Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1.[CH3:18][C:19](=[O:23])[O:20][CH2:21]C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH3:21][O:20][C:19](=[O:23])[CH:18]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[C:19]([O:20][CH3:21])=[O:23]
Reactant: Cc1ccc(Br)cc1C
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(C)c(C)c1
Temperature: 25 °C

Procedure:
(In analogy to a procedure given in J. Am. Chem. Soc. 122 (2000), 1360-1370.) To a suspension of Pd(OAc)2 (455 mg), 2-(di-tert.-butylphosphino)-biphenyl (1.21 g) and K3PO4 (39.6 g) in THF (200 ml) dimethylmalonate (12.85 g) and 1-bromo-3,4-dimethyl-benzene 15.0 g) was added under argon. The mixture was refluxed for 16 h, cooled to rt and diluted with EA (300 ml) and filtered. The filtrate was evaporated and the resulting brown oil was purified on silica gel eluting with heptane:EA 4:1 to 1:1 to give 2-(3,4-dimethyl-phenyl)-malonic acid dimethyl ester (16.2 g) as a colourless oil which slowly crystallises. 1H-NMR (300 MHz, CDCl3): 2.25(s, 3H), 2.26(s, 3H), 3.75(s, 6H), 4.59(s, 1H), 7.10–7.20(m, 3H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[C:10]([C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[S:2]([N:1]=[C:19]=[O:20])(=[O:3])=[O:4])([O:12][CH3:13])=[O:11]
Reactant: CCCCN=C=O
Reactant: COC(=O)C1=C(S(N)(=O)=O)CCC1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1

Procedure:
In 75 ml of dry xylenes was placed 4.0 g of methy 2-(aminosulfonyl)-1-cyclopentene-1-carboxylate (VIII), 6.5 ml of n-butyl isocyanate, and 0.05 g of DABCO. The mixture was heated to reflux (ca 138°) then contacted with an excess of phosgene which was condensed into the mixture from a dry-ice condenser until the reflux temperature dropped to 126°. Over several hours the temperature increased to 135° and additional phosgene was condensed into the mixture, again, lowering the temperature to 129°. This process was repeated until no temperature increase could be observed, indicating complete consumption of the sulfonamide. The mixture was then cooled and the xylenes removed under reduced pressure to yield ca 5 g of an amber oil. An infrared spectrum (neat) exhibited a strong absorption at 2230 cm-1 indicating the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31]>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[O:31])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccccn4)cc3C2=O)C(=O)N1
Yield: 49.3 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and pyridine-2-carbonyl chloride hydrochloride (0.64 g, 3.60 mmol) in THF (50 mL), was added TEA (1.46 mL, 10.50 mmol) at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and dried in vacuo to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.58 g, 49% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.17 min (99.35%); mp: 212-214° C.; 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.43-2.62 (m, 2H, CHH, CHH), 2.81-2.96 (m, 1H, CHH), 4.66 (d, J=6.4 Hz, 2H, CH2), 5.14 (dd, J=5.3, 12.6 Hz, 1H, CH), 7.61-7.66 (m, 1H, Ar), 7.80-7.90 (m, 3H, Ar), 7.97-8.07 (m, 2H, Ar), 8.67-8.69 (m, 1H, Ar), 9.64 (t, J=6.4 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 42.37, 48.98, 122.07, 122.11, 123.52, 126.73, 129.79, 131.57, 133.58, 137.86, 147.49, 148.54, 149.71, 164.29, 166.99, 167.14, 169.81, 172.72; Anal Calcd for C20H16N4O5+0.05H2O: C, 61.08; H, 4.13; N, 14.25. Found: C, 60.81; H, 3.82; N, 14.15.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:6]=1.[BH4-].[Li+].O>ClCCl>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(N2CCNC2=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Product: O=C1NCCN1c1cccc(CCO)c1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
Methyl[3-(2-oxo-1-imidazolidinyl)phenyl]acetate was dissolved in dry dichloromethane (10 vol). Lithium borohydride (2M solution in THF, 4.3 vol) was added dropwise over 1 hour at 20° C. The resulting suspension was stirred at 20° C. for 2.5 hours. Water (2 vol) is added dropwise at 20° C. over 60 minutes. The resulting suspension was concentrated to 2 vol and aqueous ammonium chloride solution (7%, acidity corrected with 10% hydrochloric acid to pH 3, 3 vol) was added. The suspension was stirred at 20° C. for 2 hours then filtered. The filter-cake was washed thoroughly with aqueous ammonium chloride solution (7%, acidity corrected with 10% hydrochloric acid to pH 3, 2 vol) and water (2 vol) until the filtrate had an acidity of pH 7. The filter-cake was dried at 80° C. to give the title compound (75% th.).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]([CH2:30][S:8][C:9]2[C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:32][CH:33]=1
Reactant: ClCc1ccnc2ccccc12
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccnc1S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccnc1SCc1ccnc2ccccc12
Yield: 52 %

