Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:14]#[N:15].[K+]>CCO.O>[C:14]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([CH3:1])[C:11]([OH:13])=[O:12])=[CH:4][CH:5]=1)#[N:15]
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC#N)cc1
Temperature: 80 °C

Procedure:
A suspension of 2-(4-bromomethyl)phenylpropionic acid (2.0 g, 8.2 mmol) and potassium cyanide (1.6 g, 24.7 mmol) in EtOH (10 mL) and water (2 mL) was heated at 80° C. in a sealed tube for 1 h. The mixture was cooled to room temperature, diluted with water (10 mL) and the EtOH was removed under reduced pressure. The remaining aqueous mixture was extracted once with EtOAc then acidified carefully with 2N HCl until pH˜3 is reached. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered, and concentrated to give 2-[4-(cyanomethyl)phenyl]propionic acid in ˜90% purity. This material was used directly in the next step. A mixture of 2-[4-(cyanomethyl)phenyl]propionic acid (1.4 g, 7.4 mmol) in MeOH (8 mL) and aqueous NaOH(SN, 8 mL, 40 mmol) was heated at 85° C. in a sealed tube for 1.5 h. The mixture was cooled to room temperature, the MeOH was removed under reduced pressure, and the remaining aqueous was extracted with once ether. The aqueous layer was acidified with 2N HCl until pH˜2 to generate a precipitate that was filtered and dried under vacuum to afford 2-[4-(carboxymethyl)phenyl]propionic acid (1.1 g, 71%) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br s, 1H), 7.15-7.22 (m, 4H), 3.61 (q, J=6.8 Hz, 1H), 3.50 (s, 2H), 1.30 (d, J=7.2 Hz, 3H); MS (Electrospray): m/z 163.1 (M-CO2H). To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethanamine bis-HCl (0.39 g, 1.3 mmol), 2-[4-(carboxymethyl)phenyl]propionic acid (0.35 g, 1.7 mmol), EDC (0.35 g, 1.8 mmol), and 1-hydroxy-7-azabenzotriazole (0.25 g, 1.8 mmol) in DMF (5 mL) was added diisopropylethylamine (1.2 mL, 6.7 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (20 mL) and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude oil that was purified by preparative reversed-phase HPLC to give 2-{4-[2-oxo-2-(((1R)-1-[5-(2,2,2-trifluoroethoxy)-pyridine-2-yl]ethyl)amino)ethyl]phenyl}propionic acid mono-TFA salt as a foam; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.6 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.49 (dd, J=2.8 and 8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.19 (s, 4H), 4.88-4.93 (m, 1H), 4.85 (q, J=8.8 Hz, 2H), 3.62 (q, J=7.2 Hz, 1H), 3.44 (s, 2H), 1.35 (d, J=8.0 Hz, 3H), 1.33 (d, J=7.6 Hz, 3H); MS (Electrospray): m/z 411.4 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2(C(OC)=O)[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[OH-].[K+].Cl.CO.[CH2:32]([OH:34])C.C1C[O:38]CC1>O>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[S:15][C:16]3[C:22]([C:32]([OH:34])=[O:38])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: CCO
Reactant: COC(=O)C1(c2ccc(OCC(C)C)c(C#N)c2)Nc2ccccc2S1
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)COc1ccc(-c2nc3cccc(C(=O)O)c3s2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methyl 2-(3-cyano-4-isobutyloxyphenyl)-1,3-benzothiazole-carboxylate (288 mg, 0.786 mmol) was dissolved in a mixed solvent (50 mL) of methanol/ethanol/THF (2/1/2), and, then a solution of potassium hydroxide (281 mg, 5 mmol) in water (10 mL) was added and stirred for one hour at room temperature. The mixture was made acidic by addition of aqueous 1M hydrochloric acid, and placed under reduced pressure to distill the solvent off. The residue was extracted with chloroform. The chloroform portion was then dried over anhydrous magnesium sulfate and placed under reduced pressure too distill the solvent off. The residual crystalline product was recrystallized from toluene, to give 230 mg (yield 83%) of the desired compound in the form of a white crystalline product.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:8][CH:9]=[C:10]2[CH2:14][NH:13][CH2:12][C:11]=12)=[O:6])[CH3:3].[CH:15]([N:18](CC)[CH:19]([CH3:21])C)([CH3:17])C.C[N:25](C)C=O>>[ClH:1].[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:8][CH:9]=[C:10]2[CH2:14][N:13]([CH2:17][C:15]3[NH:18][CH2:19][CH2:21][N:25]=3)[CH2:12][C:11]=12)=[O:6])[CH3:3]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1scc2c1CNC2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Product: CCOC(=O)c1scc2c1CN(CC1=NCCN1)C2

