Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:8]=1)O)([O-:3])=[O:2].CS(Cl)(=O)=O.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[N+:1]([CH:4]=[CH:5][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC(O)c1cccc(OCC(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])C=Cc1cccc(OCC(F)(F)F)c1
Reaction time: 2 h

Procedure:
Combine 2-nitro-1-(3-trifluoroethoxyphenyl)ethanol (6.1 g, 24.2 mmol) and methanesulfonyl chloride (2.02 mL) in dichloromethane (50 mL) and cool in an ice-bath. Add dropwise, triethylamine (7.28 mL) while maintaining the temperature near 0° C. After 2 hours, pour into ethyl acetate, wash with water, dry with Na2SO4, filter, and then concentrate to residue. Chromatograph the residue on silica gel to give 3-(2-nitrovinyl)-1-trifluoroethoxybenzene: MS (MH+) 234; 1H NMR (CDCl3) 7.97 (1H, d, J=13.6 Hz), 7.57 (1H, d, J=13.6 Hz), 7.53–7.48 (2H, m), 7.40–7.35 (2H, m).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1)[CH2:27][CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of N-phenylbenzene-1,2-diamine (1.0 g, 5.43 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (1.21 g, 5.97 mmol), HOAt (813 mg, 5.97 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.15 g, 5.97 mmol) and 4-methylmorpholine (1.31 mL, 11.95 mmol) in DCM (20 mL) was stirred at RT for 2 h. The crude reaction mixture was diluted with DCM (100 mL), then washed with a saturated solution of NaHCO3, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated to 70° C. for 18 h. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was dissolved in EtOAc (150 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was absorbed onto HM-N and purified twice by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording [(S)-1-(1-Phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tertbutyl ester (1.76 g). LCMS: RT 3.23 min [M+H-tBu]+ 352.2
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([OH:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: O=C(O)c1cccc(O)c1
Agent: Cl
Product: N=C(N)c1ccc(CNC(=O)c2cccc(O)c2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-hydroxybenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give example 67. ESI-MS m/e 343.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32]([C:38]#[N:39])([CH2:35][CH2:36]O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:36][CH2:35][C:32]3([C:38]#[N:39])[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH2:30][CH2:31]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCOc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.1 g), 4-cyano-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g) and triphenylphosphine (1.22 g) in tetrahydrofuran (40 ml) was added diethyl azodicarboxylate (2 g) with ice-cooling, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and dried under reduced pressure to give the title compound (1.6 g).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CCCN1CCC(N)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (100 ml) was added to a solution of [1-(2-cyano-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (50.0 mmol) in 1,4-dioxane (50 ml) at 25° C. The reaction mixture was stirred at 50° C. for 5 h, then was concentrated under reduced pressure to afford crude 3-(4-amino-piperidin-1-yl)-propionitrile (hydrochloride salt) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.48 (s, 2H), 3.58-3.50 (m, 2H), 3.46-3.32 (m, 2H), 3.31-3.21 (m, 1H), 3.17 (t, J=7.2 Hz, 2H), 3.13-2.95 (m, 2H), 2.15 (d, J=13.5 Hz, 2H), 2.04-1.86 (m, 2H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[N:13]=[N:14][C:15](Cl)=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)C#N)=[C:4]([Cl:22])[CH:3]=1.[OH2:23].Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:23])[NH:14][N:13]=2)=[C:4]([Cl:22])[CH:3]=1
Reactant: O
Reactant: CC(C)c1cc(C(C#N)c2c(Cl)cc(N)cc2Cl)nnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A mixture of (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl)-acetonitrile (45) (6.98 g, 19.63 mmol), water (30 mL), concentrated hydrochloric acid (120 mL) and glacial acetic acid (30 mL) was heated to 120° C. for 24 h. At this time, the reaction was cooled to room temperature and the mixture was poured onto water (250 mL). The pH was made neutral (pH=7) by the addition of a 4N aqueous sodium hydroxide solution. The suspension was placed in the freezer for 15 min. The resulting solids were filtered and washed with water and petroleum ether. The solids were collected and dissolved in hot ethyl acetate. Silica gel 60 (70-230 mesh) was added and the solvent was concentrated under vacuum. The resulting mixture was purified by flash chromatography (Biotage 75S) using silica gel eluted with 40% ethyl acetate in hexanes to 50% ethyl acetate in hexanes containing 0.5% glacial acetic acid. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (46) (4.65 g, 76%) as an off-white solid; LRMS for C14H15Cl2N3O (M+H) m/z=312. Molecular Weight=312.2012; Exact Mass=311.0592
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl.[OH:23][C@H:24]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1>ClCCl.CCOC(C)=O>[OH:23][C@H:24]1[CH2:28][N:27]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([F:21])([F:20])[F:8])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Triethylamine (TEA) (15.34 ml, 110.1 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (8.97 g, 36.7 mmol) were added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2) (6.59 g, 36.7 mmol) in dichloromethane (150 ml) in an ice bath. The mixture was warmed to room temperature and stirred overnight at RT., concentrated reaction in vacuo, dissolved in EtOAc and washed with 0.1M aqueous HCl, sat. sodium bicarbonate solution and brine. The organic layers were dried with sodium sulfate and concentrated in vacuo to yield (2S,4R)-methyl 4-hydroxy-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxylate) (3) (9.55 g, 73%) as a white semi-solid, which was used without further purification in the next step. MS m/z 376.1 (M+Na)+; retention time=1.691 min, method [1].
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[C:11]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][CH:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:18]=3)[CH2:24][CH2:25]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCS(=O)(=O)[O-])CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1
Yield: 50.6 %

