Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CN=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.Cl[C:34]1[CH:39]=[C:38]([N:40](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:37]2[N:57]=[CH:58][C:59](I)=[C:36]2[N:35]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:57]1[N:37]2[C:38]([NH2:40])=[CH:39][CH:34]=[N:35][C:36]2=[CH:59][CH:58]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccnc2ccnn12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.38 mmol, 675 mg), K3PO4 (5.96 mmol, 1264 mg), and PdCl2(dppf).CH2Cl2 (0.20 mmol, 162 mg) were added to a solution of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (1.98 mmol, 1101 mg) in dioxane (18 mL) and H2O (3 mL). The resulting solution was stirred at 70° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2 trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine: LCMS tR=3.36 Min (5 min run, UV254nm). Mass calculated for, M+ 581.2, observed LC/MS m/z 582.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:6]=1[N:13](S(C1C=CC(Cl)=CC=1)(=O)=O)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])C.[OH-].[Na+]>C(O)C>[Cl:12][C:7]1[C:6]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])=[C:5]([CH:10]=[C:9]([Cl:11])[CH:8]=1)[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)c1cc(Cl)cc(Cl)c1N(S(=O)(=O)c1ccc(Cl)cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cl)cc(Cl)c1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 69.8 %

Procedure:
A suspension of 27.0 g of 3,5-dichloro-2-[di-(4-chlorophenylsulfonyl)-amino]-benzoic acid ethyl ester, 139 ml of 2N sodium hydroxide solution and 140 ml of ethanol is boiled at reflux for 6 hours, the solid gradually dissolving. After the reaction mixture has cooled, the precipitated crystals are filtered off and dissolved in 400 ml of water. 400 ml of methanol are added, acidification with 2N hydrochloric acid is carried out, and the precipitated crystals are filtered off. 12.3 g of the title compound (m.p. 188°-190° C.) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([B:16]4[O:20]C(C)(C)C(C)(C)[O:17]4)=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.Cl.C(OCC)C>CC(C)=O.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([B:16]([OH:20])[OH:17])=[CH:12][N:11]3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)OC1(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: OB(O)c1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Yield: 199 %

Procedure:
3.60 g of 2-(4-chlorophenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine are dissolved in 112 ml of acetone and 56 ml of water; 101 ml of 1N hydrochloric acid are added thereto, dropwise and with stirring, and the mixture is stirred at ambient temperature for 24 h. The reaction mixture is then concentrated under reduced pressure. The solid obtained is titurated with diethyl ether and recovered by filtration, and then dried in an oven under reduced pressure at 60° C. 3.12 g of compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.[C:19]([C:21]1[N:22]=[C:23]([C:34]([O-])=[O:35])[N:24]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=1)#[N:20].[K+].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34]([C:23]2[N:24]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[C:21]([C:19]#[N:20])[N:22]=2)=[O:35])=[C:3]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[CH:4]=1)(=[O:11])[NH2:12]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: NC(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCC(N)=O)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a mixture of 3-(4-amino-3-cyclohex-1-enyl-phenyl)-propionamide (as prepared in the previous step, 85.0 mg, 0.378 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 117 mg, 0.383 mmol) and PyBroP (179 mg, 0.383 mmol) in 2.5 mL of DMF was added DIEA (182 μL, 1.04 mmol). After stirring at RT for 16 h, the mixture was treated with 30 mL of EtOAc and washed with H2O (2×10 mL), brine (10 mL) and dried (Na2SO4). The organic solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (0-2% MeOH/DCM) to give 156 mg (91%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C26H35N5O3Si, 494.3 (M+H). found 494.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1.C(O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2ccccc2F)cc1

