Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C([N:20](CC)CC)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[NH2:20][CH:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: OC1CCCc2ccc(-c3ccccc3)nc21
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC1CCCc2ccc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a stirred solution of 8-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinoline (3.0 g, 13 mmol) in CH2Cl2 (25 mL) at 0° C. and triethylamine (4.0 mL, 29 mmol) was added dropwise, methanesulfonyl chloride (1.6 mL, 21 mmol). The reaction mixture was stirred overnight, then saturated aqueous NaHCO3 (20 mL) was added and the resulting mixture was extracted with CHCl3 (3×20 mL), dried (MgSO4) and concentrated in vacuo. The residue was taken up in DMF (20 mL), then sodium azide (1.7 g, 26 mmol) was added and the mixture was stirred at 60° C. for 5 h. At this time, the mixture was cooled to room temperature, diluted with aqueous brine solution (20 mL) and the resulting mixture was extracted with diethyl ether (3×20 mL). The organic fractions were combined then washed with water (20 mL) and brine (20 mL) then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in MeOH/EtOAc 1:1 (20 mL) and placed in a hydrogenation flask which was flushed with nitrogen. Palladium on carbon (10%, 220 mg) was added and the mixture was shaken in a Parr hydrogenator under 45 psi of hydrogen for 8 h. The reaction was filtered through celite and the cake was washed with CHCl3 (50 mL). Evaporation of the combined filtrates afforded 8-amino-2-phenyl-5,6,7,8-tetrahydroquinoline (AMD8787) (2.2 g, 74%) as a pale yellow oil. 1H NMR (CD3OD) δ 1.77-1.87 (m, 2H), 2.00-2.05 (m, 1H), 2.36-2.40 (m, 1H), 2.74-2.85 (m, 2H), 4.30 (dd, 1H, J=9, 5 Hz), 7.31-7.46 (m, 3H), 7.55 (d, 1H, J=8 Hz), 7.69 (d, 1H, J=8 Hz), 8.11 (d, 2H, J=8 Hz); 13C NMR (CD3OD) δ 18.5, 21.1, 24.0, 52.3, 120.7, 127.7, 129.7, 130.1, 132.3, 139.6, 153.5, 155.7. ES-MS m/z 225 (M+H). This intermediate was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH2:8][O:9][S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccc(COS(C)(=O)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (50 mg, Example 112) in THF (1 mL) was added NEt3 (30 mg, 0.03 mL) under argon at −10° C. Methanesulfonyl chloride (18 mg, 0.01 mL) was added and the mixture was allowed to stir for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed successively with sat. KHCO3 solution and brine. The organic layer was dried over Na2SO4 and evaporated to give the desired compound as light yellow, viscous oil that was used without further purification (53 mg). MS (m/e)=358.1 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17][C:16]=2[CH:24]2[CH2:26][CH2:25]2)[CH:12]=[CH:13][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:59][C:60]([CH3:67])([C:62]1[S:63][CH:64]=[CH:65][N:66]=1)[NH2:61]>CN(C=O)C>[CH3:59][C:60]([NH:61][C:21]([C:19]1[CH:18]=[N:17][C:16]([CH:24]2[CH2:26][CH2:25]2)=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[N:20]=1)=[O:23])([C:62]1[S:63][CH:64]=[CH:65][N:66]=1)[CH3:67]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid triethylamine salt (1:1) (Example 3a, 0.077 g, 205 μmol) was suspended in DMF (770 μL). TBTU (78.9 mg, 246 mmol), DIEA (106 mg, 136 μl) and α,α-dimethyl-2-thiazolemethanamine hydrochloride (43.9 mg, 246 μmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 5% to 50% ethyl acetate in n-heptane) to give the desired product (48 mg, 59%) as white solid; LC-MS (UV peak area, ESI) 94%, 399.1042 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][NH:28][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH:23]=[CH:24][CH:25]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCc1cccc(Cl)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-[2-(3-chlorophenyl)ethyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.75 mmol of 2-(3-chlorophenyl)ethylamine. LC/MS [10.47 min; 496 (M+1)]
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][N:17]=[C:16]2[O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
To a slurry of cesium carbonate (13.3 mmol) in THF was added 3-aminophenol (1.45 g, 13.3 mmol). After stirring 15 minutes at room temperature, 4-chloro-6,7-dimethoxyquinazoline (3.0 g, 13.3 mmol) was added and the reaction mixture heated at 50° C. overnight. The mixture was diluted with EtOAc and washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. to give 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (3.62 g, 12.2 mmol, 91%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.51 (s, 1H), 7.37 (s, 1H), 7.09 (t, 1H), 6.50 (d, 1H), 6.43 (s, 1H), 6.38 (d, 1H), 5.30 (br s, 2H), 3.99 (s, 3H), 3.97 (s, 3H); LC-MS (ESI) m/z 298 (M+H)+.
Reaction SMILES: [ClH:1].C([O:5][C:6]1[C:11]2[O:12][CH2:13][C@@H:14]3[C@@H:19]([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:18][CH2:17][CH2:16][N:15]3[CH3:20])C=C.CN1C[CH2:25][CH2:24][C:23]1=O>>[ClH:1].[OH:5][C:6]1[C:11]2[O:12][CH2:13][C@@H:14]3[C@@H:19]([C:10]=2[C:9]([CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1)[CH2:18][CH2:17][CH2:16][N:15]3[CH3:20]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1cccc2c1OC[C@@H]1[C@@H]2CCCN1C
Agent: Cl
Product: CCCc1ccc(O)c2c1[C@H]1CCCN(C)[C@@H]1CO2
Reaction time: 3 h

