Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:37]3[CH2:40][CH2:39][CH2:38]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([CH:34]=[CH:35][CH:36]=2)[O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=2)[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][N:7]=1.NN>CCO>[NH2:20][CH2:19][C:18]1[CH:17]=[C:16]([CH:33]=[CH:32][CH:31]=1)[CH2:15][O:14][C:13]1[CH:12]=[C:11]([C:10]2[N:9]=[C:8]([CH:37]3[CH2:40][CH2:39][CH2:38]3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(CN5C(=O)c6ccccc6C5=O)c4)c3)c12
Agent: NN
Solvent: CCO
Product: NCc1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzyl}-isoindole-1,3-dione (100 mg, 0.19 mmol) was dissolved in EtOH (0.76 mL) and charged with hydrazine (60 mg, 1.89 mmol) and stirred overnight at rt. The white ppt filtered and washed with EtOH. The filtrate was concentrated in vacuo, silica gel was added in CH2Cl2, and concentrated to solid. The product was chromatographed on silica gel [Jones Flashmaster, 2 g cartridge, eluting with ˜2% 7N NH3 MeOH:CH2Cl2] and isolated the title compound as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.84-1.92 (m, 1H), 1.97-2.09 (m, 1H), 2.34-2.40 (m, 2H), 2.44-2.46 (m, 2H), 3.69 (s, 2H), 3.84-3.92 (m, 1H), 5.10 (s, 2H), 6.96 (d, J=5.2 Hz, 1H), 7.01-7.03 (m, 1H), 7.13-7.16 (m, 1H), 7.18-7.19 (m, 1H), 7.23-7.32 (m, 3H), 7.35-7.40 (m, 3H); MS (ES+): m/z 400.17 (100) [MH+].
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[C:16]([C:18]1([C:25]2[C:30]3[N:31]=[C:32]([CH:34]([CH3:36])[CH3:35])[O:33][C:29]=3[C:28]([O:37][CH3:38])=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH:34]([C:32]1[O:33][C:29]2[C:28]([O:37][CH3:38])=[CH:27][CH:26]=[C:25]([C:18]3([C:16]#[N:17])[CH2:23][CH2:22][C:21](=[C:3]4[S:8][CH2:7][CH2:6][CH2:5][S:4]4)[CH2:20][CH2:19]3)[C:30]=2[N:31]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2nc(C(C)C)oc12
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2(C#N)CCC(=C3SCCCS3)CC2)c2nc(C(C)C)oc12
Temperature: -70 °C

Procedure:
2-Trimethylsilyl-1,3-dithiane (2.1 ml, 11.01 mmol) is dissolved in absolute THF (56 ml) and cooled to −70° C. with stirring. A solution of n-butyllithium in n-hexane (6.9 ml, 11.1 mmol of a 1.6 molar solution) is then slowly added dropwise under a nitrogen atmosphere by means of a glass syringe and the mixture is stirred at −45° C. for a further 30 min. After cooling to −70° C. again, a solution of 4-cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexanone (1.5 g, 4.80 mmol, compound 3) in absolute THE (33 ml) is slowly added dropwise. The mixture is stirred at −70° C. for 1 h and then slowly warmed to RT (about 2 h). For working-up, the reaction solution is diluted with ethyl acetate (80 ml) and extracted (2 times) with 0.1 N hydrochloric acid (80 ml). The organic phase is dried using magnesium sulfate, filtered off and concentrated in vacuo. Column chromatography affords the title compound (1.34 9) as a colorless solid. TLC, silica gel (glass plates), petroleum ether/ethyl acetate (85:15), Rf=0.6.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)=[O:7]>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH:5]([S:2][CH3:1])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CSC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of sodium methanethiolate (0.43 g) at rt in methanol (15 ml) were added the (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (0.5 g, example 81.1) and a catalytic amount of tetrabutyl ammonium iodide. The mixture was then stirred at rt for 1 hr. The mixture was concentrated. The residue was taken up in EtOAc, washed with 1.0 N and brine, dried over MgSO4, filtered and concentrated. The product was isolated by chromatography (silica gel, cyclohexane/EtOAc 2:1) to give (RS)-N-(4-cyano-benzyl)-2-methylsulfanyl-2-phenyl-acetamide (0.36 g). Colorless solid. MS 297.2 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1.OS(O)(=O)=O.[CH3:16]O>O>[CH3:16][O:9][C:8]([C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[S:7][CH:6]=1)=[O:10]
Reactant: O=C(O)c1csc(CO)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1csc(CO)c1
Yield: 56 %

