Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[CH:12][N:11]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: Clc1nccc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnn(-c2nccc(N3CCOCC3)n2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-1H-pyrazole (0.74 g, 5.0 mmol) in anhydrous DMF (7 ml) was added NaH (60% dispersion in mineral oil, 0.22 g, 5.5 mmol) in a portionwise fashion over 10 minutes. The mixture was stirred like this for 30 minutes before the addition of 4-(2-chloro-pyrimidin-4-yl)-morpholine (21)(1.0 g, 5.00 mmol). The reaction was then heated under the influence of microwave radiation (120° C., 14 minutes, fixed hold time, high absorption setting). The reaction was then cooled to room temperature and water added (14 ml) which caused a precipitate to form. The solid was collected by filtration, washed with water and dried in a desiccator to give the title compound (1.44 g, 93%) in sufficiently pure form to be used without any further purification. m/z (LC-MS, ESP): 310 [M+H]+, R/T=3.08 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:35][CH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([NH:35][CH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)=[O:5]
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Reactant: NCc1nnn[nH]1
Product: Cc1cc(Oc2cc(Cl)c(C(=O)NCc3nnn[nH]3)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Yield: 40 %

Procedure:
The title compound was prepared in analogy to Example 38, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid (Example 66) and 5-(aminomethyl)-tetrazole (commercially available, CAS RN 31602-63-8) to provide 47 mg (40%) of the title compound as a light yellow solid. MS (ESI): m/z=579.142 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37]>C(Cl)Cl>[O:1]([CH2:8][C:9]([N:11]([CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[C:16]([CH3:18])([CH3:19])[S:17][C@H:13]12)[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(N(C(=O)COc3ccccc3)C(=O)OCC(Cl)(Cl)Cl)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 4.855 gms. (10 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate, 16.94 gms. (80 mmol.) of 2,2,2-trichloroethyl chloroformate, 18 ml. of N,O-(bis-trimethylsilyl)trifluoromethylacetamide, and 20 ml. of methylene chloride was prepared. The mixture was permitted to stand at room temperature overnight. The mixture then was heated at reflux for 7 hours after which it was again permitted to stand at room temperature overnight. Heating then was continued for an additional 6 hours. The mixture then was evaporated to a residue, and the residue was dissolved in benzene which then was added to a large excess of heptane. The resulting insoluble material was filtered off, dissolved in benzene, and chromatographed over silica gel using a benzene-ethyl acetate elution gradient. p-Nitrobenzyl 6-[N-(phenoxyacetyl)-N-(2,2,2-trichloroethoxycarbonyl)amino]-2,2-dimethylpenam-3-carboxylate (4.76 gms.; 72 percent) was obtained as product.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)C(=O)O
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 70.1 %

