Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(Cl)=[O:28].N1C=CC=CC=1.[C:37]1([CH2:43][O:44][C:45]([NH:47][C@H:48]2[CH2:51][NH:50][C:49]2=[O:52])=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:37]1([CH2:43][O:44][C:45]([NH:47][C@H:48]2[CH2:51][N:50]([C:49]([N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:14][CH:13]=3)[CH2:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:26])=[O:52])[C:27]2=[O:28])=[O:46])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: O=C(CNc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CN(C(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)c1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Benzyl-N-(4-benzyloxyphenyl)glycinate (694 mg, 2.0 mmole) was dissolved in 6 ml of dry toluene and cooled to 0° C. A phosgene solution (2.9 ml, 12.5% in toluene) was added to the reaction mixture followed by the dropwise solution of pyridine (0.348 ml, 4.3 mmol) with rapid stirring. The reaction was stirred for 1.5 hours at 0° C. and then allowed to warm to room temperature. The precipitate of pyridinium hydrochloride was filtered under argon, and the volatiles were removed from the filtrate. This was dissolved in 4 ml of dry tetrahydrofuran and cooled to 0° C. To this solution was added (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (440 mg, 2.0 mmole) and 36 mg (0.3 mmole) of dimethylaminopyridine. Triethylamine (0.307 ml, 2.2 mmol) was then added dropwise, and the reaction mixture was allowed to warm to room temperature and stir overnight. The product was extracted with ethyl acetate from dilute aqueous hydrochloric acid. The combined organic extracts were dried with sodium sulfate and the volatiles removed. The residue was purified by flash chromatography on silica (LPS-1) (eluting with 1:1 ethyl acetate/hexane) to yield 465 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([S:41]C)=[C:4]([C:9]2[C:10]([CH:24](O)[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:13]=[CH:12]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[S:41][CH:24]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:30]=1)[C:10]1[C:9]2=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([O:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15]2
Reactant: CSc1c(F)cc(F)cc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1SC3c1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Dissolve methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-phenyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-yl ester (7.4 g, 12 mmol) in dry methylene chloride (200 mL) and purge with nitrogen. Add triethylamine (8.3 mL, 60 mmol) followed by methanesulfonyl chloride (4.6 mL, 60 mmol). After 30 minutes, pour reaction into water and extract with methylene chloride. Wash organic layer with water, dry over sodium sulfate, filter and concentrate. Purify over silica gel, eluting with 0 to 3% methanol in methylene chloride, to yield 5.2 g (74%) of the title compound. LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=3.34 min (100%); mass spectrum (ion spray): m/z=582.2 (M+H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:29][S:28](=[O:31])(=[O:30])[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:11]=3[N:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:32][OH:33]>CCO>[OH:33][N:32]=[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([N:12]2[C:11]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[S:28](=[O:30])(=[O:31])[CH2:29][C:10]=3[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[N:13]2)[CH:15]=1)[NH2:18]
Reactant: N#Cc1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Temperature: 85 °C
Yield: 46.5 %

Procedure:
To a solution of 3-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzonitrile (0.3 g, 0.69 mmol) in EtOH (20 mL) is added 50% aq. hydroxylamine solution (0.14 mL, 2.07 mmol). The reaction mass is heated to 85° C. for 12 h. The solvent is removed completely under reduced pressure to afford 150 mg (89%) of the title compound as a white solid. MS (ESI+): 468.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:16]([C:17](=[S:20])[NH:18][NH2:19])[N:15]=[C:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:19][NH:18][C:17]([N:16]1[N:15]=[C:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:13][C:12]1([CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[S:20])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Solvent: ClCCl
Product: CC(=O)NNC(=S)N1N=C(c2cc(F)ccc2F)SC1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide (0.016 g, 0.032 mmol) in dichloromethane (1 mL) was added acetic anhydride (0.032 g, 0.32 mmol). After stirring for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure and chromatographed (10:1 hexanes/ethyl acetate) to provide the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(Cl)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-chlorothiophene-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[CH:13]=2)[CH2:7][CH2:6]1)[C:2]#[CH:3].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=2)[CH:33]=1>>[ClH:30].[ClH:30].[ClH:30].[ClH:30].[CH2:1]([N:4]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)[CH:13]=2)[CH2:9][CH2:10]1)[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=2)[CH:33]=1)[C:2]#[CH:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C#CCNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Product: C#CCN(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Product: Cl

