Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH2:9]([O:8][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc(Cl)cc[nH]1
Solvent: c1ccccc1
Product: c1ccc(COc2ccccn2)cc1

Procedure:
Reaction of 4-chloropyridone (XXXXII) with an aryl halide, such as benzyl bromide in benzene and in the presence of Ag2CO3 as described in Scheme 13 (Smith A. M.; et al. J. Med. Chem. 36, 8, 1993) and at temperature ranges of 30-80° C. afforded the corresponding 2-benzyloxypyridine (XXXXVII). This was coupled with an arylboronic acid, ArB(OH)2 under palladium-catalyzed conditions to give (XXXXIX). The benzyloxy group can be removed by treatment with a strong acid, such as trifluoroacetic, triflic, sulfuric, HCl, etc. to give pyridone (L). This was converted to the 2-halopyridine with the action of POX3, PX5 or the corresponding triflate, tosylate or mesylate, which was displaced with a primary amine RNH2 to give (LI). The nitro group was reduced under conditions described in scheme 13 and the aminopyridine was cyclized to the imidazolo[4,5-b]pyridine (LII) under conditions described in scheme 13.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([Br:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(Br)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(Br)c1
Yield: 55.8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-bromoaniline (1.98 g, 11.6 mmol) in 16 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes to yield 1.99 g of the title compound, mp 194°-196° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:13])[N:3]=1.C([SnH](CCCC)CCCC)CCC>O1CCOCC1>[Br:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[N:3][C:4]([NH2:13])=[CH:5]2
Reactant: Nc1cc2cc(Br)ccc2c(Br)n1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1COCCO1
Product: Nc1cc2cc(Br)ccc2cn1
Temperature: 100 °C

Procedure:
To a solution of 1,6-dibromoisoquinolin-3-amine (0.20 g, 0.66 mmol) and tributyltin hydride (0.19 mL, 0.73 mmol) in 6 mL of dioxane in a sealable tube was added palladium tetrakistriphenylphosphine (0.038 g, 0.033 mmol). The tube was sealed and heated to 100° C. in a Personal Chemistry microwave unit for 10 minutes. The mixture was then concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (5% to 50% EtOAc/hexanes) affording 6-bromoisoquinolin-3-amine. 1H NMR (400 MHz, CD3OD) δ ppm 8.74 (s, 1H) 7.72 (s, 1H) 7.70 (d, J=8.80 Hz, 1H) 7.27 (dd, J=8.80, 1.76 Hz, 1H) 6.68 (s, 1H).
Reaction SMILES: Cl.[C:2]([NH2:10])(=N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].C[N:18]([CH:20]=O)[CH3:19]>>[C:3]1([C:19]2[NH:18][CH:20]=[C:2]([C:3]3[CH:4]=[CH:5][C:6]([O:14][CH3:11])=[CH:7][CH:8]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: [K+]
Product: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of benzamidine hydrochloride (31.22 g, 02 mmol, 1.17 eq.) in 250 ml of DMF is added potassium carbonate (69 g, 0.5 mol). 2-bromo-4′-methoxyacetophnone is dissolved in 200 ml of DMF and added to the reaction flask dropwise at 55° C. After the addition, the reaction mixture is stirred at 60° C. for 3 h, then cooled to room temperature and poured into 1000 ml of ice-water, the mixture is extracted with ethyl acetate (150 ml×4), washed with water and brine, dried over sodium sulfate, purified through flash chromatography to give 30g of 2-phenyl-4-(4 methoxyphenyl)imidazole. 1H NMR (400 MHz, CDCl3) δ 7.86 (2H, d, J=6.8 Hz), 7.43˜7.25 (5H, m), 6.93 (2H, d, 18.8 Hz), 3.83 (3H, s); MS (+VE) m/z 251 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([N:46]3[CH2:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=4[NH:48][C:47]3=[O:57])[CH2:42][CH2:41]2)=[O:39])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:11][C:10]=1[CH3:58])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:10]([CH3:58])=[CH:11][C:12]([CH2:16][C@@H:17]([O:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([N:46]3[CH2:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=4[NH:48][C:47]3=[O:57])[CH2:44][CH2:45]2)=[O:39])[C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH2:25]2)=[O:19])=[CH:13][C:14]=1[CH3:15]
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
80 mg (0.10 mmol) ethyl 1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate in 10 mL EtOH were combined with 30 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 1 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C1c2ccc(Cl)cc2CCc2c(OS(=O)(=O)C(F)(F)F)cccc21

