Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(CCCl)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[K+].O.[CH3:15]O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:12][CH3:15])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: [OH-]
Reactant: CO
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [K+]
Solvent: O
Product: COc1cccc(F)c1[N+](=O)[O-]
Yield: 95 %

Procedure:
To a solution of 2,6-difluoronitrobenzene (5 g, 32 mmol) in methanol (50 mL) was added potassium hydroxide (1.8 g, 32.5 mmol), and the mixture was heated to reflux for 3 hr. Water was added, and the mixture was extracted with dichloromethane. The organic layer was separated, dried, filtered, and evaporated to yield 5.1 g (95%) of 1-fluoro-3-methoxy-2-nitrobenzene, 1e. MS m/z (MH+) 172.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:5]2=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH2:24]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: COc1ccccc1-c1n[nH]c2nc(Cl)ncc12
Reactant: CN(C)CCCN
Product: COc1ccccc1-c1n[nH]c2nc(NCCCN(C)C)ncc12
Yield: 12 %

Procedure:
The compound was prepared from 6-chloro-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 6) and 3-dimethylamino propylamine (Aldrich) in an analogous manner as described in Example 32 (120° C.) and 9.2 mg (12% yield) free base was obtained. Purification of the mother liquor with HPLC gave a TFA salt (50 mg, 49% yield) MS (M+H)+, 327.2.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:44]=[CH:43][C:42]([O:45]C)=[CH:41][C:38]=2[C:39]#[N:40])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:38]=2[C:39]#[N:40])[CH2:35][CH2:36]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(N2CCC(Cc3ccccc3)CC2)c(C#N)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: N#Cc1cc(O)ccc1N1CCC(Cc2ccccc2)CC1
Yield: 42.3 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 2-(4-benzylpiperidino)-5-methoxybenzonitrile (99 mg), and the resulting crude product was purified on TLC (developer, hexane: ethyl acetate=2:1) to provide 2-(4-benzylpiperidino)-5-hydroxy-benzonitrile (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[CH:13]=1.C(OC([N:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH:23]=[C:22]1[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37])=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:22]4[NH:21][C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[CH:23]=4)[C:32](=[O:37])[CH2:33]3)=[O:12])[S:7][C:6]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Product: O=C1CN(C(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2cnccc2[nH]1
Reaction time: 8 h

Procedure:
The title compound is prepared as described in EXAMPLE 123 using 6-chloro-benzo[b]thiophene-2-carboxylic acid, EXAMPLE 1 and 2-(2-oxopiperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester EXAMPLE 69. The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH2Cl2 and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a solid. The crude material can be used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](F)=[CH:8][CH:9]=2)[N:4]([CH3:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:20][CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:12])[CH:3]=1
Reactant: OCc1ccncc1
Reactant: Cn1cc(Br)c2ccc(F)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccc(OCc3ccncc3)nc21
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 3-bromo-6-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (0.4 g, 1.74 mmol) and pyridine-4-ylmethanol (0.21 g, 1.93 mmol) in DMF (5.0 mL) is added portionwise sodium hydride (0.05 g, 2.11 mmol) at room temperature and the resulting reaction mixture is stirred for 1 h. The reaction is quenched with cold brine solution and extracted with EtOAc (4×100 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by crystallization from Et2O/pentane to give the title compound (0.300 g, 0.942 mmol) as an orange-red solid. MS (m/z): 318, 320 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.73 (s, 3H), 5.48 (s, 2H), 6.76 (d, 1H), 7.47 (d, 2H), 7.50 (s, 1H), 7.78 (d, 1H), 8.56 (d, 2H).
Reaction SMILES: C(Cl)Cl.Cl.Cl.[Cl:6][C:7]1[C:8]([CH:18]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:9][C:10]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:11][CH:12]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>CCOCC>[Cl:6][C:7]1[C:8]([CH:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:9][C:10]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][S:45]([CH3:44])(=[O:47])=[O:46])=[N:11][CH:12]=1
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
To a methylene chloride solution (5.0 ml) of the N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (60 mg, 0.107 mmol) obtained in Example 173 were added triethylamine (70 μl, 0.05 mmol) and methanesulfonyl chloride (10 μl, 0.13 mmol). The resulting mixture was stirred for 20 minutes. To the reaction mixture was added ether (50 ml). The resulting mixture was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the title compound (60 mg, 99%). The resulting compound was crystallized in ethanol to afford a white solid (46 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[C:13]([O:16][CH2:17][C:18](=O)[C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:19]([C:18]1[N:14]2[N:15]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:13]2[O:16][CH:17]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1coc2c(-c3ccccc3)c(-c3ccc(S(C)(=O)=O)cc3)nn12
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 5-(4-(methylsulphonyl)phenyl)-4-phenyl-3-trimethylacetylmethoxy-pyrazole prepared according to the Example 32B [(100 mg, 0.24 mmol), p-toluenesulfonic acid hydrate (25 mg) in toluene (40 mL), and acetic acid (15 mL) was refluxed using a Dean-Stark trap to remove water, for 12 hours. The reaction mixture was concentrated in vacuo and the residue chromatographed (silica gel, 1:1 hexane/ethyl acetate) to provide the desired product (yield: 97 mg; 99%). MP 187-180° C.; MS (APCI+) m/z 395 (M+H)+; (APCI−) m/z 393 (M−H)−, 429 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ1.49 (s, 9H), 3.25 (s, 3H), 7.35 (m, 5H), 7.76 (d, J=9 Hz, 2H), 7.95 (s+d, J=9 Hz, 3H); Anal. calc. for C22H22N2O3S.0.5 H2O: C, 65.48; H, 5.74; N, 6.94. Found: C, 65.70; H, 5.69; N, 6.65.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O.O1CCOCC1>[C:19]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
piperazine-2-carboxylic acid dihydrochloride (10.0 g, 49.23 mmol) is dissolved in 1:1 dioxane/water (320 ml). 50% Aqueous sodium hydroxide is added to bring the pH to 11. BOC-ON (2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile), (15.59 g, 63.32 mmol) is dissolved in dioxane (80 ml) and added dropwise while maintaining the pH at 11 with 50% aqueous sodium hydroxide. The reaction is stirred overnight at ambient temperature. The reaction mixture is then extracted with diethyl ether (5×250 ml) and acidified to pH 2 with concentrated hydrochloric acid. The di-Boc compound is then extracted out with ethyl acetate (4×200 ml) and the acidic aqueous solution containing the desired mono-Boc product is then taken on in the synthesis.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2
Reactant: O=C1CN2Cc3cc([N+](=O)[O-])ccc3N=C2N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CN1CC(=O)NC1=N2

