Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23][CH:24]1[CH2:26][CH2:25]1)C=C)[S@:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])[CH:2]=[CH2:3]>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:7]([S@@:5]([N:4]1[CH2:1][CH:2]=[CH:3][C@@H:11]1[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23][CH:24]1[CH2:26][CH2:25]1)=[O:6])([CH3:8])([CH3:10])[CH3:9]
Reactant: C=CCN(C(C=C)c1cc([N+](=O)[O-])ccc1SC1CC1)[S@@](=O)C(C)(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N1CC=C[C@@H]1c1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: 72 °C

Procedure:
A solution of 85C (2.2 g, 5.5 mmol) in CH2Cl2 (200 mL) was degassed by bubbling argon for 8 min. To this solution was added Grubb's catalyst (2nd generation, 380 mg, 0.45 mmol). The mixture was heated at 72° C. for 5.0 h. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 85D as a major product (1.66 g, 82% yield): 1H NMR (400 MHz, CDCl3) δ ppm 0.71-0.80 (m, 2H) 1.15-1.19 (s, 9H) 1.19-1.25 (m, 2H) 2.14-2.22 (m, 1H) 3.78 (dt, J=14.50, 2.64 Hz, 1H) 4.69 (dd, J=14.50, 2.64 Hz, 1H) 5.73 (dd, J=6.15, 2.20 Hz, 1H) 5.85 (dd, J=5.05, 2.42 Hz, 1H) 5.88 (ddd, J=4.06, 2.20, 2.09 Hz, 1H) 7.69 (d, J=8.79 Hz, 1H) 8.06 (dd, J=8.57, 2.42 Hz, 1H) 8.19 (d, J=2.20 Hz, 1H), LC-MS 367 (M+H). 85E was obtained as a minor product (0.31 g, 14% yield): 1H NMR (400 MHz, CDCl3) δ ppm 0.65-0.73 (m, 1H) 0.73-0.82 (m, 1H) 1.01 (s, 9H) 1.17-1.26 (m, 2H) 2.15-2.24 (m, J=7.96, 3.90, 3.74, 3.74 Hz, 1H) 4.36-4.43 (m, 1H) 4.51-4.58 (m, 1H) 5.82 (dd, J=6.15, 2.20 Hz, 1H) 5.87 (d, J=1.76 Hz, 1H) 5.90 (dd, J=5.05, 2.86 Hz, 2H) 7.66 (d, J=8.79 Hz, 1H) 8.06 (dd, J=8.57, 2.42 Hz, 1H) 8.13 (d, J=2.20 Hz, 1H), LC-MS 367 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16]CC[CH2:13]2)=[NH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>>[CH3:13][N:12]([CH3:16])[C:10](=[N:11][S:18]([CH3:17])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: N=C(c1ccc([N+](=O)[O-])cc1)N1CCCC1
Product: CN(C)C(=NS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Part B: According to the procedure described Example 57, part C, 1.14 g (5.9 mmol) of (4-nitrophenyl)(pyrrolidin-1-yl)methanimine were reacted with methane sulfonyl chloride to yield N,N-dimethyl-N′-(methylsulfonyl)-4-nitrobenzamidine (890 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:18][C:19](=[O:38])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[OH:37])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:10])[CH:7]([O:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[CH2:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][C:19]([O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:38])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: O=C(COc1ccc(Cl)cc1Cc1cc(Cl)ccc1O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromopropionic acid tert-butyl ester (0.827 g, 3.95 mmol) in DMF (15 mL) is added [4-chloro-2-(5-chloro-2-hydroxy-benzyl)-phenoxy]-acetic acid benzyl ester (1.5 g, 3.60 mmol) and potassium carbonate (0.547 g, 3.95 mmol). The reaction mixture is stirred at RT overnight and the solvent is removed in vacuo. The crude product is dissolved in EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic portion is dried (MgSO4) and concentrated in vacuo to yield a yellow oil which is dried in a vacuum oven for 2 hours to afford the titled product which is used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH2:9]1
Reactant: O=S1(=O)CCCO1
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccccc2F)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(2-fluorophenyl)piperazine (2.5 g, 2.2 mL, 13.9 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.73 g, 14.6 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound M, 3.56 g (85%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:47]3=[O:50])=CC=2)=CC=1.COC1C=CC(C(Cl)=O)=CC=1>>[CH3:47][O:50][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COc1ccc(C(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 103 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-methoxybenzoyl chloride. The compound of example 103 was used directly without isolation for the preparation of compound of example 104.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH2:9][CH2:8][CH2:7]2.C1COCC1.[Li]CCCC.[Li]C(C)(C)C.C(O[B:39]1[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]1)(C)C>CCCCC>[CH3:46][C:41]1([CH3:47])[C:42]([CH3:45])([CH3:44])[O:43][B:39]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][CH2:8][CH2:7]3)[O:40]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccccc1NC1CCCc2cccc(Br)c21
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1NC1CCCc2cccc(B3OC(C)(C)C(C)(C)O3)c21
Reaction time: 1 h

