Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCCC1
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)cc1

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-227 using 4-fluoro-nitrobenzene and cyclohexanol (heat 1.5 hours at 55° C.). Purify the material by silica gel chromatography (Prep.2000) eluting with methylene chloride/hexane 1:1 to provide the title compound as an oil. Mass spectrum (m/e): 221.1 (M*). (Bruker 300) 1H NMR (CDCl3) δ 8.13-8.18 (2H, d), 6.90-6.93 (2H, d), 4.31-4.39 (1H, m), 1.92-2.02 (2H, m), 1.75-1.85 (2H, m), 1.50-1.62 (3H, m), 1.28-1.44 (3H, m).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][NH:6][CH:7]=1)=[O:2].[Cl:13][C:14]1[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:14]1[C:15]([N:6]2[CH:7]=[C:3]([CH:1]=[O:2])[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1n[nH]cc1C=O
Reactant: Fc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ncccc2Cl)cc1C=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a solution of ethyl 4-formyl-pyrazole-3-carboxylate (1.70 g, 10.1 mmol) and 3-chloro-2-fluoropyridine (1.99 g, 15.1 mmol) in dimethylformamide (20 mL) is added potassium carbonate (2.80 g, 20.2 mmol) and the mixture is stirred at 100° C. for 16 hours. After completion, the reaction mixture is partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer is extracted with ethyl acetate (3×25 mL) and the combined organic extracts are dried over sodium sulfate, concentrated in vacuo and purified by column chromatography over silica gel eluting with hexane/ethyl acetate (50:50) to yield 1.5 g (54%) of the title compound. MS (m/z): 280 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O1CCCCC1.[O:30]1[CH:35]=[CH:34][C:33](=[O:36])[CH:32]=[CH:31]1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([CH2:13][C:33]2([OH:36])[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: O=c1ccocc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C1CCOCC1
Product: O=S(=O)(CC1(O)CCOCC1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
A −10° C. solution of diisopropylamine (0.35 mL) in THF (5 mL) was treated with n-BuLi (1 mL, 2.5M solution in hexanes), stiired for 15 min then added via canula to a −78 C solution of 4-bromophenyl methyl sulfone (534 mg) in THF (5 mL). Stirred for 1 h, then treated with tetrahydropyran-4H-pyran-4-one (0.21 mL) and stirred for an additional 1 h. The reaction was quenched with aq. NH4Cl, diluted with water and extracted wth EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered, concentrated and purified via silica gel chromatography eluting with 10% ethyl acetate/dichloromethane to give 640 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:18][C:7]2[S:8][CH2:9][CH2:10][CH:11]3[CH2:16][C:15](=[O:17])[NH:14][N:13]=[C:12]3[C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C1(C)C=CC=CC=1>[C:26]([O:1][CH2:2][CH2:3][C:4]1[S:18][C:7]2[S:8][CH2:9][CH2:10][CH:11]3[CH2:16][C:15](=[O:17])[NH:14][N:13]=[C:12]3[C:6]=2[CH:5]=1)(=[O:28])[CH3:27]
Reactant: O=C1CC2CCSc3sc(CCO)cc3C2=NN1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCCc1cc2c(s1)SCCC1CC(=O)NN=C21
Reaction time: 3 h

Procedure:
A mixture of 1.0 g of 9-(2-hydroxyethyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one, 2 ml of triethylamine and 2 ml of acetic anhydride in 20 ml of toluene is kept on a water bath at 80°-85° C. for 3 hours. After cooling, to the mixture is added water, the organic layer is collected by a separatory funnel and concentrated. To the residue is added hexane and the precipitated crystals are collected by filtration. The resulting crystals are recrystallized from isopropyl ether to give 0.5 g of 9-(2-acetoxyethyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 106°-108° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[C:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:7]=[CH:6][CH:5]=[CH:10][CH:2]=1
Reactant: CC(=O)Nc1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h

Procedure:
The acetanilide II (13.5 g), the particular aromatic bromide III (25 g), potassium carbonate (13.2 g) and copper iodide (1.9 g) were heated (190° C.) and stirred overnight. After cooling to room temperature toluene was added and the precipitate filtered. The solution was concentrated and the excess of bromide removed by distillation under reduced pressure. The residue was dissolved in ethanol (200 ml), potassium hydroxide (10.3 g) was added and the mixture refluxed overnight. Ethanol was evaporated, the residue dissolved in dichloromethane, and washed with brine. The organic layer was dried over MgSO4 and concentrated to obtain the crude diphenyl amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[CH:22](N)=N.CC1NC=CN=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:22]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: N=CN
Agent: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 0.17 h

