Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C[O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CS(C)=O.C(OCC)(=O)C.CO.O>[Br:1][C:2]1[CH:7]=[C:6]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[C:11]([OH:19])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Br)c1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Oc2ccnc(Br)c2)c1
Temperature: 66 °C

Procedure:
A mixture of 2-bromo-4-chloro-pyridine (200 mg, 1.04 mmol), methyl-3-hydroxybenzoate (158 mg, 1.04 mmol), cesium carbonate (507 mg, 1.56 mmol) in 10 ml of anhydrous DMSO was heated at 66° C. for 5 hours. The mixture was diluted with ethyl acetate (100 ml), washed with brine (3×50 ml), dried over Na2SO4 and evaporated to give a colorless oil. The oil was dissolved in MeOH (8 ml), and 2M NaOH solution (4 ml, 8 mmol) was added. The mixture was heated at 60° C. for 20 minutes, poured into 50 ml of water, and acidified to pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-bromo-pyridin-4-yloxy)-benzoic acid as white solid. Yield: 170 mg, 56%.
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]([N:7]([CH2:21][CH3:22])[C:8]1[C:17]([N+:18]([O-])=O)=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1)[CH3:6])C.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[CH2:21]([N:7]1[C@@H:5]([CH3:6])[C:4](=[O:3])[NH:18][C:17]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[N:9][C:8]1=2)[CH3:22]
Reactant: CCOC(=O)[C@H](C)N(CC)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: CCN1c2ncc(C(=O)OC)cc2NC(=O)[C@@H]1C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
(S)-methyl 6-((1-ethoxy-1-oxopropan-2-yl)(ethyl)amino)-5-nitronicotinate (1.22 g, 3.92 mmol) was dissolved in dichloromethane (12 mL). To this solution were added triphenyl phosphite (5.0 mg, 16 umol), ammonium metavanadate (50.0 mg, 0.427 mmol) and Pt/C (5% wt., 0.200 g). The reaction mixture was hydrogenated at 100 psi at 25° C. for 18 h. The mixture was filtered through a small pad of celite and the pad was washed with dichloromethane (20 mL). The combined filtrates were concentrated in vacuo and crystallized with ethyl ether (50 mL) to afford the title compound as a white solid (0.560 g, 57%). [M+H] calc'd for C12H15N3O3, 250; found, 250.
Reaction SMILES: [Cl:1][C:2]1[C:27]([Cl:28])=[CH:26][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH-].[K+].C(O)C.C1C=CC=CC=1>O>[Cl:1][C:2]1[C:27]([Cl:28])=[CH:26][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCN(C2Cc3ccccc3Sc3cc(Cl)c(Cl)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: Clc1cc2c(cc1Cl)C(N1CCNCC1)Cc1ccccc1S2

Procedure:
The same product was prepared by the following procedure: A mixture of crude 7,8-dichloro-10-(4-ethoxycarbonylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine (3.5 g) (prepared according to the preceding Example), potassium hydroxide (1.75 g) and ethanol (3.5 ml) was refluxed for 3 hours in a bath heated to 120°-125° C. The reaction mixture was cooled and shaken with benzene and water. The isolation procedure is the same as described in the preceding Examples, yielding the crude base in an almost theoretical yield. On crystallization from acetone it melts at 131°-133° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O-])=[O:32])[CH2:27][CH2:26]2)[N:19]=1)(=[O:4])=[O:3].[Na+].[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:31]([CH:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:20]3[N:19]=[C:18]([N:13]4[C:14]5[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:17]=[CH:16][CH:15]=5)[CH:11]=[CH:12]4)[CH:23]=[CH:22][N:21]=3)[CH2:30][CH2:29]2)=[O:32])[CH2:41]1)=[O:39])[CH3:36]
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)[O-])CC2)n1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)C2CCC(Nc3nccc(-n4ccc5c(OCCCS(C)(=O)=O)cccc54)n3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Sodium 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylate (0.4 g), (R)-piperidine-3-carboxylic acid ethyl ester (0.165 g), BOP (0.537 g) and DIPEA (0.56 mL) were added to DMF (3 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, dried under reduced pressure, and purified by flash chromatography (DCM/MeOH) to give 39.6 mg of (R)-1-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarbonyl)-piperidine-3-carboxylic acid ethyl ester, MP=175.0-177.0° C.
