Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-2].[Na+].[Na+].[N+:4]([C:7]1[CH:12]=[C:11]([S:13][C:14]#N)[CH:10]=[CH:9][C:8]=1[OH:16])([O-:6])=[O:5].BrC[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].Cl>CS(C)=O.CO>[OH:16][C:8]1[CH:9]=[CH:10][C:11]([S:13][CH2:14][CH2:19][N:20]2[C:21](=[O:30])[C:22]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]3[C:24]2=[O:25])=[CH:12][C:7]=1[N+:4]([O-:6])=[O:5]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: N#CSc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CS(C)=O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCSc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
A methanol solution (15 ml) containing sodium sulfide. 9 hydrate (3.60 g) was added to 2-nitro-4-thiocyanophenol (1.96 g), which was prepared according to the method described in U.S. Pat. No. 2,562,948 (1951), in dimethyl sulfoxide (10 ml). Then N-(2-bromoethyl)phthalimide (2.54 g) was added, and the mixture was agitated for 3 hrs at room temperature, and was poured into ice water. The pH of the solution was adjusted to 5 with diluted hydrochloric acid, and the precipitate was collected to obtain N-[2-(4-hydroxy-3-nitrophenylthio)ethyl]phthalimide (2.3 g). The compound (3.5 g) was subjected to reduction under increased pressure at 70 atm in the presence of a 5% palladium carbon catalyst, and was subsequently caused to react with cyanogen bromide to yield 2-amino-5-[2-<2-(1,3-(2H)-dioxo-1H-isoindolyl)>ethylthio]benzoxazole (2 g). The benzoxazole derivative (2 g) was heated with hydrazine hydrate to yield 2-amino-5-(2-aminoethylthio)benzoxazole (1.1 g).
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=[C:7]2[CH:6]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)[O:39][N:38]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]>ClCCl.N1C=CC=CC=1>[CH3:36][C:35]1[CH:34]=[CH:33][C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:43][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:45]3)[O:39][N:38]=2)=[CH:31][C:30]=1[NH:29][C:14]([C:11]1[N:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:17])=[CH:6][C:7]2=[N:13][CH:12]=1)=[O:16]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: CC(=O)CCc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(CCC(C)=O)ccn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (86) (40 mg, 0.172 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (16 uL, 0.189 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuum. Methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (25 mg, 0.086 mmol) and anhydrous pyridine (1 mL) were added to the acid chloride. The reaction was stirred to room temperature under Argon for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(4-methyl-3-(7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F73). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 9.44-9.41 (m, 1H), 8.73 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.85 (dd, J=1.6, 8.0 Hz, 1H), 7.73 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.32-7.29 (m, 1H), 4.39-4.35 (m, 2H), 4.31-4.24 (m, 1H), 4.21-4.17 (m, 2H), 3.59 (s, 3H), 2.98-2.91 (m, 4H), 2.37 (s, 3H), 2.13 (s, 3H). MS m/z 503.2 (M+1)+.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[OH-].[NH4+:28].CCOCC>O.CO>[NH4+:28].[NH4+:28].[C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([O-:10])=[O:9])([OH:3])=[O:2].[C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([O-:10])=[O:9])([OH:3])=[O:2]
Reactant: O=C(O)COc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C(O)COc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1C(=O)[O-]
Yield: 71.9 %

