Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14]S[C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([OH:19])=[O:18])[O:12][CH2:11][CH2:10][O:9]3.C([O-])(=O)C.[Na+].O[O:26][S:27]([O-:29])=O.[K+].Cl>O.CO>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:27](=[O:29])(=[O:26])[C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([OH:19])=[O:18])[O:12][CH2:11][CH2:10][O:9]3
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC21OCCO1
Reactant: O=S([O-])OO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC21OCCO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
4.73 g (0.017 mol) of the title compound of Step E and 2.08 g (0.025 mol) of sodium acetate were added to 85 mL of methanol. The solution was cooled to about 0° C., and a solution of 17.66 g (0.029 mol) of OXONE® (purchased from Aldrich Chemical Company) in 85 mL of water was added dropwise while keeping the temperature below 6° C. The mixture was warmed to room temperature and stirred under nitrogen overnight. The mixture was diluted with 50 mL of water, cooled to about 0° C., acidified to around pH 2 with concentrated hydrochloric acid, and then extracted with chloroform (3×150 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to dryness. The residue was triturated in diethyl ether:hexane (1:9) which was decanted to yield 4.18 g of the title compound of Step F as a solid melting at 185° C. (dec). 1H NMR (Me2SO-d6): δ2.35 (s,3H), 2.5 (m,2H), 2.6 (s,3H), 3.5 (m,2H), 4.16 (m,2H), 4.2 (m,2H), 7.6 (s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[NH:13][C:12]=2[C:30]([O:32][CH3:33])=[O:31])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[CH2:43][CH2:44]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[N:13]([CH2:44][CH2:43][C:42]3[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:40]([O:39][CH3:38])[CH:41]=3)[C:12]=2[C:30]([O:32][CH3:33])=[O:31])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1c(C(=O)OC)[nH]c(C(=O)OC)c1-c1ccc(OC)c(OC)c1
Reactant: COc1ccc(CCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(OC)c(OC)cc1-c1c(-c2ccc(OC)c(OC)c2)c(C(=O)OC)n(CCc2ccc(OC)c(OC)c2)c1C(=O)OC
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A stirred mixture of 8 (297 mg, 0.58 mmol, 1.0 equiv), 3,4-dimethoxyphenethyl bromide (9,15 707 mg, 2.88 mmol, 5.0 equiv), and K2CO3 (398 mg, 2.88 mmol, 5 equiv) in DMF (5.8 mL) under Ar was warmed to 70° C. After 2.5 h, the mixture was cooled to 25° C. and solvent was removed in vacuo. Chromatography (SiO2, 3.5×15 cm, 20% EtOAc/CH2Cl2) provided 10 (372 mg, 94% yield) as a yellow oil: FABHRMS (NBA/NaI) m/z 702.2553 (M+Na+, C36H41NO12 requires 702.2526).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25]>C(O)C.P([O-])(O)(O)=O.[K+]>[CH2:1]([O:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2n(O)c1=O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Benzyl bromide (72 ml, 0.60 mol) was added to a suspension of 1-hydroxy-7-trifluoromethylquinoxaline-2,3(1H,4H)-dione (49.2 g, 0.20 mol) in 2.5 l of ethanol and 800 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4). The mixture was stirred at room temperature overnight, and filtered. The precipitate was washed with water and dried to give 59.5 g (89%) of the title compound. M.p.>220° C. decomp.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:37]1([C:43]2[CH:48]=[C:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56]([C:58]2[NH:59][CH:60]=[C:61]([C:63]#[N:64])[CH:62]=2)=[O:57])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:37]1([C:43]2[CH:48]=[C:47]([CH:49]3[CH2:50][CH2:51][N:52]([C:5](=[O:7])[CH2:4][N:2]([CH3:3])[CH3:1])[CH2:53][CH2:54]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56]([C:58]2[NH:59][CH:60]=[C:61]([C:63]#[N:64])[CH:62]=2)=[O:57])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1
Reactant: CN(C)CC(=O)O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.6 %

Procedure:
A suspension of 9.10 mg (0.0881 mmol) dimethylamino-acetic acid in 5 mL CH2Cl2 was treated with 21.7 mg (0.0852 mmol) BOP—Cl and 32.8 μL (0.235 mmol) triethylamine at RT for 50 min. This mixture was added to a suspension of 22.0 mg (0.0588 mmol) 4-cyano-1H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in the previous step) in 5 mL CH2Cl2. The mixture stirred at RT for 23 h, was diluted with CH2Cl2 (15 mL), and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification of the residue by RP-HPLC (C18) with 20-80% CH3CN in 0.1% TFA/H2O over 30 min to afford 33.6 mg (83%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 7.54 (d, 1H, J=1.6 Hz), 7.41 (d, 1H, J=8.0 Hz), 7.14 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.12-7.08 (m, 1H), 7.07 (d, 1H, J=2.0 Hz), 5.70-5.65 (m, 1H), 4.67-4.59 (m, 1H), 4.26 (q, 2H, J=16.4 Hz), 3.78-3.70 (m, 1H), 3.26-3.17 (m, 1H), 2.97-2.89 (m, 6H), 2.88-2.75 (m, 2H), 2.25-2.18 (m, 2H), 2.15-2.07 (m, 2H), 1.94-1.85 (m, 2H), 1.76-1.54 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H33N5O2, 460.3 (M+H), found 460.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](Cl)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[F:30][C:31]([F:38])([F:37])[C:32]([CH3:36])([OH:35])[CH2:33][CH3:34]>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:35][C:32]([C:31]([F:38])([F:37])[F:30])([CH3:36])[CH2:33][CH3:34])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reactant: CCC(C)(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
