Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:24](=[O:25])[N:23]3[CH2:26][CH2:27][N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:22]3=[N:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[N:35]1([C:41]([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:24](=[O:25])[N:23]3[CH2:26][CH2:27][N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:22]3=[N:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:46]3[CH:45]=[CH:44][C:43]([C:41]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:42])=[CH:48][CH:47]=3)[S:17][C:10]=12
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: O=c1c(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)cnc2n1CCN2c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2cc3nccc(Oc4ccc(-c5cnc6n(c5=O)CCN6c5ccccc5)cc4F)c3s2)cc1)N1CCOCC1
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
A suspension of 6-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (0.035 g, 0.060 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.017 g, 0.0721 mmol), Pd(PPh3)4 (0.003 g, 0.003 mmol) and lithium chloride (0.010 g, 0.240 mmol) in dioxane (1 mL) and 2M aqueous Na2CO3 (1 mL) was stirred at 100° C. for 50 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (23 mg; 59%) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 8.51 (d, 1H), 8.01 (s, 1H), 7.85-7.79 (m, 3H), 7.73-7.65 (m, 3H), 7.55-7.49 (m, 3H), 7.46 (m, 2H), 7.30 (m, 1H), 7.22, (m, 1H), 6.59 (dd, 1H), 4.33 (m, 4H), 3.95-3.36 (m, 8H). LRMS (APCI pos) m/e 646 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=2)[CH:5]=[N+:6]([O-])[CH:7]=1.P(Br)(Br)([Br:22])=O>ClCCCl>[Br:22][C:5]1[C:4]2=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=[C:3]2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: [O-][n+]1cc(Br)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Product: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a cooled (0° C.) suspension of 7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (1.7 g, 4.7 mmol) in DCE (30 mL) was added phosphorus oxybromide (4.0 g, 14.1 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for a further 2.25 hours. The reaction mixture was partitioned between DCM and sodium carbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (1.07 g, 54% yield). LCMS (Method D): RT=3.93 min, m/z: 422 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[C:19]([F:20])=[CH:18][C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[F:27])[C:9](=[O:28])[C:8]=2[C:7]([O:29][CH2:30][CH3:31])=[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=12)[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[CH2:30]([O:29][C:7]1[C:8]2[C:9](=[O:28])[N:10]([C:14]3[C:15]([F:27])=[CH:16][C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:19]=3[F:20])[CH:11]([OH:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=12)[CH3:31]
Reactant: CCOC(=O)Cc1cc(F)c(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1cc(F)c(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a stirred solution of ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3,5-difluorophenyl}acetate (0.240 g, 0.50 mmol) in THF (10 ml) and methanol (5 ml) was added sodium borohydride (0.019 g, 0.50 mmol) slowly under an argon atmosphere. This was stirred at room temperature for 15 minutes, and then a further 0.057 g (1.50 mmol) of sodium borohydride was added to drive the reaction to completion. After 1.5 hours the reaction was evaporated and quenched with an aqueous solution of ammonium chloride. This was extracted ×2 with ethyl acetate (25 ml) and the combined extracts washed with brine. The organics layer was then dried over magnesium sulphate, filtered and evaporated to give the title compound as a yellow oily solid (0.240 g, 0.49 mmol) LC/MS: Rt=3.42 and 3.46, [MH]+ 486.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH:23]([C:28](=O)[CH2:29][CH2:30][CH3:31])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1)#[N:9].C([O-])(=O)C.[NH4+:37].C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:37]/[C:28](/[CH2:29][CH2:30][CH3:31])=[C:23](/[CH2:22][C:19]1[CH:20]=[N:21][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]#[N:9])=[CH:17][CH:18]=1)\[C:24]([O:26][CH3:27])=[O:25]
