Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].O>C(Cl)Cl>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.05 g, 0.187 mmol) in DCM (1 mL) cooled to 0° C. were added triethylamine (0.038 g, 0.374 mmol) and isopropylsulfonylchloride (0.029 g, 0.206 mmol). The resulting suspension was stirred at 0° C. for 4 h and then allowed to warm up to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with DCM, poured into H2O (5 mL) and extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.023 g, 33%) as a white foam. MS: 374.1 (M+H+).
Reaction SMILES: [CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=[O:16])[CH2:7][O:8]CC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd].[C]>[CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=[O:16])[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCN(CCCC)C(=O)CO
Reaction time: 16 h
Yield: 111.1 %

Procedure:
4 g of N,N-di-n-butyl-2-benzyloxyacetamide were dissolved in 50 ml of ethanol, and a spatula tip of Pd/carbon was added. The mixture was stirred under a hydrogen atmosphere for 16 hours, and then the catalyst was filtered off and the solvent was distilled off. 3 g of an oil were isolated and were immediately reacted further.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[B]1OC2C(=CC=CC=2)[O:17]1>ClCCl.[Rh]>[C:10]1([C@@H:9]([OH:17])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: [B]1Oc2ccccc2O1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A solution of rhodium-complex (3.4 mg, 4 μmol) obtained in Example 28 in dichloromethane degassed with argon was transferred with a syringe to the reaction vessel. Dichloromethane was evaporated in vacuo, then dry toluene (1 ml) degassed with argon, styrene (41.7 mg, 0.4 mmol) and freshly distilled catecholborane (56 μl, 0.45 mmol) were added. The reaction mixture was stirred at room temperature for 2 hrs, cooled with ice-bath, and quenched with EtOH (1 ml). 2M aqueous sodium hydroxide solution (1 ml) and 30% aqueous hydrogen peroxide (1 ml) were added. The mixture was allowed to warm up to room temperature over 30 min and then stirred for 2 hrs at this temperature. Diethyl ether (10 ml) was added to the mixture, and the orange organic layer was then washed with 1M aqueous sodium hydoxide solution and then dried over sodium sulfate. After evaporation of the solvent, the product was purified by chromatography on silica gel (pentane/diethyl ether 2:1) to give 35.7 mg of the title compound. (Yield: 73%, optical purity: 92% ee)
Reaction SMILES: [ClH:1].[OH:2][C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:8][CH2:7][N:6]([CH:9]([F:23])[CH2:10][CH:11]([N+:20]([O-])=O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4]1.CO>[Pd].[H][H]>[ClH:1].[OH:2][C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:8][CH2:7][N:6]([CH:9]([F:23])[CH2:10][CH:11]([NH2:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)C(=O)c1ccccc1
Yield: 84.8 %

Procedure:
A mixture of 4.9 g of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone hydrochloride, 1.0 g of 5 % palladium on charcoal (50 % wet reagent) and 80 g of methanol was vigorously stirred in hydrogen atmosphere at room temperature until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and washed with hot methanol, and the filtrate was concentrated under reduced pressure. The residual solid was triturated with isopropanol, collected by filtration and washed with diisopropyl ether to afford 3.9 g of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-2-amino-4-fluorobutyrophenone monohydrochloride. M.P. 202°-204° C. The free base of this product was obtained by the conventional procedure. M.P. 106°-107° C (recrystallized from toluene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Br:16][C:17]1C=CC(OC(F)(F)F)=CC=1>>[Br:16][CH2:17][C:7]([C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OC(F)(F)F
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: O=C(CBr)c1cc(Br)ccc1OC(F)(F)F

Procedure:
The title compound was synthesized from 5-bromo-2-trifluoromethoxy-benzoic acid (prepared from 1-bromo-4-trifluoromethoxy-benzene by the orth-lithiation method according to Schlosser et al. Eur. J. Org. Chem. 2001, 21, 3991-3997) according to the general scheme 12.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:31][CH2:30]1
Reactant: O=CCCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCCC2CC(c3cccc([N+](=O)[O-])c3)=NO2)CC1
Yield: 48 %

