Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=O.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:26]=[C:17]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 60 %

Procedure:
5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (100 mg, 0.323 mmol) and o-phenylene diamine (38.5 mg, 0.356 mmol) were dissolved in dry THF (6 mL), and 2N HCl (2 drops) were added. The solution was heated at a gentle reflux for 30 min, and then 1N sodium bisulfite (2 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (100 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 60% yield. 1H NMR (400 MHz, CDCl3): δ 9.86 (s, 1H), 8.79 (d, 1H, J=1.2 Hz), 7.83 (m, 1H), 7.50-7.41 (m, 3H), 7.25-7.22 (m, 2H), 5.69 (dd, 1H, J=2.8 and 8.8 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.76 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[NH:20][N:19]=1>CN1CCCC1=O>[ClH:1].[Cl:16][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:17][C:18]3[CH:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[NH:20][N:19]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: Nc1cc(CC(=O)O)[nH]n1
Solvent: CN1CCCC1=O
Product: Cl
Product: O=C(O)Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1
Reaction time: 12 h

Procedure:
4-Chloro-7-(3-chloropropoxy)quinazoline was added to 1 molar equivalent of a solution of (3-amino-1H-pyrazol-5-yl)acetic acid in N-methylpyrrolidinone (NMP) and then left for a period of 12 hours. Crystallisation of the product was observed to occur with and without seeding and with and without the addition of acetonitrile as an anti-solvent. The resultant solid was isolated by filtration, washed with N-methylpyrrolidinone and acetonitrile and then dried in vacuo to yield (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid.hydrochloride as an off-white solid containing one molar equivalent of NMP:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]=1[NH:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 113.1 %

Procedure:
Methansulfonyl chloride (1.26 g, 18.43 mmol) was added to a 0° C. solution of 4-nitro-2-aminobromobenzene (1.6 g, 7.37 mmol) and triethlyamine (1.86 g, 18.43 mmol) in 20 ml of CH2Cl2. The reaction mixture was allowed to warm to room temperature and stirred 72 hr. The mixture was poured onto 50 ml of 1M HCl and extracted with 2×100 ml ethyl acetate. The extracts were washed with brine then dried (anhydrous MgSO4) and concentrated. The material was dissolved in 10 ml of methanol and treated with 10 ml of 3M NaOH solution. The mixture was stirred overnight. The methanol was removed at reduced pressure, then 10 ml of water were added and the solution was washed with 50 ml of CH2Cl2. The aqueous was acidified to pH 1 by the dropwise addition of concentrated HCl. The product was extracted with ethyl acetate (2×75 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 2.46 g of N-(2-bromo-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][O:12][S:11]2=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:18]>C(Cl)Cl.C(#N)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][O:12][S:11]2(=[O:18])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: CC(C)(C)c1ccc(CN2CCOS2=O)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2-(4-tert-butylbenzylamino)-ethanol (1190 mg, 5.74 mmol) and triethylamine (3200 μl, 22.96 mmol) in DCM (15 ml) at −15° C. was added a solution of thionylchloride (544 PI, 7.46 mmol) in DCM (4 ml) over 10 min. The reaction mixture was stirred at −10° C. for 30 min, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography to give the desired compound (790 mg, 54%) as a white solid. To a mixture of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2-oxide (790 mg, 3.12 mmol) in DCM (20 ml), acetonitrile (8 ml) and water (8 ml), at 0° C. was added NaIO4 (867 mg, 4.05 mmol) followed by RuO2 (2 mg). The reaction mixture was stirred at 0° C. for 2 h. Water was added and the phases were separated and the aqueous phase was extract with ethyl acetate. The organic layers were combined washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was then purified by flash column chromatography to give the desired product (640 mg, 76%) as an off white solid. MS (ISP) 287.0 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[OH:16]/[N:15]=[C:10](\[NH2:11])/[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(Cc1ccc(C(F)(F)F)cc1)=N\O
Yield: 84.9 %