Procedure:
A solution of 400 mg of trans-7-allyloxy-4-methyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride in 10 ml of 1-methyl-2-pyrrolidinone is heated for 2 hours at 190°, poured onto water and the products extracted with ethyl acetate. After drying over magnesium sulfate, the solvent is removed; the residue is 20 ml of ethanol is hydrogenated at 3 atm. pressure in the presence of 100 mg of 10% palladium on carbon catalyst for 3 hours. After filtration, the solvent is removed and the hydrochloride salt is prepared with ethanolic hydrogen chloride to afford trans-7-hydroxy-4-methyl-10-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 283°-285°.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]1([S:25]([O:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])[CH3:8])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)=CCC[C@@H](C)CCO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 109.6 %

Procedure:
A solution of citronellol 6 (30.0 g, 192 mmol) in 400 mL CH2Cl2 was allowed to stir at 0° C. under N2 in a 1 L round bottom flask. Triethylamine (60 mL, 430 mmol) was added in one portion, followed by DMAP (2.0 g, 1.64 mmol). Finally, benzenesulfonyl chloride (30 mL, 240 mmol) was added dropwise via syringe. After the mixture was stirred for 2 h at 0° C., it was partitioned between petroleum ether and, sequentially, 3 M aqueous HCl, water, and brine. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo at 30° C. Removal of residual solvent under high vacuum yielded citronellyl benzenesulfonate (62.4 g, 110% of theoretical) as a clear yellow oil, TLC Rf(10% MTBE/petroleum ether)=0.41. 1H NMR (CDCl3) (δ): 7.92 (m, 2H), 7.66 (m, 1H), 7.56 (m, 2H), 5.03 (m, 1H), 4.09 (m, 2H), 1.91 (m, 2H), 1.68 (m, 1H), 1.67 (s, 3H), 1.57 (s, 3H), 1.52 (m, 1H), 1.44 (m, 1H), 1.24 (m, 1H), 1.11 (m, 1H), 0.81 (d, J=6.49 Hz, 3H); 13C NMR (CDCl3) (δ): u: 136.1, 131.4, 69.2, 36.6, 35.5, 25.1; d: 133.6, 129.1, 127.7, 124.2, 28.7, 25.6, 18.9, 17.5; IR (cm−1): 2914, 1449, 1360, 1188, 944.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:22])[C:7]=1[CH:23]1[C:36]2[C:35](=[O:37])[CH2:34][C:33]([CH3:39])([CH3:38])[CH2:32][C:31]=2[O:30][C:29]2[CH2:28][C:27]([CH3:41])([CH3:40])[CH2:26][C:25](=[O:42])[C:24]1=2>O.C1COCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:22])[C:7]=1[CH:23]1[C:24]2[C:25](=[O:42])[CH2:26][C:27]([CH3:40])([CH3:41])[CH2:28][C:29]=2[O:30][C:31]2[CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](=[O:37])[C:36]1=2
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.18 g, 4.36 mmol) in water (10.5 ml) was added dropwise to a solution of the methyl 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 4-3 (1.05 g, 1.98 mmol) in THF (21 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 3 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then washed with diethyl ether. Thereafter, a 1 N aqueous solution of hydrochloric acid (4.36 ml) was added to the water layer, and the mixed solution was then extracted with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (0.75 g, yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([CH3:14])[C:12]#[CH:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:13]#[C:12][CH:11]([CH3:14])[CH3:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1cnc(Cl)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-5-iodopyridin-4-amine (Compound 11, 2.55 g, 10.0 mmol) in Et3N (35 ml) was added Pd(PPh3)2Cl2 (70 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol), and 3-methyl-1-butyne (1.2 ml, 12 mmol). The reaction was stirred at room temperature for 20 h and was quenched with H2O, extracted with EtOAc (Δ2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][F:25])[N:19]=1>>[F:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:7]=[N:6]2)[N:19]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)nn1
Product: FCc1cccc(C#CCCn2cc(-c3ccc(F)cc3)nn2)n1
Yield: 21.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole (100 mg, 0.47 mmol) and 2-bromo-6-(fluoromethyl)pyridine (97 mg, 0.51 mmol, Example 190(E)). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 32 mg (0.10 mmol, 21%) of 2-(fluoromethyl)-6-(4-(4(4 fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a yellow solid (M.P.=100-103° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:2]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:17][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1
Reactant: O=C(Cc1ccccc1)c1cccnc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(Cc1ccccc1)c1cccnc1
Reaction time: 0.25 h