900 mg of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-chloro-3-oxo-1-propenyl]-cyclopropane-carboxylate were dissolved in 3 ml of methylene chloride and 1 ml of 1-trifluoromethyl-1-methyl propanol was added thereto. The mixture was stirred for 16 hours at room temperature under inert atmosphere and away from humidity. After 3 days at room temperature, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, then with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 8--2 mixture of hexane-ethyl ether to obtain 570 mg of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(1-trifluoromethyl-1-methylpropyloxy)-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][NH:4][C:3]1=[O:11].[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].[OH-].[Li+].Cl>CN(C)C=O.O>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([CH:15]([CH3:17])[CH3:16])[C:3]1=[O:11]
Reactant: CC(C)I
Reactant: COC(=O)C1CNC(=O)N1C
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CC(C(=O)O)N(C)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
A stirred solution of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in N,N-dimethylformamide (5 ml) was cooled to 0° C. under argon and treated with sodium hydride (60% dispersion in oil) (120 mg, 3.00 mmol). After 10 minutes 2-iodopropane (0.400 ml, 4.00 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. A solution of lithium hydroxide (57.5 mg, 2.400 mmol) in water (1 ml) was added and the reaction mixture was stirred at room temperature for 30 minutes. Hydrochloric acid (2M) was added to adjust the pH of the mixture to pH 2 and the solvent was evaporated. Dimethylsulfoxide (3 ml) was added to the residue and the suspension was filtered. The filtrate was purified by mass-directed automated HPLC to give 3-methyl-1-(1-methylethyl)-2-oxo-4-imidazolidinecarboxylic acid (100 mg, 27%, over 2 steps). LC/MS [M+H]+=187.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([S:39][CH2:40][CH2:41][C:42]([NH2:44])=[O:43])=[C:35]([C:45]([F:48])([F:47])[F:46])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:8][C:4]1[CH:3]=[C:2]([C:33]2[CH:38]=[CH:37][C:36]([S:39][CH2:40][CH2:41][C:42]([NH2:44])=[O:43])=[C:35]([C:45]([F:47])([F:48])[F:46])[CH:34]=2)[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Reactant: Cc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)ccn1
Temperature: 80 °C
Reaction time: 22 h
Yield: 68.6 %

Procedure:
4-Bromo-2-methylpyridine (6.0 g, 34.9 mmol) was dissolved in dimethylformamide (60 mL) before potassium acetate (10.0 g, 102 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (10 g, 39.4 mmol) were added at room temperature. The solution was degassed and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547 mol) was added. The brown reaction mixture was stirred for 22 h at 80° C. After cooling to room temperature, 3-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (8.0 g, 24.4 mmol), potassium carbonate (8.0 g, 57.9 mmol), dimethylformamide (20 mL), and water (16 mL) were added. The mixture was degassed, stirred for 30 min at room temperature and further [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547·mol) was added. The resulting brown reaction mixture was stirred for 20 h at 60° C. After cooling to room temperature, it was poured onto water (150 mL) and extracted with ethyl acetate (1×80 mL, 2×40 mL). The combined organic extracts were washed with brine/water (1:1 v/v, mL) and brine (20 mL), methanol (16 mL) was added and the mixture was dried over sodium sulfate. Silica gel (16 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 40 mL). The combined filtrates were concentrated in vacuo. The residue was treated with toluene/n-heptane (1:1 v/v, 24 mL) and the resulting suspension was stirred for 30 min at room temperature. After filtration, the precipitate was washed with toluene/n-heptane (4:1 v/v, 10 mL) and n-heptane (10 mL) and dried in vacuo to afford the title compound as brown crystals (5.7 g, 71%). MS (EI): m/z=341.1 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H).