Reactant: [NH4+]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC/C(N)=C(\Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Process 2: A toluene (45 mL)-acetic acid (5 mL) mixture containing methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.2 g, 3.6 mmol) and ammonium acetate (8.3 g, 108 mmol) was refluxed under heating for 1 hour. After cooling to room temperature, saturated aqueous solution of sodium hydrogen carbonate was added and extraction was carried out with toluene. After washing with brine, it was dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl (Z)-3-amino-2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-2-hexenoate (1.15 g) as brown oil crude product. It was used for the next process without purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]([C:13]1[CH:35]=[CH:34][C:16]([O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH:22]([C:28]([O:30]C)=[O:29])[CH2:23][CH2:24][O:25]3)=[CH:20][C:19]=2[C:32]#[N:33])=[CH:15][CH:14]=1)=[O:12].[OH-].[Na+].O.CO>C1COCC1.Cl.C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]([C:13]1[CH:35]=[CH:34][C:16]([O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][O:25]3)=[CH:20][C:19]=2[C:32]#[N:33])=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4Cc5ccccc5C4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3Cc4ccccc4C3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 84.6 %

Procedure:
Methyl 7-(4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (12 mg, 0.026 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (1.0 mg, 0.026 mmol), water (200 μL) and methanol (200 μL). After stirring for 2 hours, the reaction was diluted with 2N HCl and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (10 mg, 86% yield). 1H NMR (400 MHz, CD3OD) δ 7.90 (d, 2H), 7.64 (s, 1H), 7.15-7.22 (m, 4H), 7.15 (d, 2H), 6.41 (s, 1H) 4.20-4.35 (m, 3H), 3.82 (bt, 1H), 3.3-3.4 (m, 2H), 2.95-3.05 (m, 2H), 2.35-2.40 (m, 1H), 2.10-2.15 (m, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(O)(=O)=O.[CH2:13]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[N+:1]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
70% Nitric acid (3.16 mL) was added dropwise to a suspension of trifluoromethanesulfonic acid (9.34 mL, 105.6 mmol) in dichloromethane (250 mL). The suspension was-cooled in a dry ice-acetone bath and a solution of 4-benzyl-benzoic acid (10.19 g, 48 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was stirred for about 2 hours at −78° C. and an additional 2 hours at room temperature. The reaction mixture was poured into crushed ice. The separated organic layer was washed with dichloromethane (2×) and the combined organic layers were dried over (Na2SO4), and solvents were evaporated. Recrystallization of the crude product from methanol/ethyl acetate gave 4-(4-nitrobenzyl)-benzoic acid (9.27 g, 58%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[CH3:21])#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:22]1[C:1]([CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:6]2[CH3:21])=[N:2][N:24]=[N:23]1
Reactant: Cc1c(Cc2cccnc2)c2ccccc2n1CCC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2cccnc2)c2ccccc2n1CCc1nnn[nH]1
Temperature: 125 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
A mixture of 1-(2-cyanoethyl)-2-methyl-3-(3-pyridylmethyl)indole (0.8 g), sodium azide (0.95 g), ammonium chloride (0.78 g) and dry dimethylformamide (12 ml) was heated with stirring at 125° C. for 20 hours and then evaporated. Water (25 ml) was added to the residue to dissolve inorganic material. The insoluble portion was crystallised from methanol/ethyl acetate to give 1-[2-(5-tetrazolyl)ethyl]-2-methyl-3-(3-pyridylmethyl)indole (0.20 g), m.p. 173°.
