Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=O)[C:7]=2[C:6]([CH3:22])=[N:5]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>C(Cl)Cl>[CH3:62][C:61]1[CH:60]=[C:59]([CH3:63])[NH:58][C:57](=[O:64])[C:56]=1[CH2:55][NH:54][C:19]([C:8]1[C:7]2[C:6]([CH3:22])=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:12]=2[CH:11]=[C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:21]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred solution of 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid (0.5 g, 1.69 mmol) in DCM (30 mL) was added EDC.HCl (0.39 g, 2.03 mmol), HOBT (2.74 g, 2.03 mmol) followed by DIPEA (1.47 mL, 8.45 mmol) and stirred at room temperature for 15 min. To the resulting reaction mixture, 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (0.257 g, 1.69 mmol) was added and stirred at room temperature for overnight. The reaction mixture was filtered and the precipitate was washed with water followed by ether and dried. The solid compound was further purified by silica gel chromatography (eluent: 10% MeOH in ethyl acetate) to afford the title compound as an off-white solid (225 mg, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 1.461 (d, J=6.4 Hz, 6H), 2.109 (s, 3H), 2.240 (s, 3H), 2.438 (s, 3H), 4.372 (d, J=4.8 Hz, 2H), 5.042-5.107 (m, 1H), 5.870 (s, 1H), 7.410 (s, 1H), 7.501-7.533 (m, 1H), 8.061 (s, 1H), 8.215 (d, J=8 Hz, 1H), 8.461 (t, J=4.8 Hz, 1H), 8.593 (d, J=4.8 Hz, 1H), 9.036 (s, 1H), 11.489 (brs, 1H). LCMS (ES+) m/z: 430.12
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][NH2:29])[CH3:27])=[CH:22][CH:21]=1>CO>[CH3:7][O:6][CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[CH:1]=[N:29][N:28]=[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:31])[F:30])=[CH:21][CH:22]=1)[CH3:27]
Reactant: CC(=NN)c1ccc(C(F)(F)F)cc1
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=O
Solvent: CO
Product: COC(C1=CN(C)CS1)c1ccccc1C=NN=C(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To 0.23 g (1 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylthiazole in 2 ml of methanol was added 0.22 g (1.1 mmol) of 4'-(trifluoromethyl)acetophenone hydrazone and stirred at room temperature for 3 hours. After completion of the reaction, methanol was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-{4-(4-trifluoromethylphenyl)-2,3-diaza-1,3-pentadienyl}benzyl]-3-methylthiazole (0.23 g, 55.4%) as oil.
Reaction SMILES: [Cl-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][NH3+:22])[CH:16]=2)=[N:3]1.C(N(CC)CC)C.[CH:30](OCCC)=[O:31]>C(O)C.ClCCl>[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][NH:22][CH:30]=[O:31])[CH:16]=2)=[N:3]1
Reactant: [NH3+]Cc1cc(-c2n[nH]c3c2CCc2ccccc2-3)ccn1
Reactant: CCCOC=O
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CNCc1cc(-c2n[nH]c3c2CCc2ccccc2-3)ccn1

Procedure:
The product from Example 19 (100 mg) was suspended in propyl form ate (10 ml) and ethanol (1.5 ml). This mixture was boiled under reflux and after 2 minutes triethylamine (0.5 ml) was added. The mixture was boiled under reflux for 4 hours and then cooled and diluted with dichloromethane (50 ml). The mixture was washed with water, then dried, filtered and evaporated to give a residue which was triturated with ether and dichloromethane to give N-{[4-(4,5-dihydro-1H-benzo[g]-indazol-3-yl)-2-pyridyl]methyl}formamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([OH:17])[CH3:16])=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(C)O)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (1.5 g, 6.6 mmol) in THF (8 mL) and methanol (8 mL) was added NaBH4 (0.4 g, 13.2 mmol) at 0° C. and the reaction was stirred at rt for about 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethylacetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 1-(5-(4-methoxyphenyl)-pyridin-2-yl)ethanol as an off-white solid (1.0 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): 8.72 (d, 1H), 7.84 (dd, 1H), 7.51 (d, 2H), 7.32 (d, 1H), 7.01 (d, 2H), 4.93 (s, 1H), 4.11 (d, 1H), 3.86 (s, 3H), 1.54 (d, 3H), LC-MS m/z calcd for [M+H]+ 230.1. found 230.