Procedure:
A suspension of [4-(trifluoromethyl)phenyl]acetonitrile (1.0 g, 5.4 mmoles), hydroxylamine hydrochloride (0.41 g, 5.9 mmoles) and NaHCO3 (0.50 g, 5.9 mmoles) in MeOH (15 ml) was refluxed for 4 hours. The reaction mixture was then concentrated to remove the solvent methanol. The residue was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated to afford the desired product (1.0 g, 84.9%) as white solid. LCMS calculated for C9H10F3N2O(M+H): 219.1; found: 219.1.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.Cl.Cl.[CH3:16][N:17]1[CH:22]2[CH2:23][CH2:24][CH:18]1[CH2:19][CH:20]([NH2:25])[CH2:21]2.[O:26]1CCCC1>>[CH3:16][N:17]1[CH:22]2[CH2:23][CH2:24][CH:18]1[CH2:19][CH:20]([NH:25][C:2]([C:3]1[NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=1)=[O:26])[CH2:21]2
Reactant: C1CCOC1
Reactant: CN1C2CCC1CC(N)C2
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Agent: Cl
Product: CN1C2CCC1CC(NC(=O)c1nc3ccccc3[nH]1)C2
Yield: 10 %

Procedure:
The reaction was carried out as described in General Procedure 2 using 2-trichloromethyl-1H-benzoimidazole (Example 1, 100 mg, 0.42 mmol) and 8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine dihydrochloride (172 mg, 0.84 mmol) in tetrahydrofuran (THF, 3 mL). Purification afforded 10 mg (10%) of the title compound. MS (ESI): mass calculated for C16H20N4O, 284.16; m/z found, 285.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.70 (br s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.76 (br s, 1H), 7.43 (br s, 1H), 7.35-7.33 (m, 2H), 4.37 (q, J=7.1 Hz, 1H), 3.25-3.23 (m, 2H), 2.49 (s, 3H), 2.39-2.33 (m, 2H), 2.23 (s, 3H), 2.23-2.18 (m, 2H), 2.02-1.96 (m, 2H), 1.97 (d, J=14.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.CO[CH:34]1[CH2:38][CH2:37][CH:36](OC)O1.C(O)(=O)C>ClCCCl.CO>[NH:21]1[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:3]2[C:2]([N:1]3[CH:34]=[CH:38][CH:37]=[CH:36]3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:20]1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3cccc3)cn2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (121 mg, 0.285 mmol) was dissolved in DCE (6 mL) and 2,5-dimethoxytetrahydrofuran (75.3 mg, 0.57 mmol) and acetic acid (2 mL) were added. The solution was heated for 1 h at 80° C. then a further aliquot of acetic acid (2 mL) was added. The solution was heated at 80° C. for a further 30 min then cooled to room temperature and partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the combined organic phases were evaporated to give an orange oil. The residue was dissolved in methanol and absorbed onto a TsOH solid phase extraction cartridge, washed once with methanol and allowed to stand for 1 h. The cartridge was then eluted with a solution of 7M ammonia in methanol and the solution was evaporated to dryness. The residue was purified by HPLC to give 5-(4-(piperidin-3-ylmethylamino)-5-(1H-pyrrol-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile (4.3 mg, 4%).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)[CH2:39][CH2:38]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Reactant: NC1CCNCC1
Solvent: ClCCl
Product: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 135 °C
Yield: 41.6 %

Procedure:
A mixture of the sulfoxide 7B (100 mg, 0.20 mmol) and 4-aminopiperidine (0.6 gm, 6 mmol) was heated in a sealed tube at 135° C. for 4 hr. The reaction mixture was taken up in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate eluted with DCM containing 5% MeOH) afforded 7C (40 mg, 42%) as a foam. Analytical HPLC retention time=1.35 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=481.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][C:11](C)=[O:12]>CS(C)=O.O1CCCC1>[C:4]1([C:1](=[O:3])[CH2:2][C:11](=[O:12])[CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=O)CC(=O)c1ccccc1

