Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].[I-].[Li+].[CH2:8]([C:10]1[C:11](=[O:27])[NH:12][C:13](=O)[NH:14][C:15]=1[C:16](=[O:25])[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)[CH3:9].[CH2:28](Br)[CH3:29]>CN(C)C=O>[CH:28]1([CH2:29][CH2:13][N:14]2[C:15]([C:16](=[O:25])[C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=3)=[C:10]([CH2:8][CH3:9])[C:11](=[O:27])[NH:12][C:1]2=[O:4])[CH2:15][CH2:10][CH:8]=[CH:9]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: O=C([O-])O
Reactant: CCBr
Agent: [I-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CCC2C=CCC2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of sodium bicarbonate (0.10 g, 1.2 mmol) and lithium iodide (13 mg, 0.1 mmol) were added to dimethylformamide solution (10 ml) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione (0.27 g, 1.0 mmol) and 2-(cyclopent-2-en-yl))ethyl bromide (0.18 g, 1.0 mmol). And then, the reaction mixture was stirred at 90° C. for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid (112 mg).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(-c3cccnc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2cc(F)ccc2-c2cc(-c3cccnc3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred suspension of 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-pyridin-3-yl-5,6-dihydrophenanthridine (0.24 g, 0.51 mmol) and cyclohexene (11.4 mL), 9.22 mmol) was treated at room temperature under nitrogen with a solution of 1.0 boron tribromide in dichloromethane (3.1 mL, 3.1 mmol). After stirring for 20 hours at room temperature, the reaction was quenched with a saturated, aqueous sodium bicarbonate solution (100 mL), and extracted with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo. The crude residue was triturated with hexane, filtered, and recrystallized from dichloromethane-methanol to afford the title compound as a homogeneous, white, crystalline solid (0.17 g, 73%), m.p. 195-200° C.;
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([CH2:35][C:17]([CH3:22])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([O:20][CH3:21])=[O:19])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: BrCC1CCCC1
Reactant: COC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 184.2 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 3.04 mL, 3.04 mmol, 1 equiv) under a N2 atmosphere was cooled to 0° C. and treated with a solution of methyl 2-phenylpropionate (0.500 g, 3.04 mmol, 1 equiv) in dry tetrahydrofuran (2 mL). The reaction was stirred at 0° C. for 2 hrs, then cooled to −78° C. and treated with hexamethylphosphoric triamide (0.4 mL) and bromomethylcyclopentane (0.745 g, 4.568 mmol, 1.5 equiv). Stirred the reaction at −78° C. and allowed the bath to slowly warm to room temperature overnight. After 15 hrs, the reaction mixture was quenched with 10% aq NH4Cl (50 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with H2O (50 mL) and brine, then dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by SiO2 flash chromatography with 2:3 dichloromethane/hexanes to give the product as colorless oil (1.38 g, 5.60 mmol, 92%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.90-1.12 m, 2 H) 1.32-1.72 m, 10 H) 1.97-2.12 (m, 2H) 3.58 (s, 3 H) 7.19-7.35 m, 5 H); MS (APCI+) m/z 247 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][OH:16])[CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN(CC)CC.[CH3:30][C:31](OC(C)=O)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:31]([O:13][CH2:12]/[C:11](/[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)=[C:14](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH2:15][OH:16])(=[O:32])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(C(CO)=C(CO)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(4-(methylsulfonyl)phenyl)-3-phenyl-2butene-1,4-diol (149 mg) and Et3N (0.2 mL) in 20 mL of CH2Cl2 was treated with Ac2O (0.05 mL) and DMAP (5 mg). After stirring for 10 min at r.t., the mixture was concentrated, and the residue was purified by flash chromatography eluted with 3:2 EtOAc/hexane to afford 40 mg of the title compound as a white solid along with 30 mg of its regioisomer as a syrup.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([OH:28])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:48])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:28][C@@H:16]1[CH2:17][CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:48])[CH2:19]2)[C@@H:25]2[C@@H:15]1[C@H:6]1[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 89 %

Procedure:
The title compound II-ax was prepared in 89% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxyandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, dmso-d6, ppm from TMS): δ 4.32 (1H, bb), 3.75 (1H, m), 2.40-1.00 (20H, m), 0.96 (3H, s), 0.78 (3H, s).
Reaction SMILES: FC(F)(F)C([NH:5]C1C=CC(CC(O)=O)=CC=1)=O.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25](CC(O)=O)=[CH:24][CH:23]=1)(=[O:20])[CH3:19].N1C=CC(=O)NC1=O>>[N:5].[C:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: O=C(O)Cc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Agent: O=c1cc[nH]c(=O)[nH]1
Product: CC(=O)Nc1ccccc1
Product: [N]

