Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(/C=C/c2cccc(I)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(/C=C/c2cccc(I)c2)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a solution of 8 (350 mg, 1.00 mmol) in CH2Cl2 (200 mL) was added BBr3 (10 mL, 1M in hexane) dropwise at −78° C. in a dry ice-acetone bath. The mixture was allowed to warm up to room temperature. Water was added while the reaction mixture was cooled at 0° C. in an ice bath. The mixture was extracted with CH2Cl2. The organic phase was dried and filtered. The filtrate was purified by flash chromatography (EtOAc: Hex, 1:9) to give 9 (296 mg, 92%). 1H NMR (200 MHz, CDCl3): δ 4.81 (s, 1H), 6.83 (d, J=16.17 Hz, 1H), 6.84 (m, 2H), 7.03 (d, J=16.32 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.36–7.57 (m, 4H), 7.84 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 94.75, 115.67, 124.96, 125.49, 128.09, 129.48, 129.87, 130.25, 135.01, 135.96, 139.90, 155.53; HRMS: m/z Calcd for C14H11IO: 321.9855; Found: 321.9840.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: C1CCNCC1
Product: CC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
A mixture of 4-fluoro-aniline (1.12 g; 10 mmol), 2-bromopropane (1.13 ml) and K2CO3 (1.38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O (2×20 ml) and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.65 g; 43%), as light yellow oil. 1H-NMR (CDCl3) 6.89-6.82 (m, 2H); 6.53-6.47 (m, 2H); 3.58-3.49 (m, 1H); 1.18 (d, 6H, J=6.25 Hz).
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[F:17][C:18]([S:21]([O-:23])=[O:22])([F:20])[F:19].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][S:21]([C:18]([F:20])([F:19])[F:17])(=[O:23])=[O:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: O=S([O-])C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CS(=O)(=O)C(F)(F)F
Reaction time: 66 h
Yield: 63 %

Procedure:
A mixture of 12.20 g (42.8 mmol) of Part B farnesyl bromide, 8.0 g (52 mmol, 1.2 equiv) of potassium trifluoromethylsulfinate (Parrish Chemical) and 1.00 g (4.3 mmol, 0.1 equiv) of 18-crown-6 in 200 mL of dry dimethylformamide was stirred for 66 hours. The dimethylformamide was evaporated at reduced pressure with minimal warming. The residue was dissolved in 600 mL of diethyl ether and washed with three 70 mL portions of H2O and 70 mL of brine, dried over MgSO4 and evaporated. Purification by flash chromatography on 200 g of Merck 9385 silica eluted with 15:85 CH2Cl2 : hexane provided 1.35 g of mixed fractions and 9.02 g (63%) of pure product. The mixed fractions were rechromatographed on 60 g of silica gel, eluting with 15:85 CH2Cl2 : hexane to provide 0.95 g (7%) of pure title product. The two portions of pure title triflone product were combined: 9.97 g (70%) of a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32](S(C)(=O)=O)=[N:31][C:30]=2[CH:38]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([CH:16]5[CH2:20][CH2:19][CH2:18][CH:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:31][C:30]=2[CH:38]=1
Reactant: CS(=O)(=O)c1nc2cc(F)ccc2o1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=C(O)C1CCCC1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4o3)cc2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (100 mg, 0.31 mmol) in dichloroethane (3 mL), 5-fluoro-2-(methylsulfonyl)-1,3-benzoxazole (80 mg, 0.37 mmol) was added and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.93 mL, 0.93 mmol) was added and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.31 mL, 0.31 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as a white solid (43.7 mg, 31.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2H), 7.90-7.80 (m, 6H), 7.50 (m, 1H), 7.30 (m, 1H), 6.95 (m, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.66 min (method 2), m/z 445.1 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[N:23]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:29][CH:30]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(S(N)(=O)=O)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with p-aminomethylbenzenesulfonamide (0.31 g, 1.4 mmol). Purification using silica gel, eluting with 4:1 CH2Cl2 /acetone, afforded a solid that recrystallized from CH2Cl2 /Et2O/hexane to give 109 as a white solid (m.p. 190-194° C.).
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O=[C:17]1[CH2:22][CH2:21][N:20]([C@H:23]([CH3:27])[CH2:24][C:25]#[N:26])[CH2:19][CH2:18]1>>[NH2:26][CH2:25][CH2:24][C@H:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14])=[CH:12][CH:11]=2)[CH2:18][CH2:19]1)[CH3:27]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Product: C[C@H](CCN)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1

