Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].C(OCC)(OCC)(OCC)C.[CH2:24]([O:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([NH:43][CH2:44][CH:45]([CH3:47])[CH3:46])=[C:37]([NH2:42])[CH:38]=[N:39]2)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]2[C:36]3[N:43]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:1]([CH2:2][CH3:3])=[N:42][C:37]=3[CH:38]=[N:39][C:40]=2[CH:41]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOC(CC)(OCC)OCC
Agent: CCOC(C)(OCC)OCC
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Yield: 34.3 %

Procedure:
The general method described in Part A of Example 3 was followed. Triethyl orthopropionate (7.66 mL, 58.1 mmol) was added in lieu of triethyl orthoacetate to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (18.68 g, 58.11 mmol) in xylenes (200 mL). At the end of the reaction, the precipitate was collected in three crops to provide 7.16 g of 7-benzyloxy-2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a light-brown solid, mp 127° C.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[N+:11]([C:14]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)([O-:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[N+:11]([C:14]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:3][C@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:19][CH:18]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.4 %

Procedure:
To a stirred solution of known tert-butyl L-(+)-lactate (1.00 g), 4-(2',4'-dinitrophenoxy)phenol (2.08 g) and triphenylphosphine (1.98 g) in dry tetrahydrofuran (58 ml) on an ice bath, diethylazodicarboxylate (1.18 ml) was added dropwise. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 19 hours. The reaction mixture was evaporated with a rotary evaporator. The residue thus obtained was purified by silica gel chromatography [silica gel 344 g, eluant:ethyl acetate-hexane (1:5)] to give tert-butyl (2R)-(+)-2-(4'-(2",4"-dinitrophenoxy)phenoxy]propionate (1.45 g). Since the product was decomosed even by high vacuum distillation, the viscous oily substance of the product thus obtained was left to stand at room temperature under high vacuum (0.25 Torr) for 2 hours, and then its physical data thereon were measured.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][N:19]([CH3:21])[C:14]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:12][C:4](=[O:5])[C:3]2[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cccc(C)c1C(=O)Cl
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 2,6-dimethylbenzoyl chloride (1.7 g, 10.1 mmol) in DCM (10 ml) was added dropwise to a mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (2.0 g, 9.2 mmol), and triethylamine (1.4 ml, 10.0 mmol) in DCM (40 ml) and stirred at room temperature for 2 h. The mixture was washed with saturated aqueous sodium hydrogen carbonate, the organic layer was separated through a phase separation cartridge and then evaporated to a white solid. Chromatography with eluent 50-100% ethyl acetate/pentane, then 0-10% methanol/ethyl acetate afforded the title product as a white solid (3.1 g, 97%). 1H NMR (CDCl3) δ: 0.85-1.00 (1H, m), 1.30-1.55 (3H, m), 1.60-1.75 (2H, m), 1.78-1.90 (2H, m), 2.21 (6H, s), 2.31 (6H, s), 5.19 (1H, d, J=6 Hz), 6.79 (1H, br d), 7.02 (2H, d, J=8 Hz), 7.16 (1H, t, J=8 Hz), 7.20-7.35 (3H, m), 7.43 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 351 (MH+). C23H30N2O requires 350. Ret. time 2.0 min. The white solid product was converted to the HCl salt using 1M HCl/diethylether to afford the salt as a white solid on evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>C([O-])(O)=O.[Na+].O.C1COCC1>[OH:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:13])[CH2:11][OH:12]
Reactant: CC(CO)(CO)c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(4-aminophenyl)-2-methylpropane-1,3-diol (1 g, 5.52 mmol, 1.0 eq) in sat. aq. NaHCO3 (4 mL), water (2 mL) and THF (4 mL) was added phenyl chloroformate (0.76 mL, 6.08 mmol, 1.1 eq) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (10 mL) and the solvent evaporated. The crude product was purified by CC using chloroform/MeOH (95:5) as eluent to get phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (1.1 g, 60%) as a white solid (TLC system: chloroform—MeOH; 9:1; Rf: 0.4).