Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][NH:10][C@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Br[C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([F:23])=[CH:16][CH:15]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.CC([O-])(C)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O.C1(C)C=CC=CC=1>[F:23][C:17]1[C:18]2[O:22][CH:21]=[CH:20][C:19]=2[C:14]([N:10]2[C@H:9]3[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]3)[NH:3][C:2]([CH3:12])([CH3:1])[CH2:11]2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(Br)c2ccoc12
Reactant: CC1(C)CN[C@@H]2CCCC[C@@H]2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CN(c2ccc(F)c3occc23)[C@@H]2CCCC[C@@H]2N1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A toluene (4 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-fluorobenzofuran (258 mg, 1.20 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3P.HBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered, and the residue was washed with AcOEt (5 ml×2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless oil (167 mg). This oil was crystallized from hexane (1 mL) to obtain (4aS,8aR)-1-(7-fluorobenzofaran-4-yl)-3,3-dimethyldecahydroquinoxaline (107 mg, yield: 35%) in a white powder form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\Cl)/[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCc1ccc(C#Cc2ccc(Br)cc2)cc1
Yield: 99.2 %

Procedure:
To a 100 mL flask containing a solution of 1-bromo-4-[(Z)-2-chloro-2-(4-ethylphenyl) vinyl] benzene (VIc) (9.540 g; 29.66 mmol) in 1,4-dioxane (48 mL; 5 vols) and MeOH (14 mL; 1.5 vols), KOH (3.328 g; 59.32 mmol) was added in one portion. Protocol and work-up was then similar with those described above. Title compound (m=8.39 g) was obtained in a 99% yield. Melting point: 117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=O.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:9]/[C:10](/[C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=[N:26]\[OH:27]
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccccc2Cl)C2CCCC2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccccc2Cl)C2CCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(2-chloro-phenyl)-3-cyclopentyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=359.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14]1
Reactant: FC1(F)CCCNC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Temperature: 130 °C
Yield: 55.5 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.1 g, 4.5 mmol), 3,3-difluoropiperidine hydrochloride (0.14 g, 0.93 mmol) and DIPEA (0.5 mL, 2.8 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 1 hr. Additional DIPEA (0.5 mL, 2.8 mmol) and 3,3-difluoropiperidine hydrochloride (0.29 g, 1.8 mmol) were added and the mixture was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to yield 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (127 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.80 (s, 3H), 3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1CCN2C(=NCCC2)CC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC=CCC1
Yield: 91.7 %

Procedure:
Heat a solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.69 mol, 193 g) in DBU (400 mL) at 80° C. for 16 h. Dilute the reaction mixture with water, extract with diethyl ether, and wash the organic layer with 1 N hydrochloric acid and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (116 g, 92%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 2.12 (br s, 2H), 3.47 (t, 2H), 3.87 (s, 2H), 5.65 (br s, 1H), 5.81 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21](I)[C:20]([Cl:24])=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:21]2[C:20]([Cl:24])=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1

Procedure:
The title compound is prepared from 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester and 2,5-dichloro-4-iodo-pyridine following a procedure analogous to that described for Intermediate 27. LC (method 7): tR=1.66 min; Mass spectrum (ESI+): m/z=355 [M+H]+.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20][C:21](C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(Cl)Cl.C(N1CC(=O)C[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O>CC(C)=O>[CH2:20]([O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C:17](=[O:19])[CH2:18][N:11]1[C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:21]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a round bottom flask containing 14.0 g (52.8 mmol) of N-Cbz-4-hydroxy-L-proline 8 was added 26 mL acetone. The solution was cooled on ice bath where 8.12 mL (0.106 mmol; 2 eq) of Jones reagent (CrO3, H2SO4, 1.3 M in water) was added. The mixture was allowed to warm to room temperature and stir for 3 h where the reaction appeared to be complete, as determined by TLC. The reaction was quenched by the addition of 6 mL isopropanol. After stirring for another 2 h the flask was placed on a glass socket rotovap and the isopropanol/acetone was removed by reduced pressure. The remaining green residue was then diluted into 200 mL water, salted with NaCl and extracted with EtOAc (3×200 mL). The organic extracts were combined, dried with MgSO4, filtered and concentrated to an oil. The remaining yellow oil was then separated by silica gel (90% CH2Cl2, 9% MeOH, 1% AcOH, Rf=0.3). The fractions containing the product were combined and concentrated by rotovap to a solid residue and then recrystallized from CH2Cl2 leaving 9.86 g (37.5 mmol) of N-Cbz-4-keto-L-proline, a 71% yield. The product material was used in the next synthetic step without further purification.
Reaction SMILES: Cl.[C:2]1([C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[C:27]1([CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH2:11]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCCN(CCc2ccc3c(c2)OCO3)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C(CC2CCCN(CCc3ccc4c(c3)OCO4)C2)c2ccccc2)cc1
Yield: 48.1 %