Procedure:
A solution of 0.65 g of 1-ethoxycarbonyl-5,6-dihydro-4h-thieno[3,4-c]pyrrole hydrochloride and 1.47 ml of N,N-diisopropylethylamine in 15 ml of dimethylformamide is poured onto a mixture of 0.75 g of 2-chloromethyl-1H-4,5dihydroimidazole hydrochloride, 0.5 ml of N,N-diisopropylethylamine and 15 ml of dimethylformamide. The mixture is subjected to ultrasound for 4 h and is then evaporated under vacuum. The residue is dissolved in 3 ml of ethanol and chromatography is carried out on a silica column with ethanol as eluent. After evaporating the solvent, the residue is treated with 5 ml of isopropanol saturated with hydrochloric acid. 0.182 g of product is obtained. Melting point: 213°-215° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH2:9]([Li])[CH2:10][CH2:11]C.[CH2:14]([Si:17](Cl)(C)[CH3:18])C=C.[NH4+].[Cl-]>C1COCC1>[CH2:9]([C:5]1[CH:6]=[C:7]([SiH:17]([CH3:18])[CH3:14])[C:2]([Br:1])=[N:3][CH:4]=1)[CH:10]=[CH2:11]
Reactant: [Li]CCCC
Reactant: Brc1ccc(Br)nc1
Reactant: C=CC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1cnc(Br)c([SiH](C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 2,5-dibromopyridine (18.6 g, 78.5 mmol) in dry THF (700 mL) at −78° C. was added n-butyllithium (31.4 mL, 2.5 M solution in hexanes, 78.5 mmol). After being stirred for 1 h −78° C., allylchlorodimethylsilane (11 g, 78.5 mmol) was added dropwise over a period of 20 min. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (5 mL) was added to the solution, and the reaction mixture was concentrated. The resulting yellow oil was concentrated, extracted with ethyl acetate/water, and the organic layer was dried, concentrated, and purified by column chromatography (1:5 ethyl acetate/hexanes) to give the desired compound as a liquid (12.7 g, 55%); 1H NMR (300 MHz, CDCl3) δ 0.19 (s, 6 H), 1.63 (d, J=7.80 Hz, 2 H), 7.10 (dt, J=6.90, 0.90 Hz, 1 H), 4.75 (s, 1 H), 5.59 (ddt, J=16.50, 10.50, 8.10 Hz, 1 H), 7.32 (d, J=8.10 Hz, 1 H), 7.50 (m, 1 H), 8.28 (d, J=2.10 Hz, 1 H); 13C NMR (75 MHz, CDCl3) −3.5 (2C), 23.2, 114.6, 127.8, 132.5, 133.4, 143.7, 143.8, 154.6. HRMS (EI) calcd for C10H14BrNSi 255.0077 and 257.0058, found 255.0054 and 257.0028.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[OH-:13].[Na+].[C:15](#N)C>>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:15]=[O:13]
Reactant: [OH-]
Reactant: CC#N
Reactant: Fc1cc2[nH]ccc2c(F)c1Br
Agent: [Na+]
Product: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
To a solution of 5-bromo-4,6-difluoro-1H-indole (1.29 g, 5.56 mmol) in acetonitrile (7.0 mL) was added N,N-dimethylformiminium chloride (1.07 g, 8.34 mmol). The reaction mixture was stirred at room temperature for 45 minutes. To the reaction mixture was added 1N NaOH (15 mL, 15 mmol). The resulting mixture was heated to 100° C. for 60 minutes, cooled to 0° C. and the resulting solid was collected via filtration, washed with water, and air-dried with vacuum to provide 900 mg of the title compound. An additional crop of solids formed in the filtrate, was collected, and dried to provide an additional 371 mg of the title compound for a total of 1.271 g (88% yield). MS (ES+) 260.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.58 (br. s, 1H), 9.93 (d, J=3.90 Hz, 2H), 8.34 (s, 2H), 7.39 (dd, J=8.49, 1.07 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1.C(COC)[O:22]C>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([O-:10])=[O:9].[OH:22][N+:17]1[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13][NH:12][C:16]=12
Reactant: COCCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCCCCCC
Product: O=C([O-])c1cccc(Cl)c1
Product: O[n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
meta-Chloroperbenzoic acid (“m-CPBA”; 25.4 g, 147 mmol) was added portionwise to 1H-pyrrolo[2,3-b]pyridine (15.0 g, 127 mmol) in 1:2 dimethoxyethane (“DME”):heptane (80:160 mL) at 10° C. The reaction was then stirred at room temperature for 1 hour. The precipitate was filtered and washed with 1:2 DME:heptane. The precipitate was then dried to give 7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate (33.0 g, 89.4% yield).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][S:7][C:8]=1/[CH:9]=[CH:10]\[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(O)=[O:2].Cl.[C:32]([CH:34]1[CH2:37][NH:36][CH2:35]1)#[N:33]>>[C:32]([CH:34]1[CH2:37][N:36]([C:1]([C:4]2[N:5]=[CH:6][S:7][C:8]=2/[CH:9]=[CH:10]\[S:11][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:2])[CH2:35]1)#[N:33]
Reactant: N#CC1CNC1
Reactant: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: N#CC1CN(C(=O)c2ncsc2/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 72.6 %

