Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:6]=[C:5]2[CH3:11]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
A solution of 5-bromo-3-methyl-1H-indazole (4.23 g, 20.0 mmol) in DMSO (150 mL) was treated with Cs2CO3 (19.55 g, 60.00 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (5.27 g, 31.0 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 1.4:5) gave the title compound (0.67 g, 11%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=1.5 Hz, 1H), 7.42 (dd, J=9.0, 1.5 Hz, 1H), 7.26 (d, J=9.0, 1H, overlapping with solvent peak), 4.43 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.58-2.55 (m, 4H), 2.53 (s, 3H), 1.79-1.74 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)=[C:12]2[O:11][N:10]=1.C(OO)(=[O:26])C.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[C:23]([OH:26])=[N:22][CH:21]=[N:20][CH:19]=3)=[C:12]2[O:11][N:10]=1
Reactant: Fc1ccc(-c2noc3c(-c4cncnc4)ccnc23)c(Cl)c1
Reactant: CC(=O)OO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3Cl)noc12
Temperature: 25 °C

Procedure:
To a vial charged with 3-(2-chloro-4-fluorophenyl)-7-(pyrimidin-5-yl) isoxazolo[4,5-b]pyridine (4.8 mg, 0.015 mmol) in acetone (Volume: 100 μl) were added peroxyacetic acid (6.18 μl, 0.029 mmol) and sulfuric acid (1.632 μl, 0.029 mmol). The reaction mixture was refluxed for 75 min, and then allowed to cool to room temperature. The reaction mixture was neutralized with 4 M NaOH and extracted with CH2Cl2 (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a yellow residue (5.0 mg, 99%). ESI MS (M+H)+=343.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCCCC2)cc1F
Temperature: 50 °C

Procedure:
A mixture of 3-fluoro-4-nitrophenol (3.07 g, 19.54 mmol), 1-(2-chloroethyl)piperidine hydrochloride (3.60 g, 19.54 mmol), cesium carbonate (19.10 g, 58.6 mmol) and potassium iodide (1.622 g, 9.77 mmol) were combined with DMF (19.54 mL), and the mixture was heated at 50° C. for 36 hours. The resulting mixture was diluted with EtOAc (50 mL), washed with water (100 mL) and the water layer extracted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL×2), 1N aqueous NaOH, and brine, and the organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was isolated as a yellow liquid (662 mg, 13% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>[Pd].CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:10]([C:11]([CH3:13])=[O:12])[C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cccnc1
Agent: [Pd]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccnc1)C(C)=O
Reaction time: 22 h

Procedure:
A mixture of pyridine-3-carboxaldehyde (48 g), ethyl acetoacetate (52 g) aqueous piperidine acetate (40% 4.8 g) and 5% palladium on charcoal catalyst (50% wet, 2.48 g) was hydrogenated at 100 p.s.i. at 30° for 22 hours. The mixture was diluted with ether, filtered and the filtrate was evaporated and distilled under reduced pressure to give ethyl α-(3-pyridylmethyl)acetoacetate (b.p. 146°/1 mmHg). This ester was refluxed with thiourea and sodium ethoxide in ethanol, and the mixture was subsequently acidified to give 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 328°-331°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18].O1CCOCC1>O1CCCC1>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(F)ccc1O
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)Oc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
4-Fluoro-2-methylphenol (4 mmol, 504 mg) in tetrahydrofuran (10 mL) under argon was treated at 0 ° C. with pyridine (8.8 mmol, 700 mg, 2.2 eq) then methyl chloroformate (4.4 mmol, 415 mg, 1.1 eq). The mixture was allowed to warm to room temperature and to stir for 45 min. It was then concentrated and dissolved in dichloromethane (10 mL), and pyridine (8.8 mmol, 700 mg, 2.2 q) then methyl chloroformate (4.4 mmol, 415 mg, 1.1 eq) were added again and allowed to react for 30 min. Then dioxane (3 mL) was added to help solubility, then pyridine (8.8 mmol, 700 mg, 2.2 eq) and methyl chloroformate (4.4 mmol, 415 mg, 1.1 eq) again 3 times. LC/MS actually showed evolution in conversion of start material after every add, but also that reaction stopped 5 min later. Achieved conversion was 85% (UV). The mixture was concentrated under reduced pressure, dissolved in dichloromethane, washed with 1M HCl aqueous solution then 10% Na2CO3 aqueous solution. Organics were dried on MgSO4 and concentrated under reduced pressure to give the title compound as an oil (2.5 mmol, 468 mg, 64% yield). M+H 185.08.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:14]([CH3:33])[C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl (3S)-3-{[tert-butyl (dimethyl) silyloxy]methyl}-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.65 g, 19.9 mmol) and iodomethane (1.37 mL, 21.9 mmol) in tetrahydrofuran (173 mL), lithium bistrimethylsilyl amide (21.9 mL, 21.9 mmol, 1M solution in tetrahydrofuran) was added in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL) was added, and the mixture was extracted with ethyl acetate (300 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 3.72 g (42%) of the title compound (single component) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:34][CH2:33][CH2:32][C:27]3([CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:26]2)[CH:20]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:30]1[CH2:29][CH2:28][C:27]2([CH2:32][CH2:33][CH2:34][N:25]([C:21]3[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][N:22]=3)[CH2:26]2)[CH2:31]1)=[O:6]
Reactant: Cc1ccnc(N2CCCC3(CCNC3)C2)c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccnc(N2CCCC3(CCN(C(=O)/C=C/C(F)(F)F)C3)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 7-(4-methyl-2-pyridyl)-2,7-diazaspiro[4.5]decane dihydrochloride (40 mg, 0.13 mmol, half of the residue from step B) and EDIPA (125 μl, 0.8 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 10 mg of a solid (0.028 mmol, 9% yield for two steps).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[CH:30]([NH:33][CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH3:1])([CH3:32])[CH3:31]
Reactant: CC(C)N
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNC(C)C)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with isopropylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 23.3, 26.5, 35.9, 43.2, 49.3, 53.2, 57.7, 59.0, 102.6, 102.9, 103.1, 105.1, 112.4, 112.4, 112.5, 112.6, 131.7, 137.7, 138.7, 161.9, 162.1, 164.4, 164.5, 169.1; MS m/z 450.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnc3c(F)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-fluoro-3-iodo-imidazo[1,2-a]pyridine (example C.30 step 2) (300 mg, 0.8 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (114 mg, 0.8 mmol) according to general procedure II. Obtained as a light brown solid (170 mg, 58%). MS (ISP) 363.2 [(M+H)+], 365 [(M+2+H)+]; mp 259° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])=[O:28]
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 71 %

