Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](OCC)=[O:16])=[CH:9]1.[BH4-].[Li+].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:9]1
Reactant: CCOC(=O)CCc1ccn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(CCCO)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
A solution of 275 mg (0.66 mmol) of the compound of Example 24 in 15 mL THF was treated with 287 mg (13.2 mmol) of lithium borohydride followed by stirring at ambient temperature for 18 h. The solution was treated with 1 mL of saturated ammonium chloride solution, diluted with ethyl acetate, and extracted with water (3×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over 20 g of 230-400 mesh silica gel eluting with 2-4% (v/v) methanol in dichloromethane. These procedures afforded 96 mg (39%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.74, 7.66, 7.38, 7.27, 7.18, 6.95, 6.61, 5.98, 4.82, 4.37, 4.27, 4.09, 3.83, 3.68, 2.88, 2.82, 2.62, 2.04, 1.79.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:23][S:20]([CH2:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)(=[O:32])=[O:31])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a mixture of ethyl 7-amino-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylate (4.8 g) and pyridine (50 mL) was added pyridine-2-sulfonyl chloride (3.0 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated, aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried (MgSO4), and concentrated. The obtained crystals were washed with diisopropyl ether, and recrystallized from acetone-hexane to give the title compound (4.68 g, yield 69%) as pale-brown prism crystals. melting point 194-195° C.
Reaction SMILES: [C:1]([CH:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)C.[CH3:13][NH:14][NH2:15]>CO>[CH3:13][N:14]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:1]=[N:15]1
Reactant: CNN
Reactant: CC(=O)C1C(=O)CCCCC1=O
Solvent: CO
Product: Cn1ncc2c1CCCCC2=O
Temperature: 0 °C

Procedure:
To an ice-cold solution of 21 grams of 2-acetyl-1,3-cycloheptanedione in 180 ml of methanol was added, dropwise, a solution of 6.2 ml of methylhydrazine in 30 ml of methanol. The resulting reaction mixture was heated at reflux for 1 hour and the solvent was then removed under reduced pressure. The residual material was partitioned between dichloromethane and brine, the aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate. The solvent was removed under reduced pressure to leave a dark oil which crystallized on standing. The solid was recrystallized from a mixture of ether and hexane to give 5,6,7,8-tetrahydro-1-methyl-4(1H)-cycloheptapyrazolone as a yellow crystalline solid melting at about 95°-97° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[I-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:27]=[CH:26][C:21]2[B:22]([OH:25])[O:23][CH2:24][C:20]=2[CH:19]=1)[C:12]#[N:13].[H-].[Na+]>O.CN(C)C=O>[CH:5]1([CH2:4][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:27]=[CH:26][C:21]3[B:22]([OH:25])[O:23][CH2:24][C:20]=3[CH:19]=2)[C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
A solution of bromomethyl cyclopropane (0.544 mL, 5.61 mmol), sodium iodide (4.20 g, 28.05 mmol), and N,N-dimethylformamide (30 mL) under a nitrogen balloon were stirred at 70° C. for 3 hours. The reaction was cooled to room temperature and 3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.500 g, 1.87 mmol) and more N,N-dimethylformamide (30 mL) was added. The reaction was cooled to 0° C. in an ice water bath and sodium hydride (0.224 g, 5.61 mmol) was added. The reaction was stirred under nitrogen balloon at 0° C. for 5 minutes and then at room temperature overnight. Water was added to quench excess sodium hydride and the solution was neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 3-(cyclopropylmethoxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.225 g, 37% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.15 (d, J=4.5 Hz, 2H), 0.43 (d, J=7.6 Hz, 2H), 1.06 (septet, J=6.7 Hz, 1H), 3.90, (d, J=6.9 Hz, 1H), 4.91 (s, 2H), 6.95 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 9.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:24]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][N:17]([CH3:24])[C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1c[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Reactant: CN(C)C=O
Product: Cc1cn(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 177°-180° C.,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[CH2:30][C:29](=[O:31])[NH:28][CH:27]([C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:5]32[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][C:6]3=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: O=C1Nc2ccc(F)cc2/C1=C/c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1ccc(F)cc12
