Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1.Cl.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[C:5]([O:17][CH:14]([CH3:16])[CH3:15])[N:4]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)O
Agent: Cl
Agent: [Na]
Product: CC(C)Oc1nc(N)nc2[nH]cnc12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Sodium (Aldrich, lot #9621CL, 4.1 g, 176.9 mmol) was reacted with 150 mL of isopropanol, 2-Amino-6-chloropurine (Sigma, lot #69F4064, 6.0 g, 35.4 mmol) was added and the reaction stirred at 50° C. for 24 hours. The solution was cooled and brought to pH 7 with 1N HCl. The solvents were evaporated to one-half volume. The precipitate was filtered, washed with water and dried to give 5.9 g (30.5 mmol, 87%); mp=204°-206° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[C:17]1[N:13]([CH:14]=[C:15]([C:21]3[N:25]([CH2:26][CH2:27][OH:28])[N:24]=[CH:23][N:22]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2)=O.[NH:30]([CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[NH2:31]>C(O)(=O)C>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]2[C:5]([C:7]3[CH:20]=[CH:19][C:18]4[C:17]5[N:13]([CH:14]=[C:15]([C:21]6[N:25]([CH2:26][CH2:27][OH:28])[N:24]=[CH:23][N:22]=6)[N:16]=5)[CH2:12][CH2:11][O:10][C:9]=4[CH:8]=3)=[CH:4][CH:3]=[N:31]2)[CH2:33][CH2:34]1
Reactant: CN1CCC(NN)CC1
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Solvent: CC(=O)O
Product: CN1CCC(n2nccc2-c2ccc3c(c2)OCCn2cc(-c4ncnn4CCO)nc2-3)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (105 mg, 0.270 mmol) in acetic acid (2.0 mL) was added hydrochloric 4-hydrazinyl-1-methylpiperidine (53 mg, 0.32 mmol). The mixture was stirred at 100° C. for 1 hour under nitrogen atmosphere. After concentration, the residue was purified by preparative HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give 257 (17 mg, 13% yield). LCMS (ESI): RT=4.05 min, m/z: 461.2 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.23 (d, J=9 Hz, 1H), 7.11 (s, 1H), 6.40 (d, J=1.5 Hz, 1H), 4.98 (t, J=10.5, 1H), 4.84 (t, J=12, 2H), 4.58 (s, 4H), 4.16 (t, J=23 Hz, 1H), 3.88-3.86 (m, 2H), 2.85 (d, J=10 Hz, 2H), 2.15-2.13 (m, 5H), 1.94 (s, 2H), 1.81 (d, J=11.5, 2H)
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)(=[O:41])=[O:40])=[O:31])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of phenyl 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate (203 mg, 0.50 mmol), 5-methylpyridine-2-sulfonamide (86 mg, 0.50 mmol) and DBU (82 μL, 0.55 mmol) in acetonitrile (5 mL) was stirred for overnight at ambient temperature. Then, the volatile components were removed by evaporation and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 145 mg (60%) of the title compound as white solids: MS (ESI) m/z 490 [M+H]+, 488 [M−H]−, 1H-NMR (DMSO-d6) δ 1.18 (3H, t, J=7.5 Hz), 2.37 (3H, s), 2.72-2.90 (4H, m), 3.23 (2H, q, J=6.0 Hz), 6.69 (1H, br), 7.40-7.59 (6H, m), 7.85-7.93 (4H, m), 8.24 (1H, s), 8.55 (1H, s).
Reaction SMILES: C1CCCCC=1.[C:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]1[O:36][C@:26]2([CH2:37][O:38]CC3C=CC=CC=3)[C@@:27](CC3C=CC=CC=3)([OH:28])[C@H:23]1[O:24][CH2:25]2)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[C:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]1[O:36][C@:26]2([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[O:24][CH2:25]2)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Oc1ccccc1[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@]2(O)Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: O=C(Oc1ccccc1[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Yield: 87.6 %

Procedure:
In a stream of nitrogen, 20% palladium hydroxide-carbon (53 mg) and cyclohexene (0.52 ml, 5.1 mmols) were added to an anhydrous ethanol (2 ml) solution of the compound (25) (54 mg, 0.10 mmol), and the mixture was heated under reflux for 2 hours. After filtration, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=80:3) to obtain a white powder (26) (30 mg, 85%).