Procedure:
The procedure of Example 1 is repeated, using in place of acetophenone 17.4 g of acetone and increasing the amount of solvent from 100 g to 150 g of dimethyl sulfoxide/tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[N:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NCC(F)(F)F)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 29.8 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (55.9 mg, 0.23 mmol) and 2,2,2-trifluoroethylamine (Aldrich Chemical Company) (95 μL, 1.15 mmol) was added a solution of K2CO3 (0.13 g, 0.92 mmol) in H2O (1.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated aqueous NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was washed with CH2Cl2 until all the color was removed. The remaining solid was recrystallized from hot MeOH to provide 21 mg (29%) of the title compound as a white solid. Mp: >310° C. MS m/z 307 (M+1), 294, 281, 226. 1H NMR (DMSO-d6; 400 MHz): δ 2.31 (s, 3), 2.52 (s, 2), 6.74 (s, 1), 7.33 (t, 1, J=7.3), 7.43 (t, 2, J=7.8), 7.92 (d, 2, J=7.3), 11.74 (s, 1), 12.22 (s, 1). HRMS: Calcd for M+H, C15H13F3N4: 307.1168. Found: 307.1160.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17].Cl.[NH2:44][OH:45]>O.C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[N:33][NH:44][OH:45])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H](n1cnc2cc(-c3ccc(C#N)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](n1cnc2cc(-c3ccc(C=NNO)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.1 %

Procedure:
To a solution of Na2CO3 (0.84 g, 7.92 mmol) in a mixture of H2O (8 mL) and THF (30 mL) was added (1R,2R)-4-[3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl]benzonitrile (0.5 g, 0.99 mmol, obtained in example 32) and hydroxylamine hydrochloride (0.35 g, 1.95 mmol). The mixture was stirred at reflux overnight, concentrated and the aqueous residue was extracted with CHCl3. The organic phase was separated, dried over Na2SO4, filtered and the filtrate concentrated to a solid which was purified by flash chromatography to give the title compound as a pale yellow solid (325 mg, 61%): mp 246°-247° C.; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.60 (s, 1H, N=CH--N), 8.18 (s, 1H, triazole), 7.86 (d, J=8.5, 2H, arom), 7.78 (d, J=8.5, 2H, arom), 7.71 (s, 1H, triazole), 7.66 (s, 1H, thiophene), 7.43 (dt, Jt =6.5, Jd =9, 1H, arom), 7.06 (ddd, Jd =2.5, Jd =8.5, Jd =14, 1H, arom), 6.89 (dt, Jd =2.5, Jt =8.5, 1H, arom), 6.09 (q, J=7.3, 1H, MeCH), 5.09 (d, J=14.2, 1H, CH(H)), 4.19 (d, J=14.2, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); MS 314 (N-ethylheterocycle, C15H14N4O2S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =+74.9° (c 1, MeOH). Analysis calculated for C25H21F2N7O3S: C 55.86; H 3.94; N 18.24; S 5.96. Found: C 55.10; H 3.84; N 17.72; S 5.69.
Reaction SMILES: [CH3:1][CH:2](C)[CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C=CCCC1NC2C(C=1)=CC=CC=2>>[CH2:4]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2][CH3:1]
Reactant: CC(C)CCc1cc2ccccc2[nH]1
Agent: C=CCCc1cc2ccccc2[nH]1
Product: CCCCc1cc2ccccc2[nH]1