Reaction SMILES: [N+:1]([CH2:4][CH:5](O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].CS(Cl)(=O)=O.C(N(CC)CC)C.O>C(Cl)Cl>[N+:1]([CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC(O)CCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
To a solution of 5.85 g (30.0 mmol) of 1nitro-4-phenyl-2-butanol in 40 mL of dry methylene chloride at 0° C. was added 3.44 g (30.0 mmol) of methanesulfonyl chloride followed by addition of 6.07 g (60.0 mmol) of triethylamine. The mixture was stirred at 0° C. for 20 min, poured into 40 mL of water and extracted with 50 mL of methylene chloride. The extracts were dried over sodium sulfate, concentrated, and the residual solid purified by column chromatography (silica gel/ethyl acetate:hexanes 1:9) to afford 4.25 g (80%) of the product as a yellow oil. Since this material slowly decomposes at room temperature, it was used immediately for the next reaction: IR (neat) 3028, 2930, 1648, 1555, 1524, 1497, 1454, 1351, 1176, 953, 931, 750, 700 cm-1 ; 1H NMR (CDCl3) δ 2.63 (2H, q, J=7.0 Hz), 2.87 (2H, t, J=8.0 Hz), 7.00 (1H, dt, J=13.5 Hz), 7.21 (2H, d, J=7.5 Hz), 7.26-7.35 (4H, m); 13C NMR (CDCl3) 5 141.55,140.18, 139.74, 128.90, 128.46, 126.81, 34.19, 30.29; EIMS m/z 177 (M+) 60, 143, 133, 130, 115, 103, 91, 77; HRMS calc'd for C10H11NO2 177.0790, found 177.0802.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[CH2:21]([N:23]([CH2:29][CH3:30])[C:24](=[O:28])/[CH:25]=[CH:26]/[CH3:27])[CH3:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:21]([N:23]([CH2:29][CH3:30])[C:24](=[O:28])/[CH:25]=[C:26](/[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1)\[CH3:27])[CH3:22]
Reactant: OCCc1cc(Br)ccc1OCc1c(F)cccc1F
Reactant: C/C=C/C(=O)N(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(CCO)c1

Procedure:
A solution of 2-[5-bromo-2-[2,6-difluorobenzyloxy)phenyl]-1-ethanol (14.07 g, 41.02 mmol) and N,N-diethylcrotonamide (8.68 g, 61.53 mmol) in 60 mL triethylamine in a thick-walled pyrex tube is degassed wish nitrogen for 15 minutes. Pd(OAc)2 (0.46 g, 2.05 mmol) and tri-o-tolylphosphine (1.25 g, 4.10 mmol) are placed into the tube, which is then sealed, and the mixture is heated to 100° for 5 hours. The mixture is diluted with EtOAc (400 mL), and white precipitate is filtered out. The filtrate is then washed with 1 N HCl (2×400 mL), H20 (1×100 mL) and brine (1×100 ni), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 3:1 EtOAc/hexane) gives (E)-3-[4-(2,6-difluorobenzyloxy)-3-(2-hydroxyethyl)-phenyl]-2-butenoic acid diethy amide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:10]([Cl:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]([CH2:35][OH:36])[CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18]([NH:28][C:29]4[CH:30]=[C:31]([CH2:35][OH:36])[N:32]=[CH:33][N:34]=4)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:10]([Cl:26])[CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(CO)ncn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2nc3c(F)cnc(Cl)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2nc3c(F)cnc(Nc4cc(CO)ncn4)c3s2)c(Cl)c1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of [3,5-dichloro-4-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)phenyl]-carbamic acid tert-butyl ester (150 mg, 0.33 mmol) in dioxane (5 mL), was added (6-aminopyrimidin-4-yl)methanol (45 mg, 0.36 mmol), XantPhos (19.4 mg, 0.033 mmol) and Cs2CO3 (218.3 mg, 0.67 mmol). The resultant mixture was degassed with argon for 10 minutes before Pd2(dba)3 (57.7 mg, 0.063 mmol) was added and the reaction mixture was heated at 100° C. for 18 hours in a sealed vial. After cooling to room temperature, the reaction mixture was filtered through Celite® washing with EtOAc (5 mL). The resultant residue was purified by column chromatography on silica gel eluting with 0-80% EtOAc in cyclohexane to afford the title compound as a white foam (102 mg, 58%). LCMS (Method D): RT=3.35 min, m/z: 538 [M+H+].