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[C:8]([NH2:12])[CH:7]=[CH:6][CH:5]=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1.CCCCCC>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([CH3:11])=[C:2]([CH3:1])[NH:3]3)=[O:23])=[CH:18][CH:19]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Cc1[nH]c2cccc(N)c2c1C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1[nH]c2cccc(NC(=O)NCc3ccc(Br)cc3)c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-Dimethyl-4-aminoindole (0.11 g, 0.7 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.17 g, 0.8 mmol) at ambient temperature. After stirring for 3 hours at ambient temperature, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0.12 g). mp 190° C. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.25 (s, 3H), 4.25 (d, 2H), 6.51 (t, 1H), 6.82 (t, 1H), 6.85 (d, 2H), 6.95 (m, 2H), 7.25 (d, 2H), 7.53 (d, 2H), 7.78 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H)+; Anal. Calcd. for C18H18N3BrO: C, 58.08; H, 4.87; N, 11.29. Found: C, 57.97; H, 4.92; N, 11.30.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]([NH2:33])[CH2:29]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.CN(C)C=O>[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]([NH:33][C:10]([C:3]1[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=1)=[O:12])[CH2:29]2
Reactant: CN1C2CCC1CC(N)C2
Reactant: O=C(O)c1nsc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1CC(NC(=O)c1nsc3ccccc13)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of benzisothiazole-3-carboxylic acid (0.93 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (2.87 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride (0.99 mmol). The reaction mixture was maintained at room temperature for 30 min under nitrogen and then HATU (1.00 mmol) was added. After 18 h, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane/methanol (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using a mixture of [90/10/1 dichloromethane/methanol/ammonium hydroxide] as the eluent, thus providing the product in 20% yield. Alternatively, the residues were purified by preparative HPLC. 1H NMR (CD3OD) δ 8.79 (dd, J=8.3, 1.0, 1H), 8.10-8.06 (m, 1H), 7.63-7.49 (m, 2H), 4.39-4.32 (m, 0.5H), 4.17-4.15 (m, 0.5H), 3.33-3.27 (m, 2H), 2.35 (s, 1.5H), 2.34 (s, 1.5H), 2.31-1.75 (m, 8H); LC/MS (EI) tR 3.76 min, m/z 302 (M++1).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[CH:24]=[C:23]2[C:22]3[N:21]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(cc(Cl)cc3c1=O)CCC2
Temperature: 140 °C
Yield: 111.3 %

Procedure:
4.9 g of ethyl ethoxymethylenemalonate was added to 4 g of 6-chloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 200 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification, the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted pH value to pH 2 to obtain 7.0 g of 9-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 282° to 286° C.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:37]1(=[O:43])[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:41]4[C:40](=[O:42])[CH2:39][CH2:38][C:37]4=[O:43])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
In an atmosphere of argon, N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-4-hydroxymethyl-N-(2-methoxyphenyl)benzamide (54 mg, 0.11 mmol), succinimide (13 mg, 0.132 mmol) and triphenylphosphine (34.6 mg, 0.132 mmol) were dissolved in THF (1 ml) to which was subsequently added dropwise diethyl azodicarboxylate (21 μl, 0.132 mmol) while cooling in an ice bath. After 30 minutes of stirring at room temperature, the reaction solution was diluted with water (10 ml) and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a PTLC (chloroform:methanol=20:1) to obtain 42 mg (66.8%) of the title compound in a light yellow amorphous form.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26](/[C:29](=[N:31]\[S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])/[CH3:30])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][S:32]([C:34]([CH3:36])([CH3:35])[CH3:37])=[O:33])([CH3:30])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1ccc(/C(C)=N\S(=O)C(C)(C)C)cc1