Procedure:
A mixture of 2-(carboxymethoxy)-5-[(2-chloro -α,α,α-trifluoro-p-tolyl)oxy]benzoic acid (2.0 g, 5.12 mmol) and concentrated ammonium hydroxide solution (0.5 mL, 7.25 mmol) in water is stirred until homogeneous and concentrated in vacuo to obtain a residue. A solution of the residue in methanol is brought to the cloud point with ether. The solution is cooled in an ice bath and the solid is collected by filtration to give the title product as a white solid (1.5 g, 72%, mp 226-227).
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([C:10]([F:15])([F:14])[CH2:11][CH2:12][CH3:13])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[H][H].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([O:36]C)=[O:35])=[CH:24][CH:23]=1>CN(C)C=O.CO>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([C:34]([OH:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[N:7]=[C:8]([C:10]([F:14])([F:15])[CH2:11][CH2:12][CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1n[nH]c(C(F)(F)CCC)n1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1nc(C(F)(F)CCC)nn1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
Under a static nitrogen atmosphere, 2.0 g (9.2 mmol) of solid 3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazole is added in small portions to 10 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and is treated with a solution of 3.0 g (9.2 mmol) of 4-bromomethyl-2′-methoxycarbonylbiphenyl (from Step 1 of Example 1) in 20 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo; the residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography separates the two isomers; the more abundant isomer is dissolved in 80 ml of ethanol and is treated with 80 ml of 10% NaOH at ambient temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid which causes the product to precipitate; filtration and drying in vacuo gives 4′-[(5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl)-2-carboxylic acid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27]CC4C=CC=CC=4)[CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.CO.Cl>[Pd]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1O
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Into a Parr pressure reactor 1-Benzenesulfonyl-3-(3-benzyloxy-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (92 mg, 0.00020 mol) was placed with Palladium (50 mg, 0.00005 mol) 10%, tetrahydrofuran (15 mL, 0.18 mol) and Methanol (1 mL, 0.02 mol) and HCl solution (3 mL, 0.04 mol). The reaction was shaken under an atmosphere of hydrogen at 50 psi for 4 hours. The mixture reaction was filtered through Celite™ and concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate/hexanes 1:1) to give 31 mg of the titled product. MS(ESI) [M+H+]+=381.11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C1C=CC=CC=1.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Br)c1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)Nc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
2-Bromo-4-aminopyridine (433 mg, 2.5 mmol) was added to 15 ml of dry benzene and the mixture warmed to dissolve the pyridine. 298 mg (2.5 mmol) of phenyl isocyanate was added to the solution and the resulting mixture stirred at room temperature for 20 hrs. The crystals which formed were collected by filtration and subjected to chromatography in a conventional manner using alumina. After developing the column with a benzene-ethyl acetate (2.5:1 volume) solvent mixture, the eluate containing the objective compound was collected. After distilling solvent off under reduced pressure, the residue was recrystallized from 70% methanol to give 308 mg of N-(2-bromo-4-pyridyl)-N'-phenylurea: yield 42.1%; m.p. 188°-189° C.
Reaction SMILES: CC([CH:5]1[CH2:10][CH:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[O:12])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11]([CH:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1)=[O:12]
Reactant: CC(C)(C)C1CC(C(=O)NCc2ccc(Cl)cc2Cl)CCN1C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)C1CCNCC1
Temperature: 25 °C
Yield: 66 %

Procedure:
A 500 mL round bottom flask equipped with a magnetic stir bar was charged with 1,1-dimethylethyl-4-({[(2,4-dichlorophenyl)methyl]amino}carbonyl)-1-piperidinecarboxylate (27.6 g, 71.2 mmol) and DCM (117 mL) at room temperature. Trifluoroacetic acid (117 mL) was added slowly, and the reaction was maintained at room temperature for 1 hour after which time LC/MS determined that the reaction was complete (Rt=6.03 min and m/e 287 [M+1]+). The volatiles were removed by rotary evaporation and the crude oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 13.5 g of N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (47 mmol, 66%) as a pale yellow solid. MS (ES) m/e 287 [M+H]+. 1H NMR (400 MHz, DMSO-D6) □ 8.6 (m, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 4.3 (m, 2H), 3.2 (m, 2H), 2.8 (m, 2H), 2.5 (m, 1H shouldering on DMSO peak), 1.8 (m, 2H), 1.7 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (101.7 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (62.5 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 51 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 51% of theory, C33H39N7O5 (613.7) Rf value: 0.56 (silica gel; dichloromethane/methanol=9:1) ##EQU76##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])[N:24]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:32][C:25]1[N:24]=[C:23]([NH:22][CH2:21][CH2:20][NH:19][C:11]2[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
1 mmol of 2-(2,4-dichlorophenyl)-6-chloro-3-nitropyridine was taken with 2 mmol of (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine and 3 mmol of N,N-diisopropylethylamine in 2 ml of DMF at 80° C. for two hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].S(Cl)(Cl)=O.[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:31][CH2:30][C:27]1[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][N:28]=1)=[O:11])#[N:2]
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: Cc1cnc(CN)cn1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cnc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)cn1
Reaction time: 3 h

Procedure:
A solution of 2-(3-Cyano-phenoxy)-nicotinic acid (0.0067 grams, 0.03 mmole) in thionyl chloride (500 μl, 6.9 mmole) was stirred at room temperature for 3 hours and concentrated under reduced pressure to give a white solid. To the residue was added pyridine (300 μl) and C-(5-Methyl-pyrazin-2-yl)-methylamine (0.0038 grams, 0.03 mmole). The mixture stood at room temperature for 3 hours and then was concentrated under reduced pressure to white solid. (0.0093 g); Anal. calcd. for C19H15N5O2: C, 66.08; H, 4.38; N, 20.26. Found: C, 56.89; H, 5.02; N, 18.31.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[O:5][CH2:6][CH2:7][CH2:8][N:9]=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[O:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: Cc1ccc(OCCCN=[N+]=[N-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCN)cc1C
Yield: 47.8 %