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1cccc2c1CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2cccc(O)c2C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an-ice cooled suspension of 8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (746 mg, 5.0 mmol, 1.0 eq.) and triethylamine (2.13 mL, 15.0 mmol, 3.0 eq.) in DCM (25 mL), benzyl chloroformate (0.83 mL, 5.5 mmol, 1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (50 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (20 mL) and 1M aq. NaOH soln. (6 mL) was added. The mixture was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×25 ml). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by CC (SiO2, Hept/AcOEt 8:2 to 7:3) to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)[CH:5]=1)(=[O:3])[CH3:2].C[Mg+].[Br-].CO.[CH:33](Cl)(Cl)Cl>C1COCC1>[CH3:26][C:23]1([CH3:27])[CH2:24][CH2:25][C:20]([C:6]2[CH:5]=[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])[CH:9]=[CH:8][C:7]=2[NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[CH:21][CH2:22]1
Reactant: ClC(Cl)Cl
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a slurry of 4-cyano-1H-imidazole-2-carboxylic acid [4-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (6.00 g, 0.0160 mol) in 100 mL of THF at −78° C. was added a solution of MeMgBr (3.0 M in THF, 22 mL, 0.066 mol) via syringe over a 20-min period. The reaction was allowed to warm to ca. 0° C. over a 30-min period at which point there was no starting material evident by thin layer chromatography (10% MeOH—CHCl3). The reaction was cooled to −78° C., quenched by the addition of saturated aqueous NH4Cl (100 mL) and allowed to warm to 0° C. The mixture was extracted with ether (2×150 mL) and dried (Na2SO4). The solvent was concentrated to afford the title compound as a white solid (6.40 g, 100%). The NMR and mass spectral data were identical to those for the compound produced in Example 14, step (d).
Reaction SMILES: Br[CH:2]([Br:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[N:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>CC(C)=O>[Br:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]=[N:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1
Reactant: CCCCCC(Br)Br
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCCCCOc1ccc(N=Nc2ccccc2)cc1
Reaction time: 4.5 h

Procedure:
A mixture of 454 g. (1.86 mol) of dibromohexane, 128.5 g of potassium carbonate and about 0.2 g of potassium iodide in 460 ml of acetone is heated to the boil. A solution of 36.9 g. (0.186 mol) of p-hydroxyazobenzene in 330 ml of acetone is then added in several portions. In order to prevent delays in boiling, the mixture is stirred constantly. After about 4.5 hours, the reaction is terminated, the still-hot solution is filtered, and a little dye is washed out of the filtered-off inorganic salts using a little acetone. The acetone is removed from the solution under slightly reduced pressure. The excess dibromohexane is subsequently removed in an oil-pump vacuum.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:17])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Br)=[O:28]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C:27](=[O:28])[CH2:26][Br:25])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)CCNC(=O)c1cc(I)ccc1N
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1cc(I)ccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
21.0 g (60.5 mmol) of 3-iodo-6-amino-N-(2-methoxycarbonylethyl)benzamide prepared as in Example 1b) were dissolved in 270 ml of dichloromethane, and 12.5 ml (90.7 mmol) of triethylamine were added. At -30° C., 7.8 ml (90.7 mmol) of bromoacetyl bromide in 80 ml of dichloromethane were added dropwise. The mixture was stirred at room temperature for 2 h and then washed with 10% strength citric acid solution and sodium bicarbonate solution, dried and concentrated. The product was recrystallized from dichloromethane, resulting in 26.1 g (92%) of pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=2[F:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=2[F:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)c1F
Yield: 85 %

Procedure:
To 5-bromo-3-(2-fluoro-3-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (86, 350.0 mg, 0.78 mmol) in tetrahydrofuran (30 mL) and water (10 mL) were added 2-thiophene boronic acid (190 mg, 1.49 mmol), tetrakis(triphenyl-phosphine)palladium(0) (40.0 mg, 0.0346 mmol) and potassium carbonate (780 mg, 5.64 mmol) under an atmosphere of nitrogen. The reaction mixture was refluxed for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound (87, 0.30 g, 85%).