Procedure:
10.8 g of benzyl 3-pyridyl ketone are stirred together with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine for 6 hours at 100°. The reaction mixture is poured onto ice/water and the resulting mixture is stirred for a further 15 minutes. The crystals which have precipitated are filtered off with suction, washed with water and dried under a high vacuum. Benzyl 3-pyridyl ketone oxime with a melting point of 122°-126° is obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5]1)([OH:3])=[O:2].[CH2:14]=O.Cl>C(O)=O.O>[CH3:14][N:5]1[CH:4]([C:1]([OH:3])=[O:2])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Solvent: O
Product: CN1Cc2ccccc2CC1C(=O)O
Yield: 53 %

Procedure:
A solution of 0.364 g (2.07 mmol) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline in 25 mL of formic acid was combined with 2.5 mL of 37% formaldehyde. The resulting mixture was allowed to reflux for approximately 17 hours. After cooling, the mixture was contentrated under reduced pressure to provide a gum. This gum was dissolved in 3.0 mL of water, adjusted to a pH 2 using hydrochloric acid and then purified using ion-exchange chromatography (Dowex 50x-8, 100 meshcation) to provide 0.21 g of a yellow powder.
Reaction SMILES: C(O)C.[O:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[C:20](Cl)[N:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:18]([NH2:17])=[N:19][C:20]([N:14]3[CH2:13][CH2:12][N:11]([C:9]([CH:5]4[O:4][CH2:8][CH2:7][CH2:6]4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:22]2=[CH:23][C:24]=1[O:30][CH3:31]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: O
Solvent: CCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of absolute ethanol (272 ml), water (68 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 32 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 48 hours. The crystals were collected by filtration, washed with absolute ethanol and dried in vacuo at 40° C. to yield 36.44 g (85.5%) of Terazosin.HCl dihydrate. See Trial M in Table I. Trial N was performed using a 10% volume of water.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[N+:20]([O-])=O)[NH:16][C:15](=[O:23])[CH2:14][CH2:13]2)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1>[Pd].CO>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[NH:9][C:10]3=[CH:11][C:12]4[CH2:13][CH2:14][C:15](=[O:23])[NH:16][C:17]=4[CH:18]=[C:19]3[N:20]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCc2cc(NC(=O)c3ccncc3)c([N+](=O)[O-])cc2N1
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2cc3[nH]c(-c4ccncc4)nc3cc2N1
Reaction time: 24 h

