Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1.C([Li])CCC.B(OC)(OC)[O:25]C.OO>C1COCC1.C1(C)C=CC=CC=1.O>[F:8][C:7]1[C:2]([F:1])=[C:3]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)[CH:4]=[CH:5][C:6]=1[OH:25]
Reactant: COB(OC)OC
Reactant: CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
37 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxybenzene was dissolved in 222 mL of THF, and 59.9 mL of butyllithium (2.67 M hexane solution) was added dropwise thereto at an internal temperature of −40° C. or lower. Then, further stirring was continued for 30 min. To this solution, 18.1 g of trimethyl borate was added dropwise at an internal temperature of −40° C. or lower, and then the temperature was increased to 0° C. Then, 24.7 mL of 30% hydrogen peroxide solution was added dropwise for 5 min, and the stirring was continued for 3 hours. Water and toluene were added thereto, and the organic layer was fractioned while the aqueous layer was extracted with toluene. The organic layers were combined and washed with water, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography, to thereby obtain 20 g of 2,3-difluoro-4-(trans-4-ethylcyclohexyl)methoxyphenol.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[F:35][C:36]([F:43])([F:42])[C:37]1[N:38]=[CH:39][NH:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+].[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(#N)C>[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([N:40]3[CH:41]=[C:37]([C:36]([F:43])([F:42])[F:35])[N:38]=[CH:39]3)[C:19]3[C:23](=[O:33])[NH:24][CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: FC(F)(F)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N[C@H]1COCC[C@H]1Nc1nc(-n2cnc(C(F)(F)F)c2)c2c(c1F)CNC2=O
Yield: 8.8 %

Procedure:
In a 10 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 4-(trifluoromethyl)-1H-imidazole (48.9 mg, 0.359 mmol) and K2CO3 (66.2 mg, 0.479 mmol) were dissolved in ACN (2 mL). The cap was sealed and the mixture was reacted at 100° C. for 16 h. The reaction mixture was subsequently filtered through a Buchner funnel to remove un-dissolved K2CO3. The solids were washed with ACN (2×5 mL) and the filtrate was evaporated to give a residue, which was treated with TFA (2 mL) at RT for 20 min to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (5 mL) and was then purified by preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a brown solid (4.2 mg, 8.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 1H), 2.05 (td, J=12.88, 7.33 Hz, 1H), 3.30-3.90 (m, 4H), 3.78-3.99 (m, 2H), 4.44 (s, 2H), 6.49 (br s, 2H), 7.54 (d, J=5.56 Hz, 1H), 7.85 (br s, 2H), 8.67-8.80 (m, 2H). [M+H] calc'd for C16H16F4N6O2, 401. found, 401.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[CH:8][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][C@H:38]4[N:50]([CH3:51])[CH2:49][CH2:48][C@@:44]5([C:45]=3[C:46]=2[OH:47])[C@@:39]4([OH:53])[CH2:40][CH2:41][C:42](=[O:52])[CH2:43]5)=[O:32])=[CH:24][CH:23]=1>C(OCC)(=O)C.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.O>[OH:47][C:46]1[C:45]2[C@:44]34[CH2:48][CH2:49][N:50]([CH3:51])[C@@H:38]([C@:39]3([OH:53])[CH2:40][CH2:41][C:42](=[O:52])[CH2:43]4)[CH2:37][C:36]=2[CH:35]=[CH:34][C:33]=1[C:31]([NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[CH:8]=[N:7][C:6]([O:5][CH3:4])=[N:11][CH:10]=2)=[CH:27][CH:26]=1)=[O:32]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CN1CC[C@]23CC(=O)CC[C@@]2(O)[C@H]1Cc1ccc(C(=O)NCCc2ccc(Br)cc2)c(O)c13
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ncc(-c2ccc(CCNC(=O)c3ccc4c(c3O)[C@]35CCN(C)[C@H](C4)[C@]3(O)CCC(=O)C5)cc2)cn1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
