Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.Cl.[OH:37][CH:38]1[CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C.C(Cl)Cl>>[F:32][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:15]2[C:14]([CH3:34])=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][N:9]([C@H:7]([CH3:8])[CH2:6][N:40]2[CH2:41][CH:38]([OH:37])[CH2:39]2)[C:10]3=[O:35])=[O:33])[CH:27]=[CH:26][C:25]=1[C:28]([F:31])([F:29])[F:30]
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: OC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n([C@H](C)CN3CC(O)C3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1

Procedure:
A solution of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.2 mmol), 3-hydroxyazetidine hydrochloride (120 mg, 1.1 mmol), triethylamine (200 mg, 2 mmol) and methylene chloride (1 mL, 20 mmol) was stirred at room temperature overnight. The volatiles were removed and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: C(N(CCCC)CCCC)CCC.Cl[CH2:15][Si:16]([CH3:19])([Cl:18])[Cl:17].[Cl:20][SiH:21]([Cl:23])[Cl:22]>>[Cl:20][Si:21]([Cl:23])([Cl:22])[CH2:15][Si:16]([Cl:18])([Cl:17])[CH3:19]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](Cl)(Cl)CCl
Solvent: CCCCN(CCCC)CCCC
Product: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 30.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.115 g (0.62 mmol) of tri-n-butylamine, 1.0 g (6.2 mmol) of (chloromethyl)methyldichlorosilane, and 4.18 g (30.9 mmol) of trichlorosilane were reacted at 200° C. for 11 hrs. The resulting mixture was distilled to give 0.50 g of 1,1,1,3,3-pentachloro-1,3-disilabutane (yield; 6%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-methylpiperidine (180 mg, 1.813 mmol) was added to the 3-(chlorosulfonyl)benzoic acid (200 mg, 0.906 mmol) in presence of Potassiumcarbonate (251 mg, 1.813 mmol) in THF (Volume: 5 ml) at room temperature and the reaction mixture was stirred for 12 h at room temperature. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography (3% CH3OH/CH2Cl2) afforded the title compound as a solid. 1H NMR (CD3OD, 400 MHz): δ 8.32 (m, 1H), 8.27 (m, 1H), 7.96 (m, 1H), 7.72 (t, 1H, J=8.0 Hz), 3.72 (m, 2H), 2.27 (m, 2H), 1.68 (m, 2H), 1.29 (m, 1H), 1.21 (m, 2H), 0.88 (d, 3H, J=6.4 Hz). ESI-MS: 284.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:41])[NH:39][CH3:40])[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:42][CH3:43])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].I[CH3:53]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:41])[N:39]([CH3:53])[CH3:40])[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:42][CH3:43])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8]
Reactant: CI
Reactant: CNC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccnc(C(=O)N(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of amide 158 (125 mg, 0.175 mmol) in THF (5 mL) is treated with sodium hydride (11 mg, 0.26 mmol, 60% dispersion in mineral oil) at 0° C. After warming to RT and stirring 0.5 h, iodomethane (0.13 mL, 0.26 mmol, 2 M solution in TBME) is added via syringe and the reaction stirred 1 h. Analysis by LC/MS at this juncture revealed the reaction is only 75% complete. Hence more sodium hydride (11 mg, 0.26 mmol, 60% dispersion in mineral oil) is added, followed after 0.5 h by iodomethane (0.13 mL, 0.26 mmol, 2 M solution in TBME). After a further hour at RT, the reaction is diluted with water (10 mL) and extracted into EtOAc (3×20 mL). The combined EtOAc phases are dried (Na2SO4) and the solvent removed in vacuo. The title compound is obtained after chromatography (gradient elution—50-80% EtOAc in heptane with 0.5% triethylamine).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(C)=O)cc1

Procedure:
1.0 g of cis-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methyl-benzo[c][1,6]naphthyridine (produced as in Example 5) is heated to 60° in a mixture of 2 cc of pyridine and 2 cc of acetic anhydride for 2 hours. The reaction mixture is then evaporated to dryness in a vacuum and the residue is crystallized from acetone. M.P. 173°-175°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]([OH:15])[CH3:14])[S:11][CH:12]=2)[CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([C:13](=[O:15])[CH3:14])[S:11][CH:12]=2)[CH:3]=1
Reactant: CC(O)c1cc(-c2cc(Cl)ccn2)cs1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 3 h

