Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1.C(O)(=O)C>[Fe].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:13])[O:6][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(N)cn1
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of 2-[2-[5-methyl-2-(2-chlorophenyl)-4-oxazolyl]ethoxy]-5-nitropyridine (1.69 g), iron dust (787 mg), acetic acid (25 ml) and water (8 ml) was stirred at 65°-70° C. for 3 hours. Insolubles were filtered off and the filtrate was evaporated under reduced pressure. To the residue was added water. The mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel chromatography. From the fraction eluted with methanol-chloroform (1:25, v/v), 5-amino-2-[2-[5-methyl-2-(2-chlorophenyl)-4-oxazolyl]ethoxy]pyridine (1.50 g, 97%) was obtained.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[S:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1>CN(C=O)C>[O:27]=[C:19]1[N:20]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:18]1[CH:15]1[CH2:16][CH2:17][S:12][CH2:13][CH2:14]1
Reactant: O=c1[nH]c2ccccc2n1C1CCSCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 1 h

Procedure:
Sodium hydride (68.3 mg of a 60% dispersion in mineral oil, 1.71 mmol) followed by tert-butyl bromoacetate (0.189 mL, 1.28 mmol) was added to a solution of 1-tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one from Step B (200 mg, 0.854 mmol) in DMF (5 mL). After 1 h, the reaction was quenched with H2O (10 mL) and extracted with CH2Cl2 (10 mL). The organic layer was washed with saturated NaHCO3 (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, gave the title compound. MS: m/z=349 (M+1).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:16]([C:27](=[CH2:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[C:36]([O:44][CH2:35]/[C:27](/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C=C(C(=O)OC(C)(C)C)C(O)CCCCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)COC(=O)c1ccccc1
Temperature: 0 °C
Yield: 81.4 %

Procedure:
Diisopropyl azodicarboxylate (5 mL, 25 mmol) is added dropwise over 5 minutes to a solution of t-butyl 2-(1-hydroxy-5-phenylpentyl)acrylate (5.59 g, 19.3 mmol), benzoic acid (3 g, 25 mmol) and triphenyl phosphine (6.5 g, 25 mmol) in THF (100 mL) at -55° C. The reaction is maintained between -55 and -50° C. for 45 minutes and then the reaction is allowed to warm to 0° C. The solution is diluted with ether (300 mL) and washed with 1 N NaOH (2×40 mL) and brine (70 mL). The resulting solution is dried (MgSO4) and concentrated in vacuo. The crude reaction product is partially dissolved in 20% ether/petroleum ether and applied to a silica gel column as a slurry. The column is eluted using gradient elution (silica, 10 to 20% ether in petroleum ether) to obtain (E)-2-t-Butoxycarbonyl-7-phenylhept-2-enyl benzoate (6.2 g, 82%): 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=7.0 Hz, 2H), 7.53-7.49 (m, 1 H), 7.41 (t, J=7.5 Hz, 2H), 7.28-7.23 (m, 2H), 7.20-7.10 (m, 3H), 6.99 (t, J=7.8 Hz, 1H), 5.05 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.36 (q, J=7.5 Hz, 2H), 1.72-1.46 (m, 4H), 1.47 (s, 9H); MS (FAB) m/e 395 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5](Cl)=[N:6][C:7]=1[Cl:8].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[Cl:8]
Reactant: Clc1nc(Cl)c(Br)c(Cl)n1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Nc2nc(Cl)c(Br)c(Cl)n2)cc1