Procedure:
6.20 g (30.2 mmol) of 3-(3,4-dimethylphenoxy)propylazide obtained in step 2 was dissolved in 150 ml of ethyl acetate and then 4.99 g of 5% Pd/C was added thereto to carry out a hydrogenation reaction at a hydrogen pressure of 40 psi for 30 minutes. The reaction mixture was passed through a Celite™ layer to remove Pd/C, concentrated under a reduced pressure to produce a residue, which was distilled under a reduced pressure to obtain 2.59 g (yield 48%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:32])[C:20]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:19]1[C:29](Cl)=[O:30].[C-:33]#[N:34].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[C:33]([CH:11]([O:12][C:29]([CH:19]1[C:20]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:18]1([CH3:32])[CH3:17])=[O:30])[C:10]1[CH:13]=[CH:14][C:15]([F:16])=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)#[N:34]
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C12C=Cc1ccccc12
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(C(=O)OC(C#N)c2ccc(F)c(Oc3ccccc3)c2)C12C=Cc1ccccc12
Yield: 79.4 %

Procedure:
5 g (0.0232 mol) of 3-phenoxy-4-fluoro-benzaldehyde and 5.4 g (0.0232 mol) of 3,3-dimethylspiro-(cyclopropane-1,1'-indene)-2-carboxylic acid chloride were together added dropwise to a mixture of 1.8 g of sodium cyanide, 2.7 ml of water, 100 ml of n-hexane and 0.5 g of tetrabutylammonium bromide at 20°-25° C., while stirring, and the mixture was subsequently stirred at 20°-25° C. for 4 hours. 300 ml of toluene were then added to the reaction mixture and the mixture was extracted twice by shaking with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a water-pump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.1 g (79.5% of theory) of 3,3-dimethylspiro-(cyclopropane-1,1'-indene)2-carboxylic acid α-cyano-3-phenoxy-4-fluoro-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[Cl:24])[CH:16]=2)=[O:14])[CH2:9]1>>[CH3:6][N:7]([CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[Cl:24])[CH:16]=2)=[O:14])[CH2:9]1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CNC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CS(=O)(=O)Cl
Product: CN(C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)S(C)(=O)=O

Procedure:
The title compound was prepared from methanesulfonyl chloride and (3-methylamino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 374/376 (MH+); HPLC Rf: 4.14 min.; HPLC purity 98%.
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]S(C(C)(C)C)=O)[CH2:18][O:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][CH:3]=1.Cl.CCCCCC>C(Cl)Cl.O1CCOCC1>[ClH:1].[NH2:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)=[CH:14][CH:13]=2)[CH2:16][O:17][CH2:18]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)COC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)COC1
Reaction time: 0.17 h

Procedure:
Deprotection/protection step: To a solution of N-(3-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}oxetan-3-yl)-2-methylpropane-2-sulfinamide (95 mg) in DCM (5 ml) was added dropwise a solution of hydrogen chloride in dioxane (4 M, 111 ul) at room temperature. The reaction mixture was stirred for 10 min. Hexane was added to the suspension and the solid was filtered to give N-[4-(3-aminooxetan-3-yl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride. To a suspension of N-[4-(3-aminooxetan-3-yl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride in THF (3 mL) chilled to 0° C. was added saturated sodium bicarbonate solution (6 mL) and followed by a solution of di-tert-butyl dicarbonate (145 mg) in THF (3 mL) dropwise. After being stirred at room temperature over night, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (59 mg, 2 steps 63%). 400 M Hz 1H-NMR (DMSO-d6) δ: 10.14 (s, 1H), 8.55 (d, J=8.7 Hz, 1H), 8.10 (brs, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.7 Hz, 1H), 4.82 (d, J=6.4 Hz, 2H), 4.68 (d, 2H, J=6.4 Hz), 1.50-1.10 (m, 9H); LCMS: 421 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=2)[OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:32]=[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47](O)=[O:48])[C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[C:34](=[O:40])[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=1)[CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:48])=[O:32]
Reactant: COc1cc(CC[C@@H](O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc(OC)c1OC
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cc(OC)c(OC)c(OC)c1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of alcohol 14 (650 mg, 1.5 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 382 mg, 1.5 mmol, followed by 1,3-dicyclohexylcarbodiinide (370 mg, 1.8 mmol), and 4-(dimethylamino)-pyridine (128 mg, 1.0 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-30% EtOAc/hexanes) to give (1R)-3-(3,4,5-trimethoxyphenyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (776 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.30-6.80 (m, 4H), 6.37 (s, 2H), 5.82 (t, J=6.1 Hz, 1H), 5.33 (d, J=5.2 Hz, 1H), 4.54 (s, 2H), 3.85 (s, 6H), 3.83 (s, 3H), 3.38 (d, J=12.6 Hz, 1H), 3.16 (td, J=12.8, 3.1 Hz, 1H), 2.60 (m, 2H), 2.45-2.05 (m, 3H), 1.70 (m, 6H), 1.50 (s, 9H), 1.45 (m, 2H), 1.25 (s, 3H), 1.23 (s, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.1, 168.2, 167.6, 158.5, 153.6, 141.7, 137.0, 130.1, 120.9, 120.2, 114.6, 113.7, 105.7, 82.7, 66.2, 61.2, 56.5, 51.7, 47.1, 44.6, 38.2, 32.9, 32.4, 28.4, 26.8, 25.3, 23.9, 23.5, 21.6, 9.1.