Procedure:
To a solution of 1-[4-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-ethanol (100 mg, 0.42 mmol) in dichloromethane (3 mL) was added PCC (111 mg, 0.5 mmol). The resulting mixture was stirred for 3 hours and then passed through Celite®. The filtrated was washed with water and the organic layer was concentrated. The resulting residue was purified by silica gel column to yield 1-[4-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-ethanone
Reaction SMILES: [N:1]1([C:7]([NH:9][C@@H:10]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([C@H:40]([CH2:45][OH:46])[CH2:41][CH2:42][CH2:43][NH2:44])[CH2:36][CH:37]([CH3:39])[CH3:38])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:40]([CH2:45][OH:46])[CH2:41][CH2:42][CH2:43][NH:44][C:11]([C@@H:10]([NH:9][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)=[O:12])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid and amine intermediate VII. The final product was obtained in 11% yield.
Reaction SMILES: [Mg].Cl[Si:3]([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Cl[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[Si:3]([CH3:6])([CH3:5])[CH3:4])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C(F)(F)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(F)(F)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
According to the above-described scheme, magnesium (243 mg, 10.0 mmol), chlorotrimethylsilane (Me3SiCl; 2.17 g, 20.0 mmol) and DMF (15 mL) were put into a two-neck reaction tube under nitrogen atmosphere. Ethyl chlorodifluoroacetate (Compound 3; 793 mg, 624 μL, 5.0 mmol) was added thereto with the reaction container being cooled in water bath, and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with diethyl ether and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Diethyl ether was distilled away under reduced pressure, and by carrying out the production by silica gel column chromatography, difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a) was obtained with a yield of 43%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:35])[C:28]([OH:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoate (25 mg, 0.049 mmol) in DCM (1 ml) was added TFA (250 μl). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified via preparative TLC (5% MeOH/DCM) to give 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoic acid (0.0174 g, 0.0382 mmol, 78%). 1H NMR (400 MHz, CDCl3): 8.04 (bs, N—H), 7.96 (s, 1H), 7.64-7.71 (m, 3H), 7.61 (s, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.6, 2.2H; 1H), 7.08 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.5 Hz, 1H), 3.74 (q, J=7.4 Hz, 1H), 1.53 (d, J=6.9 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CCCCCC(CCCN)OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCC(CCCNS(C)(=O)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred, ice cold solution of 4-(2-tetrahydropyranyloxy)nonylamine (7.29 g., 0.03 mole) in pyridine (40 ml.) is added methanesulfonylchloride (3.42 g., 0.03 mole) at such a rate as to maintain the reaction temperature at 5°-10° C. The reaction is then allowed to stand at room temperature for six hours, poured into ice water (200 ml.) and extracted with ether (2× 100 ml.). The ether is washed with ice cold 5% hydrochloric acid (2× 20 ml.), with brine (2× 25 ml.), and then dried over sodium sulfate. Evaporation in vacuo affords N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamide as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH2:41][CH3:42])=[CH:39][N:38]=[C:37]([CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH2:41][CH3:42])=[CH:39][N:38]=[C:37]([CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (260 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:14]([Cl:28])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH:25]=2)=[C:14]([Cl:28])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(=O)c3ccc(Cl)cc3)c2)c(Cl)c1
Temperature: 60 °C
Yield: 36 %

Procedure:
A mixture of {[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester (7.25 g, 0.016 mol) and 4-chlorobenzoic acid (5.13 g, 0.03 mol) in Eaton's reagent (25 mL) was heated at 60° C. for 16 h. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethylacetate 90:10) to afford pure ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-ethoxycarbonyl-amino)-acetic acid ethyl ester. (3.36 g, 36% yield)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:25])[C:23]#[CH:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:25][CH2:22][C:23]#[CH:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C#CCN
Product: C#CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Prop-2-ynylamine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-prop-2-ynyl-amine as off-white semisolid, MS: 401 (MH+, 1Br).
Reaction SMILES: [O:1]1C[CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH:2]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N+:16]([O-:18])=[O:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)n1ccnc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
To a solution of N-(2,3-epoxypropyl)phthalimide (1) (Fluka, 25.0 g, 0.123 mol) in ethanol (200 mL), 2-nitroimidazole (2) (Nippon Ghosei, 14.5 g, 0.128 mol) and potassium carbonate (1.5 g) were added, and the reaction mixture was heated under reflux for 8 hrs. The reaction mixture was cooled and the yellow solid obtained was filtered and washed with ethanol (2×75 mL). The precipitate was transferred to a one liter beaker and water was added (500 mL). The mixture was stirred for 15 min. The yellow precipitate was filtered and the solid was washed with water (3×250 mL). 2-[2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3) was obtained and dried under vacuum. Yield 32.8 g (85%). The product was pure by proton NMR and HPLC, and was used in the next step without further purification. A portion (˜2 g) of the solid was recrystallized from methanol. The melting point was 213-214° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.O>C1(C)C(C)=CC=CC=1>[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(O)c2ccccc2)cc1
Reactant: ClCCN1CCN(CC=Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C(OCCN2CCN(CC=Cc3ccccc3)CC2)c2ccccc2)cc1