Procedure:
For the preparation of the title compound, 0.517 g (0.0020 mol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 0.846 g (0.0030 mol) of Tf2O in 5 ml of pyridine are reacted by method R. C16H10ClF3O4S (Mr=390.77); GC 11.9 min
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:24])[CH2:29][CH2:28]1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: OC1CCNCC1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)N3CCC(O)CC3)ccc1OCC2

Procedure:
Following the procedure for 116, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-hydroxy piperidine to give 118 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1 Hz, 1H); 7.94 (s, 1H); 7.35 (dd, J=8.3, 2.1 Hz, 1H); 7.23 (d, J=8.3 Hz, 1H); 6.88 (s, 1H); 5.76-5.62 (m, 1H); 4.58 (t, J=5.8 Hz, 2H); 4.19 (br s, 1H); 4.07-3.98 (m, 1H); 3.82 (br s, 1H); 3.37 (br s, 2H); 3.20 (t, J=5.8 Hz, 2H); 1.95 (br s, 2H); 1.70 (d, J=3.9 Hz, 1H); 1.67-1.54 (d, J=6.6 Hz, 8H). LCMS: RT=8.77 min, M+H+=423
Reaction SMILES: [NH2-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].COC([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=O.Cl.C[CH2:32][O:33]CC>>[C:23]1([C:32](=[O:33])[CH2:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[O:5])[C:22]2[C:27](=[CH:28][CH:29]=[CH:20][CH:21]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2ccccc2c1
Reactant: CCOCC
Reactant: CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Product: O=C(CC(=O)c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4.75 gr of 50% slurry of sodium amide was suspended in 150 ml of anhydrous ether in a 250 ml round bottom flask that was equipped with a magnetic stir bar and a condenser. To this suspension was added 5.1 gr of solid acetonaphthone and continued stirring for 5 min at room temperature. After 5 minutes, 5.58 gr of methyl-2-naphthoate was added in one lot. At this point, the reaction flask was transferred to an oil bath and the bath temperature was raised so that the contents reflux gently in ether for 3 hours. The contents were then poured onto 300 gr of solid ice. On acidification with conc. HCl, solid product fell out of solution. The solid product was filtered and recrystallized in ether/methanol mixture.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:29]1[C:30]([O:43][CH2:44][C:45]2([CH3:53])[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[CH:14]1([C:29]2[C:30]([O:43][CH2:44][C:45]3([CH3:53])[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6][CH2:5]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 3, and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate with tert-butyl 5-chloro-4-((4,4-difluoro-1-methylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as colorless oil (3.69 g, 99%): MS (ES+) m/z 399.2 (M+23).
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.16 g of 3-fluoro-4-nitropyridine N-oxide [Rocz. Chem. 40, 1675 (1966), Chem. Abstr. 69, 59059d (1968)] and 2.58 g of o-chlorophenol in 250 ml of acetone is treated with 5.6 g of anhydrous potassium carbonate. The heterogeneous mixture is stirred vigorously at 25° C. for 16 hours. The mixture is filtered and concentrated at reduced pressure. The product is dissolved in 200 ml of acetonitrile and chromatographed over neutral alumina. The eluate is concentrated at reduced pressure and 3-(o-chlorophenoxy)-4-nitropyridine N-oxide is recrystallized from methanol-diethyl ether; mp 129°-131° C.
Reaction SMILES: Cl[C:2]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:5].CC[N:26]([CH2:29][CH3:30])CC.N1CC1>CCOC(C)=O>[N:26]1([C:2]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:5])[CH2:29][CH2:30]1
Reactant: O=C(NCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: CCN(CC)CC
Agent: C1CN1
Solvent: CCOC(C)=O
Product: O=C(NCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N1CC1
Yield: 84.3 %