Procedure:
4-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]butanal (25.2 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.312 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 18.3 mg (44.6%) of the target compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=2)[C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 84 (179 mg, 0.438 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was recrystallized (EtOAc:hexanes) to afford 120 mg (78%) of 85 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (br s, 6H), 2.13 (m, 4H), 6.45 (d, J=16.0 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 6.76 (dd, J=12.3 Hz, 1.7 Hz, 1H), 6.85 (t, J=8.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H) 9.76 (s, 1H), 12.31 (br s, 1H). LRMS (ESI): m/z 353 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]1[CH2:12][OH:13].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>C1COCC1>[Si:18]([O:13][CH2:12][CH:6]1[O:7][C:8]([CH3:10])([CH3:11])[O:9][CH:5]1[CH2:4][OH:3])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(CO)C(CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95801.8 %

Procedure:
To THF (50 mL), NaH (1.41 g, 0.032 mmol) was added at room temperature, followed by addition of ((4R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.0 g, 0.031 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr. After that, TBSCl (5.11 g, 0.034 mmol) was added at room temperature and stirred at room temperature overnight. The reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (8.21 g, 96%).
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10]([CH:12]1[CH:16]([C@H:17]([CH3:27])[CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:15][N:14]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:13]1)=[O:11]>N1C=CC=CC=1>[CH3:8][O:9][C:10]([CH:12]1[CH:16]([C@H:17]([CH3:27])[CH2:18][OH:19])[CH2:15][N:14]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:13]1)=[O:11]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CO
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Hydrogen fluoride-pyridine (2 mL) was added to a solution of 4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (6.0 g, 7.1 mmol) in pyridine (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 13 hours. Further 2 mL of hydrogen fluoride-pyridine was added, and the mixture was stirred for 23 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate and washing with 1N hydrochloric acid and brine. After drying over magnesium sulfate and filtration, the solvent was evaporated under reduced pressure to give 4.5 g (quantitative) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: C([O:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:21])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>C(O)C>[OH:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:21])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(OC(C)=O)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2c(nc1C)C(O)CCCC2
Reaction time: 24 h
Yield: 79 %

Procedure:
Ethyl 9-acetoxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (4.90 g, 16.81 mmol) was dissolved in ethanol (30 ml), and the solution was mixed with potassium carbonate (3.29 g) and stirred at from 0° C. to room temperature for 24 hours. There action solution was mixed with water and ethyl acetate, and the thus precipitated crystals were filtered. The resulting filtrate was extracted with ethyl acetate, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, the title compound (3.31 g, 79.9%) was obtained as pale yellow amorphous.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(C(C)C)n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)nc(C(C)C)n1

Procedure:
A mixture of 6.5 g (0.036 mol) of 4-hydroxy-2-isopropyl-6-methyl-pyrimidine and 16.8 g (0.108 mol) of phosphorus oxychloride in 40 ml of chloroform is heated at reflux for 2 hours. The solution is then concentrated under reduced pressure, the residue is poured into water and the aqueous phase is extracted twice with 100 ml of n-hexane each time. The organic phase is dried over anhydrous sodium sulphate and subsequently evaporated. There is obtained 4-chloro-2-isopropyl-6-methyl-pyrimidine in the form of an orange oil, 1H-NMR (CDCl3): 1.32 (d, CH(CH3)2), 2.48 (s, CH3), 3.17 (m, CH(CH3)2), 7.03 (s, CH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CO>[CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[CH:19][CH2:20][CH3:21]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC=COc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 12 %