Procedure:
First, a toluene (1 L) solution of pyruvic acid (440 g, 5.0 mol), n-butanol (371 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours while removing water under a nitrogen gas stream, whereby a first reaction solution was obtained. Next, the first reaction solution was cooled to room temperature (25° C.). Thereafter, toluene was removed under reduced pressure (40 mmHg) using an evaporator, and the residue was purified by reduced pressure distillation (40 mmHg, 93 to 100° C.), whereby butyl pyruvate (505 g, yield 70%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]=[C:8](Cl)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.C(O)C>O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]=[C:8]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A stirred mixture of (4-chloro-5-phenylthieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester (0.36 g, 1.08 mmol), 2-aminomethylpyridine (0.12 ml, 1.19 mmol), triethylamine (0.17 ml, 1.19 mmol) and ethanol (8 ml) was heated under reflux for 4 hours. The solution was then cooled to ambient temperature, poured into water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:2) gave {5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetic acid ethyl ester as a colourless gum (0.41 g).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=[O:4])=[O:3].[N+:17]([C:20]1[CH:21]=[C:22](CCO)C=[CH:24][CH:25]=1)([O-:19])=[O:18].[N+](C1C=CC(S(Cl)(=O)=O)=CC=1)([O-])=O>>[N+:17]([C:20]1[CH:21]=[CH:22][C:1]([S:2]([O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)(=[O:3])=[O:4])=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield using a similar procedure to description D4 starting from 2-(3-nitro-phenyl)ethanol and 4-nitrobenzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:33][N:34]([CH3:39])[CH2:35][C:36]([O:20][CH2:19][CH:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:37]
Reactant: CN(C)CC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCC1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
(5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 250 mg, 0.57 mMol), N,N-dimethylglycine (150 mg, 1.46 mMol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (300 mg, 1.56 mMol), and 4-dimethylaminopyridine (5 mg, 0.04 mMol) were suspended in 5 ml of DMF at room temperature. The mixture was stirred overnight and then concentrated. The residue was purified by chromatography (silica gel; elution with 1 to 10% methanol in dichloromethane) to give the free base of the title compound as a white solid (250 mg). Mp 185–198° C.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[OH:14][CH2:15][C:16]1[N:17]=[CH:18][S:19][C:20]=1/[CH:21]=[CH:22]\[S:23][C:24]1[C@H:25]([CH3:55])[C@@H:26]2[C@@H:43]([C@H:44]([O:46][Si:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:45])[C:42](=[O:54])[N:27]2[C:28]=1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>C1COCC1>[C:7]([O:14][CH2:15][C:16]1[N:17]=[CH:18][S:19][C:20]=1/[CH:21]=[CH:22]\[S:23][C:24]1[C@H:25]([CH3:55])[C@@H:26]2[C@@H:43]([C@H:44]([O:46][Si:47]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:52][CH3:53])[CH3:45])[C:42](=[O:54])[N:27]2[C:28]=1[C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)=[O:30])(=[O:9])[CH3:8]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3COC(C)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N-Dimethylaminopyridine (37 mg), 0.133 ml of pyridine, and 0.114 ml of acetic anhydride were added to 3 ml of a solution of 695 mg of 4-nitrobenzyl (1R,5S,6S)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-6-((1R)-1-triethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate in THF, and the mixture was stirred at room temperature for 1.5 hr. Ethyl acetate was added to the reaction solution, and the mixture was washed with brine, was dried over anhydrous magnesium sulfate, and was filtered. Silica gel (5 g) was added to the filtrate, the mixture was filtered, and the filtrate was concentrated under the reduced pressure to give 730 mg of 4-nitrobenzyl (1R,5S,6S)-2-[[(Z)-2-(4-acetoxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-6-((1R)-1-triethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:26])[C:19]([CH2:24][CH3:25])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:26])[C:19]([CH2:24][CH3:25])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCC(C)(CCCl)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
79.7 g (0.62 mole) of 4-chlorophenol and 85.6 g (0.62 mole) of potassium carbonate in 600 ml of toluene are heated under reflux for 2 hours, using a water separator. 104 g (0.53 mole) of 1,5-dichloro-3-ethyl-3-methyl-2-pentanone in 100 ml of toluene are then added at 70° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool and is stirred with 500 ml of water. The organic phase is separated off, washed with dilute sodium hydroxide solution and with water, dried over sodium sulphate and concentrated. 110 g (71.8% of theory) of 1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone of refractive index nD20 1.5092 are obtained. ##STR101##
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].O>C(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si:12]([CH3:13])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)Cl
Reactant: CNCc1ccc(C#C[Si](C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)N(C)Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
Amine 3 (90.0 g, ˜0.41 mol) was dissolved in methylene chloride (810 ml). Triethylamine (66.6 g, 0.66 mol) was added and the solution was cooled to 5° C. Methyl chloroformate (47.0 g, 0.50 mol) in methylene chloride (100 ml) was then added slowly and the reaction temperature was maintained between 10° C. and 14° C. After addition was complete, the reaction solution was stirred at room temperature for 12 hours. Water (540 ml) was added. Aqueous phase was separated. Organic phase was concentrated to dryness to afford crude compound 4. The crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 0.279 (s, 9H), 2.86 (d, br, 3H), 3.774 (s, 3H), 4.484 (s, br, 2H), 7.190 (s, br, 2H), 7.46 (d, 2H, J=8.10 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25])[C:32]1[CH:31]=[CH:30][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Reactant: CCCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoro-nitrobenzene (4.3 g) was dissolved in chloroform (200 ml) to prepare a solution. Aluminium chloride (10 g) was added to the solution, and the mixture was heated under reflux for 2 hr. The solvent was removed by evaporation before water (200 ml) was carefully added to the residue. The precipitated crude crystal (6.5 g) was collected by filtration. This crude crystal was dissolved in dimethylformamide (150 ml). Potassium carbonate (9.0 g) and benzyl chloride (4.5 g) were added to the solution, and the mixture was stirred at room temperature for 5 hr. The mixture was extracted with ethyl acetate. The extract was then washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (1.4 g, yield 27%) was obtained from the fraction of n-hexane:ethyl acetate (1:4).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH3:24].O>C1C=CC=CC=1.CCCCCC.CCOCC>[NH2:24][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: N
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C=C(N)CC(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl acetonedicarboxylate (44.1 ml, 0.3 mole) and p-toluene-sulfonic acid (0.19 g, 1 mmol) in benzene (50 ml) was bubbled NH3 gas for 30 min. The mixture was refluxed with azeotropic removal of water using Dean-Stark trap. The bubbling of NH3 gas and azeotropic removal of water was repeated three times to give a total 5 ml of water. The reaction mixture was diluted with benzene and filtered through celite. The filtrate was concentrated to give an amber oil, 50.75 g. An equal volume of ether was added to this oil and hexane added until cloudy, and stirred slowly overnight to afford a crystalline product. This crystalline was collected by filtration and washed once with 1/1 of ether/hexane to give 44.55 g (85.75%) of crystalline, mp 47°-50° C.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[S:8][C:9]([C:12]2([CH2:17][CH3:18])[O:16][CH2:15][CH2:14][O:13]2)=[CH:10][CH:11]=1)(=O)=O.O[C:20]1[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[CH2:17]([C:12]1([C:9]2[S:8][C:7]([CH2:6][O:5][C:29]3[CH:28]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:22](=[CH:21][CH:20]=3)[C:30]([O:32][CH3:33])=[O:31])=[CH:11][CH:10]=2)[O:16][CH2:15][CH2:14][O:13]1)[CH3:18]
Reactant: CCC1(c2ccc(COS(C)(=O)=O)s2)OCCO1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC1(c2ccc(COc3ccc(C(=O)OC)c(C(=O)OC)c3)s2)OCCO1