Procedure:
Drugs of the Future 2005, 30(5): 462-468 discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)-benzonitrile, which upon treatment with POCl3 yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile, followed by the aminolysis of the same intermediate yields Etravirine. It also discloses another process in which 5-bromo-2,4,6-trichloropyrimidine is reacted with 4-aminobenzonitrile in presence of diisopropylethylamine to give 4-(5-Bromo-4,6-dichloro-pyrimidin-2-ylamino)-benzonitrile, which is then reacted with 4-hydroxy-3,5-dimethylbenzonitrile to give 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile. The aminolysis of the same intermediate yields Etravirine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1CC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)nn1CC(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
A solution of 2-tert-Butoxycarbonylmethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (3 gm) in ethyl acetate (60 ml) and acetic acid (4.5 ml) was hydrogenated at 50 psi hydrogen in the presence of 1.5 gm of 10% palladium/carbon for 3 hours. The mixture was then filtered and evaporated to obtain 2.62 gm of pure title product. ESI M+1=256.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]1[O:23][CH:21]1[CH3:22]>CO>[OH:23][CH:21]([CH3:22])[CH2:20][C:7]1[CH:19]=[CH:18][C:10]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:18][CH:19]=3)[CH2:6][CH2:5]2)=[CH:9][CH:8]=1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1CO1
Solvent: CO
Product: CCCCOC(=O)c1ccc(N2CCN(c3ccc(CC(C)O)cc3)CC2)cc1
Yield: 78 %

Procedure:
A mixture of 13.1 g. (50 mmole) n-butyl 4-(piperazin-1-yl)-benzoate, 2.9 g. (50 mmole) propylene oxide and 6 ml. methanol is stirred for 24 hours at 20° C. The solvent is then evaporated off and the residue is triturated with ligroin to give a yield of 78% of theory of the desired product; m.p. 85°-86° C.
Reaction SMILES: [O:1]1[CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[O:4][CH2:3][CH2:2]1.[NH:11]1[CH:15]=[C:14]([C:16]2[S:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH:13]=[N:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:4]1[CH:9]2[CH:10]([CH2:5][N:6]([C:21]([C:18]3[CH:17]=[C:16]([C:14]4[CH:15]=[N:11][NH:12][CH:13]=4)[S:20][CH:19]=3)=[O:22])[CH2:7][CH2:8]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: C1CNC2OCCOC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCC2OCCOC2C1
Reaction time: 8 h
Yield: 8.1 %

Procedure:
Octahydro-[1,4]dioxino[2,3-b]pyridine (0.049 g, 0.34 mmol) was dissolved in acetonitrile (1 mL) then 5-(1H-pyrazol-4-yl)-thiophene-3-carboxylic acid (0.060 g, 0.31 mmol) was added then DIPEA (0.116 mL, 0.68 mmol) followed by HATU (0.141 g, 0.37 mmol). The resulting mixture was stirred overnight then further amounts of DIPEA (0.31 mmol) and HATU (0.31 mmol) were added and stirring continued overnight. The mixture was evaporated and the residue was suspended in sodium hydroxide (1 N, 2.5 mL) and stirred for 20 minutes. The mixture was extracted with DCM (×3) then the organics were dried over sodium sulfate, filtered and evaporated. The material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) over 20 minutes and the fractions containing the desired product were combined and freeze-dried to give the title compound as a white foam (0.008 g). LCMS m/z 320.19 [M+H]+ R.T.=5.95 min (Analytical Method 2).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
6-(3-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 1-bromo-3-fluorobenzene according to the procedure of Example 4, as a light yellow solid: mp 181-182° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.62-7.44 (m, 5H), 7.16 (t, 1H, J=2.22 Hz), 6.97 (d, 1H, J=8.83 Hz), 1.67 (s, 6H); MS (EI) m/z 271 ([M+H]+, 40%); Anal. Calcd. For C16H14FNO2: C, 69.91; H, 5.3; N, 5.1. Found: C, 70.0; H, 5.32; N, 4.92.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12]3[N:15]=[C:16]([NH2:18])[S:17][C:11]=3[CH2:10]2)=[N:7][CH:8]=1.[CH:21]([C:32](OCC)=[O:33])([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C(C)=CC=CC=1>[CH2:25]([O:24][C:22]([C:21]1[C:27](=[O:28])[N:15]2[C:16]([S:17][C:11]3[CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=4)[CH2:14][CH2:13][C:12]=32)=[N:18][C:32]=1[OH:33])=[O:23])[CH3:26]
Reactant: Nc1nc2c(s1)CN(c1ccc(C(F)(F)F)cn1)CC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1c(O)nc2sc3c(n2c1=O)CCN(c1ccc(C(F)(F)F)cn1)C3
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
The mixture of 5-(5-trifluoromethyl-pyridin-2-yl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (5.7 gm, 0.019 mol) and triethyl methanetricarboxylate (16.1 ml, 0.076 mol) in xylene (100 ml) was heated at 140-150° C. for 6 hours. Xylene was evaporated and diethyl ether was then added and the suspension was stirred for 15 minutes. It was filtered and washed with ether. The crude solid was digested with dichloromethane (200 ml) and filtered to remove insoluble residue. Dichloromethane layer was distilled off under vacuum to give 1.3 gm of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=O.[CH3:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[CH:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Reactant: CC1=NC(C)(C)CO1
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1C=CC1=NC(C)(C)CO1