Procedure:
A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.4 parts of formamidine hydrochloride and 2.5 parts of 2-methylimidazole is fused at 160° C for 10 minutes. Water is added to the mixture, followed by extraction with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent is evaporated, whereby 8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded. Recrystallization from ethyl acetate yields colorless flakes melting at 226° C to 227° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:26].CC(C)=O>CS(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:34][CH:33]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Yield: 30 %

Procedure:
165 mg (0.50 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 84 mg (0.50 mmol) of 4-aminobenzoic acid ethyl ester were heated together in 1.5 ml of dimethylsulfoxide at 35°-40° C. for 72 hours. A white precipitate was observed at the bottom of the flask. 10 ml acetone was added and the solid was collected by Buchner vacuum filtration. The solid was washed twice with acetone and was allowed to dry. This yielded 53 mg of 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid, ethyl ester (AIT-0079) as a white solid. m.p. 265°-269° C. Yield: 30%.
Reaction SMILES: Cl[CH:2]1[CH:8]2[CH:6]([CH2:7]2)[CH2:5][NH:4][C:3]1=[O:9].C([OH:14])(C)(C)C>>[CH:8]12[CH2:7][CH:6]1[CH2:5][NH:4][CH:2]2[C:3]([OH:9])=[O:14]
Reactant: O=C1NCC2CC2C1Cl
Reactant: CC(C)(C)O
Product: O=C(O)C1NCC2CC21

Procedure:
0.9 g of IV prepared in experiment (c) was refluxed for 16 hours in t-butanol containing 0.5 g potassium. The reaction mixture was allowed to cool, the solvent was evaporated under reduced pressure and the residue was poured into 20 ml of water. Dilute (4 N) hydrochloric acid was added until the solution was acidic and then extracted thrice with methylene chloride. The water layer was then passed over a column filled with Dowex 50W-X8 ion-exchange resin. Eluting the resin with ammonium hydroxide then gave the cis isomer of 3-azabicyclo(3.1.0)hexane-2-carboxylic acid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]2.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C-]#N.[Na+].[Cu](C#N)[C:28]#[N:29]>Cl.O>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:28]#[N:29])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)(=[O:13])[CH3:12]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)N1CCc2cc(N)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CC(=O)N1CCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 1-(5-aminoindolin-1-yl)ethanone (Aldrich, 865 mg; 4.91 mmol) in HCl (2.1 M, 2.95 mL) was treated with sodium nitrite (358 mg; 5.18 mmol) and the mixture was stirred at 0° C. for 3 hours. The solution was neutralized with sodium carbonate (3.12 g; 29.43 mmol) and the resulting mixture was added to a suspension of sodium cyanide (519 mg; 10.6 mmol) and copper cyanide (467 mg; 5.21 mmol) in water (4 mL) at 0° C. The resulting suspension was heated to 50° C., stirred for 30 minutes, cooled to 0° C. and the precipitated solid was collected by filtration. The collected solid was recrystallised from aqueous acetonitrile to give the title compound as a brown solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.16 (1H, d, J=8.3 Hz), 7.72-7.62 (2H, m), 4.23-4.11 (2H, m), 2.54 (3H, t, J=2.1 Hz), 2.23 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:16]([OH:17])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:4]=[N:3]1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:16]([O:17][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:4]=[N:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2c(O)ccc3ncccc23)cn1
Solvent: c1ccncc1
Product: Cn1cc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ncccc23)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
5-(1-Methyl-1H-pyrazol-4-yl)-quinolin-6-ol (2.9 g, 12.89 mmol) was dissolved in pyridine (30 mL) and the mixture was cooled to 0° C. in an ice bath under a flow of nitrogen. Tf2O (2.6 mL, 15.47 mmol) was added slowly. Then the reaction mixture was stirred at room temperature for 5 hours. The mixture was partitioned between dichloromethane (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was separated and washed with brine (5×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3.9 g of Trifluoromethanesulfonic acid 5-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl ester (84% yield): 1H NMR (300 MHz, CDCl3) δ: 4.05 (s, 3H), 7.48˜7.44 (m, 1H), 7.69˜7.61 (m, 3H), 8.18 (d, 1H), 8.32 (m, 1H), 8.98 (m, 1H); MS (m/z) 358 [M+H]+.
Reaction SMILES: C[Si](C)(C)Br.[CH2:6]([O:8][C:9](=[O:28])[CH:10]([NH:25]C=O)/[CH:11]=[C:12](\[CH3:24])/[CH2:13][P:14]([O:20]C(C)C)([O:16]C(C)C)=[O:15])[CH3:7].C(O)C>ClCCl>[CH2:6]([O:8][C:9](=[O:28])[CH:10]([NH2:25])/[CH:11]=[C:12](\[CH3:24])/[CH2:13][P:14]([OH:16])([OH:20])=[O:15])[CH3:7]
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
56.7 ml of trimethylbromosilane are added dropwise within a period of 15 minutes at 20° to a solution of 25.42 g of E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 102 ml of dry dichloromethane. After stirring at room temperature for 20 hours, 102 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hours. The clear reaction solution is then completely concentrated by evaporation in vacuo. The residue is concentrated by evaporation a further three times in each case after the addition of 100 ml of toluene. The oily residue is dissolved in 102 ml of ethanol, and a solution of 102 ml of propylene oxide in 102 ml of ethanol is added dropwise thereto. The product, obtained in crystalline form, is filtered off after 2 hours (room temperature) and washed with ethanol and ether. After drying (80°, 4 hours) under a high vacuum, E-2-amino-4-methyl-5 -phosphono-3-pentenoic acid ethyl ester is obtained in analytically pure form, m.p. 212° (decomp.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([C:16]([O:18]C)=O)=[C:7]([CH3:15])[C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[N:9][CH:10]=1.CC[O-].[Na+]>CCO>[CH3:15][C:7]1[C:6]2[C:16](=[O:18])[NH:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=[N:9][C:8]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1c(OCCN)cnc(OC(C)C)c1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(OC(C)C)ncc2c1C(=O)NCCO2
Yield: 65.4 %