Yield: 41 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-5-fluoro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 170b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-5-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 2 g, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-].[Na+]>Cl>[NH2:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 5-bromo-3-nitropyridine-2-carbonitrile (1.5 g, 5.3 mmol) and SnCl2-dihydrate (5.00 g, 26.3 mmol) in concentrated HCl and allow to stir at room temperature overnight. Work up by adding ice and carefully adding 10 M NaOH until basic. Extract twice with Et2O (200 mL), dry (Na2SO4) and evaporate. Purify by silica gel chromatography (75% hexane-EtOAc) to furnish 3-amino-5-bromopyridine-2-carbonitrile as a pale solid.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:19][O:20][CH3:21])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH2:31][O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.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>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([CH2:31][O:32][CH3:33])[CH:30]=[C:25]([O:24][CH3:23])[C:26]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:19][O:20][CH3:21])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COCc1cc(OC)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of tert-butyl N-[7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (300 mg) dissolved in 1,2-dimethoxyethane (10 mL) and water (5 mL) was added 2,6-dimethoxy-4-methoxymethylphenylboric acid (323 mg), tetrakis(triphenylphosphine)palladium(0) (146 mg) and barium hydroxide octahydrate (398 mg), and the reaction mixture was heated and stirred for 2 hours at 80° C. under a nitrogen stream. Water was added to the obtained reaction mixture, the reaction mixture was extracted with ethyl acetate, and the organic extract was washed with brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (245 mg) was obtained as a light yellow amorphous solid from the n-hexane:ethyl acetate (1:1) fraction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][NH:39][CH2:40][CH2:41][OH:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:39]([CH2:40][CH2:41][OH:42])[CH2:38][C:29]2[CH:30]=[CH:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCNCc1ccc2ccccc2n1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CN(C)c1cccc(N(CC(=O)N(CCO)Cc2ccc3ccccc3n2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 2-[(quinolin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:10]=[C:9]([F:17])[CH:8]=1.CN(C)[CH:20]=[O:21]>O1CCCC1>[F:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:10]=1)[CH:20]=[O:21]
Reactant: CCCOc1cc(F)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1cc(F)cc(C=O)c1
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Add n-butyl lithium (13 mL, 1.6M, 20.76 mmol) to 1-bromo-3-fluoro-5-propoxybenzene (4.40 g, 18.88 mmol) in tetrahydrofuran (100 mL) cooled in a dry ice/acetone bath over 45 minutes, maintaining the internal temperature <−70°. Stir 30 minutes and add N,N-dimethylformamide (2.76 g, 37.75 mmol). Stir 30 minutes and remove cold bath. After 1 hour, quench with saturated aqueous ammonium chloride. Wash organic layer with water and saturated aqueous sodium chloride. Dry (sodium sulfate), filter and concentrate to an oil. Purify on 120 g silica gel eluting with 0 to 10% ethyl acetate in hexanes to give 2.26 g (65.7%) of the desired compound as an oil.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.CN(C(ON1N=N[C:22]2C=[CH:24][CH:25]=[N:26][C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(NCC)C>CN(C=O)C.O>[CH2:25]([N:26]([CH2:21][CH3:22])[C:1](=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)[CH3:24]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(CC)C(=O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of m-anisic acid (0.5 g; 3.29 mmol) and HATU (1.4 g; 3.68 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (2 mL; 11.48 mmol). The reaction was stirred at room temperature for 30 min. Diethylamine (0.377 mL; 3.62 mmol) was added to the reaction. The mixture was stirred at room temperature for 1.5 d, diluted with H2O (5 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over MgSO4 and concentrated to afford Compound 15a. The crude product was used in the next reaction without further purification. MS: m/z 208.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:29])/[CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[C:15]([O:30][CH3:31])[C:14]([CH3:32])=[C:13]2[C:9]=1[C:10](=[O:33])[O:11][CH2:12]2>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:29])/[CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([OH:24])=[O:23])=[C:15]([O:30][CH3:31])[C:14]([CH3:32])=[C:13]2[C:9]=1[C:10](=[O:33])[O:11][CH2:12]2
Reactant: CCOC(=O)C(C)(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCCOCOc1c(C/C=C(\C)CC(C)(C)C(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl -4-hexenoate and compounds of Formula 109, prepared e.g, as described in Example ZA-12 and converted to compounds of Formula 112 as described in Part A above, there are obtained (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-4-hexenoic acid, m.p. 163-165 (hexane/ethyl acetate) and the corresponding compounds of Formula I-ZA-M2 as identified in the following table.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:8]([O:14][CH3:13])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(N)c1Cl
Yield: 53.1 %

