Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][C:13]=1[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:25])=[CH:14][C:13]=1[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)Oc1cc(CO)ccc1OCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(CBr)ccc1OCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a stirred solution of 0.9 g (2.2 mmol) {4-[2-(benzyloxy)ethoxy]-3-tert-butoxyphenyl}methanol and 976 mg (2.94 mmol) tetrabromo methane in 9 ml THF was added 775 mg (2.96 mmol) triphenylphosphin diluted in 4.5 ml THF at 0° C. dropwisly. The reaction mixture was stirred for 1 h at 0° C. The suspension was filtrated. The filter cake was washed with THF. The combined filtrates were concentrated in vacua. The crude product is purified by column chromatography (silica gel, hexane/ethylacetate gradient: 99:1→1:99). The desired product was obtained in 28% yield (313 mg, 0.76 mmol).
Reaction SMILES: [OH:1][C:2]1([CH3:12])[C:7](=O)[CH2:6][CH:5]2[CH2:9][CH:3]1[C:4]2([CH3:11])[CH3:10].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=1.B(F)(F)F>C1C=CC=CC=1>[CH3:12][C:2]1([OH:1])[C:7](=[N:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH:5]2[CH2:9][CH:3]1[C:4]2([CH3:11])[CH3:10]
Reactant: NCc1cccnc1
Reactant: CC1(O)C(=O)CC2CC1C2(C)C
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(O)C(=NCc2cccnc2)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a stirring solution of (+)-2-hydroxy-3-pinanone (10.00 g, 59.4 mmol) in benzene (500 mL) was added 3-pyridylmethylamine (6.66 mL, 65.4 mmol) in one portion. Boron trifluoride diethyletherate (0.7 mL, 5.9 mmol) was added in one portion and the reaction was refluxed under N2 for 5 h and then stirred at room temperature for an additional 16 h. The benzene was removed by rotary evaporation and the resulting residue was stirred in saturated NaHCO3 solution (100 mL) for 1 h. This was then extracted with chloroform (3×100 mL) and the combined extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation. The resulting dark brown oil was purified by column chromatography, using a chloroform:methanol gradient (9:1 to 1:1, v/v) as eluent. The light yellow oil was then dissolved in hot ethyl acetate (50 mL) and placed in a −4° C. freezer for 16 h. After warming to room temperature, the resulting crystals were filtered, washed with cold ethyl acetate, and dried using a hi-vacuum pump to yield 8.59 g of white powder (52.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][Br:11]
Reactant: COc1ccc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COc1ccc(CBr)cc1Cl
Temperature: 25 °C
Yield: 104.6 %

Procedure:
3-Chloro-4-methoxytoluene 8 (2.6 mL, 19.2 mmol) was dissolved in dichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 21.1 mmol) was added followed by AIBN (36.0 mg). The reaction was heated to reflux for 19 hrs., then cooled to room temperature and the precipitate was filtered off. The filtrate was diluted with dichloromethane and washed with 0.5 M aqueous sodium bicarbonate, followed by water. The organic mixture was dried over sodium sulfate, filtered and concentrated under vacuum to yield 9 (4.73 g, 82%). The benzyl bromide was used as the crude material without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.5 %

Procedure:
3-Chloro-2-nitro aniline (5.0 g, 28.97 mmol) and NBS (5.42 g, 30.42 mmol) were combined in THF (200 mL) and stirred at rt for 15 h. Concentration and purification (SiO2, EtOAc/hexanes) afforded the title compound (0.84 g): 1HNMR (400 MHz, CDCl3) δ 7.46 (d, J=8.9 Hz, 1H), 6.63 (d, J=8.9 Hz, 1H), 4.7 (s, 2H); MS (ESI) m/z 253 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br>>[Br:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: BrCc1cccc(Br)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(Br)c2)cc1

Procedure:
Analogously to Method D, 4.14 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 2.31 g of 3-bromobenzyl bromide are reacted. The title compound is obtained as a yellowish oil. Rf=0.40 (1:2 EtOAc-heptane); Rt=6.45.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:7]([OH:8])[CH2:6][C@H:5]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([I:18])[C:12]3=[C:11](C)[N:10]=2)[O:4]1.[OH-].[NH4+:21]>>[NH2:21][C:11]1[N:10]=[C:9]([C@@H:5]2[O:4][C@H:3]([CH2:2][OH:1])[CH:7]([OH:8])[CH2:6]2)[N:14]=[C:13]2[NH:15][N:16]=[C:17]([I:18])[C:12]=12
Reactant: Cc1nc([C@H]2CC(O)[C@@H](CO)O2)nc2[nH]nc(I)c12
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nc([C@H]2CC(O)[C@@H](CO)O2)nc2[nH]nc(I)c12