Procedure:
Using general procedure A with 4-(tert-butyl-dimethyl-silanyloxy)-phenylamine (Swenton, John S.; et al., J. Org. Chem., 54, 1, 1989, 51-58) (1.28 g, 5.73 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.05 g, 6.32 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine as a yellow oil (1.81 g, 84% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CCOC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
1.50 g (3.98 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate), 658 mg (3.98 mmol) of ethyl 4-aminobenzoate, 566 mg (3.98 mmol) of Oxima and 620 μl (3.98 mmol) of DIC in 39 ml of dimethylformamide were reacted according to General Method 5B. Filtration gave the title compound. Yield: 1.87 g (85% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([C:11](=[O:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[O:18][CH2:19][CH3:20].C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH:11]([OH:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[O:18][CH2:19][CH3:20]
Reactant: CCOc1cc(C(=O)CS(C)(=O)=O)cc(OCC)c1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(O)CS(C)(=O)=O)cc(OCC)c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 26 g. of 4'-amino-3',5'-diethoxy-2-(methylsulfonyl)-acetophenone in 350 ml. of ethanol and 350 ml. of water was treated with a solution of 7.0 g. of sodium borohydride in 90 ml. of water. There was also added 0.5 g. of sodium hydroxide. The mixture was stirred for 17 hours at room temperature, cooled with ice, diluted with 500 ml. of water and filtered under vacuum. After recrystallization from methanol, there was obtained 4-amino-3,5-diethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 166°-168° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=2.[NH:18]1C=CN=[CH:19]1>C1(C)C(C)=CC=CC=1>[N:12]1([CH2:11][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[CH:13]=[CH:19][N:18]=[CH:14]1
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1CN(C)C
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1Cn1ccnc1
Yield: 89.4 %

Procedure:
Treatment of 2, N,N-trimethyl-5-nitro-1H-indole-3-methanamine (J.Org.Chem.,28,2921(1963)) (5.60 g) with imidazole (1.90 g) in xylene (100 ml) according to the method of Preparation 1 gave the title compound (5.50 g),m.p. 240°-242° C. Found: C,61.02; H,4.41; N,21.68. C13 H12N4O2 requires: C,60.92; H,4.72; N,21.87%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:5]([C:4]([F:3])([F:14])[F:15])=[N:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% [w/w] dispersion in mineral oil, 632 mg, 15.8 mmol) was added portionwise to a stirred solution of 4,5,6,7-tetrahydro-3-(trifluoromethyl)-indazole (3.00 g, 15.8 mmol) in DMF (60 mL), and the mixture stirred at RT for 30 min. Tert-butyl bromoacetate (2.33 mL, 15.8 mmol) was added and the reaction mixture stirred at 80° C. for 2 h, and allowed to cool to RT. Water (50 mL) was added and the resulting solution extracted with EtOAc (3×200 mL), washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to afford (3-Trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid tert-butyl ester.
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Br[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1[CH3:24]>>[CH3:24][C:15]1[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[C:18]([CH3:20])=[CH:19][C:14]=1[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: Cc1cc([N+](=O)[O-])c(C)cc1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
Prepared from tert-butyl 3-iodoazetidine-1-carboxylate and 1-bromo-2,5-dimethyl-4-nitrobenzene by following the general protocol as described in Billotte, S. Synlett 1998, 379.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:13][C:14]1[C:23]2[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N+:17]([O-])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]1[C:23]2[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N:17]=[C:16]([Cl:3])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(OCc3ccccc3)cc[n+]([O-])c2c1C
Product: COc1ccc2c(OCc3ccccc3)cc(Cl)nc2c1C
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 90.4 %

Procedure:
POCl3 was added under inert atmosphere at −78° C. to 4-benzyloxy-7-methoxy-8-methylquinoline N-oxide (62, 2.5 g, 8.47 mmol). Then the reaction mixture was allowed to warm up to room temperature, then heated to reflux. After 35 min, the solution was cooled to room temperature and the excess of POCl3 was evaporated under reduced pressure. The residue was partitioned between ice-cooled water and AcOEt, dried (Na2SO4) and evaporated. The residue was triturated in ether, then filtered and successively washed with small portions of methanol and ether to give 2.4 g (90.4%) of the target product 63 as a white powder: m/z=314 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.[H][H]>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:22]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Yield: 89.1 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propenoate (1.80 g), 5% palladium-carbon (2.32 g) and tetrahydrofuran (30 ml) was stirred overnight in a hydrogen atmosphere at room temperature. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propionate (1.61 g, yield: 89%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([O:10][C:11](=[O:24])[C:12]([O:14][C:15]([CH3:23])([CH2:17][CH2:18][O:19]C(=O)C)[CH3:16])=[O:13])([CH3:9])[CH3:8])(=O)C>C(Cl)Cl.C(NC(C)C)(C)C>[C:12]([O:14][C:15]([CH3:23])([CH2:17][CH2:18][OH:19])[CH3:16])(=[O:13])[C:11]([O:10][C:7]([CH3:9])([CH2:6][CH2:5][OH:4])[CH3:8])=[O:24]
Reactant: CC(=O)OCCC(C)(C)OC(=O)C(=O)OC(C)(C)CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(CCO)OC(=O)C(=O)OC(C)(C)CCO