Procedure:
A solution of 2-chloro-N-(6-hydroxyhexyl)-3,5-dinitrobenzamide (16) [for preparation see Example 14 below] (118 mg, 0.34 mmol) and Et3N (200 mg) in EtOAc (200 mL) was treated with aziridine (100 mg) at room temperature for 3 h. The mixture was diluted with EtOAc and washed three times with water, after dry, concentrated under reduced pressure until about 20 mL, the yellow solid was collected and gave 101 mg product (84%); 1H NMR [(CD3)2SO] δ 8.74 (d, J=2.8 Hz, 1 H), 8.63 (m, 1 H), 8.29 (d, J=2.8 Hz, 1 H), 4.31 (m, 1 H), 3.39 (m, 2 H), 3.25 (m, 2 H), 2.37 (s, 4 H), 1.56 (m, 2 H), 1.43 (m, 2 H), 1.33 (m, 4 H). Anal. (C15H20N4O6) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([C:16](C)(C)[O:17][SiH2]C(C)(C)C)[S:15][C:11]=2[C:10]([I:25])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH2:16][OH:17])[S:15][C:11]=2[C:10]([I:25])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2sc(C(C)(C)O[SiH2]C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(I)c2sc(CO)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To 5-(tert-butyl-dimethyl-silanyloxymethyl)-3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [410 mg, 0.83 mmol, Intermediate (73)] in tetrahydrofuran (5 mL) was added a 1.0M TBAF solution in tetrahydrofuran (0.92 mL, 0.92 mmol) at 0° C. The solution was stirred at 0° C. for 1 hour. The solvent was removed and the residue was chromatographed through silica gel (dichloromethane/ethyl acetate, 90/10 as eluant) to afford 5-hydroxymethyl-3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [230 mg, 73%, Intermediate (80)] as a white powder. LC/MS: 380.97 (M+H), RT=2.8 minutes.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:9]=2[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH3:24]I>>[CH3:24][N:7]1[C:8](=[O:22])[C:9]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:11]=[N:12][C:13]=2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:23]
Reactant: CI
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2CCCCCC(C)=O
Product: CCCCn1c(=O)n(C)c(=O)c2c1ncn2CCCCCC(C)=O
Reaction time: 46 h
Yield: 80.1 %

Procedure:
The reaction is performed according to example 15 from 3-(n-butyl)-7-(6'-oxoheptyl)-xanthine and methyl iodide, but at a temperature of the mixture of 50° C. under stirring for 46 hours. Prior to the distillation at a bath temperature of 140° C. and 0.02 mmHg the product is purified by column chromatography at silica gel 60 (Merck) with methylene chloride/acetone (80:2) as eluent. 1-Methyl-3-(n-butyl)-7-(6'-oxoheptyl)-xanthine was obtained as a viscous oil (nD20 1.5280; yield 80.1%, referred to reacted 3-(n-butyl)-7-(6'-oxoheptyl)-xanthine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].O[NH:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[NH:15]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:13]=1
Reactant: COC(=O)CCCCC(=N)NO
Reactant: COc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Yield: 34.4 %

Procedure:
Add 2-methoxybenzoyl chloride (5.20 g, 35 mmol) to a solution of methyl 5-(N-hydroxycarbamimidoyl)pentanoate (5.3 g, 34 mmol) in pyridine (50 mL) under nitrogen at 0° C. and then heat the mixture at reflux for 6 h. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate and wash with 1 N HCl. Wash the combined organic extracts with brine, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:4), to afford methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.4 g, 33% over two steps): 1H NMR (CDCl3) δ 1.7-1.85 (m, 2H), 1.85-2.00 (m, 2H), 2.35 (t, 2H), 2.95 (t, 2H), 3.65 (s, 3H), 3.95 (s, 3H), 7.00 (m, 2H), 7.45 (t, 1H), 8.00 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>>[NH:17]1[C:16]([NH:15][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:10])=[N:20][N:19]=[N:18]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)ccn1
Yield: 60.5 %