Reaction SMILES: C1([O:7][C:8](=S)[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:7])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 82 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][C:17]1[NH:18][CH:19]=[C:20]([CH3:24])[C:21]=1[C:22]#[N:23].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br-:15].[NH2:16][C:17]1[NH:18][C:19]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N+:9]=2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:20]([CH3:24])[C:21]=1[C:22]#[N:23]
Reactant: Cc1c[nH]c(N)c1C#N
Reactant: Brc1cccc[n+]1Cc1ccccc1
Agent: [Br-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1c(-c2cccc[n+]2Cc2ccccc2)[nH]c(N)c1C#N
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, 1.81 g (5.5 mmol) of N-benzyl-2-bromo-pyridinium bromide [for preparation see J. Heterocyclic Chem. 28,1083 (1991)] are added to 605.5 mg (5.0 mmol) of 2-amino-3-cyano-4-methyl-pyrrole [for preparation see Synthesis (1976), 51] in 40 ml of methylene chloride and 639 μl (5.5 mmol) of lutidine. After 5.5 hours' stirring at RT, the reaction mixture is concentrated by evaporation to approximately half its original volume. Filtering the suspension and washing with methylene chloride/ethyl acetate (1:1) and ethyl acetate/hexane (1:1) yield the title compound; 1H-NMR (300 MHz, DMSO-d6): 10.83 (s, 1H), 9.10 (d, J=7, 1H), 8.49 (t, J=7, 1H), 7.96 (m, 2H), 7.30 (m, 3H), 6.95 (m, 2H), 6.57 and 5.80 (2s, each 2H), 1.76 (s, 3H); FAB-MS: (M+H)+ =289.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[O:19][CH3:20])[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:20][O:19][C:12]1[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:31][C:30]2[C:22]([CH3:21])=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[CH:8]=1
Reactant: COc1cccc(-c2cc3nccc(Cl)c3o2)c1OC
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: COc1cccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)c1OC

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(2,3-dimethoxyphenyl)furo[3,2-b]pyridine (30.00 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.89 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (15 mg, 37%). (HPLC (method F): 99%, RT: 4.00 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.16 (s, 1H), 8.59 (s, 1H), 7.97 (d, J=5.5, 1H), 7.60 (d, J=7.6, 1H), 7.43-7.36 (m, 1H), 7.36-7.27 (m, 2H), 7.20-7.11 (m, 2H), 7.00 (d, J=8.5, 1H), 6.52 (s, 1H), 6.10 (d, J=5.5, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.36 (s, 3H); MS (m/z) 400 [M+H]+, RT: 3.3 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[N:11]1[C:12](=[O:20])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:23]1=[O:24]
Reactant: COC(=O)[C@H](NC(=O)c1ccccc1N)C1CCCCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C1CCCCC1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 133 %

Procedure:
To a solution of (R)-(2-amino-benzoylamino)-cyclohexyl-acetic acid methyl ester (1.08 g, 3.72 mmol) in THF (30 mL) is added trichloromethyl chloroformate (550 mg, 2.78 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give the desired (R)-cyclohexyl-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (1.17 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH2:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:14]
Reactant: N#Cc1ccc(F)cc1CBr
Reactant: CNC
Product: CN(C)Cc1cc(F)ccc1C#N
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 2-(bromomethyl)-4-fluorobenzonitrile (423 mg, 1.9 mmol) and 2.0 M dimethylamine (4 mL) was stirred at room temperature for thirty minutes. The mixture was then concentrated, purified by normal phase flash column chromatography, on a 20 g silica gel column (5-45% ethyl acetate/hexanes gradient), and concentrated in vacuo to yield 2-((dimethylamino)methyl)-4-fluorobenzonitrile (241 mg, 1.35 mmol, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.59, 5.37 Hz, 1H), 7.42 (dd, J=9.94, 2.69 Hz, 1H), 7.35 (td, J=8.46, 2.69 Hz, 1H), 3.56 (s, 2H), 2.19 (s, 6H).