To a degassed mixture of ethanol and water (4:1, 20 mL) was added 2-methoxypyrimidin-5-ylboronic acid (0.67 g, 4.4 mmol), Na2CO3 (1.24 g, 11.7 mmol) and N-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphinan-3-carboxamide (2) (1.5 g, 2.9 mmol). The reaction mixture was further degassed and then Pd(PPh3)4 (0.32 g, 0.3 mmol) added. The reaction mixture was heated in a microwave reactor at 120° C. for 25 min. and cooled. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1:1 brine/water (3×35 mL). The organic phase was dried over MgSO4, filtered and evaporated. The resulting residue was further purified on silica eluting with dichloromethane/methanol (9:1) to give 4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide (3) (0.50 g, 32%) as a yellow foam.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]3[C@H:17]4[C@H:27]([CH2:28][CH2:29][C@:12]23[CH3:13])[C@:25]2([CH3:26])[C:20]([CH:21]=[C:22]([C:30]#N)[CH2:23][CH2:24]2)=[CH:19][CH2:18]4)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:38].[K+].Cl.[OH2:41]>C(O)CO>[C:32]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]3[C@H:17]4[C@H:27]([CH2:28][CH2:29][C@:12]23[CH3:13])[C@:25]2([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([OH:41])=[O:38])[CH2:23][CH2:24]2)=[CH:19][CH2:18]4)=[O:10])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
0.8 g of N-diphenylmethyl-3-cyanoandrosta-3,5-diene-17β-carboxamide [prepared as described in step (c) above] and 6.0 g of potassium hydroxide were dissolved in a mixture of 14 ml of water and 20 ml of ethylene glycol, and then the mixture was heated under reflux for 16 hours. At the end of this time, the reaction mixture was cooled to room temperature and made acidic by the addition of dilute aqueous hydrochloric acid. The mixture was then extracted three times with methylene chloride. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order and dried over anhydrous magnesium sulfate. The mixture was then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 35 g of silica gel using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 12:88 by volume as the eluent, to give 650 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:19][S:20]([CH3:23])(=[O:22])=[O:21]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[N:6][CH:7]=1
Reactant: CS(C)(=O)=O
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(Br)cn1
Temperature: -17 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-fluoro-pyridine (2.00 g) dissolved in tetrahydrofuran (20 mL) was added dropwise to a solution of sodium hexamethyldisilazide (2 mol/L in tetrahydrofuran, 28.5 mL) in tetrahydrofuran (20 mL) cooled to ca. −17° C. Dimethylsulfone (4.30 g) was added and stirring continued in the cooling bath for 1 h. The cooling bath was then removed and the solution was stirred at room temperature for one more h. Aqueous NH4Cl solution and brine were added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was evaporated. The residue was treated with little ethyl acetate to precipitate the title compound. Yield: 1.73 g (63% of theory); LC (method 3): tR=2.01 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)CC#N)cc2)cc1
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)C(C#N)=C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 19.3 g of methyl 4-(3-{4-[(cyanoacetyl)amino]phenyl}propyl)benzoate, 18 mL of cyclohexanone, and 100 mL of toluene was added dropwise 5.0 mL of morpholine at room temperature. In a reaction device in which a Dean-Stark type dehydration tube was installed, the reaction mixture was stirred for 8 hours under heating and refluxing. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-chloroform and ethyl acetate-chloroform) to obtain methyl 4-[3-(4-{[cyano(cyclohexylidene)acetyl]amino}phenyl)propyl]benzoate in the form of a reddish brown amorphous substance as a crude product. ESI+:417
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH2:9]([CH2:11][NH2:12])[OH:10].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>O>[C:1]([C:3]1[C:4](=[O:6])[N:12]([CH2:11][CH2:9][OH:10])[C:13]([OH:18])=[CH:14][C:15]=1[CH3:17])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)CC(C)=O
Reactant: NCCO
Solvent: O
Product: Cc1cc(O)n(CCO)c(=O)c1C#N
Temperature: 90 °C
Reaction time: 20 h

Procedure:
Step 1) Ethyl cyanoacetate (56.5 parts) was added dropwise over 0.25 hours to a stirred solution of ethanolamine (76.25 parts) in water (18 parts) while maintaining the temperature at less than 30° C. Ethyl acetoacetate (65 parts) was then added while maintaining the temperature at less than 30° C. The mixture was stirred at 90° C. for 20 hours, cooled and poured into water (500 parts), the product isolated by filtration, washed with water and dried to give 3-cyano-6-hydroxy4-methyl-1-(2-hydroxyethyl)pyrid-2-one (45 parts).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:9]=1[NH:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=O.[CH3:24]/[C:25](/[NH2:29])=[CH:26]\[C:27]#[N:28].[CH2:30]([CH:33]1[CH2:38][C:37](=O)[CH2:36][C:35](=[O:40])[CH2:34]1)[CH2:31][CH3:32]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:36]3[C:35](=[O:40])[CH2:34][CH:33]([CH2:30][CH2:31][CH3:32])[CH2:38][C:37]=3[NH:29][C:25]([CH3:24])=[C:26]2[C:27]#[N:28])[CH:7]=[C:8]([S:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:9]=1[NH:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Reactant: COCCNc1c(Br)cc(C=O)cc1S(=O)(=O)N1CCOCC1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCCOC)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of the product of step d (61 mg), 3-aminocrotonitrile (12.3 mg) and 5-propylcyclohexane-1,3-dione (23.1 mg) in ethanol (5 ml) was stirred at 80° C. for 17 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method B). Yield: 57 mg. MS-ESI: [M+H]+=607.3/609.3; HPLC: Rt=16.51 min. (diast. 1) Rt=16.83 min. (diast. 2) (method 1). Diast. ratio: 9:1
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:8]=1[CH:9]=O.[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.[CH3:27][O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32]>C(O)(C)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:8]=1[CH:9]1[C:20]([C:19]([O:25][CH3:26])=[O:24])=[C:21]([CH3:23])[NH:33][C:31]([CH3:32])=[C:30]1[C:29]([O:28][CH3:27])=[O:34]
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)/C=C(/C)N
Reactant: CS(=O)(=O)c1ccc(OCCCCBr)c(C=O)c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCBr
Yield: 53 %

Procedure:
7.6 g of 2-(4-bromobutoxy)-5-methylsulfonylbenzaldehyde, 2.6 g of methyl acetoacetate and 2.9 g of 3-aminocrotonic acid methyl ester were dissolved in 16 ml of isopropanol, and the solution was heated for 5 hours. After cooling, precipitated crystals were collected by filtration, and recrystallized from methanol to give 6.3 g of dimethyl 4-[2(4-bromobutoxy)-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13]CC)=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([C:16]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[C:3]=1[Cl:29].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([C:16]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[C:3]=1[Cl:29]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3-c3ccccn3)c(Cl)c(Cl)c2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2)c1ccnn1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
1.5 g of ethyl 4,5-dichloro-6-(1-[2-pyridyl]-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate are dissolved in a mixture of 18 ml of tetrahydrofuran and 2 ml of water. 177 mg of lithium hydroxide monohydrate are added to the solution and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water and 1N hydrochloric acid are added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 1.35 g of 4,5-dichloro-6-[1-(2-pyridyl)-5-pyrazolylcarbonyl]-1,3-benzodioxole-2-carboxylic acid. Yield: 96%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].I[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:24]=2)[N:19](C(OC(C)(C)C)=O)[N:18]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:28])=[O:29])[CH:24]=3)[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(Br)c3)c2c1
Temperature: 20 °C
Yield: 69.4 %

Procedure:
N-[3-(3-Bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the follow way: 1.6 g of (3-bromophenyl)boronic acid, 8.7 ml of a saturated aqueous sodium hydrogencarbonate solution and 0.11 g of tetrakis(triphenylphosphine)palladium[0] are added successively to a suspension, maintained under an atmosphere of argon, of 2.3 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate in 90 ml of dimethylformamide. The reaction mixture is refluxed for 5 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is hydrolyzed with 200 ml of water and extracted with 200 ml and then 100 ml of ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The brown oil thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a dichloromethane/methanol (99/1 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a yallow lac. This product is repurified by chromatography on a silica column (particle size 63-200 μm), with pure dichloromethane as eluent. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.73 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a white foam melting at 104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 29.3 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.150 g, 0.348 mmol) was dissolved in methylene chloride (3.5 ml) and after adding thereto in sequence copper acetate (0.070 g, 0.383 mmol), 4-pyridylboronic acid (0.086 g, 0.696 mmol), Molecular Sieves 4A (0.150 g), triethylamine (0.088 g, 0.870 mmol) and pyridine (0.069 g, 0.870 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.052 g, 0.102 mmol, 29%).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C1COCC1.B.CSC>O>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Agent: B
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1Br
Yield: 99.5 %

Procedure:
To a mixture of 4-bromo-3,5-dimethoxybenzoic acid (50.0 g, 192 mmol) and THF (1 L) was added borane-methyl sulfide (27.1 mL, 286 mmol) while cooling on ice, and the mixture was heated to reflux for 1 hour. Water was slowly added to the mixture while cooling on ice, and then the solvent in the mixture was distilled off under reduced pressure. Water and ethyl acetate were added to the residue. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (47.3 g, 191 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](O)=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N1C=CN=C1)([N:35]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](=[O:30])[NH2:35])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(N)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(2,6-dichlorobenzoyl)-4-(2-carboxyphenyl)-L-phenylalanine methyl ester (52.6 mg) was dissolved in anhydrous THF (1 mL), carbonyldiimidazole (36.1 mg) was added and the mixture was stirred at room temperature under N2 for 2 h. Ammonium hydroxide (29% aqueous solution, 135 μL) was added and the mixture was stirred for an additional 22 h. The mixture was then extracted with EtOAc. The extract was washed with 1N HCl, sat. NaHCO3 and brine, dried (MgSO4) and evaporated. The residue was purified through a silica gel column using toluene/EtOAc (1:1) as an eluent to give N-(2,6-dichlorobenzoyl)-4-(2-carbamoylphenyl)-L-phenylalanine methyl ester (48.1 mg. ESMS: m/z 471 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:19])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C.C1([O:26]C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:5])=[O:19])=[O:26])(=[O:18])[CH3:17]
Reactant: COc1ccccc1
Reactant: CC(=O)SCCCN1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(3-Acetylthiopropanyl)-L-proline-t-butyl ester (4.7 g.) is dissolved in a mixture of anisole (34 ml.) and trifluoroacetic acid (68 ml.) and the mixture is kept at room temperature for 1 hour. The solvents are removed in vacuo and the residue is precipitated from ether-hexane several times. The residue (3.5 g.) is dissolved in acetonitrile (25 ml.) and dicyclohexylamine (2.8 ml.) is added. The crystalline salt is filtered and recrystallized from isopropanol. Yield 3.8 g. m.p. 176°-177°. The salt is reconverted to 1-(3-acetylthiopropanoyl)-L-proline as in Example 1, yield 1.25 g., m.p. 89°-90° (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([CH2:5][CH3:6])[C:3]#[N:4].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[CH3:1][C:2]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)([CH2:5][CH3:6])[CH:3]([NH2:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(C)(C#N)N1CCCC1
Reactant: [Li]c1ccccc1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CCC(C)(C(N)c1ccccc1)N1CCCC1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The title compound (13.4 g, 94%) was prepared from 2-methyl-2-(1-pyrrolidinyl)butanenitrile D21 (9.6 g, 0.063 mol) and phenyllithium in dibutylether (63 ml of a 2M solution; 0.126 mol) in THF (200 ml), followed by reaction with sodium borohydride (3.5 g, 0.092 mol) in methanol (200 ml) in a similar manner to that described in D5, except that after addition of the sodium borohydride stirring was continued with ice cooling for 0.5 hours then at room temperature for 66 hours. Mass spectrum (Electrospray LC/MS), ES+: Found 233 (MH+). C15H24N2 requires 232. Ret. times 0.78 and 1.06 min.