Reaction SMILES: [Na].[CH3:2][C:3]1[O:7][C:6](=[O:8])[NH:5][N:4]=1.[CH2:9]([O:16][CH2:17][C:18](=[O:21])[CH2:19]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.O.[Cl-].[Na+].O>[CH2:9]([O:16][CH2:17][C:18](=[O:21])[CH2:19][N:5]1[N:4]=[C:3]([CH3:2])[O:7][C:6]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCl)COCc1ccccc1
Reactant: Cc1n[nH]c(=O)o1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(CC(=O)COCc2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5-methyl-1,3,4-oxadiazol-2-one sodium salt (34.6 g, 284 mmol) in DMF (200 mL) at 0° C. was added dropwise a solution of 1-benzyloxy-3-chloro-propan-2-one (56.4 g, 284 mmol) in DMF (80 mL). After completion of the addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The obtained reaction mixture was diluted with water and brine and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried (Na2SO4). After evaporation of the solvent the desired product was obtained as a brown oil. Purification by flash chromatography (25% EtOAc/heptane) furnished the desired product as a yellowish oil. 1H NMR (400 MHz, CDCl3) 2.27 (s, 3H), 4.27 (s, 2H), 4.62 (s, 2H), 4.75 (s, 2H), 7.30-7.46 (m, 5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>CO.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][NH:10][C:9](=[O:12])[NH:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1NC=C(C(=O)O)C(c2ccc(F)cc2)N1
Yield: 71.5 %

Procedure:
4-(4-Fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (3.6 g) was suspended in 67 mL MeOH and 2.5 M NaOH (23 mL) was added. The mixture was heated at 65° for 6 hours, then cooled, diluted with water and acidified with conc. HCl. The resulting precipitate was recovered by filtration and air dried to yield 4-(4-fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(2.3 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([C:34]([N:36]5[CH2:37][CH2:38][CH2:39][CH2:40]5)=[O:35])[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CNC1)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidin-3-ylpyrrolidin-1-ylmethanone (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to afford 365 as a white solid (65 mg, 48%). LCMS (Method G): RT=6.26 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.73 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 3.86 (m, 6 H); 3.83 (s, 3 H); 3.69-3.63 (m, 2 H); 3.55-3.42 (m, 5 H); 3.39-3.27 (m, 4 H); 1.98-1.82 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([OH:20])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C=O)C.O>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:30][C:29]([O:28][CH3:27])=[O:32])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)CBr
Reactant: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[(trans-4-hydroxycyclohexyl)amino]-7-methylquinazolin-8-ol (20 g, 0.073 mol) in DMF (160 mL) was added K2CO3 (10.6 g, 0.077 mol) in one portion at room temperature. Then a solution of bromoacetic acid methyl ester (11.5 g, 0.075 mol) in DMF (40 mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (150 mL), dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product. The crude product was re-crystallized from EtOH (150 mL) to give the title compound (13 g, 51.4%) as an off-white solid.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][C:15]([O:18][C:19]([NH:21][CH2:22][CH2:23][NH2:24])=[O:20])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH:24][CH2:23][CH2:22][NH:21][C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:7])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
Mono-methyl isophthalate (10.0 g, 55.5 mmol), t-butyl n-(2-aminoethyl)carbamate (8.89 g, 55.5 mmol, 1.0 eq) and EDCI (12.2 g, 63.8 mmol, 1.15 eq) were dissolved in 270 mL DCM, followed by the addition of DIPEA (29.0 mL, 166 mmol, 3.0 eq). The reaction was allowed to stir at room temperature overnight. It was then taken up in 100 mL of DCM, washed with a 1:1 solution of 1.0 N HCl in brine, water, and a 1:1 solution of brine in saturated NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford the product as a light yellow solid (12.81 g, 72%).