Procedure:
To a solution of 30.8 g (97.5 mmol) (8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)(2-methylphenyl)amine in 500 ml THF 39.0 ml (97.5 mmol) of 2.5M nBuLi in hexanes was added at −80° C. in argon atmosphere. The resulting mixture and stirred for 1 h at this temperature, and then 125 ml (200 mmol) of 1.7M tBuLi in pentane was added. The obtained mixture was stirred for 1 h at the same temperature. Further on, 36.3 g (195 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added. After that the cooling bath was removed, and the resulting mixture was stirred for 1 h at room temperature. Then, 10 ml of water was added, and this mixture was evaporated to dryness. The residue was diluted with 500 ml of water, and the title product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. Yield 24.8 g (70%) of a yellow oil. Anal. Calc. For C23H30BNO2: C, 76.04; H, 8.32; N, 3.86. Found: C, 76.29; H, 8.60; N, 3.59. 1H NMR (CDCl3): δ 7.68-7.69 (m, 1H, 7-H in tetrahydronaphtalene); 7.24-7.33 (m, 3H, 5,6-H in tetrahydronaphtalene and 5-H in 2-methylphenyl); 7.13 (m, 1H, 3-H in 2-methylphenyl); 7.04 (m, 1H, 6-H in 2-methylphenyl); 6.74-6.77 (m, 1H, 4-H in 2-methylphenyl); 5.38-5.39 (m, 1H, 1-H in tetrahydronaphtalene); 3.78 (m, 1H, NH); 2.85-3.02 (m, 2H, 4-H in tetrahydronaphtalene); 2.21-2.26 (m, 1H, 3- or 3′-H in tetrahydronaphtalene); 2.12 (s, 3H, CH3 in 2-methylphenyl); 1.81-2.00 (m, 3H, 3′- or 3-H and 2-H in tetrahydronaphtalene); 1.20 (s, 6H, CH3 in BPin); 1.13 (s, 6H, CH3 in BPin).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 22.2 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-(trifluoromethyl)phenylboronic acid 62 mg, sodium carbonate 57 mg and polymer-carried bis(acetato) triphenylphosphine palladium (II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 2.0 mol/L Sodium hydroxide aqueous solution 1.0 mL and ethanol 6.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 0.5 mol/L Hydrochloric acid was added to the reaction mixture. Solid matter was filtrated, it was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(4-(trifluoromethyl)phenyl)benzoic acid 18 mg of pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13]C(C#N)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:19]([C:18]([OH:21])=[O:20])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1CCC(OCc2ccccc2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1CCC(OCc2ccccc2)CC1

Procedure:
The crude 4-benzyloxycyclohexane-1-nitrile (4.0 g) was refluxed with stirring with a mixture of glacial acetic acid (16 ml) and concentrated hydrochloric acid (24 ml) for 20 hours. The reaction mixture was cooled, the solid removed by filtration and washed with water. The product was ground with 2M sodium hydroxide solution (70 ml) and then diluted with water. Unchanged nitrile was removed by filtration and the filtrate acidified with concentrated hydrochloric acid. White crystals separated and were collected by filtration, washed with water and dried to yield 4-benzyloxycyclohexane-1-carboxylic acid m.p. 170°-180° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[C:59]([N:63]1[C:67]([NH2:68])=[CH:66][C:65]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=2)=[N:64]1)([CH3:62])([CH3:61])[CH3:60].CC(C)([O-])C.[Na+]>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:59]([N:63]1[C:67]([NH:68][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:66][C:65]([CH2:69][C:70]2[CH:71]=[CH:72][C:73]([Cl:76])=[CH:74][CH:75]=2)=[N:64]1)([CH3:62])([CH3:60])[CH3:61]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Reactant: CC(C)(C)n1nc(Cc2ccc(Cl)cc2)cc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)n1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 150 °C
Yield: 39.8 %