Procedure:
A solution containing 4,4'-Dihydroxybiphenyl (5 g,26.75 mmol), KOH (1.65 g, 29.5 mmol) and methanol (50 ml) was refluxed for 2 hours. 4-Bromo-1-butene (3.975 g, 29.5 mmol) in methanol (10 ml) was added dropwise over a period of 2 hours to the refluxing reaction mixture. The refluxation was continued for 24 hours. The solvent was then removed. The product was then extracted by dichloromethane (50 ml) and dichloromethane was then removed. The resulting solid was washed with 10% potassium hydroxide solution (17 ml), filtered and recrystallized from ethanol: water (1.1 v/v) mixture. Yield 12%, m.p. 155-157° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]3[CH2:28][CH2:29][CH2:30][O:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: C1CNOC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCCO3)ccc2n1CC1CCOCC1
Yield: 34.6 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), isoxazolidine hydrochloride (44 mg, 0.40 mmol), DIPEA (0.2 mL, 149 mg, 1.15 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 24 mg (36%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.61 (m, 4 H), 1.63 (s, 9 H), 2.02-2.19 (m, 2 H), 2.25-2.42 (m, 1 H), 3.29-3.38 (m, 2 H), 3.64-3.73 (m, 2 H), 3.86 (t, J=7.13 Hz, 2 H), 3.88-3.96 (m, 2 H), 4.49 (d, J=7.42 Hz, 2 H), 7.98 (d, J=1.56 Hz, 1 H), 7.99 (s, 1 H), 8.24 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C20H29N3O4S+1.20 TFA+0.20 EtOAc (561.99): C, 49.58; H, 5.70; N, 7.48. Found: C, 49.74; H, 5.53; N, 7.46.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[O:9])=[C:4]([Cl:20])[CH:3]=1.[F:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[Cl:20][C:4]1[CH:3]=[C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:22]=2[F:21])[CH:7]=[CH:6][C:5]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[CH3:19])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Compound 492 (5.4 g, 15.2 mmol) was dissolved in dry 1,4-dioxan (150 mL) in a 200 mL screw cap vessel. 2,4-Difluoroaniline (1.7 mL, 16.7 mmol) was added and argon was blown over the mixture. Cs2CO3 (14.9 g, 45.7 mmol), BINAP (0.38 g, 0.6 mmol) and Pd(OAc)2 (0.14 g, 0.6 mmol) were added and argon was blown through the mixture and the screw cap vessel was closed. The mixture was stirred at 100° C. for 7 h. The reaction mixture was poured into H2O (100 mL) and EtOAc (200 mL). The water phase was extracted with EtOAc (×3) and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using CH2Cl2/petroleum ether (40-60) 2:3→1:1→1:0 followed by EtOAc as the eluent to afford the title compound as a yellow crystalline compound.
Reaction SMILES: C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.[CH2:19]1[CH2:25][S:22](=[O:24])(=[O:23])[NH:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][O:46][C:47]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:48]=1[CH2:49]O>O1CCCC1>[CH3:45][O:46][C:47]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:48]=1[CH2:49][N:21]1[CH2:20][CH2:19][CH2:25][S:22]1(=[O:24])=[O:23]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: O=S1(=O)CCCN1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCS2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
A solution of 1,1-(azodicarbonyl) dipiperidine (1.874 g, 7.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a 0° C. solution of 1,3-propanesultam (0.6 g, 4.95 mmol), triphenylphosphine (1.95 g, 7.4 mmol), and 2,4-dimethoxybenzyl alcohol (1.0 g, 6.2 mmol) in anhydrous tetrahydrofuran (20 mL). The resultant solution was stirred at 0° C. for 3 hrs, warmed to room temperature and stirred for a further 16 hrs. The solution was concentrated under reduced pressure and suspended in ethyl acetate/hexanes to precipitate a white solid. The solid was removed by filtration and the filtrate purified by silica gel chromatography (25-70% ethyl acetate/hexanes) to give a pale yellow oil (0.505 g). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.28 (dd, 1H, J=0.6, 7.8 Hz), 6.49-6.44 (m, 2H), 4.17 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.19-3.13 (m, 4H), 2.32-2.23 (m, 2H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=2)[N:13]=[CH:12][C:11]=1[C:22]([OH:24])=[O:23].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=2)[N:13]=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncc(C(=O)O)c(Cl)c2n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)O)c(OCc3ccccc3)c2n1
