Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](OC)=[O:5].C(Cl)Cl>CO>[OH:5][CH2:4][C:3]1[C:2]([CH3:1])=[N:11][CH:10]=[CH:9][C:8]=1[C:12]([F:15])([F:13])[F:14]
Reactant: COC(=O)c1c(C(F)(F)F)ccnc1C
Solvent: CO
Solvent: ClCCl
Product: Cc1nccc(C(F)(F)F)c1CO

Procedure:
Methyl 2-methyl-4-trifluoromethylnicotinate was reduced using the procedure as given in step 1 of Example 3. 3-Hydroxymethyl-2-methyl-4-trifluoromethylpyridine was obtained as a pale yellow waxy solid(TLC Rf = 0.31 (97:3 CH2Cl2 :MeOH)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)[N:9]=[CH:8][CH:7]=[C:6]2[O:28][C:29]1[C:30]([CH3:39])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2.NN>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:28][C:29]1[C:30]([CH3:39])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
2-{3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propyl}-isoindole-1,3-dione (compound 380) (21 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Hydrazine (13 mg) was added to the solution, and the mixture was stirred at room temperature for 4 hr. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (15 mg, yield 100%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O.O1CCOCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH3:25])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O)C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 81.8 %

Procedure:
Methyl 6-(benzenesulphonylmethyl)-2-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-(furan-3-yl)benzoate (Intermediate 125, 0.054 g) was added to a solution of lithium hydroxide monohydrate (0.034 g) in water (0.3 ml) and dioxane (1 ml) and the mixture was stirred and heated at 130° C. for 30 minutes. The reaction mixture was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was acidified with formic acid and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 6-(benzenesulphonylmethyl)-2-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-(furan-3-yl)benzoic acid (0.043 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:19]#[C:20][NH2:21].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:20](=[NH:19])([O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:12]=1)[NH2:21]
Reactant: N#CN
Reactant: Cc1ccc(Oc2ccc(CCO)cc2)cc1F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1F
Temperature: 55 °C
Yield: 25.8 %

Procedure:
To a solution of 2-{4-[(3-fluoro-4-methylphenyl)oxy]phenyl}ethanol (1 g, 4.06 mmol) and cyanamide (0.205 g, 4.87 mmol) in dry THF (15 mL) under nitrogen was added triflic acid (0.433 mL, 4.87 mmol). The mixture was heated at 55° C. for 2 h. Purification via reverse phase flash chromatography afforded the title compound (420 mg, 1.047 mmol, 25.8% yield) as white solid. LCMS: rt=2.61 min, [M+H+]=229
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17]O.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:17][C:16]([O:20][CH3:21])=[O:19])(=[O:3])=[O:2]
Reactant: COC(=O)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a solution of triflic anhydride (3.7 ml, 20.0 mmol) in methylene chloride (10 ml) at -5° C. under argon, was added dropwise over 30 minutes a solution of methyl glycolate (1.8 g, 20.0 mmol), pyridine (1.55 ml, 20.0 mmol), and anhydrous methylene chloride (5 ml). The reaction was allowed to stir at between 0°-5° C. for 1.5 h. The mixture was then washed with water several times. The organic extract was then washed with water, brine, and dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, methylene chloride) afforded the title compound as a colorless oil (3.0 g, 68%).
Reaction SMILES: Br.N1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12](O)[CH:13]=3)[C:8]2=[O:18])C=CN=C1.C([O-])(O)=O.[Na+]>O>[C:8]1(=[O:18])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH2:7]1
Reactant: O=C1c2ccc(O)cc2CCC1n1ccnc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CC=Cc2ccccc21

Procedure:
2-(1-imidazolyl)-3,4-dihydro-6-hydroxy-1(2H)-naphthalenone hydrobromide (1.35 g) was dissolved in water. The solution, basified with NaHCO3, extracted with CH2Cl2, dried and evaporated, gave 1.15 g of 2-(1-imidazolyl)-3,4-dihydro-6-hydroxy-1(2N)-naphthalenone.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:41])(C)C.CCOCC>CC(CC)=O>[ClH:41].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(CCc1ccccc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(3-phenylpropionyl)-1,4,8-triazaspiro[4,5]decan-2-one (360 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (2.9 mL), water (8 μL), TMSCl (107 μL), and ether (10 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(3-phenylpropionyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 323 mg (83%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:6]([F:32])[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][C:6]=2[F:32])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester (130 mg, 0.26 mmol) was dissolved in THF/MeOH (5 ml) and treated with 1 N NaOH (1.2 ml) for 1.5 h. The reaction mixture was concentrated under reduced pressure diluted using water and extracted with diethyl ether. The aqueous phase was acidified using a 5% KHSO4/10% K2SO4 mixture and extracted with ethyl acetate (3×). The combined organic fractions were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure (103 mg). Crude product (50 mg) was purified using preparative RP(C18) chromatography: lyophilisate 22 mg;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])=[O:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:2]1[CH2:18][CH2:19][O:20][CH:1]1[C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17]
Reactant: OCCO
Reactant: O=Cc1cc2n(c1)CCc1ccccc1C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CCn2cc(C3OCCO3)cc21
Temperature: 0 °C