Procedure:
A solution of 21.5 g (0.067 mol) of 2-(4-bromophenyl)-hexafluoro-2-propanol and 6.8 g (0.067 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 8.7 g (0.08 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 30 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.005 g of hydroquinone monomethyl ether. 18.8 g (71 percent of theory) of 2-(4-bromophenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 66° to 69° C. (under 0.13 mbar) were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1C=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[NH:34]1CCCCC1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][N:34]=1
Reactant: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1
Reactant: C1CCNCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cn1
Yield: 99.4 %

Procedure:
2-[4-(N-monomethyl)aminophenyl]-6-hydroxybenzothiazole (45, 520 mg, 2.03 mmol) was dissolved in tetrahydrofuran (15 mL) and (BOC)2O (974 mg, 4.46 mmol) and N,N-dimethylaminopyridine (DMAP; 496 mg, 4.06 mmol) were sequentially added thereto. After agitating the resulting reaction mixture for 16 hours at room temperature and removing the solvent under reduced pressure, the mixture was dissolved again in dichloromethane (40 mL). Then, after adding piperidine (4.0 mL, 40.6 mmol), the reaction mixture was agitated for 1 hour at room temperature and ammonium chloride aqueous solution was added. After extracting the organic compound with dichloromethane and removing water using sodium sulfate, column chromatography yielded the target compound 2-[2-(N-monomethylamino)pyridin-5-yl]-6-hydroxybenzothiazole (12-4, 519 mg, 72%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[N:17][OH:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: ON=C1CCCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
7.2 g of 1-benzylazacycloheptan-4-one are added to a solution of 3.1 g of hydroxylamine hydrochloride and 2.9 g of sodium acetate in 30 ml of water at 60° C. After 2 hours, the mixture is cooled and made alkaline with 2N sodium hydroxide solution. The mixture is extracted four times with diethyl ether, the organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is triturated with petroleum ether, filtered off with suction and employed without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3([CH3:26])OCC[O:22]3)[CH:19]=2)[N:14]([CH2:27][CH3:28])[C:13]1=[O:29])=[O:11].O1CCCC1.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](=[O:22])[CH3:26])[CH:19]=2)[N:14]([CH2:27][CH3:28])[C:13]1=[O:29])=[O:11]
Reactant: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C3(C)OCCO3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C(C)=O)ccc21
Reaction time: 1 h
Yield: 73 %

Procedure:
N-(2,4-Difluorophenyl)-1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindol-3-carboxamide (636 mg., 1.58 mmoles) was dissolved in 15 ml. of tetrahydrofuran to which was added 10 ml. of 1N hydrochloric acid. The solution was stirred for one hour followed by the addition of an equal volume of water. The resulting precipitate was filtered, vacuum dried and recrystallized from diisopropyl ether - methylene chloride, 412 mg. (73% yield), m.p. 160°-161° C.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:14]([C:15](Cl)=[O:16])=[C:13]([Cl:21])[CH:12]=1>>[Br:10][C:11]1[CH:12]=[C:13]([Cl:21])[C:14]([C:15]([C:3]2[C:4]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:16])=[C:18]([Cl:20])[CH:19]=1
Reactant: c1cc2cc[nH]c2cn1
Reactant: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Product: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2cnccc12