Procedure:
A solution of 3-(2,2-diphenyl-1-ethenyl)-1-(3,4-methylenedioxyphenethyl)piperidine hydrochloride (135 mg) (Example 14) in EtOH (20 ml) was stirred at 40° C. under a hydrogen atmosphere of 45 psi in the presence of 10% palladium on charcoal. The mixture was filtered and the filtrate evaporated. The residue was partitioned between dichloromethane and 2M aqueous sodium hydroxide solution and the organic layer was dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 2.5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (60 mg, 50%) which was characterised as a hemihydrate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=3)[C:3]=12.CC(O)=O>Br.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: COc1ccc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccccc3)c3ncnc(N)c23)cn1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2ccc(O)nc2)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
3-(1-(4-amino-3-(6-methoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Example 60, 28 mg, 0.057 mmol) was dissolved in HBr 33% in CH3COOH (2 ml, 36.8 mmol) and stirred at 60° C. for 4 hr. The reaction was then diluted with 3 ml of water and the resulting mixture purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (6.9 mg, 25.4%) as yellowish solid.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[CH3:8][Si:9]([CH3:16])([CH3:15])[O:10][C:11]#[C:12][CH2:13][CH3:14]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Br:7][C:6]1[C:2]([C:14]#[C:13][CH2:12][CH2:11][O:10][Si:9]([CH3:16])([CH3:15])[CH3:8])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: CCC#CO[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCC#Cc1cscc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
Into a 250 mL 4 necked RB flask equipped with a magnetic stirring bar, thermometer, rubber septum, argon inlet and reflux condenser with argon outlet (tubed to a silicon oil bubbler) is added 55.0 g (229 mmol) of 3,4-dibromothiophene, 15.6 g of triethylamine, 9.75 g (68.5 mmol) of trimethylsiloxy-1-butyne, 170 mg of triphenylphosphine, 140 mg of copper iodide and 490 mg of dichlorobis(triphenylphosphine) palladium(II). The mixture is heated with a silicon oil bath to 60° C. under argon with stirring for 2 hrs. The cooled mixture is then concentrated on a rotary evaporator at reduced pressure and the residue taken up in 200 mL of hexanes and washed with 2×25 mL of water and the pentane phase dried over sodium sulfate and then concentrated on a rotary evaporator. The residue was chromatographed through neutral silica gel eluted with 2/1 methylenechloride/hexanes to yield 4.8 g of 3-bromo-4(trimethylsiloxybutynyl)thiophene as a light yellow oil which was used directly to prepare 2-hydroxyethylselenolo[2,3-c]thiophene.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23]CC2C=CC=CC=2)[NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][OH:23])[NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11]1
Reactant: c1ccc(COCC2CNCC(COCc3ccccc3)NCCOCCN2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCC1CNCC(CO)NCCOCCN1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
5,9-Bis(benzyloxymethyl) -1-oxa-4,7,10-triazacyclododecane (0.24 g, 0.6 mmol) was dissolved in methanol (10 ml) . Ammonium formate (0.20 g, 3 mmol) and 10% Palladium on carbon (0.40 g) were added and the mixture was stirred under a nitrogen atmosphere at 50° C. for 16 hours. The catalyst was filtered off and washed with methanol (5 ml). The filtrate was evaporated and the 5,9-Bis-(hydroxymethyl)-1-oxa-4,7,10-triazacyclododecane was isolated as a colourless oil. Yield 0.12 g (86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[CH2:37])=[CH:30][CH:29]=2)[C@H:10]([O:38][CH2:39][C@H:40](O)[CH2:41][O:42]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:38][CH2:39][C@H:40]2[CH2:41][O:42]2)[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[CH2:37])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2CO2)cc1

Procedure:
In analogy to the procedure described in example 1(j) the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium hydroxide in dimethylsulfoxid to yield the (3R,4R,5S)-4-(4-allyloxy-phenyl)-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45](O)=[O:46])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:45](=[O:46])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Product: CCn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 72 %

Procedure:
Following the procedure for Example 506 starting with (R)-N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (330 mg, 72%). 1H-NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.66 (s, 1H), 8.15-8.05 (m, 1H), 7.45-7.35 (m, 1H), 7.30-7.15 (m, 3H), 6.31 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 4.07 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.25-2.10 (m, 2H), 2.10-1.70 (m, 4H), 1.57 (s, 9H) 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: O.[Sn](Cl)Cl.[CH2:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[CH:6]=[CH2:7].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH:6]=[CH2:7]
Reactant: C=CCOc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOc1cc(F)ccc1N
Reaction time: 4 h
Yield: 47.2 %