Procedure:
A mixture of 5 gm. of 6,11-dihydro-2-formyl-5H-pyrrolo[2,1-b][3]benzazepin-11-one, 2.5 gm. of ethylene glycol, 0.5 gm. of p-toluenesulfonic acid and 100 ml. of toluene is refluxed for 16 hr. in an apparatus designed to remove water formed during the reaction (Dean-Stark apparatus). The reaction mixture is cooled to 0° C. and washed rapidly with ice cold 5% sodium carbonate solution (2 × 50 ml.) and dried over Na2SO4. Evaporation of the solvent leaves 6,11-dihydro-2-(2-dioxolanyl)-5H-pyrrolo[2,1-b][3]benzazepin-11-one as an oil which is of sufficient purity for use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5](Br)[C:6](=[O:8])[CH3:7].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([N:11]=[N+:12]=[N-:13])[C:6](=[O:8])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CC(Br)C(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(N=[N+]=[N-])C(C)=O
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a solution of 2.23 g (10.67 mmol) of 3-bromo4-oxo-pentanoic acid methyl ester in 11 mL of DMF at 0° C. was added 690 mg (10.67 mmol) of sodium azide. After warming to RT over 2.5 h, the reaction was diluted with water and extracted with diethyl ether/hexane (1:1). The layers were separated, the organics dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using diethyl ether/hexane (gradient of 1:4 to 2:3) to give 1.07 g (58% yield ) of the title compound: low resolution MS (FAB) m/e 172 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH3:13][N:14]([CH3:22])[C:15](=[O:21])[NH:16][C:17](=[NH:20])[S:18][CH3:19]>C(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3]([N:20]=[C:17]([S:18][CH3:19])[NH:16][C:15]([N:14]([CH3:22])[CH3:13])=[O:21])=[O:4]
Reactant: CSC(=N)NC(=O)N(C)C
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSC(=NC(=O)N(C)C)NC(=O)N(C)C
Temperature: 25 °C

Procedure:
5.4 Parts of dimethylcarbamoyl chloride is combined with 10 parts pyridine and stirred until the temperature returns to 25° C. 8.0 Parts methyl 4,4-dimethylthioallophanimidate (a compound of formula II), in 50 parts methylene chloride is added in one portion. The mixture is refluxed overnight, then cooled to give a white solid. The solid is removed and the organic layer is extracted with 200 parts water at pH 3, dried and evaporated to give 5 parts methyl N-dimethylcarbamoyl-4,4-dimethylthioallophanimidate (a compound of formula I), m.p. 115.5°-117.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.[OH-].[Na+].OS(O)(=O)=O>O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)n1
Yield: 65.7 %