Procedure:
100 mg (0.75 mmol) of 2-methyl-1H-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 286 mg (0.75 mmol) of 3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propylmethanesulfonate and 310 mg (2.25 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH2Cl2) to obtain 159 mg (yield 51%) of the title compound.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CS(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:12]1[C:13]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:30]
Reactant: CCOC(=O)CCCCCBr
Reactant: c1ccc2c3c([nH]c2c1)CCCC3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCn1c2c(c3ccccc31)CCCC2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
A RB flask fitted with reflux condenser containing tetrahydrocarbazole (1.71 g, 10.0 mol) was dissolved in DMSO (30 mL), treated with potassium tert-butoxide (1M solution in THF, 12 mL) and stirred at 110° C. for 20 min. Ethyl 6-bromohexanoate (1.67 mL, 10.0 mmol) was added and the mixture stirred at 110° C. for 60 min. The reaction was quenched with a 1:1 brine:water solution (120 mL) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by column chromatography (25% ethyl acetate in hexane) afforded the title compound (1.01 g, 32%). 1H NMR (400 MHz, CDCl3): δ 7.52 (m, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 7.12 (m, 1H), 4.18 (q, 2H, J=7.1 Hz), 4.04 (t, 2H, J=7.4 Hz), 2.78-2.73 (m, 4H), 2.33 (t, 2H, J=7.5 Hz), 2.00-1.92 (m, 4H), 1.80-1.75 (m, 2H), 1.72-1.66 (m, 2H), 1.42 (m, 2H), 1.30 (t, 3H, J=6.9 Hz). ESI-HRMS (m/z): [M+H]+ calcd. for C20H27NO2, 314.2115. found, 314.2103.
Reaction SMILES: S(=O)(=O)(O)N.[C:6]1([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])=[O:20].[Na+]>O.CC(C)=O>[C:6]1([N:12]2[CH:16]=[C:15]([C:17]([OH:20])=[O:18])[CH:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cnn(-c2ccccc2)c1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cnn(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
Sulphamic acid (253 mg, 2.6 mmol) in water (0.5 mL) was added at 0° C. to a mixture of phenyl-1H-pyrazole-4-carbaldehyde (0.5 g, 2.34 mmol) in acetone (3 mL). After 5 minutes sodium chlorite (315 mg, 3.5 mmol) was added and the resulting mixture was stirred at 0° C. for 30 minutes. Water was added and the solid obtained was isolated by filtration to afford 140 mg (85% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH:30]=[CH2:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH3:31]
Reactant: [H][H]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Yield: 63.6 %

Procedure:
A solution of 4-[2-(4-benzyloxy-2-vinylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.30 g, 3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid (0.65 g, 64%):
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][C:16](=O)[NH:15][C:14]=3[CH:20]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CSC.B.Cl.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][NH:15][C:14]=3[CH:20]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COc2ccc(S(=O)(=O)c3ccccc3)cc2N1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)NCCO2
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 6-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (1.42 g g., 4.9 mmol) in 10 ml anhydrous THF was brought to reflux, and borane-dimethyl sulfide complex (2.45 mL, 10 M in THF, 24.5 mmol) was added dropwise via syringe. The solution was refluxed for 3 hours, and the solution was cooled to room temperature and ethanolic HCl (3 mL, 2 N) was added dropwise. The resulting solution was refluxed for 1 hour and then cooled to room temperature. The reaction mixture was poured into 50 mL water, the resulting solution made basic with potassium carbonate and extracted three times with 25 mL Et2O. The organic fractions were washed with 50 mL brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (30 to 50% EtOAc in hexanes) to give 1.12 g of 6-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (83%) as a yellow solid. MS: 276 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)CO>[Cl:19][C:15]1[CH:14]=[C:13]([C:12]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1cccc(Cl)c1
Solvent: OCCO
Product: NC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Temperature: 190 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
A suspension of N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]-3-chlorobenzamide (8.7 g, 0.029 mole) in 200 ml of ethylene glycol was heated at 190° C. for 40 minutes. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water to produce a white precipitate. The mixture was refrigerated and the precipitate was filtered, washed with water, and dried under high vacuum at room temperature overnight, then at 60° C. for 6 hrs. The sample was recrystallized from methanol-water (~40/60) and refrigerated. The crystalline precipitate was filtered, washed with water, and dried under high vacuum at room temperature overnight. The sample was redried under high vacuum at 60° C. overnight to give 5.48 g (66%) of title compound, mp. 245°-47° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH3:41])[CH2:16][NH:17][C:18]1[N:19]([CH2:37][C:38]#[C:39][CH3:40])[C:20]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])[N:23]=[CH:22][C:21]=2[N:36]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI.O>CS(C)=O>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH3:41])[CH2:16][N:17]([C:18]1[N:19]([CH2:37][C:38]#[C:39][CH3:40])[C:20]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])[N:23]=[CH:22][C:21]=2[N:36]=1)[CH3:1])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC#CCn1c(NC[C@H](C)NC(=O)OC(C)(C)C)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CC#CCn1c(N(C)C[C@H](C)NC(=O)OC(C)(C)C)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C