Procedure:
To a mixture of 4-iodo-N-thiazol-2-yl-benzenesulfonamide (100 mg, 0.3 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol, 0.04 equiv), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19 mg, 0.033 mmol, 0.12 equiv) and 2-tert-butyl-5-(4-chloro-benzyl)-2H-pyrazole-3-ylamine (86 mg, 0.33 mmol, 1.2 equiv) in 3.7 mL of anhydrous 1,4-dioxane was added sodium tert-butoxide (79 mg, 0.82 mmol, 3.0 equiv). The vial was capped, and the reaction mixture was heated 30 min at 150° C. in the microwave. The crude reaction mixture was filtered through celite then concentrated in vacuo. The residue was taken up in chloroform-methanol, concentrated onto celite, and purified via automated flash chromatography (12 g SiO2, gradient from hexanes to ethyl acetate). The appropriate fractions were collected, concentrated in vacuo, then lyophilized from water-acetonitrile to afford the product as an off-white solid (60 mg, 40%).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH:12]=[C:13]2[CH2:21][O:22][CH2:23][C:24]#[C:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CO>[OH:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH:12]=[C:13]2[CH2:21][O:22]/[CH:23]=[CH:24]\[CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH2:5][C@@H:4]([OH:30])[CH2:3]1
Reactant: CC(C)(O)C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CC(C)(O)C/C=C\OCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.9 %

Procedure:
1α,3β-Dihydroxy-17-(4-hydroxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene (78 mg, 0.189 mmol), quinoline (12.3 mg, 0.0952 mmol), 5% palladium/barium sulfate (16 mg) and methanol (5 ml) were stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, evaporated for remove the solvent and purified by column chromatography (dichloromethane: methanol=20:1) to give the titled compound (61 mg, 78%) as a colorless glassy substance.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:11][C:4]1[CH:3]=[C:2]([NH:25][CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH:19]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NCc1cccc(-c2ccccn2)c1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccccn2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 43.5 %

Procedure:
To a solution of 4,6-dichloronicotinamide (73 mg, 0.38 mmol) in NMP (0.75 mL) was added (3-(pyridine-2-yl)phenyl)methanamine (77 mg, 0.42 mmol) and DIPEA (0.22 mL, 1.33 mmol). After stirring at 80° C. for 15 h, the mixture was added water, the resulting precipitate was collected by filtration to give 6-chloro-4-(3-(pyridine-2-yl)benzylamino)nicotinamide (56 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:21]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccccc3)n2)CC1
Temperature: 115 °C
Yield: 73.4 %

