Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.O>[NH2:24][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(C(=O)O)cc(NCc2ccccc2)c1-c1ccccc1

Procedure:
To a stirred solution of 3-benzylamino-5-nitro-4-phenylbenzoic acid (3.0 g) in a mixture of pyridine (15 ml) and water (15 ml), sodium dithionite (6.0 g) is added in portions during about 15 minutes. The mixture is heated on a steam bath for about 30 minutes, and is then evaporated in vacuo. The residue is treated with cold 1 N acetic acid (about 50 ml) and after cooling, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization twice from aqueous ethanol, 5-amino-3-benzylamino-4-phenylbenzoic acid is obtained with a melting point of 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH3:11].CS(O)(=O)=O.[CH2:23]([SH:26])[CH2:24][SH:25].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH3:11])[S:26][CH2:23][CH2:24][S:25]1
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)n1ccnc1
Reactant: SCCS
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(n1ccnc1)C1(c2ccc(Cl)cc2Cl)SCCS1

Procedure:
A mixture of 6 parts of 1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)-1-propanone and 30 parts of methanesulfonic acid was stirred till all solid entered solution. After cooling, 5.5 parts of 1,2-ethanedithiol were added while nitrogen gas was introduced. The whole was stirred overnight at room temperature. The reaction mixture was diluted with trichloromethane till a volume of 150 parts. This solution was added dropwise to a vigorously stirred solution of potassium carbonate in water. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was converted into the nitrate salt in 2-propanol. 2,2'-Oxybispropane was added till turbid and the formed salt was allowed to crystallize. It was filtered off and dried, yielding 6 parts of 2-(2,4-dichlorophenyl)-2-[1-(1H-imidazol-1-yl)ethyl]-1,3-dithiolane; mp. 141.9° C. (compound 29).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].C([CH2:19][CH2:20][NH:21][C:22]1C=CC(C=O)=C[CH:23]=1)C1C=CC=CC=1>>[CH2:22]([N:21]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:10]=[C:20]1[CH3:19])[CH3:23]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=Cc1ccc(NCCCc2ccccc2)cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21
Yield: 86.1 %

Procedure:
Following a procedure similar to that described in Example 4A but employing 6.5 g. of 81.9% sodium p-toluenesulfinate, 6.3 g. of 95% 4-(benzylethylamino)benzaldehyde and 3.8 g. of 86.1% 1-ethyl-2-methyl-1H-indole, there was obtained 15.3 g. of 3-{[4-benzylethylamino)phenyl](4-methylphenylsulfonyl)methyl}-1-ethyl-2-methyl-1H-indole as a gray tar-like product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C.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>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:8][C:9]=2[CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)C)CC1

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropylphenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 mmol) in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 95° C. for 5d. The title compound, 200.0 mg (99%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Clc1cccc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1cccc(Cl)c1

Procedure:
The title compound, light brown solid, m.p. 99° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Yield: 68.2 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-methoxyphenyl isocyanate (1.31 mL, 9.51 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 1.85 g of the title compound as a solid. mp 238-240° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 5 °C

Procedure:
To a flask were added 2 g benzimidazole, 3.5 g potassium carbonate, 20 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.2 g Benzyl chloride were added and the mixture was heated to 5° C. for 16 hrs. The reaction was quenched with 40 ml water and 7 ml 3M hydrochloric acid and cooled to 5 C. The product was filtered and washed with water. The product was recrystallized by dissolving in 10 ml 2-propanol at reflux, hot filtered and 30 ml hexane were added. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 1.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH:49]([N:62]1[CH2:67][CH2:66][N:65]([CH2:68][CH2:69]O)[CH2:64][CH2:63]1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1(C)C=CC=CC=1>[CH3:24][C:6]1[NH:7][C:8]([CH3:23])=[C:9]([C:20]([O:22][CH2:69][CH2:68][N:65]2[CH2:64][CH2:63][N:62]([CH:49]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:67][CH2:66]2)=[O:21])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Temperature: 72.5 °C
Yield: 54.4 %