Procedure:
This compound was prepared by a method similar to that described in example 11 (method 1) except that [4-(2,2,2-trifluoro-acetylamino)-phenyl]-acetic acid (prepared by the method of K. D. Janda et al, as described in J. Amer. Chem. Soc. 1991, 113, 291) was used in place of (4-acetylamino-phenyl)-acetic acid. A mixture of products arising from mono-alkylation at the 1 position of the 1H-pyrimidine-2,4-dione and bis-alkylation at both the 1 position of the 1H-pyrimidine-2,4-dione and acetanilide nitrogen were obtained. When this mixture of compounds was directly subjected to the conditions used to effect cyclization to the xanthine the trifluoroacetyl groups were removed by hydrolysis. A 2:1 mixture of 8-(amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione and 3-butyl-8-(4-butylamino-benzyl)-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione was obtained which was separated by chromatography using silica gel eluted with 96:4 chloroform/methanol. MS, m/z(M+)=421.1914.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(=O)([O-])[O-:9].[K+].[K+].[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2>C(Cl)(Cl)Cl>[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2.[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)CCCBr
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C([O-])CCCBr
Reaction time: 120 h

Procedure:
Five portions of 4-bromobutanoylchloride (0.35 ml×5) and potassium carbonate (0.4 g×5) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl3 dried over P2O5 and stirred for 5 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([O-:3])=[O:2].[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#N.Cl.[OH2:23]>CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:18](=[O:23])[C:17]([Cl:21])([Cl:20])[Cl:16])([O-:3])=[O:2]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1Nn1cccc1
Reactant: O
Agent: Cl
Solvent: CCOCC
Product: O=C(c1cccn1Nc1ccccc1[N+](=O)[O-])C(Cl)(Cl)Cl

Procedure:
A cooled solution of 40.5 g 1-(2-nitrophenylamino)-pyrrole (prepared as described in Example 1b) and 43 g trichloroacetonitrile in 650 ml of absolute ether is saturated with gaseous hydrogen chloride. The mixture isstirred with cooling for 24 hours. Water is added carefully and then ether.The ether phase is washed with brine, dried and concentrated to give the heading compound, m.p. 145°-148° (recrystallised from ether/petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]([C:8]([Cl:14])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(C)c(C(=O)O)o1
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)Cl)o1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2,4-dimethyl-oxazole-5-carboxylic acid (30 mg) in DCM (2.0 mL), oxalyl chloride (3.0 eq) was added at room temperature. The reaction mixture was stirred for 30 minutes. Solvents were evaporated and dried under vacuo to afford 2,4-dimethyl-oxazole-5-carbonyl chloride.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13].C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:20]1[CH2:21][CH2:22][N:17]([S:14]([C@@H:12]([C@:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])([OH:29])[CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(S(=O)(=O)[C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Reaction time: 0.5 h