Procedure:
9.25 g (43.2 mmol) of 5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethyl methanesulphonate are dissolved in 100 mL of 2-butanone, and 9.07 g (43.2 mmol) of dimethyl 4-hydroxyphthalate (prepared in Example 1(b)), 6 g of potassium carbonate (43.2 mmol) and 20 mg of sodium iodide are added. The mixture is refluxed for 12 hours, cooled and filtered. The filtrate is concentrated under reduced pressure and then purified by chromatography on a column of silica. A yellow oil is obtained (m=12.70 g; Y=73%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:18])[S:5]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=1[CH3:17])(=[O:7])=[O:6].[CH3:19]I>CN(C)C=O>[CH3:18][N:4]([CH3:3])[S:5]([C:8]1[S:12][C:11]([N:13]([CH3:19])[C:14](=[O:16])[CH3:15])=[N:10][C:9]=1[CH3:17])(=[O:6])=[O:7]
Reactant: CI
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)N(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1nc(C)c(S(=O)(=O)N(C)C)s1
Reaction time: 16 h
Yield: 81.6 %

Procedure:
6.0 g of sodium hydride (60% dispersion in mineral oil, 0.151 mol) were added dropwise at 0° C. to a solution of 36.2 g (0.137 mol) of N-{5-[(dimethylamino)-sulphonyl]-4-methyl-1,3-thiazol-2-yl}acetamide in dimethylformamide. Then 21.4 g (0.151 mol) of methyl iodide were added dropwise from a syringe. After TLC showed complete conversion, the mixture was quenched by adding a saturated ammonium chloride solution. The mixture was evaporated to dryness, and the residue was taken up with water, stirred for 16 h and filtered off. After the residue had been dried in vacuo it was further purified by chromotography on silica gel with toluene/ethyl acetate (15-66% ethyl acetate) as mobile phase. 31.0 g of a white powder were obtained (Rf=0.43 (toluene/ethyl acetate=1/2), yield 74%).
Reaction SMILES: [CH:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]([CH3:26])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]([CH3:26])([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCO)cc1)Oc1ccc(C(C)C)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]-2-methylpropionate (0.66 g), which is the product of Reference example 9(d), triethylamine (0.36 ml) and methanesulfonyl chloride (0.15 ml) and the reaction mixture was treated to afford the desired compound (0.64 g) as a syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH-].[K+].Cl>O.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Yield: 59.9 %

Procedure:
To 22.3 g (0.1 mol) 5-benzyloxyindole in 110 ml (1.0 mol) 1-bromo-4-fluorobenzene were added 28 g (0.5 mol) powdered potassium hydroxide and 6.4 g (0.1 mol) Cu as powder. The suspension was heated to reflux for 2 h. At RT, ether and water were added, the mixture was acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with a gradient hexane-hexane/EtOAc 19:1-9:1 yielded 19 g (60%) 5-Benzyloxy-1-(4-fluoro-phenyl)-1H-indole as colorless solid, MS: 318 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:29][NH2:30]>O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:30][CH3:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: CN
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccc(F)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(700 mg, 1.7 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) and the reaction mixture was refluxed at 180° C. for 15 hours in the pressure tube. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:1) to obtain 440 mg of desired compound as solid in 64% of yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,4,6-trichloropyrimidine (5.5 g, 30 mmol) in tetrahydrofuran (15 mL) was added dropwise to a solution of aniline (2.8 mL, 1 equivalent) in tetrahydrofuran (25 mL). N,N-diisopropylethylamine (5.2 mL) was added and the solution was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with 3% ethyl acetate in hexane, followed by 15% ethyl acetate in hexane. The eluent was removed, giving 4,6-dichloro-N-phenyl-2-pyrimidinamine (1.11 g, 4.6 mmol, 15%, Rf=0.4 in 3% ethyl acetate in hexane).