Reactant: COC(C)=O
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCOc1ccc(C(C)(CC(=O)OC)NS(=O)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
To a stirred solution of diisopropylamine (3.86 mL, 27.1 mmol) in THF (40 mL) at −78° C. was added n-butyllithium (22.57 mL, 27.1 mmol) dropwise. The reaction was slowly warmed up to −20° C. and stirred for 45 min. The reaction was cooled to −78° C. and methyl acetate (2.006 g, 27.1 mmol) was added dropwise. After 30 min, chlorotitanium triisopropoxide (8.09 mL, 33.8 mmol) in THF (40 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h. Intermediate 107A (4 g, 13.54 mmol) in THF (15 mL) was added dropwise and the reaction was stirred at −78° C. for 2 h. The reaction was quenched by addition of sat'd NH4Cl solution and stirred vigorously while warmed to rt. The mixture was filtered through Celite® and washed with EtOAc. The filtrate was washed with H2O, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (4.33 g, 87%) as a light yellow oil. LCMS Anal. Calc'd for C19H31NO4S 369.20, found [M+H] 370.2. 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=8.80 Hz, 2H), 6.85 (d, J=8.80 Hz, 2H), 3.95 (t, J=6.46 Hz, 2H), 3.62 (s, 3H), 2.05 (s, 2H), 1.74-1.80 (m, 2H), 1.74 (s, 3H), 1.44-1.54 (m, 2H), 1.29 (s, 9H), 0.98 (t, J=7.43 Hz, 3H).
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:11][N:10]([C:29]([NH:28][CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[O:30])[CH2:9]2)=[O:6])[CH:24]=[CH:25][CH:26]=[CH:27][CH:3]=1
Reactant: O=C=NCC1CCCO1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NCC2CCCO2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 29 mg (0.23 mmol) of 2-(isocyanatomethyl)tetrahydrofuran and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (81% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:30]([O:37][C:38]([CH2:40][C:41]1([OH:47])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][C:23]([C:26]([N:44]3[CH2:45][CH2:46][C:41]([CH2:40][C:38]([O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:39])([OH:47])[CH2:42][CH2:43]3)=[O:27])=[CH:24][N:25]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1(O)CCNCC1)OCc1ccccc1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2ncc(C(=O)O)cn2)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2ncc(C(=O)N3CCC(O)(CC(=O)OCc4ccccc4)CC3)cn2)cc1

Procedure:
Prepared by reacting 2-[4-[N-(benzyloxycarbonyl)-amidino]-phenyl]-5-carboxy-pyrimidine with 1.2 equivalents of N,N-carbonyl-diimidazole in dimethylformamide at 5° C. followed by the addition of 1.2 equivalents of 4-[(benzyloxycarbonyl)-methyl]-4-hydroxy-piperidine-hydrochloride and 1.2 equivalents of N-methylmorpholine at ambient temperature.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][C:20](=N)N)=[CH:15][CH:14]=1)[CH3:11].ClC[CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[CH3:11][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][CH2:20][CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH3:9]
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
A mixture of 1-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl]thio]methanimidamide maleate (1:2) (2.23 g), N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (0.9 g) and potassium carbonate (3.46 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo; the residue suspended in water (50 ml) and extracted with ether (2×40 ml). The aqueous fraction was evaporated in vacuo and magnesium sulphate and tetrahhydrofuran (100 ml) added. After 18 hours, the mixture was filtered and the filtrate evaporated to give a semi-solid which was chromatographed (silica/methanol). The appropriate eluate was evaporated in vacuo to give the title compound (0.3 g), which had an n.m.r. identical to that of the product according to Example 1 above.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:12][CH2:13][CH2:14][Cl:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]2[O:26][CH2:27][O:28][C:20]=12>>[Cl:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[N:5]=[CH:4][N:3]=[C:2]2[NH:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]2[O:26][CH2:27][O:28][C:20]=12