Procedure:
In dichloromethane (10 ml) was dispersed 1[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H ,1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine.dihydrochloride (Compound 20, 0.40 g) obtained in Working Example 14. To the dispersion were added, under ice-cooling, triethylamine (0.40 ml) and acetic anhydride (0.13 g). The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was then washed with water, dried and concentrated. The concentrated was subjected to a silica gel chromatography (eluent: dichloromethane/methanol=20/1) for purification. The object fraction was concentrated and processed with hydrogen chloride, followed by addition of isopropyl ether to give 1-acetyl-4-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine (Compound 25).hydrochloride (336 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:29])[NH:12][C:13]1[C:14]([CH3:28])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26]O)=[CH:20][CH:19]=1)[CH3:9].[NH:30]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[N:32]=[CH:31]1>>[CH3:38][O:37][C:35]([C:33]1[N:32]=[CH:31][N:30]([CH2:26][C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:28])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:29])=[CH:19][CH:20]=2)[CH:34]=1)=[O:36]
Reactant: COC(=O)c1c[nH]cn1
Reactant: Cc1noc(-c2ccc(C#CCO)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Product: COC(=O)c1cn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cn1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: {5-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-3-methyl-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and methyl 4-imidazolecarboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:30]
Reactant: Cc1ccc(F)c(CC(=O)O)c1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(CC(=O)N2CCc3cc(-c4coc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.6 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 2-fluoro-5-methylphenylacetic acid (78 mg, 0.464 mmol), HATU (185 mg, 0.487 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about an hour, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven overnight to give 3-{1-[(2-fluoro-5-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (174 mg, 0.412 mmol, 94% yield) as a beige solid. LC/MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.27 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 5.53 (s, 2H), 6.93 (d, J=6.06 Hz, 1H), 7.03-7.18 (m, 3H), 7.30 (d, J=8.08 Hz, 1H), 7.40 (s, 1H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.13 (d, J=8.08 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:21][OH:22])[C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][C:32]2[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=2)[CH2:26][CH2:25]1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:21][O:22][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:30][CH:27]3[CH2:26][CH2:25][O:24][CH2:29][CH2:28]3)[CH:37]=2)[C:10]=1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCC2CCOCC2)c1
Reactant: COc1cccc2c(OCc3ccccc3)c(C)c(CO)nc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c(OCc3ccccc3)c(C)c(COc3cccc(OCC4CCOCC4)c3)nc12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of [4-(benzyloxy)-8-methoxy-3-methylquinolin-2-yl]methanol (250 mg) in THF (10 mL) were added 3-(tetrahydro-2H-pyran-4-ylmethoxy)phenol (185 mg) and 1,1-(azodicarbonyl)dipiperidine (245 mg), followed by dropwise addition of tributylphosphine (0.24 mL) at room temperature and stirring. After 1 hour, tributyl phosphine (0.24 mL) was added thereto, followed by stirring for 12 hours. Ethyl acetate was added to the reaction mixture, and then insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography twice (eluent for the first round: hexane/ethyl acetate=80/20˜67/33˜60/40, eluent for the second round: chloroform˜chloroform/methanol=95/5), and also by thin layer silica gel chromatography (developer: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-8-methoxy-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (340 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepentanoate(10.0 g), 2-methylimidazole(7.20 g), potassium carbonate(12.1 g) and N,N-dimethylformamide(80 ml) was stirred for 2 hours at 120-130° C. Water was added to the reaction mixture to give ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanoate(9.97 g, 88%). This was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms. mp 93-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cl)cc1CC(=O)O
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COC(=O)Cc1cc(Cl)ccc1OC
Yield: 94.1 %

Procedure:
A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742,1250, 1150, 1028; 1H NMR (300 MHz, CDCl3)δ 3.56 (2H, s), 3.66 (3H, s), 3.76 (3 H, s), 8.75 (1H, d, J=8.6 Hz), 7.13 (1H, d, J=2.5 Hz), 7.17 (1H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34])=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[F:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4F)CC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2cccc(N3CCN(c4ccccc4F)CC3)c2)Nc2c(C(=O)O)cc(F)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
A mixture of afford 6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.30 g, 0.61 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.26 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=478.3.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([Cl:29])[N:16]=1>>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:15]([NH2:14])=[N:16][C:17]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([CH:2]4[O:1][CH2:5][CH2:4][CH2:3]4)=[O:7])[CH2:13][CH2:12]3)=[N:18][C:19]2=[CH:20][C:21]=1[O:27][CH3:28].[ClH:29]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 73.3 %

Procedure:
The procedures of Example 9 were followed except that Compound 3 from Example 1 (3.0 grams, 16.3 mmole) and 4-amino-2-chloro-6,7-bismethoxy quinazoline III (3.8 grams, 16.1 mmole) were reacted to obtain 5.0 grams of Terazosin hydrochloride (Yield: 73%). After alkalification, 4.7 grams of white Terazosin solid was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14](Cl)=[N:15][CH:16]=1>O1CCOCC1>[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]([O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6])=[N:15][CH:16]=1
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (5.31 g, 133 mmol) in 1,4-dioxane (250 ml), ethyl glycolate (12.56 ml, 133 mmol) was added drop wise over a period of 30 minutes ensuring that the temperature was maintained below 30° C. The resulting thick suspension was stirred at room temperature for 15 minutes. In a separate 11 round-bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in 1,4-dioxane (150 ml) to give a brown solution. The suspension of sodium hydride and ethyl glycolate was added drop wise over a period of 30 minutes at 0° C. The resulting reaction mixture was heated to 80° C. overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([S:10]([Cl:13])(=[O:12])=[O:11])=[C:8]([C:14](Cl)=[O:15])[S:7][C:6]=2[CH:17]=1.[CH3:18][OH:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([S:10]([Cl:13])(=[O:12])=[O:11])=[C:8]([C:14]([O:19][CH3:18])=[O:15])[S:7][C:6]=2[CH:17]=1
Reactant: CO
Reactant: O=C(Cl)c1sc2cc(Cl)ccc2c1S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc2cc(Cl)ccc2c1S(=O)(=O)Cl

Procedure:
Prepared analogous to Example 1(c) from 6-chloro-2-chlorocarbonyl-benzo-[b]-thiophene-3-sulfonic acid chloride and methanol in the presence of chloroform.