Procedure:
A mixture of methyl 5-(2-aminoethoxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131e, 1.2 g, 2.2 mmol) and NaOEt (3.0 g, 45 mmol) in dry EtOH (60 mL) was refluxed for 14 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in H2O (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give 6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131f, 0.34 g) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:22][CH:21]=1)[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1.[OH-].[Na+].Cl>C(O)C>[C:16]([C:7]1[CH:6]=[C:5]([S:4][CH2:3][C:2]([C:20]2[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([OH:28])=[O:27])=[CH:33][CH:34]=2)=[O:1])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(C(=O)CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1)C(=O)O

Procedure:
4.86 g (0.01 mol) of ethyl 2-{4-[1-oxo-2-(4-hydroxy-3,5-di-tert-butylphenylthio)ethyl]phenoxy}isobutyrate, 70 ml of ethanol and 12 ml of 1N sodium hydroxide solution are introduced into a round-bottomed flask equipped with a magnetic stirrer. The whole is heated under reflux for 1 hour 30 minutes, then cooled, neutralised with 12 ml of 1N hydrochloric acid solution and concentrated to dryness. The residue is taken up in ether. The whole is washed with water, dried over sodium sulphate and concentrated to dryness. The residue is chromatographed on 300 ml of Amicon silica (0.035-0.070 mm) while eluting first with pure dichloromethane and then with a mixture of dichloromethane and methanol (97:3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.Cl.Cl.[NH2:24][CH2:25][C:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[NH2:32][C:26]1([CH2:25][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCC1(N)CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of 4-chloro-3-nitroquinoline (25.0 g, 120 mmol) and triethylamine (84 mL, 599 mmol) in dichloromethane (500 mL) was added 1-(aminomethyl)cyclohexanamine dihydrochloride (36.2 g, 180 mmol). The reaction was allowed to warm to rt and stirred for 20 h. The reaction was transferred to a separatory funnel and washed with water (200 mL). The water was back-extracted with dichloromethane (2×500 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield N-[(1-aminocyclohexyl)methyl]-3-nitroquinolin-4-amine as a yellow solid (35.5 g, 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.C(O)C>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[S:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Sc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1.8 g, 5.0 mmol, prepared in analogy to the one in Example 17-1), benzenethiol (0.66 g, 6.0 mmol) and N,N-dimethylpyridin-4-amine (0.74 g, 6 mmol) in dry ethanol (40 mL) was stirred at room temperature for 3 days. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (gradient eluting with 10-20% ethyl acetate in hexanes) to afford 1.0 g of the desired product (yield was 45%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)=[O:7].[OH-].[K+].[I:20]I>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:20])=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)=[O:7]
Reactant: II