Reaction SMILES: C([O:3][C:4](=O)[NH:5]/[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[CH:7]\[C:8]#[N:9])C.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH:30][NH2:31])=O)[CH2:24][CH2:23]1)[CH3:21].O>CN1CCCC1=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[NH:5][C:4](=[O:3])[N:31]2[N:30]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)[N:9]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1F
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
2.0 g (4.12 mmol) of ethyl[(Z)-2-cyano-1-(2,4-difluorophenyl)ethenyl]carbamate (Example 37A) and 916 mg (4.95 mmol) of 1-(propan-2-yl)piperidin-4-carbohydrazide (Example 38A) were dissolved in 24 ml of N-methylpyrrolidone, and the mixture was stirred under argon at an oil bath temperature of 160° C. in a flask with fitted calcium chloride drying tube for 6 h. The reaction mixture was cooled to RT, water (50 ml) was added and the mixture was stirred for 15 min. The mixture was extracted with ethyl acetate (three times 50 ml each) and the combined organic phases were freed from the solvent. The residue was purified by preparative HPLC (Method 11). This gave 660 mg (41% of theory) of the product.
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+]>CC(O)C.O>[C:25]([C:20]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([OH:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]2([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:21][CH2:22][CH2:23][CH2:24]1)([OH:27])=[O:26]
Reactant: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1(CCCCCC(O)CCCCCC2(C(=O)O)CCCC2)CCCC1
Reaction time: 19 h
Yield: 102.9 %

Procedure:
To a mixture of 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (5.00 g, 12.7 mmol) in iPrOH (30 mL) and H2O (30 mL) was added NaOH (1.07 g, 26.3 mmol). To the resulting clear solution, NaBH4 (0.38 g, 10.0 mmol) was added. After 19 h, the reaction mixture was concentrated in vacuo. The remaining residue was dissolved in H2O (50 mL) and acidified with aqueous HCl (6M, 15 mL). The resulting mixture was extracted with Et2O (100 mL, 2×50 mL), and the combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated in vacuo to give 1-[11-(1-carboxycyclopentyl)-6-hydroxyundecyl]-1-cyclopentanecarboxylic acid (5.18 g, 99%, contains 4% (w/w) Et2O) as a thick, light yellow oil that slowly crystallized on standing. mp=: 76-77° C. 1H NMR (CDCl3); δ=3.56 (br s, 1H), 2.16-2.11 (m, 4H), 1.64-1.61 (m, 12H), 1.51-1.18 (m, 20H). 13C NMR (CDCl3): δ=184.3 (2×), 71.4, 54.2 (2×), 39.2 (2×), 36.9 (2×), 36.2 (2×), 35.7 (2×), 29.5 (2×), 25.9 (2×), 25.2 (2×), 25.1 (2×), 25.0 (2×).
