rotatory evaporation and the resulting solution diluted with more water (200 ml) cooled on ice and acidified to pH 2–3 with hydrochloric acid under vigorous stirring. The precipitate was filtered off washed twice with water, twice with ethanol and ether and finally dried in vacuum at 50° C. over night to give a white solid, 11.0 g (100% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH:20]1([CH:23]=O)[CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[C:3]([NH:11][CH2:23][CH:20]2[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=CC1CC1
Reactant: Nc1c(Cl)cnc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1cnc2[nH]ccc2c1NCC1CC1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
In a round bottom flask, 5-chloro-1H-pyrrolo[2,3-b]pyridin-4-ylamine (22, 0.21 g, 1.25 mmol) is combined with 3.5 mL of ethanol, acetic acid (0.38 g, 6.25 mmol), silica bound sodium cyanoborohydride (1.1 g, 1.02 mmol), and cyclopropanecarbaldehyde (23, 0.26 g, 4 mmol). The reaction mixture was stirred over night at room temperature, heated up to 145° C. until the reaction was complete, filtered, concentrated, and purified by flash chromatography to provide compound as a solid (24, 0.191 g; yield=69%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>CN(C=O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([O:3][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1cnc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cnc3ccccc3n2)ncn1
Reaction time: 0.25 h

Procedure:
40 mg (0.92 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.10 g (0.68 mmol) 2-hydroxyquinoxaline in 1.5 mL DMF and the mixture was stirred for 15 min. Then 0.11 g (0.69 mmol) 4,6-dichloropyrimidine were added and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was eliminated i.vac., and the precipitated product was suction filtered and dried.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.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>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.1 g, 10 mmol), o-tolylboronic acid (1.5 g, 1.1 eq), tetrakis(triphenylphosphine)palladium (575 mg, 0.05 eq), and sodium carbonate (5.5 g, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-o-tolylquinoline-3-carbaldehyde was obtained as white solid. 1H-NMR (CDCl3) 9.96 (s, 1H), 8.83 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.74 (d, J=6.3 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.36-7.46 (m, 4H), 2.84 (s, 3H), δ 2.30 (s, 3H). Mass Spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: [O:1]([CH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]1[C:22]([OH:29])=[N:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[OH:29][C:22]1[C:21]([CH2:20][NH:19][C:16]([C:13]2[N:14]=[N:15][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[CH:11][CH:12]=2)=[O:18])=[C:26]([CH3:27])[CH:25]=[C:24]([CH3:28])[N:23]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)nn2)c(O)n1
Yield: 79.3 %

Procedure:
A mixture solution of 6-(1-phenoxyethyl)pyridazine-3-carboxylic acid (60 mg, 0.2 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (37 mg, 0.2 mmol), 1-Hydroxybenzotriazole (30 mg, 0.2 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.2 mmol) and triethylamine (0.1 mL) in dichloromethane (50 mL) was stirred at room temperature for 18 hours. The mixture solution was diluting with ethyl acetate (50 mL), washed with water (20 mL). The organic layer was concentrated, the residue was purified by column chromatography (silica-gel, dichloromethane/methanol=30:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-phenoxyethyl)pyridazine-3-carboxamide as a yellow solid (60 mg, 64%). LRMS (M+H+) m/z: calcd 379.17. found 379. HPLC Purity (214 nm): 95%. 1H NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 8.20 (d, J=9 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.15-7.25 (m, 2H), 6.82-6.91 (m, 3H), 5.96 (s, 1H), 5.76-5.78 (m, 1H), 4.63 (d, J=6 Hz, 2H), 2.36 (s, 6H), 1.70 (d, J=6 Hz, 3H).