Temperature: -40 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Benzyl alcohol (5.78 g, 53.43 mmol, 2.5 eq) is added at −45° C. to a stirred solution of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid (5.1 g, 21.37 mmol, 1.0 eq) in N,N-dimethylformamide (100 mL), followed by sodium hydride (2.46 g, 53.43 mmol, 2.5 eq). After 2 hours stirring at −40° C. and 24 hours stirring at room temperature, the reaction mixture is quenched with ice water, the pH is adjusted to 3-4 by the addition of a 2N hydrochloric acid aqueous solution. The resulting precipitate is collected by filtration, washed with water and dried under high vacuum to afford 4-benzyloxy-6-methoxy-[1,5]naphthyridine-3-carboxylic acid as a light red solid (6.5 g, 98% yield).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.C(N(CC)CC)C.[NH2:29][C:30]1[C:31]([C:47]([NH:49][NH:50][C:51]([C:53]2[CH:54]=[C:55]3[C:60](=[CH:61][CH:62]=2)[CH2:59][N:58]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:57][CH2:56]3)=[O:52])=O)=[N:32][C:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:44])[CH3:43])[CH:37]=2)=[CH:34][N:35]=1>ClCCl>[NH2:29][C:30]1[C:31]([C:47]2[O:52][C:51]([C:53]3[CH:54]=[C:55]4[C:60](=[CH:61][CH:62]=3)[CH2:59][N:58]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:57][CH2:56]4)=[N:50][N:49]=2)=[N:32][C:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:43])[CH3:44])[CH:37]=2)=[CH:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)NNC(=O)c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)ccc2C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3nnc(-c4nc(-c5ccnc(C(C)(C)C#N)c5)cnc4N)o3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
PS—PPh3 (145.6 mg, 0.3042 mmol) was suspended in dichloromethane (6.269 mL). Iodine (77.21 mg, 15.66 μL, 0.3042 mmol) was added and the mixture was stirred for 10 minutes before triethyl amine (63.10 mg, 86.91 μL, 0.6236 mmol) was added. After 5 minutes tert-butyl 6-[[[3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazine-2-carbonyl]amino]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (92 mg, 0.1521 mmol) was added as a solution in dichloromethane (3.919 mL) the mixture was stirred at ambient temperature for 1 hour. The resin was filtered off and the filtrate was washed with aqueous saturated sodium bicarbonate. The extracted organic phase was then dried over MgSO4 and concentrated in vacuo. The residue was taken onto the next step as is. (118.7 mg, assumed 100% yield). LC/MS m/z 539.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=[O:22])[C:17]=3[CH:23]=2)[C:3]1=[O:24].[SH:25][CH2:26][CH2:27][CH2:28]O.[Bi](Cl)(Cl)Cl.C(#N)C>C(OCC)C>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]4[S:25][CH2:26][CH2:27][CH2:28][O:22]4)[C:17]=3[CH:23]=2)[C:3]1=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: OCCCS
Agent: Cl[Bi](Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCCCS4)c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (2.86 g, 8.05 mmol), 3-mercapto-1-propanol (0.600 ml, 6.84 mmol), bismuth (III) chloride (0.090 g, 0.285 mol) and acetonitrile is stirred overnight at room temperature. Additional 3-mercapto-1-propanol (0.200 ml, 2.31 mmol) and bismuth (III) chloride are added and the resultant mixture is concentrated in vacuo. The residue is chromatographed with ethyl acetate-hexanes to afford a solid, which is taken up in diethyl ether, washed with water, once with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords the title compound as a white solid (1.15 g, 33.2%, mp 125-130° C.) which is identified by NMR spectral analysis.