Procedure:
A mixture of 2-methoxy-5-nitrobenzaldehyde, 16 g, (U.S. Pat. No. 4,367,234), 2,4,4-trimethyl-2-oxazoline, 30 ml, (Aldrich Chemical Company), para toluenesulfornic acid, 0.5 g, in toluene, 100 ml, is refluxed overnight under a water separator. The mixture is evaporated, the residue dissolved in diethylether, 800 ml, and washed with water. The diethyl ether layer is separated, concentrated, and filtered to give 11.1 g of 4,5-dihydro-2-[2-(2-methoxy-5-nitrophenyl)ethenyl]-4,4-dimethyloxazole after recrystallization from diisopropyl ether; mp 115°-116° C.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]([CH3:32])[CH2:11][C@H:12]1[CH2:17][N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][NH:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][C@H:12]1[CH2:17][N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][N:13]1[C:40](=[O:42])[CH3:41])[CH3:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCN[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (S)—N-benzyl-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-2-yl)-N-methylmethanamine dihydrochloride, (Example 42, Compound 130) (96.5 mg, 0.20 mmol) in CH2Cl2 (2 mL) at 0-5 C was treated with triethylamine (84 ul, 0.60 mmol) followed by acetyl chloride (22 uL, 0.30 mmol). The reaction mixture was allowed to warm to room temperature and stir 1 h. After this time the reaction mixture was treated with a saturated aqueous solution of NaHCO3 (1 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 100% EtOAc then 5% MeOH/EtOAc as eluant to afford product as an oil (65 mg, 72%). LC/MS (Method B) 2.57 min, [M+1]+ 452. Potency class ND.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>CN(C=O)C>[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[N:6]([S:34]([CH3:33])(=[O:36])=[O:35])[C:5]=1[C:20]1[N:24]([C:25]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)[N:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(S(C)(=O)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
Sodium hydride (12 mg of a 60% dispersion in mineral oil, 0.30 mmol) was added to a solution of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (94 mg, 0.23 mmol) in DMF (1.5 mL) under a nitrogen atmosphere. The mixture was stirred for 5 minutes and the resultant yellow solution was treated with methanesulfonyl chloride (32 mg, 21.4 μL, 0.28 mmol). The mixture was stirred for 2 h then treated with water and extracted with EtOAc. The organic phase was washed with water and brine then dried (sodium sulfate) and concentrated in vacuo. T he residue was purified by chromatography using silica gel eluting with 25%-60% ethyl acetate in cyclohexane. The product thus obtained was freeze-dried from acetonitrile-water to afford the title compound (54 mg) a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH3:11])[C:4]=1[O:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:7]1[C:6]([CH3:10])=[C:5]([CH3:11])[C:4]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:8]=1[CH3:9])=[O:25]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1c(C)cc(C)c(C)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1c(C)c(C)c(C(=O)CCCCCBr)c(C)c1OC
Reaction time: 0.75 h
Yield: 16.6 %