Procedure:
To a suspension of 9.18 g. (3.4×10-2 mole) of 7-Nitro-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one hydrochloride in 95% ethanol (300 ml.) was added 10 ml. of concentrated hydrochloric acid and 0.45 g. of 10% Pd/C catalyst. The mixture was placed on a Paar hydrogenator, shaken until theoretical hydrogen absorbed, removed and water (150 ml.) added to effect dissolution of precipitate. The mixture was filtered under suction, the catalyst washed with 95% ethanol and the mixture evaporated to dryness yielding 9.02 g. of a yellow powder. Purification of the free base was effected yielding 7-Amino-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one; m.p. >275°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:12][OH:13])[NH2:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(Cc1ccc(Cl)cc1)=NO
Temperature: 80 °C
Yield: 83.3 %

Procedure:
To a stirred solution of 2-(4-chlorophenyl)acetonitrile (1 g, 6.5 mmol) in ethanol (20 mL) at room temperature, hydroxylamine hydrochloride (4.5 g, 65.6 mmol) and potassium carbonate (12.5 g, 91 mmol) were added and heated at 80° C. overnight. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed with water and brine, and dried over sodium sulfate. Solvent was removed under vacuum to afford 2-(4-chlorophenyl)-N′-hydroxyacetimidamide (1 g, 83%) as an off-white solid. 1H NMR: 400 MHZ, DMSO-d6: δ 3.26 (s, 2H), 5.43 (s, 2H), 7.29-7.30 (m, 2H), 7.34-7.34 (m, 2H), 8.91 (s, 1H). LCMS: RT 0.89 min. LCMS (ES-API), m/z 186.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:37])[CH2:35]Cl)[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:38][NH:39][CH3:40]>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:37])[CH2:35][N:39]([CH3:40])[CH3:38])[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CNC
Reactant: Nc1nccn2c(CC3CCN(C(=O)CCl)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 80 °C

Procedure:
1-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-2-chloro-ethanone (77.00 mg, 0.15 mmol) was transferred to a pressure reaction vessel and dissolved in 3.15 mL of 2M dimethylamine solution in THF. The reaction was heated at 80° C. overnight. The crude product was then condensed and purified by a 5 g Jones silica gel (dry loaded with silica gel; eluted with 100% CH2Cl2→2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=0.80), 8.28 (1H, d, J=8.23), 8.19 (2H, dd, J=2.04, J=1.55), 7.93 (3H, m), 7.53 (3H, dd, J=1.70, J=1.70), 7.53 (3H, m), 7.23 (1H, d, J=5.08), 7.15 (1H, d, 5.06), 5.52 (2H, m), 4.63 (1H, d, J=14.08), 4.04 (1H, d, J=11.88), 2.43 (2H, q), 2.97 (4H, d, J=6.08), 2.60 (1H, t), 2.43 (6H, s), 2.29 (1H, m), 1.86 (2H, d, J=12.96), 1.30 (2H, m); MS (ES+): m/z 520.11 (5) [MH+]; HPLC: tR=1.73 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CC(O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([NH:9][C:12]2[CH:13]=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of N,N-dimethyl-m-phenylenediamine (1.36 g, 10 mmol), 6-chloro-pyrimidin-4-ylamine (1.30 g, 10 mmol), 2-propanol (10 mL) and HCl conc. (0.45 mL, ˜5 mmol) is shaken for 16 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-concentrated Na2CO3 solution and ethyl acetate. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (ethyl acetate/CH3OH). The combined pure fractions are evaporated to afford the title compound. Beige solid, HPLC: tR=1.53 min (gradient F), ESI-MS: 230.3 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Reactant: C1CNCCNC1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCCNCC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 64.3 %