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([NH2:12])=[O:11])=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: NC(=O)N(Cc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)N(Cc1ccc(N)cc1)OCc1ccccc1
Yield: 42.5 %

Procedure:
10% Palladium carbon (0.3 g) was added to 80 ml of ethyl acetate solution containing 4.76 g of 1-benzyloxy-1-(4-nitrobenzyl)urea. The reaction mixture was stirred overnight under normal pressure in an atmosphere of hydrogen, and then insoluble materials were removed by filtration. After evaporating the solvent under a reduced pressure, the resulting residue was purified by silica gel column chromatography (eluant: chloroform:methanol=10:1) to obtain 1.82 g of 1-(4-aminobenzyl)-1-benzyloxyurea.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH:9]3[CH2:18][CH2:19][OH:20])=[CH:4][C:3]1=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH:9]3[CH2:18][CH:19]=[O:20])=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCCC3CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CCCC3CC=O
Reaction time: 1 h
Yield: 81 %

Procedure:
The above alcohol (60 mg, 0.21 mmol) was dissolved in dichloromethane (5.0 mL) and Dess-Martin reagent (2×135 mg, 0.63 mmol) was added in two portions and stirred for 60 min. A saturated solution of sodium bicarbonate (3.0 mL) was added, followed by solid sodium thiosulfate. The mixture was stirred vigorously and extracted with dichloromethane. The organic layer was washed with water (2×5 mL), brine (2×5 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified over a short silica gel chromatography column to give 48 mg of the desired aldehyde, (+)-2-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)ethan-1-al (81% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl.CCOCC>[CH3:16][O:15][C:12]1[CH:13]=[C:14]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)[CH:9]=[CH:10][C:11]=1[O:17][CH3:18]
Reactant: COc1ccc(Br)cc1OC
Reactant: C[C@@H]1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(N2CCN[C@H](C)C2)cc1OC
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A mixture of (R)-(−)-2-methylpiperazine (2.0 g, 20 mmol), 4-bromo-1,2-dimethoxybenzene (4.33 g, 20 mmol) and sodium tert-butoxide (2.88 g, 30 mmol) was prepared in anhydrous toluene (50 mL). The solution was degassed by argon bubbling for 10 min. Then palladium(II) acetate (220 mg, 1 mmol) and (+/−)-BINAP (500 mg, 0.8 mmol) were added. The resulting mixture was heated at reflux for 4 hours. Then the reaction mixture was cooled to RT and diluted with Et2O (50 mL). The salts were removed by filtration on Celite and the solvents were removed under reduced pressure to give a dark brown oil. Purification by flash chromatography (CHCl3/MeOH) gave a brown oil. This oil was taken up with DCM/Et2O, treated with activated charcoal at RT for 10 min and filtered on Celite. The solvents were removed under reduced pressure to give 1.33 g (28%) of the title compound as a yellow oil. M+(ESI): 237.2. HPLC (Condition A), Rt: 1.2 min (HPLC purity: 93.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:24][CH2:23][C:21]2[O:20][N:19]=[C:18]([C:11]3[C:12]([F:17])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=3[Cl:9])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1cc(-c2c(F)ccc(F)c2Cl)no1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Fc1ccc(F)c(-c2cc(COc3ccc(Br)cn3)on2)c1Cl
Temperature: 25 °C
Yield: 64.9 %

Procedure:
2,5-Dibromopyridine (12.6 g, 53.0 mmol) and [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-methanol (10.0 g, 40.7 mmol) were dissolved in toluene (400 mL). tBuONa (5.87 g, 61.1 mmol), xantphos (1.42 g, 2.45 mmol) and Pd2(dba)3 (732 mg, 0.800 mmol) were added to the sol. The resulting mixture was refluxed overnight, and was allowed to cool down to rt. The mixture was filtered through Celite (washed with EtOAc), and was washed with aq. sat. NaHCO3 (1×) and brine (2×). The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the crude by FC (EtOAc/heptane 10:90) yielded the title compound (10.6 g, 65%). LC-MS: tR=1.10 min; ES+: 400.66.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:15])[NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: CN(C)CCN
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: CN(C)CCNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), N,N-dimethylethylenediamine (40 mg, 0.46 mmol) and DIPEA (0.2 mL, 1.1 mmol) in DMF (2 mL). MS (LC-MS): 374.2 [M]+; tR (HPLC conditions c): 3.87 min.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23][CH:24](Cl)[CH2:25][CH2:26][CH3:27].O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>CN(C)C=O>[CH3:38][O:39][CH2:40][CH2:41][N:42]1[C:2]2[N:7]3[N:8]=[C:9]([CH3:20])[C:10]([C:11]4[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=4[CH3:19])=[C:6]3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23][CH:24]1[CH2:25][CH2:26][CH3:27]
Reactant: COCCN
Reactant: CCCC(Cl)CCc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c2N1CCOC
Temperature: 150 °C
Reaction time: 48 h

Procedure:
7-Chloro-6-(3-chlorohexyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (170 mg, 0.406 mmol) was dissolved in 2-methoxyethylamine (2 mL), followed by heating under reflux for one hour. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated, to give a pale yellow oil. The oil was dissolved in N,N-dimethylformamide (10 mL), and sodium iodide (62 mg, 0.416 mmol) and potassium carbonate (172 mg, 1.25 mmol) were added thereto. The mixture was stirred at 150° C. for two days. After cooling, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (5-10% ethyl acetate/hexane), to give the title compound (60 mg, 0.143 mmol) as a pale yellow oil.