Procedure:
A mixture of 5-hydroxymethyl-thiophene-3-carboxylic acid (14.5 g, 91.7 mmol), concentrated H2SO4 (5.2 mL, 93.5 mmol) and methanol (250 mL) is heated to reflux for 3.5 h. After cooling, the mixture is poured into water and extracted with dichloromethane (3×). The combined extracts are washed successively with saturated aq NaCl, aq NaHCO3 and water followed by drying over Na2SO4, filtration and concentration in vacuo. The residue is purified by distillation to give 5-hydroxymethyl-thiophene-3-carboxylic acid methyl ester (8.8 g, 56%) as a clear oil: bp 155-157° C./6-7 mbar; 1H NMR (CDCl3, 300 MHz) δ 7.98 (s, 1 H), 7.35 (s, 1 H), 4.78 (s, 2 H), 3.80 (s, 3 H), 2.63 (s, 1 H).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]([O:12][P:13]([CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>N1C=CC=CC=1.ClCCl>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23]([C:22]1[CH:26]=[CH:27][C:19]([CH2:18][P:13](=[O:14])([O:12][CH2:10][CH3:11])[O:15][CH2:16][CH3:17])=[CH:20][CH:21]=1)=[O:24])#[N:9]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: N#Cc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Reaction time: 12 h

Procedure:
A 15.7 g portion of anthranilonitrile was dissolved in 50 ml of pyridine. While the solution was stirred under ice-cooling, a solution of 40.7 g of 4-[(diethoxyphosphoryl)-methyl]benzoyl chloride in 50 ml of dry dichloromethane was added dropwise. The stirring was continued at room temperature for 12 hours, after which the reaction mixture was diluted with 200 ml of dichloromethane and washed with diluted hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-n-hexane to provide 25.9 g of diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzyl-phosphonate as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[I-].[K+]>CN(C=O)C>[CH2:34]([S:9]([C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[C@@H:12]1[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[C:14](=[O:31])[N:13]1[CH3:32])(=[O:11])=[O:10])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cc2ccccc2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 101 μmol; purity 32%) was suspended in DMF (1 ml). Benzyl bromide (173 mg, 1.01 mmol; 10 eq.) was then added, and the mixture was heated in a closed tube at 110° C. for 24 h. Molecular sieve (4 Å), potassium iodide (110 mg, 0.66 mmol) and further benzyl bromide (173 mg, 1.01 mmol; 10 eq.) were then added, and the reaction mixture was again heated in a closed tube at 100° C. for 6 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (49.3 mg, 89% of theory).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([CH:21]=[O:22])[CH:8]=1)(=O)=O.B(O)(O)[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:18][C:15]1([CH3:17])[CH2:14][CH2:13][C:12]([CH3:19])([CH3:20])[C:11]2[CH:10]=[C:9]([CH:21]=[O:22])[CH:8]=[C:7]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]1=2
Reactant: CC1(C)CCC(C)(C)c2c(OS(=O)(=O)C(F)(F)F)cc(C=O)cc21
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C=O)cc3c2C(C)(C)CCC3(C)C)cc1
Temperature: 90 °C
Yield: 85 %