Procedure:
A solution of 2,3-dichloro-4-nitroaniline (25 g) and sodium methoxide (25 g) in methanol (250 ml) is stirred and heated at reflux under a nitrogen atmosphere for 5.5 hours. The reaction mixture is poured into water (1.5 l), the precipitated yellow solid is collected and dried. This material is purified by chromatography on silica gel using 1:1 hexane/ether eluent. The eluents are collected and evaporated to dryness to afford 13 g of title compound, m.p. 118°-123° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: c1ccc(CN2CCC(COC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of 1-benzylpyrrolidine-3-methanol (1.72 g) (J. Org. Chem., 1961, 26, 1521) and bromodiphenylmethane (4.94 g) in xylene (150 ml) was heated under reflux for 3 hours, allowed to cool to room temperature, diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 20% ethyl acetate plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.57 g) as a pale brown oil which was charcterised by its 1H-NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[N:3]=1.C[O-].[Na+]>C(O)C(C)C.CO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2([C:9]3[NH:1][C:2]4=[N:3][C:4]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[O:27])[CH2:21]5)=[CH:5][CH:6]=[C:7]4[N:8]=3)[CH2:13][CH2:12]2)[CH:15]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5cccnc5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
To a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridin-3-yl)cyclopropanecarboxamide (35 mg, 0.081 mmol) in isobutanol (500 μL) was added sodium methoxide (18 mg, 0.335 mmol) in methanol (250 μL). The reaction mixture was shaken 110° C. for 18 h. The solvent was evaporated under a nitrogen stream. The residue was partitioned between water (0.5 mL) and ethyl acetate (1.5 mL×3). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via HPLC to afford (R)-(1-(2-(1-(pyridin-3-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (7.2 mg). MS (ESI+) (M+H) 417.3; HPLC retention time 1.59 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>ClCCl>[N:57]1([S:61]([NH:64][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([CH2:12][O:13][C:14]3[CH:15]=[N:16][C:17]([CH:21]4[CH2:23][CH2:22]4)=[C:18]([Cl:20])[CH:19]=3)=[CH:4][C:5]=2[F:11])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
To a stirred solution of 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoic acid (Preparation 27, 500 mg, 1.4 mmol) in dichloromethane (40 mL) was added HATU (639 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.78 mL, 4.49 mmol), the mixture was left to stir for 15 minutes. Azetidine-1-sulfonamide (Preparation 19, 573 mg, 4.21 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then washed with saturated aqueous NH4Cl (30 mL) and brine (30 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure to give the crude product as an orange oil. This was purified by column chromatography on silica (eluent 1:1 heptane/EtOAc) to give the title compound as an off-white solid (450 mg, 67%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:14][C:13](=O)[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=1)[CH3:3].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(CN(C)C)[nH]c(=O)c2cc1OC
Product: COc1cc2nc(CN(C)C)nc(Cl)c2cc1OC
Yield: 93 %

Procedure:
A mixture of 2-((dimethylamino)methyl)-6,7-dimethoxyquinazolin-4-(3H)-one (100 mg) and phosphorous oxychloride (10 mL) was refluxed for 2 h. Excess of POCl3 was evaporated under vacuum and the reaction mixture was attained to rt. The mixture was poured into ice cold water and basified with aqueous ammonia solution. The solution was extracted with chloroform (3×100 mL) and the combined CHCl3 layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an off-white color solid (100 mg, 93%), mp 78-80° C. 1H NMR (400 MHz, CDCl3): δ 7.41 (1H, s), 7.38 (1H, s), 4.05 (6H, s), 3.82 (2H, s), 2.42 (6H, s); LC-MS (positive ion mode): m/z 282, 284 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])#[N:22]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccc(C#N)c2)c1
Yield: 43.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (176 mg, yield: 43.4%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[NH:17]C(=O)OCC>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[NH2:17]
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 110 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Ethyl alcohol (50 ml) and a 2N aqueous solution of sodium hydroxide (100 ml) were added to the thus-obtained ethyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate, followed by stirring for 4 hours while heating in an oil bath at 110° C. After completion of the reaction, the solvent was distilled off, and the residue was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with a saturated aqueous sodium chloride, dried, and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (9.36 g, 40.8 mmol, 97% yield). 1H-NMR Spectrum (CDCl3, TMS, ppm): δ1.40-2.07 (8H, m), 3.72 (2H, br s), 4.57 (1H, m), 6.35 (1H, d, JHF =8.0 Hz), 6.98 (1H, d, JHF =10.5 Hz). IR Spectrum (KBr, disk, cm-1): 2980, 1635, 1510, 1423, 1250, 1190.