Procedure:
0.96 g potassium-tert-butoxide are added to an ice-cooled solution of 0.39 g (S)-2-[(2-tert-butyloxycarbonylamino-propyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 5 ml dimethylsulphoxide. The mixture is stirred at ambient temperature, until the solution is clear. Then 53 μl methyl iodide are added, and the solution is stirred for a further 3.5 h at ambient temperature. Then water is added to the reaction solution, the precipitate formed is separated off and washed with water. The dried precipitate is purified by chromatography through silica gel (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[CH:10][C:8]1=[O:9])[CH3:6]>C(O)(=O)C>[CH2:5]([N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([N+:1]([O-:4])=[O:2])[C:8]1=[O:9])[CH3:6]
Reactant: CCn1c(=O)cc(O)c2cc(C)ccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCn1c(=O)c([N+](=O)[O-])c(O)c2cc(C)ccc21

Procedure:
Concentrated nitric acid (2.5 ml; d, 1.42) was added to a suspension of 1-ethyl-4-hydroxy-6-methyl carbostyril. (1.82g. 0.009 mole) in glacial acetic acid (10 ml) and the mixture warmed to 100°C. The solid dissolved and the 3-nitro derivative immediately solidified as a yellow solid. After cooling the solid was filtered, washed well with water and dried in vacuo over P2O5, m.p. 192°-4°C; (Found; C, 58.16; H, 5.02; N, 11.29; C12H12N2O4 requires; C, 58.06; H, 4.87; N, 11.29%).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][CH2:11][CH:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(O)COc1ccccc1

Procedure:
2-Phenoxymethyl-oxirane (0.15 g, 1.00 mMol) and sodium methoxide (0.054 g, 1.00 mMol) were dissolved in 10 ml of MeOH, then the reaction mixture was refluxed for 3 hours. The solvent MeOH was removed and the residue was extracted with ethyl acetate (3×20 ml), it was washed with brine, dried over MgSO4. The crude product was purified by column (25% EtOAc/Hexane) to yield 1-methoxy-3-phenoxy-propan-2-ol, whose structure is depicted below:
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:35][CH3:36])[CH2:5][CH2:6][N:7]([S:28]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:30])=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:3].ClCl.Cl.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:35]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]([S:28]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:30])=[O:29])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([Cl:1])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:36]
Reactant: CCCCS(=O)(=O)N(CCN(CC)CC)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Cl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCS(=O)(=O)N(CCN(CC)CC)c1ccc(C(Cl)=C(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
N-(2-Diethylaminoethyl)-4'-(β-phenylstyryl)butanesulfonanilide hydrochloride (10.5 g., 0.02 mole, refer to Procedure 51) is dissolved in a mixture of 300 ml. of carbon tetrachloride and 20 ml. of chloroform. The mixture is stirred and 39 ml. of a carbon tetrachloride solution containing 1.4 g. (0.02 mole) of chlorine is added thereto during 30 min. The mixture is kept at room temperature for an additional 30 min. and then refluxed for 1 hr. Vigorous evolution of hydrogen chloride gas is apparent during this period. The reaction mixture is allowed to cool and then neutralized with 100 ml. of aqueous 5% sodium hydroxide. The organic layer is separated, dried over magensium sulfate, and the solvent evaporated yielding 11.0 g. of the desired product. The material is purified by chromatography on an alumina column having dimensions 1 inch by 15 inches and eluting sequentially with 1:1 benzene-octane; benzene; benzene-chloroform, and finally with chloroform and collecting the eluate in 20 fractions. Fractions 15-19 are combined and the desired product recovered as the citrate salt, m.p. 65°-70°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH3:12].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([F:1])[CH:3]=2)=[O:22])=[CH:24][CH:25]=1)[CH3:12]
Reactant: CCOCCOc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(O)cc1F
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(C(=O)Oc2ccc(C#N)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 3-fluoro-4-cyanophenol (1.5 g, 11 mmols) dissolved in dry pyridine (5 cc) was added a solution of 4-(β-ethoxyethoxy)benzoic acid chloride (2.5 g, 11 mmols) dissolved in dry toluene (10 cc), followed by heating the mixture with stirring at 60° C. for 3 hours, thereafter adding it to water (100 cc), washing the resulting separated toluene layer with 6N-hydrochloric acid, 2N-NaOH aqueous solution and water, in this order, drying over anhydrous sodium sulfate, distilling off toluene from the toluene layer and recrystallizing the resulting oily residue from ethyl alcohol (10 cc) to obtain the objective 3-fluoro-4-cyanophenyl 4-(β-ethoxyethoxy)benzoate (2.1 g) (yield: 64%).