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:25][CH2:24][N+:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:26][C:27]1[N:28]=[C:29]([CH3:33])[NH:30][C:31]=1[Cl:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][C:27]1[N:28]=[C:29]([CH3:33])[N:30]([CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][N:16]([C:13]3[N:12]=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:15][N:14]=3)[CH2:25][CH2:24]2)[C:31]=1[Cl:32]
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Reactant: c1ccc(COc2cnc(N3CC[N+]4(CCCC4)CC3)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(OCc3ccccc3)cn2)CC1
Yield: 68.9 %

Procedure:
A mixture of 3.59 g (8.85 mmol) of 8-(5-benzyloxy-2-pyrimidinyl)-8-aza-5-azoniaspiro [4.5]decane bromide, 1.47 g (9.73 mmol) of 4,5-dichloro-2-methylimidazole and 4.89 g (35.41mmol) of potassium carbonate in 72 ml of dimethylformamide is refluxed for 12 hours and filtered hot. The dimethylformamide is evaporated and the product is chromatographed on silica gel, yielding 2.90 g (69%) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]-1-piperazinyl}-5-benzyloxypyrimidine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[C:5]#[C:6][C:7](=[N:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](F)(F)[F:9])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[C:38]([F:44])[C:37]=1[O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:8]([F:9])=[C:7]([NH:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:32][CH2:33][CH3:34])[N:43]=2)=[C:38]([F:44])[C:37]=1[O:45][CH3:46]
Reactant: COc1c(Cl)ccc(CN)c1F
Reactant: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C

Procedure:
In a typical reaction, N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine is mixed with about a 2.5 to 3 fold excess of (4-chloro-2-fluoro-3-methoxyphenyl)methyl amine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous terahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1
Reactant: COCn1c(=O)c2c(c3ccc(CO)cc31)NCCC2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3ccc(CCl)cc31)NCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Anhydrous dichloromethane (10 ml) was added to the compound (50.0 mg, 0.182 mmol) prepared in step 5, and thionyl chloride (0.016 ml, 0.219 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and poured into sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (51.4 mg, yield: 96%, white solid). The compound was used in the following reaction without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(=O)C.N1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH:16]=1.[NH2:24][C:25]1C=CC=C[C:26]=1C#N>C1COCC1>[NH2:24][C:25]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=[CH:16][CH:26]=1
Reactant: N#Cc1ccccc1N
Reactant: c1ccc2[nH]cnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3-4 eq) was added to the benzimidazole acetate (1.0 eq) in THF (at a constant temperature ranging from −78° C. to 0° C.). After 20 minutes, a solution of the 2-aminobenzonitrile (1.1 eq) in THF was then added. The resulting mixture was allowed to warm to room temperature, stirred for 1-3 hours and was then heated to approx. 40° C.-65° C.(1 hour to 12 hours). The mixture was cooled to 0° C. and quenched with NH4Cl (aq, saturated). The aqueous phase was extracted with Ch2Cl2 or EtOAc, and the organic extracts were collected, dried (Na2SO4), and filtered. Evaporation of the solvent under reduced pressure and purification of the residue by silica gel chromatography or HPLC provided the 4-amino quinoline products.
Reaction SMILES: C([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:17])[CH:6]=1)(=O)C.Cl>O1CCOCC1>[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:17])[CH:6]=1
Reactant: CC(=O)Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 145b from 4-acetylamino-2-fluoro-5-nitro-benzoic acid and half-conc. hydrochloric acid in dioxane.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])([O:16][CH3:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(Cl)cc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a suspension of NaH (0.7 g, 60% in mineral oil, 17.5 mol) in DMF (30 mL) was added dropwise a solution of 4-(5-chloro-2-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 5b (4.0 g, 11.7 mol) in DMF (10 mL) at 0° C. After being stirred at this temperature for 30 min, MeI (0.9 ml 0.0145 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to obtain crude 4-(5-chloro-2-methoxy-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester 5c (3.8 g), which was used directly in next step.
Reaction SMILES: [CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.Br>O>[CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ncc(-c2ccc(OC)cc2)s1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCc1ncc(-c2ccc(O)cc2)s1
Reaction time: 16 h
Yield: 63 %

Procedure:
Then, in a 500 ml-three-necked flask, 11.6 g (35.0 mM) of 2-decyl-5-(4-methoxyphenyl)tiazole, 93 ml of acetic acid and 102 ml of 47%-hydrobromic acid were placed, followed by heat-stirring for 16 hours at 100°-110° C. After the reaction, the reaction mixture was poured into cool water, followed by extraction with benzene. The organic layer was successively washed with water, 5%-sodium hydrogenecarbonate aqueous solution and water, followed by distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from toluene to obtain 7.0 g of 2-decyl-5-(4-hydroxyphenyl )thiazole (Yield: 63.1%).