Procedure:
The cleavable diol is made in the following manner. To a solution of compound (73) in methylene chloride, diisopropylamine is added and the solution is stirred until reaction is complete. A standard aqueous workup is done and the diol should remain in the organic phase. Evaporate the solvent and collect bis(4-hydroxy-2-methylbutan-2-yl) oxalate (74).
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:11][C:12]1[C:13]([OH:18])=[CH:14][C:15]2[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:10])([CH3:3])[C:16]=2[CH:17]=1
Reactant: Oc1ccccc1Br
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21

Procedure:
36.6 g (0.2 mol) of 2,5-dichloro-2,5-dimethylhexane, 34.6 g (0.2 mol) of 2-bromophenol and 400 ml of dichloromethane were introduced successively into a three-necked flask. 26.6 g (0.2 mol) of AlCl3 were added in small amounts at 0° C. and stirring was carried out until gas evolution had ceased (violent reaction). The reaction mixture was poured into water and the organic phase was separated by settling, washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). After evaporating the solvents, 20.6 g (36%) of the expected phenol were recovered.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>CCO.CCOC(C)=O.[Pd]>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH2:29])[N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nccc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 170 mg (0.38 mMol) 5-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 19 ml EtOH/EtOAc 1:1 in hydrogenated in the presence of 80 mg Pd/C (10%; Engelhard 4505). The catalyst is filtered off and the filtrate diluted with EtOAc and sat. Na2CO3/H2O 1:1. The aqueous layer is extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc/hexane 3:2→EtOAc) gives the title compound: MS: [M+1]+=416; TLC(hexane/EtOAc 3:7): Rf=0.14; HPLC: AtRet=12.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:7](=[O:19])[NH:6][CH2:5]2.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1.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.COCCOC>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=3[CH3:31])[C:24]([NH:23][CH:20]3[CH2:21][CH2:22]3)=[O:41])=[CH:11][CH:10]=2)[CH2:5][NH:6][C:7]1=[O:19]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NCc2cc(Br)ccc2N1c1ccccc1Cl
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: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)CNC(=O)N2c1ccccc1Cl

Procedure:
To a stirred mixture of 6-bromo-1-(2-chlorophenyl)-3,4-dihydroquinazolin-2(1H)-one (0.1993 g, 0.5903 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.2134 g, 0.7084 mmol) and Pd(PPh3)4 (0.03411 g, 0.02952 mmol) was added 1,2-dimethoxyethane (5.000 ml) followed by 2N Na2CO3(aq) (0.7379 ml, 1.476 mmol) under nitrogen. The mixture was heated to reflux for 24. After cooling, the mixture was filtered through a short path of Celite and the filter cake was washed with EtOAc (3×10 mL). The combined organic layers were concentrated to give a crude product, which was purified using flash column chromatography (50% EtOAc in hexanes to 100% EtOAc) to afford 3-(1-(2-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-N-cyclopropyl-4-methylbenzamide as a white solid. MS m/e 432 (M+H)+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)=[O:7])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:2][C:1]1[O:7][C:6]([C:8]2[C:12]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1nsc2ccc([N+](=O)[O-])cc12
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2nsc3ccc([N+](=O)[O-])cc23)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-acetyl-2-[(5-nitro-1,2-benzisothiazol-3-yl)carbonyl]hydrazine(4.55 g, 0.0163 mol) and acetonitrile at room temperature is added phosphorous oxychloride (14.9 g, 0.0972 mol). The resultant mixture is heated to reflux, stirred two hours, cooled to room temperature and filtered to afford the title compound as an off-white solid (mp>250° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:37]3[CH:38]=[N:33][CH:34]=[N:35][CH:36]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: OB(O)c1cncnc1
Product: CCCCCCc1cccc(-c2nc(-c3cncnc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow oil. MS: 501.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([C:16]2[O:21][C:20](=[O:22])[CH2:19][CH2:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[CH2:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C1CCC=C(c2ccccc2)O1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 5-oxo-5-phenylpentanoic acid benzyl-methyl amide was prepared by refluxing N-methylbenzylamine (10.5 mmol) and 6-phenyl-3,4-dihydro-pyran-2-one (10.5 mmol) in toluene for one hour. The reaction was allowed to stir overnight at room temperature. It was poured into 100 mL of ethyl acetate and 100 mL of 1N HCl. The organic extracts were washed with 100 mL of 1N NaOH, 100 mL of water and dried over MgSO4. The crude product was flash chromatographed (CH2Cl2 /MeOH 98/2) to afford a liquid. 1H NMR (CDCl3) δ 2.0-2.2 (m, 2 H), 2.5 (t, 2 H), 2.93/2.96 (s/s, 3 H), 3.0-3.2 (m, 2 H), 4.5/4.6 (s/s, 2 H), 7.1-7.6 (m, 8 H), 7.8-8.0 (m, 2 H).