Procedure:
(4-Bromo-2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone was prepared from 1H-Pyrrolo[2,3-c]pyridine and 4-bromo-2,6-dichloro benzoyl chloride (Compound No. 10).
Reaction SMILES: [CH3:1][N:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1)=[O:4]>C(O)(C(F)(F)F)=O.ClCCl>[CH3:1][N:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1)=[O:4]
Reactant: CN(C(=O)CCCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CCCCSc1nc2ccccc2n1CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
tert-Butyl {2-[4-(methyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor F-01b, 25.6 mg, 0.06 mmol) is dissolved in TFA/dichloromethane (1:1, 3 ml) and stirred for 3 h at rt. Evaporation of the solvent in vacuo and drying under high vacuum yields the title compound (19.4 mg) in 87% as a yellow oil: tR=5.20 min (LC-1), ESI-MS (pos.): m/z 398.20 [M+H]+, ESI-MS (neg.): m/z 396.19 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.56 (m, 4H, CH2CH2), 2.05 (m, 2H, CH2C═O), 3.14 (s, 3H, NMe), 3.22 (m, 2H, SCH2), 5.00 (s, 2H, CH2CO2), 7.18-7.32 (m, 5Harom), 7.38 (m, 2Harom), 7.53 (m, 2Harom).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(Cl)Cl.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(OC(=O)C)C.C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:23])=[CH:6][N:5]2[C:24]=1[CH3:25]
Reactant: C1COCCN1
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1cccc(C)c1CNc1cc(C(=O)N2CCOCC2)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.44 mmol) were added to methylene chloride (10 ml). Morpholine (0.12 g, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was added to a column with silica gel and purification by chromatography using ethylacetate:methylene chloride (1:1) as eluent gave 0.12 g (66%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)COCC[Si](C)(C)C)=[N:8][C:4]=2[CH:3]=1.[CH:42]1([CH:45]=O)[CH2:44][CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl.O1CCCC1.C(O)(=O)C>[CH:42]1([CH2:45][N:22]2[CH2:23][CH2:24][C:19]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=4)=[CH:29][CH:30]=3)([CH2:10][O:9][C:7]3[NH:8][C:4]4[CH:3]=[C:2]([Cl:1])[C:40]([Cl:41])=[CH:39][C:5]=4[N:6]=3)[CH2:20][CH2:21]2)[CH2:44][CH2:43]1
Reactant: O=CC1CC1
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#Cc1cccc(-c2ccc(C3(COc4nc5cc(Cl)c(Cl)cc5[nH]4)CCN(CC4CC4)CC3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 0.045 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidin-4-yl}-biphenyl-3-carbonitrile 55 (0.073 mmol, 1 eq) in 0.5 mL of 1,2-dichloroethane at room temperature was added 6.6 μL of cyclopropanecarboxaldehyde (0.088 mmol, 1.2 eq) and acetic acid (0.005 mL, 1% v/v). The mixture was stirred at room temperature for 1 h followed by the addition of 0.023 g of NaBH(OAc)3 (0.105 mmol, 1.5 eq). The reaction was stirred at room temperature for 16 h and then the solvent was removed by rotary evaporation to yield 0.052 g of the crude product. This intermediate was dissolved in 2 mL of tetrahydrofuran and tetrabutylammonium fluoride on silica gel (1.0-1.5 mmol/g, 0.16 g, 2 eq) was added. The mixture was heated to 60° C. for 16 h then filtered and the resin washed with 10 mL of tetrahydrofuran. The filtrate was concentrated by rotary evaporation and the crude product was purified by flash silica gel chromatography eluting with 1% methanol in dichloromethane with 3% triethylamine to give 0.007 g of the desired product 4′-[1-cyclopropylmethyl-4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidin-4-yl]-biphenyl-3-carbonitrile 57 MS (ESI): Calcd m/z for C30H28Cl2N4O.H+=531.2. Found m/z 530.9/532.9 [(M+1)+/(M+3)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].C(=O)([O-])O.[Na+]>C(O)C.O>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:18][OH:19])=[CH:9][C:8]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 55.5 %

Procedure:
To a suspension of 4-formyl-2-methyl-benzoic acid tert-butyl ester (Example I17) (60.3 g) and hydroxylamine hydrochloride (38.05 g) in ethanol (580 ml) was added a solution of sodium hydrogen carbonate (46 g) in water (60 ml). The reaction mixture was stirred at 50° C. for 3.5 hours. The solvent was removed and the residue diluted with ethyl acetate and water. The phases were separated and the organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate and heptane to give 4-(hydroxyimino-methyl)-2-methyl-benzoic acid tert-butyl ester (35.72 g) as a white crystalline powder. 1H-NMR (CDCl3, 400 MHz): 7.86 (s, 1H), 7.70 (s, 1H), 7.45 (m, 2H), 2.60 (s, 3H), 1.60 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:17]([O:19]CC)=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCO.Cl>C1COCC1.O>[C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate from Step A (2.48 g, 8.15 mmol) and 1.0 N sodium hydroxide (8.96 mL, 8.96 mmol) in THF (50 mL), H2O (10 mL), and EtOH (20 mL) was stirred at ambient temperature for 18 h. The mixture was acidified with hydrochloric acid to about pH 3 and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=340 (M+Na+CH3CN).