Procedure:
Triethylamine (66 μL, 0.47 mmol) was added to a solution of 2-mercapto-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Reference Compound No. 8-3, 52 mg, 0.17 mmol) and 4-(chloromethyl)quinoline (Reference Compound No. 5-1, 28 mg, 0.16 mmol) in anhydrous N,N-dimethylformamide (11.0 mL) at room temperature, and the mixture was stirred for 18 hours. Ethyl acetate (50 mL) was added thereto, then the whole was washed with saturated aqueous sodium hydrogencarbonate solution (5 mL) and brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 40 mg of the title compound as a white amorphous (Yield: 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH2:28])[C:22]2=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH:28][C:15]([C:11]3[C:12]([CH3:14])=[N:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][CH:10]=3)=[O:17])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 66.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.34 mmol), DIPEA (158 mg, 4.02 mmol) and HATU (1.60 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 h. DMF is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (3×20 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-60% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (340 mg) as a solid. MS: 380 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 2.86 (s, 3H), 6.84 (d, H), 7.12-7.35 (m, 2H), 7.52 (q, H), 7.63 (t, H), 8.10-8.43 (m, 2H), 8.98 (br, N—H).
Reaction SMILES: [OH2:1].Cl[C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[H-].[Na+].Cl>O1CCCC1>[Cl:17][C:10]1[C:4]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[C:3]([OH:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
3.2 ml (177.6 mmol, 4.2 eq) of water and 11.04 g (41.96 mmol; 1.0 eq) of 2,6-dichloro-N,N-dimethyl-3-nitrobenzamide (41.96 mmol; 1.00 eq.) in solution in 130.00 ml of tetrahydrofuran were added to a suspension of 7.16 g (179.01 mmol; 4.3 eq) sodium hydride in 250 ml of tetrahydrofuran cooled to 0° C. After 10 min, the reaction medium was stirred at ambient temperature for 19 hours. The reaction medium was hydrolyzed with a 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with a 1 N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue (11.82 g) was chromatographed on silica gel (300 g prepacked column, eluent heptane/ethyl acetate from 40% to 80% of ethyl acetate, 150 ml/min). 6.10 g of 6-chloro-2-hydroxy-N,N-dimethyl-3-nitrobenzamide were obtained in the form of a yellow solid. Yield=59%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:29]4[CH:34]=[CH:33][C:32]([O:35][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=4)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[NH4+]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(O)cc2)cc1
Reaction time: 2 h

Procedure:
(1S,2S)-2-(4-{(R)-4-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-5-trifluoromethyl-indan-1-yloxy}-phenyl)-cyclopropanecarboxylic acid ethyl ester (90 mg, 0.15 mmol is suspended in dry tetrahydrofuran (4.5 mL) and tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.3 mL, 0.3 mmol) is added. The mixture stirred for 2 hours then diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried and concentrated under vacuum. The residue is purified by flash chromatography (eluent: 0-20% EtOAc in cyclohexane) to give an impure product which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][CH:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([CH:12]1[CH2:11][N:9]2[C:10]3[C:6]([C:7]([CH2:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22])=[C:8]2[CH2:14][CH2:13]1)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[N+:28]=[N-:29]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(OS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred solution of propyl {4-fluoro-7-[(methylsulfonyl)oxy]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate (1 eq) in DMF (0.15M) at 0° C. was added sodium azide (1.2 eq). The reaction mixture was stirred at 60° C. for 6 h. The reaction was quenched by addition of water and NH4Cl, extracted with EtOAc, washed with water, brine, dried and evaporated. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexanes (0 to 50%) to give the desired material as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.N>Br>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: Br
Agent: N
Solvent: O
Product: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 95.6 %

Procedure:
The product from step (i) (1.5 g) in concentrated hydrobromic acid (30 ml) was heated under argon at 130°-135° C. for 21/2 hours. The solution was cooled, poured into water (150 ml) and basified with aqueous ammonia. The precipitate was filtered, washed with water and dried to give 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.36 g) as a solid: m.p. 310°-312° C.; NMR(d6DMSO) δ8.2(2H,d); 6.8(4H,m); 6.66(2H,d); 3.45(4H,m); 3.08(4H,m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29].Cl>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C#CCCCO
Agent: I[Cu]I
Agent: [Pd]
Agent: Cl
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To 2.25 g (6.25 mmol) Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol-5-yl ester in 12.5 ml piperidine were added 360 mg (0.31 mmol) tetrakis(triphenylphosphine)-palladium followed by 60.0 mg (0.31 mmol) copper iodide. The solution was evaporated and flushed with argon prior to the addition of 450 μl (4.95 mmol) 4-pentynol at 80° C. over a period of 45 min. Further 0.45 ml (4.95 mmol) 4-pentynol were added and the solution was stirred for 2 h. The mixture was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Purification by column chromatography with CH2Cl2/MeOH 19:1 yielded 1.4 g (76%) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol as light yellow waxy solid, MS: 293 (M).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>O1CCOCC1.FC(C1C=CC=CC=1)(F)F>[C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)[CH2:18][C@@H:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)C[C@@H]1Cc1ccccc1
Temperature: 180 °C
Yield: 89.6 %