Reaction SMILES: [CH3:1][CH:2]([OH:4])C.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[OH:19][CH:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:24]([CH3:33])([CH3:32])[O:23][C:21]1=[O:22]>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C>[OH:19][CH:20]([CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([OH:23])([CH3:33])[CH3:32])[C:21]([O:4][CH2:2][CH3:1])=[O:22]
Reactant: CC(C)O
Reactant: CC1(C)OC(=O)C(O)C1c1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC#N
Product: CCOC(=O)C(O)C(c1ccccc1)C(C)(C)O

Procedure:
A mixture of 3 mmol of diethyl cinnamate, 3 ml of 2-propanol, 0.6 mmol of N-hydroxyphthalimide, 0.015 mmol of cobalt(II) acetate, 0.03 mmol of acetylacetonatocobalt(III), and 1 ml of acetonitrile was stirred at 70° C. in an oxygen atmosphere (1 atm) for 12 hours. A gas chromatographic analysis of products in a reaction mixture revealed that α-hydroxy-β-phenyl-γ,γ-dimethyl-γ-butyrolactone and ethyl 2,4-dihydroxy-4-methyl-3-phenylpentanoate were formed in yields of 18% and 24%, respectively. The conversion rate from diethyl cinnamate was 61%.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:17]3[C:18]([O:22][CH3:23])=[N:19][CH:20]=[CH:21][C:16]=3[N:15]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:14]=2)[CH:8]=1)(=O)=O.Cl.[CH3:33][NH:34][CH3:35].[I-].[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[N:15]1[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[C:17]=2[C:13]([C:9]2[CH:8]=[C:7]([CH2:6][N:34]([CH3:35])[CH3:33])[CH:12]=[CH:11][CH:10]=2)=[N:14]1
Reactant: CNC
Reactant: COc1nccc2c1c(-c1cccc(COS(C)(=O)=O)c1)nn2-c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nccc2c1c(-c1cccc(CN(C)C)c1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 3-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzyl methanesulfonate (75 mg), dimethylamine hydrochloride (79 mg) and sodium iodide (29 mg) in DMF (1 mL) was added triethylamine (0.135 mL), and the mixture was stirred at 90° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (62 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[C:24]1([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1.CI.[NH4+].[Cl-]>C1COCC1>[CH3:33][O:32][C:30]([C:24]1([CH3:1])[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1)=[O:31]
Reactant: COC(=O)C1=CCCCC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C)C=CCCC1
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to 78° C. and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at 78° C. and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to 5° C. over 2 h. An aqueous saturated solution of NH4Cl was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[CH:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)no1
Temperature: 70 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (5-methylisoxazol-3-yl)carbamate (200 mg, 0.731 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.141 ml, 0.812 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (119 mg, 44.0%) as a solid.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C@:32]23[CH2:40][O:39][CH2:38][C@@:37]2([F:41])[CH2:36][S:35][C:34]([NH2:42])=[N:33]3)[CH:31]=1.[O:44]1[CH2:47][CH2:46][CH:45]1[CH2:48][O:49][C:50]1[N:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1>ClCCl>[NH2:42][C:34]1[S:35][CH2:36][C@:37]2([F:41])[CH2:38][O:39][CH2:40][C@:32]2([C:30]2[CH:31]=[C:26]([NH:25][C:56]([C:53]3[CH:52]=[N:51][C:50]([O:49][CH2:48][CH:45]4[CH2:46][CH2:47][O:44]4)=[CH:55][N:54]=3)=[O:57])[CH:27]=[CH:28][C:29]=2[F:43])[N:33]=1