Procedure:
To a suspension of 2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid monomethyl ester (5 gm), dicyclohexyl carbodiimide (3.08 gm) and dimethylamino pyridine (0.25 gm) in toluene (30 ml) at room temperature was added 2-(4-benzhydryl piperazine-1-yl)ethanol (7.5 gm). Reaction mass was then heated to 70-75° C. for 2 hours. Reaction mass was then cooled to room temperature and filtered. Toluene layer was concentrated under vacuum to get manidipine base (5 gm).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:43]=[CH:44][CH:45]=1)[O:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][C@H:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[C@H:25]([CH3:37])[CH2:24]3)=[CH:19][CH:18]=2)[C:13]([C:38](=[O:40])[NH2:39])=[N:12][C:11]=1[CH2:41][CH3:42])(=[O:4])[CH:2]=[CH2:3].O1CCOCC1.[ClH:52]>O1CCCC1>[ClH:52].[ClH:52].[ClH:52].[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:43]=[CH:44][CH:45]=1)[O:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:37])[CH2:24]3)=[CH:19][CH:18]=2)[C:13]([C:38]([NH2:39])=[O:40])=[N:12][C:11]=1[CH2:41][CH3:42])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C4)cc3)c(C(N)=O)nc2CC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)c(C(N)=O)nc2CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (2R,6S)-4-[4-({6-[3-(acryloylamino)phenoxy]-3-carbamoyl-5-ethylpyrazin-2-yl}amino)phenyl]-2,6-dimethylpiperazine-1-carboxylate (175 mg) and tetrahydrofuran (3 mL) was added a 4 M hydrogen chloride dioxane solution (3 mL), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the obtained residue was washed with ethyl acetate and then dried at room temperature to obtain 5-[3-(acryloylamino)phenoxy]-3-({4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]phenyl}amino)-6-ethylpyrazine-2-carboxamide trihydrochloride (157 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:12]([CH3:14])[CH3:13])[C:6]=1[C:7](OCC)=[O:8].[CH:15]([NH2:17])=O>>[OH:8][C:7]1[C:6]2[C:5]([CH:12]([CH3:14])[CH3:13])=[CH:4][S:3][C:2]=2[N:1]=[CH:15][N:17]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(C(C)C)csc1N
Product: CC(C)c1csc2ncnc(O)c12

Procedure:
Using ethyl 2-amino-4-isopropylthiophene-3-carboxylate (800 mg, 3.8 mmol) and formamide (5 ml), a similar procedure to a) in Production Example 208 was carried out to obtain 4-hydroxy-5-isopropylthieno[2,3-d]pyrimidine (330 mg, 1.7 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1S[CH:9]=[CH:10][CH:11]=1)[OH:6].CN[CH2:14][CH2:15]C(C1SC=CC=1)=O>>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:15]=[CH:14][CH:9]=[CH:10][CH:11]=1)[OH:6]
Reactant: CNCC[C@H](O)c1cccs1
Reactant: CNCCC(=O)c1cccs1
Product: CNCC[C@H](O)c1ccccc1

Procedure:
In particular, it opens up the possibility of obtaining enantiomerically pure or enantiomerically enriched (S)-3-methylamino-1-(2-thienyl)-1-propanol in a simple manner starting from 3-methylamino-1-(2-thienyl)-1-propanone. Likewise, enantiomerically pure or enantiomerically enriched (S)-3-methylamino-1-phenyl-1-propanol can be obtained in a simple manner starting from 3-methylamino-1-phenyl-1-propanone.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([CH:12]([OH:14])[CH3:13])=[C:10]([Cl:15])[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([Cl:15])[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:22][CH:23]=1
Reactant: CC(O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
3.7 g of 1-[3-(4-bromobenzyl)-5-chloro-2-phenyl-3H-imidazol-4-yl]ethanol is dissolved in 20 ml of acetic acid and slowly treated at 15° C. with a solution of 15.6 g of (NH4)2Ce(NO3)6 in 30 ml of water. The mixture is stirred at 10° C. for 30 minutes, then allowed to warm to RT. It is diluted with 200 ml of water and adjusted to pH=5 using NaHCO3, and the product is filtered off with suction. Chromatography once each with DIP and MTB yields 2.0 g of a colorless oil.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.Cl.[Na]>O1CCCC1>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: CCOC1=CCc2cccc(N)c2C1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: Nc1cccc2c1CC(=O)CC2
Temperature: 40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (1.07 g, 5.65 mmol) in tetrahydrofuran (30 mL) was added solution of aqueous 2N HCl (10 mL), and stirred at 40° C. for 1 hour. The mixture was neutralized with addition of sodium bicorbonate, and the product was extracted with ethylacetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.71 g; 78% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:9][CH2:8]2)[CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: Cc1cnn(C2(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnn(C2(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 220.8 %