Procedure:
4-Propargylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (227 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (226 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a tetrahydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 4-chlorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([O-])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Na+].CN(C=O)C.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([Cl:28])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of sodium 5-(4-trifluoromethylphenyl)thiophene sulfonate (1.50 g) and DMF (498 mg) in thionyl chloride (7.5 ml) was stirred for 2 hours at 50° C. The mixture was concentrated and partitioned between AcOEt and 3% aqueous sodium bicarbonate. The organic layer was separated, washed with 3% aqueous NaHCO3 solution and brine, dried over sodium sulfate and evaporated in vacuo after filtration to give 1.39 g of 5-(4-trifluoromethylphenyl)thiophene-2-sulfonylchloride as a solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:21](=[O:40])[C:22]=1[CH2:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]2[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:25]=1[F:39])[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:21](=[O:40])[C:22]=1[CH2:23][C:24]1[C:25]([F:39])=[CH:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[NH:3][C:4](=[O:7])[O:5][N:38]=2)=[CH:28][C:29]=1[F:30])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1c(F)cc(-c2ccccc2C#N)cc1F
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1c(F)cc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogen carbonate (2.50 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (1.21 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.65 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.CC(O)=O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCc2ccc(O)cc2O1

Procedure:
A mixture of ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate (10 g, 41 mmol) in MeOH (20 ml) and AcOH (20 ml) was hydrogenated at 50 Psi for 4 days. Filtration and evaporation gave the title compound. Yield: 9.2 g. MS m/z (rel. intensity, 70 eV) 222 (M+, 44), 149 (bp), 148 (22), 147 (46), 121 (25).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18]O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C(Cl)(Cl)Cl>ClCCl>[Br:40][CH2:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(CC1CCCCC1)Nc1ccccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(CC1CCCCC1)Nc1ccccc1CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-cyclohexyl-N-[2-(2-hydroxyethyl)phenyl]acetamide (780 mg) in dichloromethane (20 mL) were added triphenylphosphine (938 mg) and carbon tetrabromide (1.12 g) at room teperature. The solution was stirred at room temperature for 1 hour. Chloroform was added and the solution was washed in turn with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=7:3) to give the title compound (450 mg).
Reaction SMILES: [Si](N[CH:19]([CH3:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C[N:29](C)[CH2:30][CH2:31]N(C)C.[Li]CCCC.CCCCCC.[S:47]1C=C[C:49]2[CH2:52][CH2:53][C:54](=O)[C:48]1=2>CCOCC.C1COCC1.Cl>[NH2:29][CH:30]([C:25]1[CH:24]=[C:23]([CH3:26])[CH:22]=[CH:21][C:20]=1[C:19]1[C:27]2[S:47][CH:48]=[CH:49][C:52]=2[CH2:53][CH:54]=1)[CH3:31]
Reactant: CN(C)CCN(C)C
Reactant: O=C1CCc2ccsc21
Reactant: Cc1ccc(C(C)N[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2=CCc3ccsc32)c(C(C)N)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of compound of Example 23 (3.7 g, 9.9 mmol) and N,N,N',N'-tetramethylethylenediamine (0.75 mL, 5.0 mmol) in dry ether (70 ml) was cooled to 0° C. and treated with a solution of n-BuLi (2.5M) in hexane (8.0 mL, 20.0 mmol). The mixture was stirred at 0° C. for 0.25 hour and then at room temperature for an additional 3 hours. At this point the mixture was cooled to -78° C. A solution of 4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (1.40 g, 10.1 mmol) in dry THF (15 ml) was then added dropwise and the resulting mixture was stirred at -78° to -60° C. over 1 hour. The reaction was quenched by addition of saturated NH4Cl solution and was allowed to warm to room temperature. The mixture was diluted with ether and H2O. The ether layer was separated and concentrated to leave an oil which was taken up in a mixture of 1N HCl (70 mL) and THF (105 mL). The resulting solution was stirred at room temperature overnight. Following removal of most of the THF in vacuo, the solution was extracted twice with ether. The extracts were set aside for later recovery of unreacted 4,5-dihydro-6H-cyclopenta[b]-thiophen-6-one while the aqueous layer was made basic by addition of solid NaOH and extracted twice again with ether. These extracts were combined, dried (Na2SO4) and concentrated in vacuo to leave an oil. This was placed under high vacuum and warmed to remove α,4-dimethyl-benzenemethanamine. Following flash chromatography on silica gel using EtOAc as eluant, the title compound was isolated as an oil (180 mg, 7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].C(OCC)C.O>CN(C=O)C>[CH3:14][N:15]([CH:17]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:16]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CN(C)C=Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 140 °C