Procedure:
To a solution of 2,6-dichloropyrazine 114 (0.1 g, 0.67 mmol.) and (S)-1-Boc-2-benzylpiperazine 107 (0.37 g, 1.34 mmol) in dioxane (2 mL) and trifluoromethylbenzene (2 mL) was added diisopropylethylamine (0.26 g, 2.0 mmol). The reaction mixture was heated in a microwave reactor at 180° C. for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 2-[(S)-4-Boc-3-benzylpiperazinyl]-6-chloropyrazine 115 (0.234 g, 0.6 mmol).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:21][C:22]3[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=3)=[N:3][CH:4]=[C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:6]=2)[N:9]=1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Reactant: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cnc(Nc2cnc(C)c(NS(C)(=O)=O)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 335 Step 3) (0.050 g, 0.179 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.043 g, 0.215 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.145 mL, 0.716 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was partitioned between sat. NH4Cl and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (25 mg). MS (ESI pos. ion) m/z: 461.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (d, J=2.63 Hz, 6H) 2.52 (s, 3H) 3.06 (s, 3H) 3.61-3.73 (m, 2H) 4.09-4.23 (m, 2H) 7.77 (br. s., 1H) 7.89 (br. s., 1H) 8.17 (d, J=2.92 Hz, 1H) 8.33 (d, J=1.75 Hz, 1H) 8.42 (d, J=3.07 Hz, 1H) 8.65 (s, 1H) 9.29 (br. s., 1H) 11.76 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:8][CH:7]=1)=O.CI.CN(C)[CH:36]=[O:37]>>[CH:36]([CH2:3][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=2[C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:10][CH:11]=1)=[O:37]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NC=O)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NCC=O)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%; 40 mg) was added to an ice-cooled solution of ethyl 5-[4-(formylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.35 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at ambient temperature for 30 minutes, and to the resulting mixture was added methyl iodide (0.23 g) at 5° C. The mixture was stirred at ambient temperature for 1.5 hours and poured into ice-water. The precipitates were collected, washed with water, and dried in vacuo to give ethyl 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.34 g).
Reaction SMILES: NN.[C:3]([C:6]1[O:7][C:8]2[C:9](=[C:11]([S:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=1)(=O)[CH3:4].C(=O)([O-])[O-].[K+].[K+].O>C=C.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:21]([NH:20][S:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:8]2[O:7][C:6]([CH2:3][CH3:4])=[CH:10][C:9]=12)(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)c2cc(C(C)=O)oc12
Agent: C=C
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2c(S(=O)(=O)NCc3ccccc3)ccc(OC)c2o1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
Hydrazine (6.96 g) was added to a suspension of Example 2 (10 g) in ethylene glygol (120 ml) at 38° C. The mixture was heated and potassium carbonate (7.7 g) was added at 65° C. Heating was continued until a temperature of 170° C. was attained. The mixture was cooled to room temperature and poured into a mixture of brine (300 ml), water (300 ml) and ethyl acetate (300 ml). The aqueous layer was extracted with ethyl acetate (2×300 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was applied to a silica column and eluted with 30% ethyl acetate in heptane to provide the title compound as an off-white solid (5.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:15][C:16]([CH:31]1[CH2:34][NH:33][CH2:32]1)([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.O.FC(F)(F)C(O)=O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([N:33]1[CH2:34][CH:31]([C:16]([CH3:17])([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)(=[O:19])=[O:20])[CH3:15])[CH2:32]1)=[O:9]
Reactant: CC(C)(C1CNC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(F)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C1CN(C(=O)c2cc(F)ccc2S(C)(=O)=O)C1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 10 ml vial was added 5-fluoro-2-(methylsulfonyl)benzoic acid (35.5 mg, 0.163 mmol), 3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine (50 mg, 0.163 mmol), Bop reagent (79 mg, 0.179 mmol), diisopropylethyl amine (0.142 ml, 0.813 mmol) and 1 ml dimethylformamide. The resulting solution was stirred at room temperature for 1 hour. It was diluted with 1 m dimethyl sulfoxide, 0.5 ml water and 0.1 ml trifluoroacetic acid. This mixture was loaded on to reverse phase column directly eluted with water acetonitrile gradient solvent to give the title compound as a fluffy white solid after lyophilizing.