Procedure:
Into a 100 mL pear shaped flask containing tert-butyl 1-(4-methyl-1H-pyrazol-1-yl)cyclopropanecarboxylate (218 mg, 0.981 mmol) were added dichloromethane (5 mL) and trifluoroacetic acid (0.2 mL, 3 mmol). The clear solution was stirred at room temperature for 30 minutes after which another 0.3 mL of trifluoroacetic acid were added. The mixture was stirred at room temperature for 45 minutes and another 0.3 mL of trifluoroacetic acid were added. The mixture was stirred at room temperature for 18 h. The solvent and excess of trifluoroacetic acid were removed under reduced pressure to afford the title compound (360 mg). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.78 (m, 2H), 2.02 (m, 2H), 2.17 (s, 3H), 7.54 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:10][C:11]1[N:12]=[CH:13][C:14]([C:15]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(Br)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
To a solution of 1H-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol) in dichloromethane (50 mL) was added 6-bromo-nicotinoyl chloride (86, 2.6 g, 0.012 mol) at −10° C. After the solution turned clear, aluminum trichloride (10.2 g, 0.0765 mol) was added in one portion with vigorous stirring. The reaction mixture was stirred at −10° C. for 30 minutes, then was allowed to warm to room temperature and stirred at room temperature overnight. The reaction was quenched with ice water and neutralized with sodium bicarbonate. The solution was extracted with dichloromethane, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a white solid (87, 0.35 g, 11%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=[CH:25][CH:26]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1470 mg, 4.62 mmol) in acetonitrile (10 mL) was added tert-butyl (3-hydroxyphenyl)carbamate (966 mg, 4.62 mmol) and K2CO3 (1280 mg, 9.24 mmol) and the mixture heated at 80° C. with stirring overnight. The reaction was then cooled to rt, EtOAc (20 mL) added, washed with water (50 mL), the aqueous layer extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a light oil. Upon standing, the light oil solidified to give the title compound (2052 mg, 90% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38-9.83 (m, 1H) 7.73 (d, J=3.78 Hz, 1H) 7.41-7.46 (m, 2H) 7.51 (s, 1H) 6.97 (dt, J=5.98, 2.68 Hz, 1H) 6.58 (d, J=3.78 Hz, 1H) 5.64 (s, 2H) 3.54-3.67 (m, 2H) 1.54 (s, 9H) 0.91-0.96 (m, 2H) 0.00 (s, 9H). LCMS (ESI, pos): m/z (ESI+) for C23H31ClN4O4Si 491.20 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[CH:6][CH:7]=[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=12.C(N(C(C)C)CC)(C)C.[CH2:27]([OH:30])[CH2:28][OH:29]>>[CH3:15][O:14][C:12]1[C:11]([O:16][CH3:17])=[CH:10][C:9]2[CH:3]([CH2:2][O:29][CH2:28][CH2:27][OH:30])[O:4][CH2:5][CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: COc1cc2c(cc1OC)=C(CBr)OC=CC=2
Reactant: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)C(COCCO)OCCC2
Yield: 89 %