Procedure:
A solution of 2.956 g (16 mmol) of 1,2-dimethoxy-3,4,6-trimethylbenzene in 10 mL of methylene chloride was added to 2.40 g (18 mmol) of aluminum chloride and 3.80 g (18 mmol) of 6-bromohexanoyl chloride in 30 mL of methylene chloride cooled in an ice bath. The solution was kept at 3° for 45 minutes and then at 23° for 42 hours. An additional 2.0 g of aluminum chloride and 3.0 g of 6-bromohexanoyl chloride were added and the reaction mixture was stirred at reflux for 22 hours. Workup as in Example 131 and purification by HPLC using 4% ethyl acetate-hexane gave 0.95 g of 6-bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave a molecular ion at m/z 356 (C17H25BrO3).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:16]([O-])=O)(=[O:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:16])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)cnc2c([N+](=O)[O-])cccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1c(C(C)=O)cnc2c(N)cccc12
Yield: 87 %

Procedure:
A mixture of 3-acetyl-4-methoxy-8-nitroquinoline (230 mg), ammonium chloride (30 mg) and iron (313 mg) in ethanol (3 ml) and water (0.8 ml) was refluxed for 2 hours. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 3-acetyl-8-amino-4-methoxyquinoline (175.7 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[N:11][C:5]2=[N:4][C:3]=1Cl.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[N:11][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nc2cccnc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1nc2cccnc2nc1-c1ccccc1
Temperature: 25 °C

Procedure:
2,3-Dichloropyrido[2,3-b]pyrazine (step 2) (500 mg, 2.5 mmol) in dry dioxane (10 ml), under nitrogen was treated with phenylboronic acid (305 mg, 2.5 mmol), potassium carbonate (691 mg, 5 mmol) in water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (144 mg, 0.125 mmol). The resulting mixture was heated using microwave radiation at 100° C. for 1 hour. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (×3). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with 0-30% EtOAc/iso-hexane to afford the title compound as a solid;
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:17]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[C:14]=2[C:15]#[N:16])=[CH:6][CH:5]=1
Reactant: OCc1ccc(Br)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 4-bromobenzyl alcohol (1.48 g; 7.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and refrigerated overnight. The resulting precipitate is removed by filtration and dried under vacuum at 30° C. overnight to give 1.82 grams 2-(4-bromobenzyloxy)-6-fluorobenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)=[O:4].[C:15]([O:19][C:20](=[O:39])[C@@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26])[CH2:22][NH2:23])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12](=[O:14])[NH:23][CH2:22][C@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]23[CH2:36][CH:35]4[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]4)[CH2:30]2)[CH2:38]3)=[O:26])[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:39])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C=Cc1ccc(C(=O)O)s1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)C=Cc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Yield: 32.4 %

Procedure:
The title compound was synthesized analogously to example 3, step a) from 360 mg (1.84 mmol) of 5-(2-methoxycarbonyl-vinyl)-thiophene-2-carboxylic acid and 650 mg (1.84 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-amino-propionic acid tert-butyl ester. After chromatography (silica gel; ethyl acetate/n-heptane (1/1, v/v)) 326 mg of the title compound were obtained as colourless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:25].[OH-].[NH4+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)([C:22]([NH2:23])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(NC2(C#N)CCN(Cc3ccccc3)CC2)c1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl-4-cyano-4-(3-methylphenylamino)-piperidine (7.6 g) and 90% sulfuric acid (53 mL) was heated 70° C. until all the solid dissolved (~1 h). The resultant mixture was stirred at the temp. for 30 min., and poured into a mixture of ice (80 g) and concentrated ammonium hydroxide (75 g). The solution was basified with ammonium hydroxide, and extracted with chloroform. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.