Procedure:
In the same manner as in step c) in Example 3, 716 mg of the title compound was prepared from 859 mg of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole and 237 mg of 3-cyanoazetidine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:29]1[CH:30]=[C:25]([NH2:24])[CH:26]=[CH:27][C:28]=1[S:31]([NH2:34])(=[O:33])=[O:32])=[O:6]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc(N)ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 34.2 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 4-aminobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 7 mg (34%) of the title compound.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>O1CCCC1>[CH3:21][N:16]1[C:17]2[CH2:18][CH2:19][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][C:12]=2[CH2:13][CH2:14][C:15]1=[O:20]
Reactant: O=C1CCC2=C(CCC(OC(=O)c3ccccc3)C2)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CCC2=C1CCC(OC(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
46.5 g. of the isomer mixture containing about 60 percent of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinoline-2-one and 40% of the 3,4,4a,5,6,7-hexahydro isomer were dissolved in 400 ml. of tetrahydrofuran (THF). 80 ml. of methyl iodide were added and the resulting mixture cooled in an ice-water bath. 9.6 g. of sodium hydride (as a 50 percent suspension in mineral oil) were added in portions. After all of the sodium hydride suspension had been added, the cooling bath was removed and the reaction mixture stirred at ambient temperature under a nitrogen atmosphere for about 4 hours. The reaction mixture was then diluted with water and the aqueous mixture thoroughly extracted with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. The chloroform was removed by evaporation to dryness in vacuo leaving as a residue an orange oil weighing 47.3 g. Crystallization of the residue from an ether-hexane solvent mixture yielded crystals of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41]([OH:42])[N:40]=[N:39][C:37]=2[CH:38]=1.[H-].[Na+]>CN(C=O)C>[N:41]1([O:42][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[C:8](=[C:18]4[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:25])[CH2:20][CH2:19]4)[C:9]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=4[CH2:11][CH2:12][C:3]=23)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=2[N:39]=[N:40]1
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: On1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(On4nnc5ccccc54)ccnc32)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of the title compound from Example 261 (1.0 grams) in dry DMF (60 mL) was added HOBT (1.4 grams), sodium hydride (0.2 grams, 60% in mineral oil) and distilled water (0.5 mL). The solution was stirred at 25° C. under nitrogen while being irradiated with a 200 Watt lamp for 20 hours. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2 and saturated aqueous sodium bicarbonate and after two hours, the organic phase was separated, dried over MgSO4 and concentrated. Purification by flash column chromatography (silica gel) using 3-5% MeOH-CH2Cl2 afforded the title compound (Yield 1.1 grams, 87%, MH+564).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]1(C1C=C(F)C=C(F)C=1C#N)[F:15])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:33]([O:37][C:38](=[O:47])[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].C[N:49]([CH:51]=O)C>>[C:1]([O:5][C:6](=[O:26])[N:7]([C:11]1[CH:10]=[C:9]([F:15])[CH:8]=[C:13]([O:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:47])[CH:41]=2)[C:12]=1[C:51]#[N:49])[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[F:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1C=CC(I)=CC1(F)c1cc(F)cc(F)c1C#N
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(N(C(=O)OC(C)(C)C)c3ccc(I)cc3F)c2C#N)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
500 mg 2(2-Cyano-3,5-difluoro-phenyl)-(2-fluoro-4-iodo-phenyl)-carbamic acid tert-butyl ester (1.05 mmol, 1 eq.) and 412 mg Cs2CO3 (1.27 mmol, 1.2 eq) were dissolved in 5.5 mL DMF and treated with 265 mg (3-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.27 mmol. 1.2 eq.) dissolved in 5.5 mL DMF. The resulting mixture is stirred at 50° C. for 16 h. Extractive workup provided a crude product containing the desired target compound as a mixture of regioisomers along with a smaller fraction of the product of double substitution. This mixture was advanced without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][NH:25][CH3:26]>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:16]([N:25]([CH3:26])[CH3:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CNC
Reactant: O=Cc1ccccc1
Product: CN(C)C(c1ccccc1)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 140 °C
Yield: 77 %