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (5 g, 32 mmol) in DMF (32 ml) was added dimethylformamide dimethyl acetal (5.56 ml, 42 mmol) and the mixture warmed at 140° C. for 18 hours in Argon atmosphere. Then the solution was allowed to reach room temperature and diethyl ether (100 ml) and water (100 ml) was added. The organic layer was washed with water (2×100 ml) and brine (1×100 ml), dried (MgSO4) and solvent concentrated at reduced pressure, affording N,N-dimethyl-2-(4-fluoro-2-nitrophenyl)ethenylamine as a red solid. No further purification was necessary.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:12][N:11]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[O:2][CH3:1]
Reactant: COC1CCCCC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC1CCCCC1=NO
Temperature: 70 °C

Procedure:
A mixture of 2-methoxycyclohexanone (39.0 mmol), hydroxylamine hydrochloride (72 mmol), and sodium acetate (48.8 mmol) in ethanol and water was heated at 70° C. overnight. Ethanol was removed, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give 1-(hydroxyimino)-2-methoxycyclohexane.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[C:8]([CH3:27])=[CH:7][C:5]=2[N:6]=1.OS(O)(=O)=O.[CH3:33]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:19]([O:21][CH3:33])=[O:20])[C:8]([CH3:27])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Preparation of (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid from above in MeOH (25 mL) was added H2SO4 (200 μL). The reaction mixture was stirred at rt overnight. EtOAc (20 mL) and saturated NaHCO3 solution (50 mL) were added. The layers were separated, dried, filtered, and concentrated in vacuo. The crude mixture was a mixture of the desired (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate and (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate. t-Butyl acetate was added (20 mL) and perchloric acid (500 μL). The mixture was stirred at rt for 3 hr, where all (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate was converted to (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. EtOAc (10 mL) and saturated NaHCO3 solution (50 mL) were added. The layers were separated, dried, filtered, and concentrated in vacuo. LCMS-ESI+: calc'd for C21H23ClN2O3S: 419.1 and 421.1 (M+H+); found: 419.2 and 421.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([CH:20]=O)[C:9]3[C:14]([C:15]=2[Cl:19])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]([CH3:28])([CH2:26][OH:27])[CH2:24][OH:25]>>[ClH:19].[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([CH2:20][NH:22][C:23]([CH3:28])([CH2:26][OH:27])[CH2:24][OH:25])[C:9]3[C:14]([C:15]=2[Cl:19])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(Cl)c3ccccc3c(C=O)c2c1
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NCc1c2ccccc2c(Cl)c2ccc(C(C)(C)C)cc12
Product: Cl

Procedure:
Using the reductive amination procedure described in 1, 2-tert-butyl-10-chloro-9-anthracenecarbaldehyde (41B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((2-tert-butyl-10-chloro-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride.1/4H2O mp 249°-250° (dec), (EtoH/Et2O), (C, H, Cl, N).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][N:10]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(-c2n[nH]c3cc(Cl)ncc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
6-Chloro-3-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine (1 g, 4.04 mmol) was dissolved in DMF (20 mL) and cooled to 0° C. Sodium hydride (0.242 g, 6.06 mmol) was then added and the reaction mixture stirred for one hour. Trityl chloride (1.351 g, 4.85 mmol) was then added and the reaction mixture warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with water and stirred at 0° C. for one hour to promote perception. The solid was filtered and rinsed with water. The solid was diluted with DCM and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (2-30% EtOAc/isohexane) to give 6-chloro-3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.63 g, 3.33 mmol, 82%). MS ESI calc'd. For C31H21ClFN3 [M+1]+ 490, found 490.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the coupling procedure for Example 17 from 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 3-chlorophenyl boronic acid. A yellowish solid: mp 108-109° C.; 1H-NMR (DMSO-d6) δ 7.69 (t, 1H, J=1.7 Hz), 7.59 (d, 1H, J=7.8 Hz), 7.35-7.50 (m, 3H), 7.32 (dt, 1H, J=8.1, 1.1 Hz), 6.91 (s, 1H), 6.87 (d, 1H, J=8.4 Hz), 5.35 (m, 1H), 1.60 (s, 3H), 1.59 (s, 3H); MS (ESI) m/z 340 [M−H]−.