Procedure:
Tin (II) chloride hydrate (8.5 g, 38 mmol, 5 eq) was added to a solution of 2-allyloxy-4-fluoro-1-nitro-benzene (1.5 g, 7.6 mmol) in ethyl acetate (20 ml) at room temperature and the mixture was stirred for 4 hr. The reaction mixture was neutralized with triethylamine and then partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 2-allyloxy-4-fluoro-phenylamine (0.6 g, 50%). The crude compound was used in the next stage without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1C(=NO)C.P(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[C:22](#[N:24])[CH3:23].CC(N(C)C)=O>>[CH3:23][C:22]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:24]=1
Reactant: CC#N
Reactant: CC(=NO)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClP(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1
Temperature: 22.5 °C

Procedure:
To a mixture of 1-(2,4-dihydroxy-phenyl)-ethanone oxime (4.2 g, 25 mmol) and acetonitrile/dimethylacetamide (20 mL, 3:1) cooled by a water bath (20-25° C.) was added dropwide phosphorus chloride (2.4 mL, 26.2 mmol) over a period of fifteen minutes. The mixture was stirred for an additional thirty minutes before it was poured into ice water containing sodium acetate (6 g). The mixture was stirred for ten minutes, filtered, and the filter cake was washed with water and dried in vacuo to give the title compound as a yellow solid (3.15 g): 1H NMR (CDCl3, 200 MHz): δ=7.45 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[OH:28][CH:25]1[CH2:24][CH2:23][N:22]([CH:19]2[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[S:57])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:17][CH2:18]2)[CH2:27][CH2:26]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reaction time: 48 h
Yield: 25 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (131 mg) and (+)-10-camphorsulfonic acid (70 mg) in ethanol (3.0 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.54 ml) at room temperature, followed by stirring for 2 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (1 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (46.5 mg, 25%) as white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:44][OH:45])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])=[CH:32][CH:31]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C[O:49]CC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:44][OH:45])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]([NH2:28])=[O:49])[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)=[O:37])=[CH:32][CH:31]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Yield: 76.6 %

Procedure:
1-[3-(6-tert-Butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-3-[4-(morpholine-4-carbonyl)phenylamino]-1H-pyrazole-4-carbonitrile (52 mg, 0.0861 mmol) was dissolved in 4 mL of THF and 0.4 mL of water. Then dihydrogen tris(dimethylphosphinito)hydroplatinate (CAS#173416-05-2, 3 mg, 8% eq) was added. The mixture was refluxed for 1 hr. TLC indicated complete consumption of the starting material. LC/MS indicated the clean product formed with the correct MW. The mixture was evaporated to dryness and then dissolved in dichloromethane, dried over sodium sulfate and filtered. After the evaporation of solvents, the residue was purified through flash column chromatography (24 g silica gel, methanol in dichloromethane, 0% to 5% in 16 minutes) to give 1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a white solid (41 mg, 76.6% yield). LC/MS clacd for C34H35N7O5 (m/e) 621.27, obsd 622.1 (M+H, ES+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9H) 3.41-3.71 (m, 8H), 4.37 (br. s., 2H), 4.74 (br. s., 1H), 7.36 (d, J=6.3 Hz, 3H), 7.49-7.71 (m, 5H), 7.80 (br. s., 1H), 8.04 (d, J=9.1 Hz, 2H), 8.25 (d, J=6.6 Hz, 1H), 8.56 (br. s., 2H), 9.44 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)=[C:9]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:8]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>ClCCl>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)=[O:21])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)N3CCN(C)CC3)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 76.8 %

Procedure:
In a round bottom flask, under an atmosphere of argon, 4′-(3-ethoxy-3-oxopropyl)-2′-(3-methoxypropoxy)biphenyl-4-carboxylic acid (0.48 g, 1.2 mmol) was dissolved in dichloromethane (20 mL). EDCl (0.29 g, 1.5 mmol), HOBT (0.20 g, 1.5 mmol) and diisopropylethylamine (1.08 mL, 6.2 mmol) were added at room temperature. After consumption of all the acid, N-methylpiperazine (0.11 mL, 1.0 mmol) was added and the mixture, was stirred for 18 hrs. The organic layer was washed twice with water. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol, 90/10) to yield 0.36 g (62%) of the desired product as a yellow oil.