Procedure:
A mixture of 0.500 g (1.66 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.498 g (4.97 mmol) of homopiperazine in acetonitrile (5 mL) is heated at 175° C. in a microwave reactor for 90 minutes. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.390 g (66.8%) of 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-pyridin-3-yl)-benzamide as a red oil.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].CS([O-])(=O)=O.[OH-].[Na+]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[C:8]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(O)ccc2c1CCO2
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(O)c(C(C)(C)C)c2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
In a solution of 2.84 g of 4-t-butyl-5-hydroxy-2,3-dihydrobenzofuran [J. Org. Chem. 53, 4135 (1988)] in 10.0 g of t-butyl alcohol and 20 ml of chloroform was added dropwise 10 ml of methane sulfonate under ice-cooling. The mixture was stirred at 0° C. for 15 minutes, then poured into ice water. Then, the mixture was neutralized with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane) to give 1.78 g of 4,7-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran as a white crystal (yield 48%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]1[OH:12].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]1[OH:12])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)N1CCC(Br)C(O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 84 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the bromide (70 mg, 0.27 mmol, Example 307) in dimethylformamide (3 mL), sodium azide (80 mg, 1.23 mmol) was added and the mixture was stirred at 84° C. overnight. The solvent was removed and the residue was chromatographed (50% ethyl acetate/hexanej to give the desired product as a colorless oil. 51 mg, 86%. H1NMR (300MHz, CDCl3), ppm: 1.60-1.70 (m), 1 H; 2.05-2.20(m), 1 H; 2.80-3.05 (m), 2 H; 2.83 (s), 3H; 3.10 (br), 1 H (OH); 3.40-3.51 (m), 1 H; 3.51-3.62 (m), 1 H. 3.65-3.80 (m), 2 H.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCCCO
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCCO)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-aminobutan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.53 (m, 2 H) 1.53-1.64 (m, 2 H) 2.44 (s, 3 H) 3.27-3.33 (m, 2 H) 3.44 (br. s., 2 H) 4.43 (br. s., 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.07-8.27 (m, 1 H) 8.41 (d, J=6.57 Hz, 2 H) 8.70 (t, J=5.43 Hz, 1 H) 8.85-8.97 (m, 1 H) 12.82-13.57 (m, 1 H). MS m/z [M+H]+ 392.2
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](OS(C)(=O)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:14]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CS(=O)(=O)OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCn2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-phenyl-1H-imidazole (1 g, 8.75 mmoles) in DMF (8 mL) is added NaH 60% dispersion in mineral oil (455 mg, 11 mmoles). The reaction mixture is stirred at room temperature for 1 hour, then methanesulfonic acid phenethyl ester (example 4D) (1.84 g, 9.12 mmoles) is added. The reaction mixture is then heated at 60° C. for 2 hours. Water is added, and the aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) (100:0) then (98:2) to give 1-phenethyl-4-phenyl-imidazole.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[N:16]([CH:31]([CH3:33])[CH3:32])[C:17]3[C:22]([C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=1.[OH-].[Na+].N1CCOCC1>CO.C(OCC)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:31]([CH3:33])[CH3:32])[C:15]=2/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:34])[C:3]([OH:35])=[O:2])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2c(-c3ccc(F)cc3)c3ccccc3n2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCN1
Solvent: CO
Solvent: CCOCC
Product: CC(C)n1c(/C=C/COc2ccc(C(=O)C(=O)O)cc2)c(-c2ccc(F)cc2)c2ccccc21
Yield: 75.7 %

Procedure:
As in Example 19, (E)-4-[3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester (0.354 g) in methanol (5 mL) was treated with 1N sodium hydroxide (0.9 mL). The usual work up gave 0.4 g of a oil, which was dissolved in diethyl ether and morpholine (0.07 g) was added. Crystallization was induced and the recovered solid was recrystallized from dichloromethane-ethyl acetate to provide 0.26 g of (E)-4-[3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indole-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid (1:1) morpholine salt as a colorless solid, mp 151°-152° C.