Reaction SMILES: C[O-].[Na+].O1CCCC1.[CH:9]1([N:12]2[C:17](=[O:18])[C:16]3[C:19]([NH:26][C:27]4[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=4)=[C:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:15]=3[N:14]([C:38]3[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:39]=3[F:45])[C:13]2=[O:46])[CH2:11][CH2:10]1.C(O)(=O)C>CO>[CH:9]1([N:12]2[C:17](=[O:18])[C:16]3=[C:15]([NH:14][C:38]4[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:39]=4[F:45])[N:22]([CH3:23])[C:21](=[O:24])[C:20]([CH3:25])=[C:19]3[N:26]([C:27]3[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=3)[C:13]2=[O:46])[CH2:10][CH2:11]1
Reactant: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)n(C3CC3)c(=O)n(-c3cccc(NS(C)(=O)=O)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, to a solution (18.5 g) of 28% sodium methoxide in methanol was added tetrahydrofuran (284 ml), N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 45 (28.4 g) obtained in Step 1 was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid (12.5 ml) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added to the obtained solid, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight, and the crystals were collected by filtration and dried. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added again to the obtained crystals, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight. The crystals were collected by filtration and washed with a 9:1 mixed solvent of methanol and water and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide 46 (26.35 g, yield 93%) as white crystals.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12]2[C:13]([CH3:25])=[N:14][C:15]([NH2:24])=[N:16][C:17]=2[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:24][C:15]1[N:14]=[C:13]([CH3:25])[C:12]([CH2:11][C:7]2[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=2)=[C:17]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:16]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(C(=O)OCC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A solution of the product from step (iii) (0.7 g) in THF (10 mL) was added to a solution of lithium aluminium hydride (1M in THF, 4.1 mL) in THF (10 mL) at 0° C. The mixture was stirred at rt for 2 h, sodium sulfate decahydrate (10 g) was added and the suspension stirred for 1 h. The suspension was filtered and the filtrate diluted with saturated aq ammonium chloride (20 mL). The aqueous phase was separated and the organic phase dried and evaporated under reduced pressure to give the subtitle compound 0.60 g, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([N+]([O-])=O)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([O:35][C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][C:31]=2[F:36])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Reactant: Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2cc(Cl)nc3[nH]ccc23)c(F)c1
Temperature: 120 °C

Procedure:
A mixture of 1.80 g (9.11 mmol) of 6-chloro-4-nitro-1H-pyrrolo[2,3-b]pyridine, 3.78 g (27.3 mmol) of potassium carbonate and 3.17 g (18.2 mmol) of sodium dithionite in 26 ml of DMSO is degassed. 2.32 g (18.2 mmol) of 4-amino-2-fluorophenol are added, and the mixture is heated at 120° C. for 4 hours. The mixture is then diluted with ethyl acetate and filtered off with suction through Celite®. The filtrate is washed twice with sodium carbonate and once with sodium chloride solution, dried over sodium sulfate and concentrated. The product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 100:2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl.C([O-])(O)=O.[Na+]>[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2cccc(Cl)c2Cl)CCN1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a suspension of 2-piperazinone (5.3 g, 52.9 mmol) in dry dichloromethane (DCM) (76 ml) was added triethylamine (16.23 ml, 116 mmol) and finally 2,3-dichlorobenzoyl chloride (12.20 g, 58.2 mmol) dropwise (exothermic). The mixture was stirred at room temperature. After 1 hour the mixture was diluted with DCM (150 mL) and sat. NaHCO3 (150 ml), the phases were separated and the aqueous layer extracted with DCM (2×100 ml). The combined organic fractions were washed with brine and dried over MgSO4. Evaporation gave 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (12 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21](Br)[C:20]=2[F:27])=[O:16])[C@@H:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[F:27][C:20]1[C:19]([CH2:18][O:17][C:15]([N:11]2[C@H:12]([CH3:14])[CH2:13][NH:8][CH2:9][C@@H:10]2[CH3:28])=[O:16])=[C:24]([F:25])[CH:23]=[CH:22][C:21]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH3:29]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)OCc1c(F)ccc(Br)c1F