Procedure:
2.4 g. (7.7 mmole) 6-isonicotinoylamino-7-nitro1,2,3,4-tetrahydroquinolin-2-one were hydrogenated in 100 ml. methanol in the presence of 0.4 g. 10% palladium on charcoal. After filtering off the catalyst and evaporating the filtrate, the residue was boiled for 24 hours with 80 ml. ethanol and 15 ml. concentrated hydrochloric acid. The evaporation residue was treated with water and ammonia, filtered off with suction and recrystallised from methanol to give 1.3 g. (62% of theory) of the title compound; m.p. above 300° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:36]1[CH:37]=[CH:38][C:39]([C:44]([F:47])([F:46])[F:45])=[C:40]([CH:43]=1)[C:41]#[N:42].C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@@H:27]([OH:28])[C:36]3[CH:37]=[CH:38][C:39]([C:44]([F:45])([F:46])[F:47])=[C:40]([CH:43]=3)[C:41]#[N:42])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: N#Cc1cc(I)ccc1C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(F)(F)F)c(C#N)c3)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-iodo-2-(trifluoromethyl)benzonitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([O:26][CH3:27])=[N:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH2:29]O)=[CH:8][CH:7]=1.[C-:31]#[N:32].[Na+].C(Cl)C1C=CC=CC=1>O1CCCC1.C(=O)([O-])O.[Na+].O.CS(C)=O.N1C=CC=CC=1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([O:26][CH3:27])=[N:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH2:29][C:31]#[N:32])=[CH:8][CH:7]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C)n1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCc1ccccc1
Solvent: O
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Thionyl chloride (0.56 mL, 7.65 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (1.43 g, 3.83 mmol) and pyridine (0.10 mL) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A solution of sodium cyanide (375 mg, 7.65 mmol) in water (1.0 mL) was added to the resulting benzyl chloride in dimethylsulfoxide (20 mL), and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the precipitate was collected by filtration, washed with diisopropyl ether to give the title compound as a colorless powder (1.42 g, 3.71 mmol, 97% in 2 steps).
Reaction SMILES: [C@@H:1]([C@H:5]1[CH2:9][O:8][C:7]([CH3:10])=[N:6]1)([CH2:3][CH3:4])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:24]([N:31]1[C@@H:35]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]([CH2:43]I)[O:33][C:32]1([CH3:46])[CH3:45])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[C:24]([N:31]1[C@@H:35]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]([CH2:43][CH2:10][C:7]2[O:8][CH2:9][C@H:5]([C@H:1]([CH2:3][CH3:4])[CH3:2])[N:6]=2)[O:33][C:32]1([CH3:45])[CH3:46])([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: CC[C@H](C)[C@H]1COC(C)=N1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)C(CI)OC1(C)C
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@H](C)[C@H]1COC(CCC2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CC2CCCCC2)=N1
Reaction time: 0.5 h

Procedure:
3.76 g of 4(S,S)-sec.-butyl-2-methyloxazoline and 4.0 ml of N,N,N',N'-tetramethylethylenediamine are dissolved in 100 ml of THF and, at -78° C., added dropwise to 14.9 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise. The mixture is stirred at this temperature for 30 min and then 1.15 g of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5(R,S)-iodomethyloxazolidine in 10 ml of THF are added dropwise. The reaction solution is stirred at R.T. for 1 h and is poured into 200 ml of saturated aqueous NaHCO3 solution, and the mixture is extracted 3 times with 200 ml of EA. Drying over Na2SO4 and concentration in vacuo is followed by chromatography on silica gel (mobile phase MTB/diisopropyl ether 1:1). The title compound is obtained as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:36])[CH2:21][NH:22][C:23]([CH3:35])([CH3:34])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]([NH:22][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:36])([CH3:35])[CH3:34])=[CH:26][CH:27]=1)[CH3:33]
Reactant: CCOc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(CC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)cc1

Procedure:
1.5 g (2.8 mmol) of 6-benzyloxy-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one in 80 mL methanol are hydrogenated with 250 mg palladium on charcoal (10%) as catalyst at ambient temperature and normal pressure. The catalyst is suction filtered and the filtrate is evaporated down. The residue is dissolved in 5 mL ethanol by heating, seeded, and diluted with ethyl acetate. The solid precipitated is filtered off and washed. White solid. Yield 1.0 g (83%, hydrochloride); melting point: 232° C.-235° C.; mass spectrometry: [M+H]+=401.