Procedure:
Refer to 28b) using 2-(but-1-en-4-yl) indole as the starting material.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[N:11]1([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[N:11]1[CH2:16][CH2:15][N:14]([CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:13][CH2:12]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COC(=O)CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCC(C)N1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A mixture of 1.10 g of methyl 5-oxo-hexanoate as synthesized in above step 7-14-A, 1.36 g of 2-piperazin-1-ylquinoline, 20 mg of p-toluenesulfonic acid and 50 ml of toluene was heated under reflux for 16 hours, and the formed water was azeotropically removed. The solvent was concentrated under reduced pressure. The residue was dissolved in 50 ml of tetrahydrofuran, and the solution was stirred at room temperature for an hour while hydrogen chloride gas was introduced thereinto. Then 380 mg of sodium cyanotrihydroborate as dissolved in 10 ml of methanol was added, followed by 2 hours' stirring. To the solution, 0.1N aqueous potassium hydroxide was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:n-hexane=1:1) to provide 977 mg (45%) of methyl 5-(4-quinoline-2-ylpiperazin-1-yl)hexanoate.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:20].CCCCCC.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:3]12[O:20][CH:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)N1CC=CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
Into a solution of 10 (2.27 g, 12.1 mmol) in CH2Cl2 (20 mL), a solution of 3-chloroperoxybenzoic acid (5.43 g, 77% pure, 24.3 mmol) in CH2Cl2 (40 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. After the reaction was complete as determined by TLC (hexane/ethyl acetate, 1/1, v/v), saturated Na2CO3 solution (50 mL) was added into the reaction vial slowly with stirring. The reaction mixture was stirred for 30 min. The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using hexane/ethyl acetate (3/1, v/v) as the mobile phase to afford the product as a sticky oil (1.54 g, 62%). 1H NMR (CDCl3): δ 2.04-2.18 (m, 2H), 3.09-4.40 (m, 6H), 7.28-7.47 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][CH2:19][C@@H:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCn1cc(Br)cn1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a mixture of 4-bromopyrazole (1.26 g, 8.57 mmol) and cesium carbonate (4.66 g, 14.3 mmol) in DMF (20 mL) was added (3S)-3-((tert-butoxycarbonyl)amino)-4-(4-chlorophenyl)butyl methanesulfonate (2.70 g, 7.15 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was diluted with DCM and washed with H2O (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (EtOAc/Hexanes, 0-25%) to give the product as an off-white solid (2.86 g, 93%). LCMS (API-ES) m/z: 428, 430 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:14])=[CH:13][CH:12]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: CN(C)c1ccc(C=CC(=O)O)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1ccc(N(C)C)cc1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 2.0 g of 4-dimethylaminocinnamic acid, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-dimethylaminocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OCC)(=[O:15])[C:10](OCC)=[O:11]>>[NH:8]1[C:10](=[O:11])[C:9](=[O:15])[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1cccnc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cccnc2[nH]c1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 2,3-diaminopyridine (75 g, 687 mmol) in diethyl oxalate (291 ml, 2131 mmol) under N2 was heated to 120° C. After 1 h, the ethanol was distilled off the reaction mixture and the temperature was elevated to 160° C. for a further 2 hours. The reaction mixture was allowed to cool to RT and diluted with diethyl ether (200 ml). The resulting suspension was stirred for 1 hour and the solid was isolated by filtration and dried in a vacuum oven. The solid was suspended in ethanol (500 ml) and sonicated for 1 hour. The suspension was filtered and dried (vacuum oven overnight) to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]([CH:23]2[CH2:25][CH2:24]2)(O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[C:15]([CH:23]2[CH2:24][CH2:25]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(O)(c2ccccc2)C2CC2)ccn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(C=C(c2ccccc2)C2CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
[4-(2-Cyclopropyl-2-hydroxy-2-phenyl-ethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (280 mg, 0.79 mmol) and 4-dimethylaminopyridine (97 mg, 0.79 mmol) are dissovled in pyridine (3.0 mL) and thionyl chloride (0.12 mL, 1.6 mmol) is added at 0° C. After the mixture is stirred for 3 hrs at room temperature, saturated NaHCO3 aqueous solution (4 mL) is added along with water (20 ml). The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 6%) affords 94 mg of the desired product.