Procedure:
A mixture of 51.5 g (0.25 mol) of 2,4-di-tert-butylphenol, 26.5 g (0.25 mol) of benzaldehyde and 42.3 g (0.375 mol) of a 40% aqueous solution of dimethylamine is heated in a closed vessel at 140° C. for 10 hours, the internal pressure rising to 5 bar. After cooling to room temperature, the reaction mixture solidifies. Crystallisation of the residue from isopropanol yields 65.2 g (77%) of 2,4-di-tert-butyl-6-(dimethylamino-phenyl-methyl)-phenol, m.p. 120-123° C. (compound (202), Table 2). Molecular weight C23H33NO (339.52). Analysis, calculated: C 81.37; H 9.80; N 4.13%. Analysis, found: C 81.25; H 9.86; N 4.00%. 1HNMR (300 MHz, CDCl3, ppm): 1.19 (s, 9H); 1.44 (s, 9H); 2.26 (s, 6H); 4.34 (s, 1H); 6.75 (d, 1H); 7.29 (m, 6H); 12.43 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([O:33][C:34]1[CH:39]=[N:38][CH:37]=[C:36]([Sn](C)(C)C)[N:35]=1)([CH3:32])[CH3:31]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]([O:33][C:34]1[N:35]=[C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH:16][CH:17]([CH3:18])[CH3:19])[O:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:3]=2)[CH:37]=[N:38][CH:39]=1)([CH3:32])[CH3:31]
Reactant: CC(C)Oc1cncc([Sn](C)(C)C)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(NC(C)C)n4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(OC(C)C)n3)c3cc(-c4noc(NC(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 43.7 %

Procedure:
Argon gas was bubbled through a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (450 mg, 0.86 mmol) and 2-isopropoxy-6-(trimethylstannyl)pyrazine (311 mg, 1.03 mmol) in dry DMF (4.5 ml) for 15 min. To the mixture was added CuI (163 mg, 0.86 mmol) and Pd(PPh3)4 (99 mg, 0.086 mmol) and argon gas was further bubbled for additional 15 min. The reaction was heated at 90° C. for 1 h then cooled to RT. The reaction was quenched with ice cold water. The resulting suspension was filtered and washed with water. The solid was purified with basic alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (200 mg, 43.5%). MS (ESI, pos. ion) m/z: 533.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:32]=[CH:31][C:20]([CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5]>CO.C1COCC1.O1CCOCC1.[Pd]>[Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][CH:22]([C:23]([O:25][CH3:26])=[O:24])[C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4Cl)ccc32)cc1)C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4Cl)ccc32)cc1)C(=O)OC
Temperature: 25 °C

Procedure:
The compound obtained in Example 37 is dissolved in a methanol/THF/dioxane solvent mixture and then a catalytic amount of palladium-on-carbon is added and the reaction is stirred at ambient temperature under a hydrogen atmosphere. The palladium-on-carbon is then filtered off and the solvents are removed by evaporation under reduced pressure. The resulting residue is taken up in isopropyl ether and stirred magnetically. The resulting precipitate is filtered off and recrystallised from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:4]([O:14]C)[CH:3]=1.C[S-].[Na+].Cl>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Br)cc(OC)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(O)cc(Br)c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-methylethoxy]benzene (9.21 g, 33.5 mmol) synthesized in Example (78b) was dissolved in 1-methyl-2-pyrrolidone (100 mL), and sodium thiomethoxide (2.75 g, 37.3 mmol) was added, followed by stirring at 130° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 2N hydrochloric acid (500 mL) was added, and extraction was carried out with diethyl ether (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-25%) to afford the desired compound (8.30 g, yield 95%) as a colorless liquid.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][C:8](=[O:38])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:37])[C@@H:19]([N:29]4[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1.O>C(O)C>[C:1]([S:3][CH2:7][C:8](=[O:38])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:37])[C@@H:19]([N:29]4[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)(=[O:4])[CH3:2]
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)SCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 60.7 %

Procedure:
Potassium thioacetate (1.32 g) was added to a solution of the 21-chloro-compound of Example 2 (2.22 g) in ethanol (11.1 ml). The mixture was heated under reflux in an atmosphere of nitrogen for 40 min and then poured into water (100 ml). The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from methanol to give (2β,3α,5α)-21-(acetylthio)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (1.46 g). m.p. 181°-182° C.; [α]D +131.9° (c 0.88).