Procedure:
tert-Butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 1.0 mmol) and phenylboronic acid (183 mg, 1.5 mmol) were dissolved in toluene (10 mL) and the solution was purged with argon for 10 min. Potassium phosphate (426 mg, 2.0 mmol) was added to the reaction mixture, followed by a catalytic amount of Pd2(dba)3 (9 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol). The reaction mixture was then heated to 115° C. for 10 h, cooled to room temperature, diluted with EtOAc, and filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 30% EtOAc in petroleum ether) to get tert-butyl 4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate (250 mg, yield 73%). 1H NMR (300 MHz, MeOD) δ 8.28-8.23 (m, 3H), 7.46-7.43 (m, 3H), 7.34 (m, 1H), 3.80-3.77 (m, 4H), 3.56-3.53 (m, 4H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C19H24N4O2: 340.19. found: 341.2 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[N:3]=[C-:2]1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.COC1C=C[C:29]([CH2:30][O:31][CH2:32][CH2:33]C=O)=CC=1.P([O-])([O-])([O-])=O.OO>C(Cl)Cl.C(N(CC)CC)C>[O:1]1[CH2:5][C:4](=[O:6])[N:3]=[C-:2]1.[CH3:29][CH2:30][O:31][CH2:32][CH3:33]
Reactant: COc1ccc(COCCC=O)cc1
Agent: CCCC[B+]CCCC
Agent: O=C1CO[C-]=N1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.21 g of the oxazolidone 15 in 40 ml of methylene chloride at -78° C. was added 13.64 ml of a 1M dibutylboron triflate in methylene chloride solution and 2.6 ml of triethylamine. The reaction solution was stirred at 0° C. for 30 minutes, then it was cooled to -78° C. 3-(4-Methoxybenzyloxy)propanaldehyde (2.4 g) in 4 ml of methylene chloride was added and the reaction solution was stirred 30 minutes at -78° C. and then at RT for 1.5 hour. At the end of this time 100 ml of pH7 phosphate buffer was added, followed by addition of 30% aqueous hydrogen peroxide to the mixture at 0° C. The mixture was then extracted twice with diethyl ether and the aqueous phases were dried with sodium sulfate. The solution was concentrated under vacuum and chromatography of the residue over silica gel (2 hexanes: 1 EtOAc) provided the title compound.
Reaction SMILES: [N+]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[C:12]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:5]1([NH:6][C:20]2([Cl:21])[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[CH2:12]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:4]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)C1=CC=CC(Cl)(Nc2ccccc2)C1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
To a stirred solution of 20.0 g (0.145 mole) of 2-nitroaniline 1, 28.0 g (0.146 mole) of 2,3-dichlorobenzoic acid in 200 mL dry dimethyl sulfoxide, 20.0 g (0.19 mole) of anhydrous sodium carbonate is added. The reaction mixture is heated at 110° C. for 5 hours under nitrogen atmosphere. The dimethyl sulfoxide solvent from the reaction mixture is removed under high vacuum and dried. The crude product is extracted three times each time with 100 mL methylene chloride by partitioning into water. The combined methylene chloride layer is dried over anhydrous sodium sulfate and filtered. Solvent from the filtrate is removed under reduced pressure and dried. The crude residue is chromatographed on a silica gel 60 column (230-400 mesh) using 25% ethyl acetate in hexane as an elution solvent. The fractions containing the desired product are combined and the solvent removed under reduced pressure to yield 20.0 g (47%) of N-phenyl N-(1-chloro 3-carboxyphenyl) amine 9.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]2[O:26][CH3:27])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]=[C:16]2[O:26][CH3:27])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Temperature: 0 °C

Procedure:
A solution of 5 g of isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate in 20 ml of methylene chloride is treated while stirring and cooling at 20°-25° C. with 25 ml of concentrated sulphuric acid. The reaction mixture is stirred at room temperature for 20 minutes and poured onto 100 g of ice. The orqanic phase is separated, the aqueous phase is extracted twice with 15 ml of ethyl acetate each time and the combined organic phases are washed to neutrality with water. Subsequently, the solution is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is recrystallized from diethyl ether/ n-hexane. There is obtained 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoic acid, m.p. 205°-210° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=O)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[F:8].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:37]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([NH:51][NH2:52])=[O:50])=[C:47]([CH2:55][CH3:56])[C:46]=1[CH3:57])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:52][NH:51][C:49](=[O:50])[C:48]2[CH:53]=[CH:54][C:45]([O:44][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:46]([CH3:57])[C:47]=2[CH2:55][CH3:56])=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[F:8]
Reactant: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1C
Reactant: COc1cc(CC(=O)O)cc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C(=O)NNC(=O)Cc2cc(F)c(F)c(OC)c2)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
340 mg of 2-(3,4-difluoro-5-methoxyphenyl)acetic acid (B2) are dissolved in 7.0 ml of N,N-dimethylformamide under a dry argon atmosphere. 484.3 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 130.2 mg of N-hydroxybenzotriazole and 526.0 mg of 4-benzyloxy-2-ethyl-3-methylbenzohydrazide (B1) are subsequently added. The reaction solution is stirred at room temperature for 18 h overnight. When the reaction is complete (TLC check), 100 ml of water are added, and the mixture is stirred for 30 min and subsequently extracted three times with 75 ml of ethyl acetate each time. The combined organic phases are dried over Na2SO4, filtered off with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent gradient: dichloromethane/0-20% by vol. of ethanol), giving 321 mg of the title compound as a colourless oil; MS: 937.3 (2M+H+); TLC: Rf=0.50 (dichloromethane/methanol 95:5 parts by volume).