Procedure:
26.5 g (0.11 mol) of methyl (2′-fluoro[1,1′-biphenyl]4-yl)acetate are introduced into 50 ml of ethanol and, at room temperature, a solution of 12.8 g (0.19 mol) of potassium hydroxide pellets in 25 ml of water is added. The mixture is then heated under reflux for 4 h. After cooling, the crude mixture is concentrated in vacuo, and the residue is dissolved in 100 ml of water and acidified with concentrated hydrochloric acid. The precipitate is filtered off and washed several times with water, and the solid is dried. Example VI is obtained in the form of white crystals.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=[C:9](C2N(C)N=NN=2)[CH:10]=[O:11])=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[C:33]([C:36]2[N:37]=[N:38][N:39]([CH3:41])[N:40]=2)[CH:34]=O)=[CH:28][CH:27]=1.C1(P(=CC=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)=[C:33]([C:36]2[N:37]=[N:38][N:39]([CH3:41])[N:40]=2)[CH:34]=[CH:9][CH:10]=[O:11])=[CH:43][CH:44]=1
Reactant: Cn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 90.5 %

Procedure:
The general procedure of Example 8 was repeated, except that the 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal utilized therein was replaced by 0.67 g (21.0 mmoles) of 3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenal [prepared in Example 7]. The reaction was carried out with 0.64 g (21.0 mmoles) of triphenylphosphoranylidene acetaldehyde to yield 0.66 g (90.5%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][O:16][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCO)c3ccccc32)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc32)c1
Yield: 62.8 %

Procedure:
A solution of 3-(2-Hydroxy-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester (0.41 g, 1.16 mmol), TsCl (0.23 g, 1.22 mmol), triethylamine (0.2 mL, 1.4 mmol) in dichloromethane (10 mL) was stirred at room temperature for 48 h. The solvent was removed under reduced pressure and the residue dissolved in EtOAc. The organic solution was washed with 10% KHSO4, dried over Na2SO4, and purified by silica gel chromatography (hexanes/EtOAc, 1/2) to give 0.37 g of 1-(3-methoxycarbonyl-phenyl)-3-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-indole-2-carboxylic acid methyl ester as a yellow oil (63% yield): 1H NMR (CDCl3, 300 MHz) δ 2.37 (s, 3H), 3.52 (t, J=7.24 Hz, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 4.34 (t, J=7.06, 2H), 7.00 (d, J=8.24 Hz, 1H), 7.17–7.31(m, 4H), 7.44 (d, J=8.02 Hz, 1H), 7.56–7.67(m, 4H), 7.93 (t, J=1.72 Hz, 1H); 8.13 (dt, J=7.82, 1.34 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][C:13](=O)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]([CH2:19][C:20]([NH2:22])=[S:21])#[N:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[SH:21][C:20]1[C:19]([C:17]#[N:18])=[C:13]([CH3:14])[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1
Reactant: COc1ccc(C(=O)CC(C)=O)cc1OC
Reactant: N#CCC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(C)c(C#N)c(S)n2)cc1OC
Yield: 98.4 %

Procedure:
5.0 g (22.5 mmol) 1-(3,4-dimethoxyphenyl)butane-1,3-dione, 2.9 g (29.2 mmol) cyanthioacetamide and 4.0 g (29.2 mmol) potassium carbonate are added by stirring to 170 ml acetone at room temperature for 21 h. Then, the solvent is removed and the residue is just dissolved in ethanol/water (1:1). Following acidification with glacial acetic acid, the resulting precipitate is sucked off, washed with some water, suck dried and dried in vacuo at 50° C. 6.34 g (98%) 2-mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridine-3-carbonitrile is obtained.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.CCN(CC)CC.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[CH2:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:4][C@@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:2]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in US Pat. Pub. No. 2012/0101280](50 g, 160 mmol) in CH2Cl2 (500 mL), and Et3N (51.7 g, 512 mmol) was cooled to 0° C. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with water, extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo to provide (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate as a light yellow oil which was used directly without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.O.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CN
Solvent: O
Product: CNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
2-Chloromethylbenzimidazole (3.00 g, 18.01 mmol) was dissolved in aqueous methylamine (50 mL, 40 wt % in H2O) at 10° C. under N2. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 4 hours. Water was added and the mixture extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by HPLC (gradient methanol/methylene chloride) to afford 0.650 g (22%) of pure product as a tan solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccccc1I
Temperature: 25 °C
Reaction time: 23 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 2-iodobenzoic acid (8.70 g, 35.1 mmol) and potassium carbonate (20.2 g, 176 mmol) in 100 mL of acetone was added benzyl bromide (5.00 g, 29.2 mmol). The mixture was stirred at room temperature for 23 hours and the solid was filtered off. The solid was rinsed with acetone (2×30 mL). The filtrate was concentrated in vacuo. The residue was dissolved in 200 mL of ether and washed with saturated sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). The ether layer was dried (magnesium sulfate), filtered and concentrated in vacuo to give 8.63 g (87%) of benzyl 2-iodobenzoate A.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([SH:11])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12]N(C)C=O.[H-].[Na+].IC>O>[CH3:12][S:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[N:10]=1
Reactant: Nc1ncnc2sc(S)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSc1nc2c(N)ncnc2s1
Reaction time: 4 h