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(F)c(COC(=O)N2[C@H](C)CNC[C@@H]2C)c1F
Temperature: 25 °C

Procedure:
A mixture of 46.33 mg (0.1 mmol) cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid 1-(3-bromo-2,6-difluoro-benzyl) ester 4-tert-butyl ester, 16.71 mg (0.11 mmol) 2-methoxyphenylboronic acid, 3.65 mg (0.005 mmol) dichloro(1,1′-bis(diphenylphosphino) ferrocene)palladium (II) dichloromethane adduct and 0.11 ml of a 2M Na2CO3 aq. solution in 1.2 ml dioxane was heated for 17 h to 85° C. The mixture was filtered and 0.15 ml 4N HCl in dioxane was added and the mixture heated for 3 h to 65° C. After cooling to ambient temperature 0.2 ml triethylamine and water were added to dissolve the mixture. The solution was subjected to reversed phase preparative HPLC eluting with a water/acetonitrile gradient to yield after evaporation of the solvents 28.2 mg (66%) of the title compound. MS (ISP): 391 MH+
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:18])C(=O)C1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:18])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.0 g, 52.32 mmol, 1.0 eq) in DMF (40 mL), NIS (15.7 g, 57.55 mmol, 1.1 eq) was added at 0° C. The reaction mixture was stirred overnight at room temperature. Water (40 mL) was added to the reaction mixture, extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (14.6 g, 100% in yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]([O:41][CH3:42])[CH2:32][C@H:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34](O)=[O:35])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C@H:31]([O:41][CH3:42])[CH2:32][C@H:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:35])=[CH:29][CH:30]=1
Reactant: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (73.8 mg, 0.63 mmol), HOBT (340 mg, 2.5 mmol), NaHCO3 (423 mg, 2.9 mmol), and the (S)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)hexanoic acid in 30 mL DCM was added EDC.HCl (407 mg, 2.1 mmol) as solid. The reaction mixture was stirred for 3 h at room temperature and then the solvent was removed under reduced pressure. The product was isolated by flash column chromatography, eluting with 10% to 60% EtOAc/Hexane gradient solvent to give 128 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[Na+]>CCO.CC(O)=O.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Br)cc2cccnc12
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(Br)cc2cccnc12
Yield: 905.1 %

Procedure:
To a solution of 6-bromo-8-nitro-quinoline (4 g, 1.58 mmol) in EtOH/HOAc/H2O (50 mL/50 mL/25 mL) was added iron metal (3.18 g, 5.69 mmol). The resulting solution was heated at reflux for 3 hours. The cooled reaction mixture was neutralized with 2.5 N NaOH, filtered through celite to remove iron solids and washed with EtOAc. The eluent was extracted into EtOAc (3×200 mL), combined, dried over NASO4 and concentrated. The resulting oil was purified by column chromatography (40% EtOAc/hexanes) affording 3.19 g (91%) of a yellow solid: mp 142-145° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:21])[CH:10]=[C:11]([CH2:16][CH2:17][C:18](O)=[O:19])[C:12]=2[O:14][CH3:15])[N:7]([CH2:22][CH3:23])[CH:6]=1.C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C1COCC1.O>[CH3:1][N:2]([CH3:25])[C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:21])[CH:10]=[C:11]([CH2:16][CH2:17][C:18]([NH2:27])=[O:19])[C:12]=2[O:14][CH3:15])[N:7]([CH2:22][CH3:23])[CH:6]=1
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)O)cc(F)c21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(N)=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of 28-2 (180 mg, 0.51 mmol), HATU (388 mg, 1.02 mmol), DIPEA (220 mg, 1.7 mmol) and ammonium chloride (73 mg, 1.36 mmol) in THF (10 mL) was stirred at room temperature overnight. Water (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over MgSO4, filtered and evaporated to give crude product, which was purified by preparative TLC (petroleum ether/ethyl acetate=1:1) to afford 28-3 (150 mg, 84%) as a yellow solid. LRMS: calc 349.2 and found: 350.0 [M+1].