Procedure:
1.4 g (3.8 mmol) of 3-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthyl 1,1,1-trifluoromethanesulfonate are dissolved in 50 mL of DME, followed by 625 mg (4.6 mmol) of p-tolylboronic acid. 485 mg (11.4 mmol) of lithium chloride and 4.6 mL (9.2 mmol) of 2 M potassium carbonate solution are added to the reaction medium, which is then degassed with a flow of nitrogen and then heated to 90° C. 220 mg of tetrakis(triphenylphosphine)palladium are added and the reaction medium is stirred at reflux for 20 hours, then hydrolysed and extracted with ethyl acetate. The residue obtained is purified by chromatography, to give an orange-colored oil (m=980 mg; yield=85%).
Reaction SMILES: [CH2:1]([N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:12]([O:14]C)=O)[CH3:7])[CH2:2][CH:3]([CH3:5])[CH3:4].O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:56].Cl.[NH2:58][C@@:59](C)([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:60]([OH:74])[CH2:61][NH:62][C:63]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]#[CH:73])[CH:67]=2)[CH2:65][CH2:64]1>O1CCCC1.CO.O.C(OCC)(=O)C>[ClH:56].[ClH:56].[F:82][C:80]1[CH:81]=[C:76]([CH:77]=[C:78]([F:83])[CH:79]=1)[CH2:75][C@H:59]([NH:58][C:12](=[O:14])[C:11]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:9]([CH2:8][N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH3:7])[CH:10]=1)[C@H:60]([OH:74])[CH2:61][NH:62][C:63]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]#[CH:73])[CH:67]=2)[CH2:65][CH2:64]1
Reactant: COC(=O)c1cc(C)cc(CN(C)CCC(C)C)c1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@](C)(N)Cc3cc(F)cc(F)c3)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3cc(C)cc(CN(C)CCC(C)C)c3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-{[isopentyl(methyl)amino]methyl}-5-methylbenzoate (250 mg, 0.95 mmol) in tetrahydrofuran/methanol/water (2:1:1, 8 mL) is added lithium hydroxide monohydrate (80 mg, 1.9 mmol), and the reaction is stirred at room temperature 16 h. The solution is concentrated under reduced pressure, redissolved in DMF (5 mL), and diisopropylethylamine (660 μL, 3.8 mmol), HATU (540 mg, 1.4 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochloride (450 mg, 1.05 mmol) are added. The reaction stirred at room temperature 2 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 588.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]1>CN(C=O)C.C(N(CC)CC)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
1,2-dichloro-4-(chloromethyl)benzene (390 mg, 1.99 mmol)) was added to a solution of tert-butyl 4-piperidinylcarbamate (400 mg, 2.0 mmol) in DMF (25 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 3 hrs and then concentrated in vacuo. To the solution of the solid in dichloromethane was added (30 ml) trifluoroacetic acid (6 ml) was added and stirred at room temperature for 2 hrs. The solution was diluted with dichloromethane and washed with two portions of water. The combined water washings were treated with 2M NaOH to pH 10 and extracted with ether. The ether was dried (Na2SO4), filtered and evaporated to leave a yellow residue (300 mg, 1.16 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)C2CCCCC21

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2,5-dione (3.6 g) in acetic acid (50 ml) is hydrogenated for 120 hours at 3 atmospheres pressure using platinum oxide (1.2 g) as catalyst. The catalyst is filtered off and the filtrate evaporated under reduced pressure. The residue is distributed between dichloromethane (200 ml) and saturated aqueous sodium bicarbonate (100 ml). The dichloromethane solution is washed with water (50 ml), dried over sodium sulfate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel eluting with 0-50% ethyl acetate in toluene. The fraction eluting with 50% ethyl acetate in toluene is collected to give 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2,5-dione used without further purification for the next synthetic step.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25][CH:24]2[CH2:27][NH:28][CH2:29][CH:23]12.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:28]2[CH2:27][CH:24]3[CH:23]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC2CN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)CC21
Temperature: 140 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (180 mg, 0.537 mmol, Example 1, Step I), tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate hydrochloride (334 mg, 1.34 mmol), and DIEA (0.234 mL, 1.34 mmol) in n-BuOH (2 mL) was stirred at 140° C. for 5 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The residue obtained was purified by reverse phase HPLC (Gilson) to provide tert-butyl 5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (50 mg, 18% yield).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([C:16]1[C:17](=[O:24])[O:18]C(C)=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14].CI>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:13]([C:16]1[C:17](=[O:18])[O:24][C:7]([CH2:5][CH3:6])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1cc(O)c(C(C)=O)c(=O)o1
Temperature: -10 °C
Yield: 47.1 %