Procedure:
To a stirred and cooled (below 25° C.) mixture of 13.9 parts of 7-aminothiazolo[5,4-d]pyrimidin-2-thiol and 180 parts of N,N-dimethylformamide were added portionwise 4.3 parts of a sodium hydride dispersion 50% while cooling. After stirring for 1 hour, 11.5 parts of iodomethane were added dropwise at a temperature below 25° C. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 5.9 parts of 2-(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (intermediate 46). From the filtrate, the aqueous layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding fraction of 3.9 parts of 2-(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (intermediate 46). Total yield: 9.8 parts (65.6%) of 2 -(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (intermediate 46).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:8]([N+:16]([O-:18])=[O:17])=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.[OH-].[Na+].CN(C)[CH:23]=[O:24]>>[CH:23]([C:12]1[C:11]2[C:15](=[C:7]([CH3:6])[C:8]([N+:16]([O-:18])=[O:17])=[CH:9][CH:10]=2)[NH:14][CH:13]=1)=[O:24]
Reactant: Cc1c([N+](=O)[O-])ccc2cc[nH]c12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c([N+](=O)[O-])ccc2c(C=O)c[nH]c12
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Phosphorus oxychloride (0.878 mL, 9.42 mmol) is added to a stirred solution of dimethylformamide (5 mL). A solution of 7-methyl-6-nitroindole (1.5 g, 8.56 mmol) in dimethylformamide (2 mL) is added dropwise at room temperature at a rate so as to keep the temperature of the reaction mixture below 35° C. The solidified mixture is heated to 35° C. and stirred for 30 minutes. The reaction mixture is allowed to cool to room temperature and is treated with 25 mL of 5 N aqueous sodium hydroxide solution. This addition produces an exothermic reaction. This reaction mixture is extracted with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude residue is recrystallized from ethyl alcohol to yield 1.3 g of 3-formyl-7-methyl-6-nitroindole as a yellow solid (74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[CH3:11][CH:12]([CH3:16])[CH2:13][CH2:14][NH2:15].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(O)c(Br)c1
Yield: 73.5 %

Procedure:
Combine 3-Bromo-4-hydroxy-benzaldehyde (1.5 g, 7.5 mmol) with 3-methylbutylamine (867 μL, 7.5 mmol), MeOH (25 mL) and molecular sieves 3A (5.8 g) and stir at room temperature overnight. Add NaBH4 (1.4 g, 37.3 mmol) and stir at room temperature for 2 hours. Filtrate over celite with MeOH and eliminate the solvent. Purify by SCX ion-exchange chromatography to afford the title compound (1.5 g, 75%). 1H-NMR (CD3OD, 300 MHz): 7.52 (d, 1H, J=2.0 Hz), 7.17 (dd, 1H, J=2.0 and 8.5 Hz), 6.87 (d, 1H, J=8.5 Hz), 3.80 (s, 2H), 2.79-2.74 (m, 2H), 1.76-1.63 (m, 1H), 1.54 (q, 2H, J=6.8 Hz), 0.99 (d, 6H, J=6.56 Hz). 13C-NMR (CD3OD, 300 MHz): 158.6, 134.9, 130.7, 128.6, 118.8, 112.7, 53.3, 47.9, 38.6, 27.8, 23.3.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:19][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(=O)cc(C)o1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)cc(C)s1
Temperature: 100 °C
Yield: 181.6 %