Reactant: O=C(O)c1cnc(OCC2CCO2)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)COC[C@@]2(F)CS1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(OCC5CCO5)cn4)ccc3F)COC[C@@]2(F)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride 50 wt % solution in ethyl acetate (8.90 μL, 1.50 mmol) is added to a microwave vial containing a mixture of (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine (81.2 mg, 0.285 mmol), 5-(oxetan-2-ylmethoxy)pyrazine-2-carboxylic acid (140 mg, 0.300 mmol) and anhydrous dichloromethane (10 mL). The vial is sealed and the mixture stirred at room temperature overnight. The mixture is then partitioned between water and dichloromethane and the layers separated through a Phase Separating cartridge. Organics are combined and the solvent evaporated under reduced pressure. The resulting oil is dissolved in methanol, filtered, and purified by preparative-HPLC (Phenomenex Gemini 10 μm 50*150 mm C-18) (CH3CN and water with 10 mM ammonium bicarbonate, 10% to 100% CH3CN over 10 minutes at 120 ml/min) (1 injection). Fractions bearing product are concentrated to dryness overnight in a centrifugal evaporator to give the title compound as a white solid (40 mg, 28%). ES/MS (m/e): 478.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([Si:4]([CH3:25])([CH3:24])[O:5][CH2:6][CH:7]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:8][O:9][Si:10]([CH3:16])([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:3].[CH2:27](O)[CH:28]([CH3:30])[CH3:29].[I-].[K+]>O.ClCCl>[CH2:27]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([CH:7]([CH2:8][O:9][Si:10]([CH3:15])([CH3:16])[C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6][O:5][Si:4]([CH3:24])([CH3:25])[C:2]([CH3:26])([CH3:1])[CH3:3])=[CH:18][CH:19]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CO
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CNc1ccc(C(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)aniline (193.1 mg, 0.488 mmol), isobutanol (0.090 mL, 0.976 mmol), potassium iodide (162 mg, 0.976 mmol), [Cp*IrCl2]2 (3.89 mg, 4.88 μmol) and water (3 mL) was prepared in a microwave vial. The reaction vessel was sealed and heated by microwaves to 150° C. for 1.5 hours. After cooling, the solution was diluted with water and dichloromethane (20 mL), then the organic phase separated (hydrophobic frit) and concentrated in vacuo. The crude was purified by flash silica (Si) chromatography (using a 0-100% dichloromethane-cyclohexane gradient) to give the desired product, 155.9 mg. LCMS (M+1) 452, RT 1.96 mins.
Reaction SMILES: Cl.C([N:9]1[C:17]2[N:16]3[N:18]=[C:19]([CH3:30])[C:20]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=4[CH3:29])=[C:15]3[N:14]=[C:13]([CH3:31])[C:12]=2[CH2:11][CH2:10]1)C1C=CC=CC=1.O.C(O)C>[H][H].[C].[Pd]>[C:26]1([CH3:27])[CH:25]=[C:24]([CH3:28])[CH:23]=[C:22]([CH3:29])[C:21]=1[C:20]1[C:19]([CH3:30])=[N:18][N:16]2[C:17]3[NH:9][CH2:10][CH2:11][C:12]=3[C:13]([CH3:31])=[N:14][C:15]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4Cc2ccccc2)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4)c(C)c1
Yield: 71.6 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a mixture of 8-benzyl-3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (4.7 g) which is a free compound of the compound prepared in Example 26, water-containing 5% palladium carbon (3.0 g) and ethanol (300 mL), followed by stirring at room temperature for two days in hydrogen atmosphere. After filtering through Celite, the filtrate was evaporated, which was neutralized with an aqueous solution of sodium bicarbonate. The resulting solid was filtered, and dissolved in a mixed solution of dichloromethane, methanol and ethyl acetate. After filtering off the insoluble matter, the mixture was purified by silica gel column cromatography (10-67% ethyl acetate/hexane), to give the title compound as white crystals (2.6 g). 1.0 g of a raw material was recovered.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:8]([CH:18]([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH2:35])=[O:34])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(O)(C)(C)C>[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:2]2[CH:3]=[C:4]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:8]([CH:18]([CH3:20])[CH3:19])[C:5]3=[N:6][CH:7]=2)=[O:34])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]
Reactant: CC(C)[C@H]1c2ncc(Cl)cc2CN1C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(CC(N)=O)cc1
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CCS(=O)(=O)c1ccc(CC(=O)Nc2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Temperature: 110 °C
Yield: 57.1 %

Procedure:
To a flame-dried vial equipped with a stir bar was added tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (74.7 mg, 252 μmol), 2-(4-(ethylsulfonyl)phenyl)acetamide (68.6 mg, 302 μmol), and potassium phosphate (64.1 mg, 302 μmol). Tert-butanol (1.5 mL) was added, then the mixture was degassed with N2 for 15 min. Tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 252 nmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (4.9 mg, 10.1 μmol) were added to the mixture, then the vial was sealed and heated at 110° C. for 15 h. The mixture was cooled to rt, then partitioned between EtOAc (15 mL) and brine (15 mL). The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 100%) to afford 70.2 mg of Tert-butyl(S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (57%). LC-MS tR=0.90 min in 1 min chromatography, MS (ESI) m/z 488.5 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of rotamers): δ 8.58 (s, 0.5H), 8.54 (s, 0.5H), 8.10 (s, 1H), 7.89 (dd, J=8.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 4.77 (d, J=15.6 Hz, 1H), 4.51 (m, 2H), 3.87 (s, 2H), 3.21 (q, J=7.2 Hz, 2H), 2.46-2.37 (m, 1H), 1.52 (s, 9H), 1.22 (t, J=7.6 Hz, 3H), 1.02 (d, J=6.8 Hz, 1.5H), 0.99 (d, J=6.4 Hz, 1.5H), 0.77 (d, J=7.2 Hz, 1.5H), 0.73 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: [Br:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.CN([CH:21]=[O:22])C.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH:21]=[O:22]
Reactant: Fc1cccc(I)c1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(I)c(Br)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a cooled (−78° C.) solution of 2-bromo-1-fluoro-3-iodo-benzene (10.5 g, 35 mmol) in THF (100 mL) under nitrogen was added LDA (2.0 M, 21 mL, 42 mmol). The mixture was stirred for 1 h at −78° C. and then DMF (4.0 mL, 52 mmol) was added slowly. The reaction mixture was stirred for a further 1 h and then saturated aqueous ammonium chloride (50 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic fractions were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by flash chromatography (5% ethyl acetate:hexanes) afforded 2.3 g (20%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, J=9.0, 6.6 Hz, 1H), 7.69 (dd, J=9.0, 1.5 Hz, 1H), 10.08 (d, J=0.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ−109.18 (d, J=7.3 Hz, 1F).
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=O)(=[O:25])=[O:24])[CH:17]=[CH:16]2.[N:32]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([CH2:26][C@@H:27]([OH:31])[C:28]([N:42]1[CH2:41][CH2:40][CH:39]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]3=[O:38])[CH2:44][CH2:43]1)=[O:30])(=[O:24])=[O:25])[CH:17]=[CH:16]2
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
WSC (0.19 g) was added to a mixture of (2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g), 1,4′-bipiperidin-2-one (0.18 g) and HOBt (0.15 g) in DMF (15 mL) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with dichloromethane and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.26 g, 54%) as a colorless powder.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=1)=[O:6].C1COCC1.O.[OH-].[Li+]>CC(=O)OCC.O>[C:21]([SiH2:20][O:19][C:18]([CH3:26])([CH3:25])[C:14]1[CH:13]=[C:12]([C:11]2[O:10][CH:9]=[N:8][C:7]=2[C:5]([OH:6])=[O:4])[CH:17]=[CH:16][CH:15]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ncoc1-c1cccc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ocnc2C(=O)O)c1
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-oxazole-4-carboxylic acid methyl ester (673 mg, 1.94 mmol) in 1:1 THF:H2O (6.4 mL) was treated with lithium hydroxide monohydrate (115 mg, 2.71 mmol). The resulting mixture was stirred for 2.5 h. EA (20 mL) was added and the organic phase was washed with 1N HCl (10 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=1.07 min, [M+H]+=334.13.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O.[Cu]I>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Cc1ccccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36,4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), CuI (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with iPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.