Procedure:
A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MEOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H2SO4 and filtered. The solid was washed with cold water and dried to give of 2,4-dichloro-6-methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C@@:15]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)([CH2:20][N+:21]([O-])=O)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni].O>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C@:15]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[CH2:20][N:21]=2)=[CH:9][C:8]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Alternatively, the title compound can be obtained by carrying out the following experiment: To a vigorously stirred solution of 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (100 mg) in ethanol (6 mL) was added Raney Nickel (1.44 g, 50% suspension in water, previously washed with dry ethanol) and the reaction was stirred at room temperature under hydrogen (1 atm) for one hour. Then the solution was filtered over celite, and the resulting filtrate was concentrated in vacuo to give the title compound (78 mg) as a pale yellow solid. Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 5.77 minutes (91.43%), 8.71 minutes (3.79%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[O:27][CH:28]([CH3:30])[CH3:29])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Cl:26][C:21]1[C:20]([O:27][CH:28]([CH3:30])[CH3:29])=[C:19]([S:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)(=[O:17])=[O:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1c(Cl)cc(Cl)cc1S(=O)(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
The mixture of 2-(3,5-dichloro-2-isopropoxy-benzenesulfonylamino)-indan-2-carboxylic acid ethyl ester (31) (248 mg, 0.52 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (32) as white solid (230 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:27]([O-])=O)=[CH:4][CH:3]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CS(C)=O.CO.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:27][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)CCC1
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4ccccc4)nc4ccc(Cl)nc43)cc2)CCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (1 g, 2.4 mmol) in DMSO/MeOH (4:1, 20 mL), were added benzaldehyde (0.32 mL, 3.2 mmol) and sodium dithionite (2.0 g, 9.5 mmol). The mixture was heated at 100° C. for 22 h and 1M-NaOH was added to the mixture with cooling in an ice bath until the pH becomes 9. The mixture was diluted with THF (50 mL) then Boc2O (1.5 g) was added and mixed stirred for 2 h at rt. The mixture was filtered through celite and the water phase was extracted with ethyl acetate (×2). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. After evaporation, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (520 mg) as a white solid (46%). To a suspension of tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.1 mmol) in toluene/ethanol/saturated NaHCO3 (3/3/0.3 mL), were added 3-(4-morphoryl)phenylboronic acid (65 mg, 0.22 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol). The mixture was heated at 100° C. for 13.5 h. After evaporation under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give the titled compound (69 mg) as a white solid. 1H-NMR (CDCl3) δ: 8.17 (1H, d, J=8.6 Hz), 7.78 (1H, d, J=8.6 Hz), 7.62 (3H, d, J=7.4 Hz), 7.54 (3H, t, J=8.0 Hz), 7.42 (2H, td, J=5.6, 3.2 Hz), 7.40-7.37 (1H, m), 7.36-7.31 (3H, m), 6.94 (1H, dd, J=8.0, 1.7 Hz), 3.89 (4H, t, J=4.6 Hz), 3.22 (4H, t, J=4.9 Hz), 2.65-2.32 (4H, m), 2.20-2.11 (1H, m), 1.93-1.90 (1H, m), 1.47-1.19 (9H, m); LC/MS: 602 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([S:9](/[CH:8]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])(=[O:11])=[O:10])=[CH:17][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOC(=O)C=O
Product: CCOC(=O)/C=C/S(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from ethyl glyoxalate and 4-(4′-trifluoromethoxyphenyloxy)-phenyl methyl sulfone following the procedures of Examples 126A, 126B and 75B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([NH:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40])=[O:7]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)c(Cl)c2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 87.6 %

Procedure:
To a solution of 3-chloro-4-(1-phenoxyethyl)benzoic acid (262 mg, 1.0 mmol), 1-hydroxybenzotriozole (202 mg, 1.5 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol) triethylamine (0.4 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as a white solid (360 mg, 88%). LRMS (M+H+) m/z: 410.14. found 410. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), δ 8.33 (d, J=5.1, 1H), 7.47 (s, 1H), 7.34 (m, 2H), 67.20 (m, 2H), 6.88 (m, 3H), 5.84 (s, 1H), δ 5.54 (q, J=6, 1H), 4.25 (d, J=4.5, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 3.06 (d, J=6, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([NH2:10])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: Nc1cccnc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a stirred suspension of 2-nitro-pyridin-3-ylamine (5.06 g, 36.40 mmol) and sodium acetate (2.99 g, 36.46 mmol) in acetic acid (40 mL), a solution of bromine (2.5 mL, 48.79 mmol) in acetic acid (8 ml) was added drop-wise and the reaction mixture was stirred overnight. The acetic acid was removed under reduced pressure. The residue was cooled to 0° C., neutralized with saturated sodium bicarbonate solution to adjust the pH to ˜7, and extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was triturated with ethyl acetate to afford compound (5) (5.1 g) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C4C(C=CC=3OC2)=NON=4)C1=O.Br[CH2:45][C:46]1[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=1.C(OC1C=CC(CCl)=NC=1)C1C=CC=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: ClCc1ccc(OCc2ccccc2)cn1
Agent: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Product: CCOC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9.67 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one to replace 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one, and ethyl 4-(bromomethyl)benzoate to replace 5-(benzyloxy)-2-(chloromethyl)pyridine, ethyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.21-7.16 (m, 2H), 7.03 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H), 4.67 (d, J=8.7 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.22-4.19 (m, 2H), 4.15-4.12 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 458.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].Cl.C(=O)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[C:11]=1[C:12]#[N:13])[CH3:2]
Reactant: N#Cc1c(F)cccc1F
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1cccc(F)c1C#N
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A mixture of cyanoacetic acid ethyl ester (26.7 mL, 251 mmol), 2,6-difluorobenzonitrile (33.2 g, 239 mmol) and potassium carbonate (82.5 g, 597 mmol) in dimethyl sulfoxide (120 mL) was stirred at +55° C. for 16 hours and poured into ice-water mixture (ca. 400 mL). It was acidified with conc. aq. HCl with caution (CO2 evolution) and extracted with ethyl acetate (600 ml). The organic phase was washed with brine (100 mL) and evaporated to give 55.1 g of a pale yellow solid that was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): 1.35 (t, J=7.0 Hz, 3H), 4.34 (m, 2H), 5.13 (s, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.33 (dd, J=7.9 Hz, J=13.9 Hz, 1H).