Reactant: O=C(NCCCO)c1cc2cc(F)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(NCCCO)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide, prepared as in reference 11, (4.89 g, 20.7 mmol) in DMF (100 mL) is added KOH (3.48 g, 62 mmol) and I2 (5.78 g, 22.8 mmol). It is stirred at room temperature for 1 hour and concentrated. Water is added to the residue and the mixture is acidified with HCl. The mixture is extracted with EtOAc (100 mL×2). The combined organic layers are washed with Na2S2O3 (1M, 50 mL), brine (100 mL), and dried with Na2SO4. Solvent is removed to give 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide; 1H NMR (DMSO-d6) δ 1.73 (quint, 2H, J=6.0 Hz), 3.39 (q, 2H, J=6.0 Hz), 3.54 (t, 2H, J=6.0 Hz), 4.54 (bs, 1H), 7.06-7.16 (m, 2H), 7.46 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 8.00 (t, 1H, J=6.0 Hz), 12.10 (s, 1H); m/z [M++1] 363.0.
Reaction SMILES: O=[C:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]2)[CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=O.[NH:21]([CH2:23][CH2:24][OH:25])[NH2:22]>C(O)C>[OH:25][CH2:24][CH2:23][N:21]1[C:5](=[O:7])[CH2:4][CH:3]([CH3:8])[C:2]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)=[N:22]1
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)CCC(=O)N2C
Reactant: NNCCO
Solvent: CCO
Product: CC1CC(=O)N(CCO)N=C1c1ccc2c(c1)CCC(=O)N2C
Yield: 80.2 %

Procedure:
A solution of 2.72 g of 4-oxo-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid and 1.5 g of 2-hydrazinoethanol in 30 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off and recrystallized from isopropanol to give 2.5 g of 6-[2-(2-hydroxyethyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 171°-173° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=O)[NH2:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:17])=O>P(Cl)(Cl)(Cl)=O>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: NC(=O)c1ccc2ncnc(O)c2c1
Reactant: O=S(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2ncnc(Cl)c2c1

Procedure:
A mixture comprising 2 g of 4-hydroxy-6-carbamoylquinazoline, 30 ml of thionyl chloride and 60 ml of phosphorus oxychloride was heated under reflux for 20 hours. The reaction mixture was concentrated under a reduced pressure and the obtained residue was dissolved in 100 ml of ethyl acetate. The obtained solution was washed with water (150 ml), dried over magnesium sulfate and concentrated under a reduced pressure. The obtained residue was introduced into a silica gel column, followed by eluting with ethyl acetate and acetone to give 800 mg of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[OH-:8].[Na+].C1(NC2CCCCC2)CCCCC1.[F:23][C:24]1[N:29]=[C:28]([C:30]#[N:31])[C:27]([OH:32])=[N:26][CH:25]=1>O>[F:23][C:24]1[N:29]=[C:28]([C:30]([NH2:31])=[O:8])[C:27]([OH:32])=[N:26][CH:25]=1
Reactant: N#Cc1nc(F)cnc1O
Reactant: [OH-]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH2:2][C:3]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:6][C:7](=[O:16])[NH:8][CH2:9]2)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: O=C1NCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1NCc2cc(C(=O)CBr)ccc2N1

Procedure:
Bromoacetyl chloride (6.2 g) is added dropwise to a stirring mixture of 3,4-dihydro-2(1H)-quinazolinone (2.6 g) and anhydrous aluminum chloride (6.3 g) in carbon disulfide (60 ml). The reaction mixture is stirred under reflux for 4.5 hours, the carbon disulfide decanted, and the residue treated with HCl (6N). The resulting solid is poured into ice water, filtered, the filtered solid washed with water and dried in vacuo, affording the desired product, which is used in the next step without further purification.