Reaction SMILES: CO[CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18].B(F)(F)F.P(=O)([O-])[O-]>C(Cl)Cl>[CH3:14][O:13][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[P:15]([O:19][CH2:20][CH3:21])(=[O:22])[O:16][CH2:17][CH3:18]
Reactant: COc1cc(C(OC)OC)ccc1Cl
Reactant: CCOP(OCC)OCC
Agent: FB(F)F
Agent: O=[PH]([O-])[O-]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of dimethyl acetal 3 (4.3 g, 20 mmol), sieve-dried CH2Cl2 (20 ml) and triethyl phosphite (4.1 ml, 24 mmol) was stirred under argon at -78° C. Boron trifluoride ethereats (2.95 ml, 24 mmol) was added dropwise at -78° C., the solution was stirred 5 min and stored overnight at -20° C. The next day the reaction was warmed to room temperature and stirred 5 hours to complete phosphonate formation. With vigorous stirring, the reaction was quenched with solid NaHCO3 followed by 40 ml saturated NaHCO3 solution. After gas evolution ceased, 40 ml CH2Cl2 and 20 ml H2O were added, the biphasic mixture was partitioned and the CH2Cl2 phase was recovered, dried over Na2SO4 and evaporated. After pumping in vacuo, the oil was purified on a silica gel plug, eluting with CH2Cl2 to yield phosphonate 4 as a light yellow oil (6.01 g., 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)([O-:11])=[O:10]>C(O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1
Solvent: CCO
Product: Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
The mixture of p-toluidine (10 g) and 2-nitrobenzaldehyde (14.1 g) in anhydrous ethanol was heated to reflux for 3 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with diethyl ether and petro ether to give 4-methyl-N-(2-nitrobenzylidene)aniline as yellow solid (17.3 g, yield 77.2%). LC/MS m/e obsd. (ESI+) [(M+H)+] 241.2.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:26]=[O:27])C.[OH-].[Na+]>O>[CH:26]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ccsc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
POCl3 (80 mmol, 7.32 mL) was added at 0° C. to a solution of 2,3-diphenylthiophene (18 g, 76 mmol) in DMF (18 mL, 0.23 mol). At the end of the addition, the reaction mixture was allowed to warm to room temperature and refluxed for 3 h. Then it was cooled to room temperature and poured into a mixture of ice and a 10% solution of sodium hydroxide in water. The oily precipitate obtained was filtered and washed with cold methanol and hexane. The residue was crystallized. Yield 15 g (75%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCOCC2)c1S(C)(=O)=O
Yield: 80.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (1 g, 2.62 mmol), morpholine (274 mg, 3.1 mmol) and N,N-diisopropyl ethyl amine (406 mg, 3.1 mmol) were heated at 100° C. in dry N,N-dimethylformamide (10 mL) for 30 min. The reaction mixture was evaporated to dryness, and the residue extracted with dichloromethane, 10% Na2CO3 and sat. NaCl. The crude product was purified by chromatography on silica gel in dichloromethane/ethyl acetate 5:1. One obtained 913 mg (80%) of a yellow foam. MS: m/z=433 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1cccc(Cl)c1F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1c(Cl)cccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(3-chloro-2-fluorobenzyloxy)pyridine (2.00 g, 0.0079 mol), 4chlorophenyl isothiocyanate (1.61 g, 0.0095 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield2.37 g (71%),m.p. 174°-176 ° C.