Procedure:
1.16 g of 4-chloro-2-pyridinecarboxylic acid, 25 ml of thionyl chloride and 0.82 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 1.0 g of N-(5-tetrazolyl)-4-chloro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [ClH:1].Cl.N[C@@H]1CCN([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)C1.C(OC(=O)[NH:35][C@@H:36]1[CH2:40][CH2:39][N:38](C(=O)C(C2(O)CCCCC2)C2C=CC=C(OC(F)(F)F)C=2)[CH2:37]1)(C)(C)C>>[ClH:1].[ClH:1].[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]2([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH3:9])[OH:28])[CH2:37]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: N[C@@H]1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CC(c1cccc(OC(F)(F)F)c1)C1(O)CCCCC1N1CC[C@@H](N)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl((3R)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}pyrrolidin-3-yl)carbamate. MS (ESI) m/z 373; HRMS: calcd for C19H27F3N2O2+H+, 373.20974; found (ESI, [M+H]+), 373.2097.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring a troom temperature for 1 h, the slurry was partitioned between NaHCO3 solution and EtOAc (warmed to dissolve solid). The organic phase was washed with H2O, 4% aqueout HCl solution, H2O, saturated NaHCO3, brine and dried with Na2SO4. After concentrating in vacuo the residue was triturated with EtOAc to give the title compound (47.4 mg, 82%) as a yellow solid.
Reaction SMILES: [OH2:1].[O-2:2].[Mg+2].[CH3:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][O:11][C:12]([N:14]=[N+]=[N-])=[O:13])=[CH:8][CH:7]=1>O1CCOCC1>[CH2:10]=[C:9]([CH2:8][CH2:7][CH2:6][NH:14][C:12]([O:11][CH2:10][C:9]1[CH:17]=[CH:18][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)=[O:13])[C:17]([OH:2])=[O:1]
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Reactant: O
Reactant: [O-2]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: C=C(CCCNC(=O)OCc1ccc(OC)cc1)C(=O)O

Procedure:
To a solution of 3.8 grams (53 mmol) of the product from part E in 100 ml. of water were added 6.4 grams (159 mmol) of magnesium oxide with stirring followed by a solution of 12.2 grams (59 mmol) of p-methoxybenzyloxycarbonyl azide in 100 ml. of p-dioxane. The resulting slurry was stirred at room temperature for two days. The mixture then was filtered through Hyflo and diluted with 200 ml. of ethyl acetate. AG50W-X2 Dowex 50 ion-exchange resin (200 ml. wet volume) was added, and the mixture was stirred at room temperature for 2 hours. The resin then was removed by filtration and washed with water. The filtrate layers were separated, and the aqueous layer was extracted twice with 200 ml. of ethyl acetate. The combined ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo to give 15.5 grams of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1([N:13]=[C:14]=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[OH:4][CH2:3][C:2]([NH:1][C:14]([NH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:15])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: S=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(CO)NC(=S)Nc1ccccc1
Yield: 59.2 %

Procedure:
In 500 g of chloroform was dissolved 2-amino-2-methyl-1-propanol (61.6 g, 0.69 moL). Then, 300 g of chloroform solution containing phenyl isothiocyanate (81.6 g, 0.6 moL) was slowly added dropwise to the mixture over one hour, while stirring. Upon completion of the addition, the resulting mixture was stirred for 12 hours at room temperature. The precipitated crystals were refluxed with heat to be dissolved and then recrystallized. The crystals thus obtained were collected by filtration, washed with 20 mL of diethyl ether three times, and then dried under reduced pressure at room temperature to give 80.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-N′-phenylthiourea (yield 60%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([NH:17][NH2:18])=O)[CH:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+]>C1COCC1>[CH3:23][C:22]1[N:24]=[C:15]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[O:14][N:13]=2)[NH:17][N:18]=1
Reactant: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a solution of 5-(4-(trifluoromethoxy)phenyl)isoxazole-3-carbohydrazide (4.4 g, 15.3 mmol) and acetimidamide hydrochloride (2.2 g, 23.0 mmol) in dry THF (100 mL) was added NaOH (920 mg, 23.0 mmol), and the resulting mixture was refluxed for 16 h. The solution was then cooled to RT and concentrated under reduced pressure, the residue was partitioned between H2O (80 mL) and EtOAc (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether:EtOAc=1:2) to afford the title compound as a yellow solid (2.1 g, 44.3%). MS (ES+) C13H9F3N4O2 requires: 310. found: 311 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[C:15]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Agent: Cl
Solvent: CCO
Product: Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Temperature: 0 °C
Yield: 92.2 %

Procedure:
There were mixed 29.7 g of 7-acetylamino-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one, 30 ml of ethanol and 300 ml of 6N hydrochloric acid. The mixture was refluxed for 1 hour. The reaction mixture was introduced into 3 liters of ice water. The resulting crystal was collected by filtration and recrystallized from ethanol to obtain 23.5 g (yield: 92.2%) of 7-amino-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 154°-155° C.