Procedure:
A solution of diisopropylamine (2.6 mL, 18.1 mmol) in anhydrous tetrahydrofuran (5 mL) under argon at −40° C. was treated dropwise with n-butyllithium (7.0 mL, 2.5 M in hexanes). The resulting solution was allowed to warm to −10° C. over 15 minutes. In a separate flask, hexamethylphosphoramide (2 mL) and 3-acetyl-6-methyl-4-hydroxy-2-pyrone (923 mg, 5.49 mmol) were combined and azeotroped to dryness with benzene (3×25 mL) before being dissolved in anhydrous tetrahydrofuran (5 mL). To the LDA solution at −78° C. was added dropwise over 5 minutes the solution of hexamethylphosphoramide and 3-acetyl-6-methyl-4-hydroxy-2-pyrone. The reaction mixture became a solid red/orange mass after the addition was complete and was kept at −78° C. for 40 minutes before methyl iodide (0.38 mL, 6.04 mmol) was added in a single portion. The reaction flask was removed from the cooling bath and swirled vigorously by hand as it warmed to room temperature over 20 minutes. Over this time the solid mass dissipated and became a coarse precipitate. The reaction mixture was poured into 30 mL 1 N hydrochloric acid and organics were extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with 5% aqueous sodium bisulfite and brine (30 mL each), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10% ethyl acetate in hexanes+1% acetic acid) to afford 3-acetyl-6-ethyl-4-hydroxy-2-pyrone (471 mg, 47%) as a white solid: LRMS (ES+) m/z [M+H]+. found 183 (Exact mass=182.06). Used without further characterization.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[N:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: Cc1cncc(B(O)O)c1
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: COCCOC
Solvent: O
Product: Cc1cncc(-c2cc(C=O)c(C)o2)c1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 5-methyl-3-pyridineboronic acid (1.6 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.6 g, 81%) as a white crystal.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][CH:10]1[CH3:19])C1C=CC=CC=1.Cl.C[C@H]1[C@@H](N)CCOC1>>[CH3:18][S:15]([N:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[C@H:10]([CH3:19])[CH2:11]1)(=[O:17])=[O:16]
Reactant: CC1CN(S(C)(=O)=O)CCC1NCc1ccccc1
Agent: C[C@@H]1COCC[C@@H]1N
Agent: Cl
Product: C[C@@H]1CN(S(C)(=O)=O)CC[C@@H]1N

Procedure:
Racemic cis 1-methanesulfonyl-3-methyl-piperidin-4-yl-amine was prepared in the same manner from racemic benzyl-(1-methanesulfonyl-3-methyl-piperidin-4-yl)-amine. In this instance, 1 atm H2 was used instead of 55 psi, and the HCl treatment was omitted.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH:11]([CH3:13])[CH3:12])([O-:10])=[O:9]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 97.8 %

Procedure:
To a solution of 2-fluoronitrobenzene (0.5 mL, 4.7 mmol) in DMSO (10 mL) is added isopropylamine (0.6 mL, 7.1 mmol), followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. overnight. The reaction is then cooled to room temperature and poured over ice H2O and extracted ethyl acetate. The organic layer is washed with H2O, brine, dried (Na2SO4) and concentrated to afford the title compound (828 mg, 97%) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[Si]([C:15]([F:18])([F:17])[F:16])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:15]([F:18])([F:17])[F:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(Br)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1.5 g, 7.5 mmol) in THF (20 mL) was added TMSCF3 (2.2 g, 15.5 mmol) at 0° C. and then TBAF (1.1 mL, 1.0 M in THF). The mixture was stirred at RT for 1 h, then diluted with HCl (3.0 M, 10 mL), stirred at RT for 1 h and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol as an off-white solid.