Procedure:
A mixture of 3.67 g (12.2 mmoles) of 1-bromomethyl-7,8-dimethoxy-2-benzoxepin, 2.12 ml (12.2 mmoles) of diisopropylethylamine, and 15 ml of ethylene glycol is heated at 100° for 7 hours. The reaction mixture is then cooled and extracted with methylene chloride, then with water and finally with brine. The organic layer is filtered through Na2SO4, taken to dryness, and chromatographed on silica gel to give 3.06 g (89%) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol: mass spectrum: M+ (m/e=282).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][CH2:14]2.[Cl-].[NH4+]>C(OCC)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:16][CH2:15][CH2:14]2
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC=C2c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of phenylmagnesium bromide in diethyl ether (3.0 M, 23 mL, 69 mmol) was added dropwise to a solution of 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one 27 (10.0 g, 56.7 mmol) in diethyl ether (100 mL) at room temperature. The reaction mixture was heated at reflux for 1.5 h. An additional portion of phenylmagnesium bromide solution (10 mL, 60 mmol) was added to the cooled reaction mixture, and the resultant mixture was heated at reflux for an additional 2.5 h. The cooled mixture was poured into a saturated solution of ammonium chloride (200 mL), and stirred for 15 min. The organic layer was separated, washed with a saturated solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the resultant oil was treated with a solution of sulfuric acid (8 mL) in acetic acid (30 mL) at room temperature for 1.5 h. Ice water (300 mL) was added to the solution, and the product was extracted into dichloromethane (200 mL), washed with water, and a saturated aqueous solution of sodium bicarbonate, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using ethyl acetate 0 to 3% in hexanes as the eluent, to give the 6-methoxy-1-phenyl-3,4-dihydronaphthalene 28 in two crops 4.0 g (29%) and an impure fraction 5.02 g (37%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[S:33][C:34]([Cl:38])=[C:35]([NH2:37])[CH:36]=1)(=[O:31])=[O:30])([CH3:27])[CH3:26]>>[Cl:38][C:34]1[S:33][C:32]([S:29](=[O:31])(=[O:30])[NH:28][C:25]([CH3:26])([CH3:27])[CH2:24][OH:23])=[CH:36][C:35]=1[NH:37][C:20]([C:19]1[CH:18]=[N:17][N:11]2[C:12]([CH:14]3[CH2:16][CH2:15]3)=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][C:10]=12)=[O:21]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Pale-yellow solid. (ISN) 580.0 [(M−H)−]; mp 238-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH:18](C#N)[C:19]([O:21]CC)=O)([C:16]#[N:17])[C:7]1=[O:26].Br.C(O)(=[O:34])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]2([CH2:18][C:19](=[O:21])[NH:17][C:16]2=[O:34])[C:7]1=[O:26]
Reactant: CCOC(=O)C(C#N)C1(C#N)C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccc(F)cc21
Reactant: CC(=O)O
Agent: Br
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(F)cc12

Procedure:
A solution of ethyl 2-[1-(3,4-dichlorobenzyl)-3-cyano-5-fluoro-2-oxo-3-indolinyl]-2-cyanoacetate (E) (2.0 g.) in 48% w/v hydrogen bromide in acetic acid (25 ml.) was heated under reflux for 3 hours. The solution was evaporated to half volume and poured into water (20 ml.). The mixture was extracted with ethyl acetate (2×50 ml.). The combined extracts were washed with water (2×50 ml.), brine (50 ml.), dried (MgSO4) and evaporated. The residual solid was recrystallised from 2-propanol/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-5'-fluoro-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.49 g.), m.p. 253°-254° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:30]=[C:29]([NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Nc1nc(Cl)nc2ccccc12
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)nc2ccccc12

Procedure:
EXAMPLE 81 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-quinazolin-4-yl-amine (2-chloro-quinazolin-4-ylamine was prepared from 2,4-dichloroquinazoline and ammonia in THF at room temperature; N. B. Chapman, G. M. Gibson, F. G. Mann, J. Chem. Soc., 1947, 890–899): MS (m+1)=426.