Procedure:
2,6-Dimethyl-4-pyranone (0.25 g, 2.0 mmol) in toluene (10 ml) was treated with Lawesson's reagent (0.22 g, 1.1 mmol) and heated at 100° C. for 3h. A further quantity of Lawesson's reagent (0.22 g, 1.1 mmol) was added and the mixture heated at 100° C. for 0.75h. The mixture was allowed to cool, then purified on silica gel 60 eluting with ethanol and dichloromethane (1:9) to give the title compound (0.28 g, 98%).
Reaction SMILES: [Cl:1]C1C=C(C=CC=1Cl)N.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22](=[O:23])[CH2:21][S:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].C1NCSC1=O.S(Cl)(Cl)=O>>[Cl:1][CH:21]1[S:20][CH2:19][N:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[C:22]1=[O:23]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CSCN1c1ccc(Cl)c(Cl)c1
Agent: O=C1CNCS1
Solvent: O=S(Cl)Cl
Product: O=C1C(Cl)SCN1c1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichloroaniline was converted to 3-(3,4-dichlorophenyl)-4-thiazolidinone as outlined in Example 1. This thiazolidinone, which had a melting point of 145°-146° C., was chlorinated with thionyl chloride to form 5-chloro-3-(3,4-dichlorophenyl)-4-thiazolidinone having a melting point of 100°-103° C. Recrystallization of this product from ethanol gave 3-(3,4-dichlorophenyl)-5-ethoxy-4-thiazolidinone which had a melting point of 61°-65° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:26][CH2:27][O:28][CH3:29])[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO.[Pd].[C]>[CH3:19][C:14]1([CH3:20])[CH2:13][CH:12]([N:21]([CH2:26][CH2:27][O:28][CH3:29])[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: COCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O

Procedure:
6 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-(2-methoxyethyl)methanesulfonamide were dissolved in 100 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. The crude product was crystallized using diisopropyl ether, 4.6 g, m.p. 115-117° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:6]([O:16][CH3:17])=[C:7]([CH:9]([O:13]CC)OCC)[CH:8]=1.C[Mg]Br.[O:25]1[CH2:29]CCC1.Cl.[O:31]1CCCC1>>[CH:18]1([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([CH:9]=[O:13])[C:6]=2[O:16][CH3:17])[C:29]([OH:25])=[O:31])[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(OCC)c1cc(Br)cc(C2CCC2)c1OC
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Product: COc1c(C=O)cc(C(=O)O)cc1C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To magnesium (106 mg), tetrahydrofuran (3.5 mL), 5-bromo-3-cyclobutyl-1-diethoxymethyl-2-methoxybenzene (1.33 g) and a 0.97M methylmagnesium bromide-tetrahydrofuran solution (1.32 mL) was added, and then the mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled to 0° C. and stirred under a carbon dioxide atmosphere for 15 hours, and then 2N hydrochloric acid (10 mL) was added and the mixture was stirred at mom temperature for 1 hour. The organic solvent was distilled off under reduced pressure and then extracted with diisopropylether. The organic layer was extracted with 1N sodium hydroxide added thereto, and then the aqueous layer was washed twice with diisopropylether. The aqueous layer was acidified with 4N hydrochloric acid added thereto, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (458 mg) as a brown solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][CH2:12][O:13][C:14]([CH3:16])=[O:15].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:16][C:14]([O:13][CH2:12][CH3:11])=[O:15])([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 106.8 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (40 mL, 40 mmol) was cooled to −70° C. under a nitrogen atmosphere. EtOAc (3.91 mL, 40 mmol) was slowly added dropwise thereto. The reaction mixture was stirred for 10 min at −70° C. stirred and a solution of 1-(tert-butyloxycarbonyl)-4-piperidone (7.34 g, 36.84 mmol, Lancaster, order number: 13361) in THF (16 mL) was slowly added dropwise thereto. After heating the reaction solution to 0° C., water (50 mL) was added and the reaction mixture repeatedly extracted with ether. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. 11.31 g of the desired product 4-ethoxycarbonylmethyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (A1) were obtained and further reacted without purification.