Procedure:
2 g of 60% sodium hydride in paraffin oil were added to a solution of 10 g (0.05 mol) of 4-methylbenzhydrol in 100 ml of anhydrous xylene. The reaction mixture was refluxed for half an hour and then 12.7 g (0.05 mol) of 1-(2-chloroethyl)-4-(3-phenyl-2-propenyl)piperazine (German pat.appl.2.431.178) in 50 ml of xylene were added dropwise. The reaction mixture was refluxed for another three hours and then cooled and poured into water. The organic layer was separated off, washed with water and concentrated. The residue was purified by column chromatography (Silicagel) with chloroform/ethylacetate/methanol/ammonia (25:25:1:0.5) as the eluent which yielded 1-[2-[(4-Methylphenyl)phenylmethoxy]ethyl]-4-(3-phenyl-2-propenyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 74 %

Procedure:
A solution of 9.3 g of 6-methoxy-1-indanone, 11.8 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 9.2 g (74%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1)([CH3:3])[CH3:2].[Na+].Cl[CH2:14][C:15]([O-:17])=[O:16].[OH-].[K+]>O>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[O:11][CH2:14][C:15]([OH:17])=[O:16])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(C(C)C)c1
Reactant: O=C([O-])CCl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCC(=O)O)cc(C(C)C)c1
Yield: 62.9 %

Procedure:
3-Isopropyl-5-methylphenol (44.0 g, 0.29 mol) and chloroacetic acid sodium salt (35.0 g, 0.3 mol) was dissolved in 180 mL of H2O, and then KOH (86%, 20 g, 0.3 mol) was added slowly. The reaction mixture was refluxed overnight and thereafter concentrated by distillation. After cooling, the mixture was acidified to pH 1, and then extracted with EtOAc. The organic layer was washed H2O, dried over MgSO4, and concentrated. The solid was recrystalized in 5% isopropanol in hexane to give pure 3-isopropyl-5-methylphenoxyacetic acid (38 g, 63%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]1[C:17]([F:18])=[C:16]([N:19](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[C:5]1[C:17]([F:18])=[C:16]([NH2:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(Cc2ccccc2)Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCN(C)C(=O)c1cc(N)c(F)c(C(=O)OCC)c1

Procedure:
Dissolve 5-dibenzylamino-6-fluoro-N-methyl-N-propyl-isophthalamic acid ethyl ester (275 mg, 0.595 mmol) in ethanol (6 mL). Add 10% Pd/C to the solution (50 mg). Stir the black slurry under a balloon containing hydrogen gas for 2.5 days. Filter the slurry through a pad of filtering agent and wash with ethanol. Concentrate the filtrate to give the title compound as a crude product.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][CH2:23][C:24]([CH3:26])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:26][C:24]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:23]=1[CH2:22][C:21]([O:28][CH3:29])=[O:27]
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Yield: 65.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone (0.228 g; 0.7 mmol), methyl levulinate (0.099 mL; 0.77 mmol), chlorotrimethylsilane (0.357 mL; 2.8 mmol) in DMF (2.8 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.194 g (66%) of the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M54) (0.36 g, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (182 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2>C(O)C>[N:29]1[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:7][C:6]=3[CH:19]=2)=[C:22]2[C:26]([N:25]=[CH:24][NH:23]2)=[N:27][CH:28]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Solvent: CCO
Product: O=C(Nc1nc2cc(Nc3ncnc4nc[nH]c34)ccc2s1)c1ccccc1

Procedure:
N-[5-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and 6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80° C. for 4 h. The resulting precipitate was separated by filtration and washed with ethanol (68 mg, 0.174 mmol, 94%). LC/ESI-MS: m/z=388 [M+H]+; m/z=386 [M−H]−; Rt=3.13 min.