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCl
Product: COc1cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c2cc1OCCCl
Yield: 59 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 59% yield; NMR Spectrum: (CDCl3) 3.95 (t, 2H), 4.05 (s, 3H), 4.4 (t, 2H), 6.1 (s, 2H), 7.05 (s, 1H), 7.2 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.75 (s, 1H); Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH3:11][O:12][CH2:13]Cl>O1CCCC1.ClCCl>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(O)no1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamino in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](=[NH:15])[NH2:14].O=[C:17]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40](C(C)(C)C)[N:39]=[N:38][N:37]=2)=[CH:26][CH:25]=1)[C:19](OC)=[O:20]>>[CH2:45]([C:17]1[NH:14][C:13]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:15][C:19](=[O:20])[C:18]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:46][CH2:47][CH3:48]
Reactant: N=C(N)CCc1ccc2ccccc2c1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2-c2nnnn2C(C)(C)C)cc1)C(=O)OC
Product: CCCCc1[nH]c(CCc2ccc3ccccc3c2)nc(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
Following example 4.2, a mixture of 1.75 g of 3-(napht-2yl)propanimidamide and 3.3 g of methyl 3-oxo-2-[[2'-(1-[1,1-dimethylethyl]-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]heptanoate is heated at 100° C., for 3.50 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 2.9 g of the product in the form of a pale yellow paste. 1.5 g of the foregoing product are dissolved in a 30% solution of bromhydric acid in acetic acid. It is heated at 90° C., for 5 hours and evaporated under vacuum. The residue is taken up with dichloromethane. The organic phase is washed with water and dried on sodium sulfate. The solvent is evaporated to give 1.1 of the product in the form of a beige powder. The crude product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 0.63 g of the product in the form of a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]3)=[CH:8][CH:7]=2)[CH2:20][CH2:19]1
Reactant: O=C1CCc2ccc(OCCCCl)cc2N1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: Cc1ccccc1
Product: O=C1CCc2ccc(OCCCN3CCC(O)(c4ccccc4)CC3)cc2N1

Procedure:
2.4 Grams of 7-(3-chloropropoxy)-3,4-dihydrocarbostyril and 4.0 g of 4-hydroxy-4-phenylpiperidine were mixed with 150 ml of toluene and heated under refluxing condition for 24 hours. After cooling the reaction mixture, the precipitates formed were collected by filtration and washed with water, then recrystallized from ethanol. 2.8 Grams of 7-[3-(4-hydroxy-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril was obtained as in the form of colorless flake-like crystals. Melting point: 215° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])OC1C=CC=C[C:10]=1[O:15][C:16]([CH3:20])([CH3:19])[C:17]#[CH:18].CC[O:25]CC>>[CH3:19][C:16]([CH3:20])([O:15][C:10]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:25])[C:17]#[CH:18]
Reactant: CCOCC
Reactant: C1CNCCN1
Reactant: C#CC(C)(C)Oc1ccccc1OC(=O)[O-]
Product: C#CC(C)(C)OC(=O)N1CCNCC1

Procedure:
A stirred mixture of 25.8 g (0.3 mole) of piperazine and 30.6 (0.15 mole) of 1,1-dimethylpropynoxyphenyl carbonate was heated at 90° for 18 hrs. The reaction mixture was cooled and partitioned between excess 5% NaOH solution and 100 ml of CH2Cl2. The layers were separated and the water layer extracted twice more with 100 ml portions of CH2Cl2. The organic extracts were dried (MgSO4), filtered and evaporated to an orange oil. Distillation through a 4-inch Vigreaux column gave 18.3 g (62%) of light yellow oil which solidified on standing, m.p. 35°-8°. The hydrochloride salt prepared in ether and recrystallized from acetonitrile had a m.p. of 193°-4° dec. Calc. for C10H17ClN2O2 (232.71): C, 51.61; H, 7.36; Cl, 15.23; N, 12.04. Found: C, 51.37; H, 7.39; Cl, 15.19; N, 11.92.