Procedure:
Compound 8 (6.8 g, 17.35 mmol) was stirred in 200 mL of concentrated ammonium hydroxide (sealed container) at room temperature for 36 h. The mixture was evaporated and the residue was precipitated from acetonitrile-ether. The solid was filtered and dried: 5.36 g (82%) yield. NMR and spectral data on this compound is identical to
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: C[Si](C)(C)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of iodobenzene (1 mmole) in DME (5 mL) was treated with trimethylsilylacetylene (2 mmole), Pd(PPh3)2Cl2 (0.035 mmole), CuI (0.08 mmole) and triethylamine (4 mmole), and the resulting reaction mixture was stirred under nitrogen at room temperature for 5 h. Evaporation followed by chromatography gave 1-trimethylsilyl-2-phenylacetylene as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(OCC)C>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(COc1ccc(C(=O)CBr)cc1)NCc1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)NCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 2-[4-(bromoacetyl)phenoxy]-N-(phenylmethyl)acetamide (1.40 g) (preparation described in EPO 052442) in acetonitrile (5 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (1.14 g) in acetonitrile (20 ml). After stirring overnight the liquors were decanted from the residual gum, then concentrated in vacuo. Purification by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane, gave a solid. Trituration of this solid with diethyl ether gave the title compound, 95 mg: m.p. 150°-151° C.; NMR (d6DMSO) δ8.67(1H,bt) 8.15(2H,d), 8.00(2H,d), 7.26(5H,m), 7.06(2H,d), 6.81(2H,d), 4.66(2H,s), 4.34(2H,d), 3.84(2H,s), 3.33(4H,t), 2.54(4H,t); m/e 445 (M+H)+ ; calculated for C26H28N4O3. 0.25H2O: C, 69.5; H, 6.4; 12.5. found: C, 69.6; H, 6.4; N, 12.3%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Cl)cc23)cc1

Procedure:
A solution of 4,6-dichloro-3-nitroquinoline (Compound of Preparation E, 4.0 g, 16.46 mmol) and 2-(4-aminophenyl)-2-methylpropanenitrile (2.63 g, 16.46 mmol) in acetic acid (350 ml) was stirred for 2 hours. Water was added and the yellow precipitate was filtered off, washed with water and saturated aqueous NaHCO3. The yellow solid was dried to obtain the title compound. Yield: 5 g (83%); 1H NMR (DMSO-d6, 300 MHz): δ 10.074 (s, 1H), 9.062 (s, 1H,), 8.552-8.558 (d, 1H, J=1.8 Hz), 7.995-8.025 (d, 1H, J=9 Hz), 7.875-7.912 (t, 1H), 7.437-7.466 (d, 2H, J=8.4 Hz), 7.100-7.128 (d, 2H, J=8.4 Hz), 1.664 (s, 6H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:31][CH2:30][C:25]4(OCC[O:26]4)[CH2:24]3)=[CH:19][CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:31][CH2:30][C:25](=[O:26])[CH2:24]3)=[CH:19][CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC4(C3)OCCO4)cc1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC(=O)C3)cc1)C2=O

Procedure:
A mixture of 6-butoxy-2-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)phenyl]-3,4-dihydro-2H-isoquinolin-1-one (1.40 g), p-toluenesulfonic acid (57 mg) and acetone (40 mL) was boiled under reflux for 12 hours and then concentrated. The residue was partitioned between sodium carbonate solution and ethyl acetate. The organic phase was dried and concentrated. The product with the molecular weight of 378.48 (C23H26N2O3) was obtained in this way; MS (ESI): 379 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccc(Cl)cc5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (300 mg, 0.767 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (246 mg, 0.997 mmol), Na2CO3 (203 mg, 1.917 mmol) and Pd(PPh3)4 (89 mg, 0.077 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washed with EtOAc (150 mL), evaporated, and then chromatographed to afford the title compound (305 mg). LC-MS (ES) m/z=476 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[N:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[BH3-]C#N.[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)[N:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc3c(c2)CCN3)ncn1
Reaction time: 1 h

Procedure:
A solution of 6.21 g (21.9 mMol) 6-(1H-indol-5-yloxy)-pyrimidine-4-carboxylic acid ethyl ester in 70 ml acetic acid is cooled in an ice bath. Then 6.88 g (109 mMol) NaBH3CN are added and stirring is continued for 1 h. After addition of 17 ml water, the mixture is concentrated in vacuo. The resulting brown oil is re-dissolved in EtOAc and a 1:1 mixture of water and sat. NaHCO3, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to the crude title compound: MS: [M+1]+=286.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])[CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:5]1[CH:4]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A mixture of 4-(chloromethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]pyridine (0.472 g), methyl 2-(3-hydroxyphenyl)acetate (0.249 g), anhydrous potassium carbonate (0.415 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetate as a colorless oil (0.597 g, 90%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:23](=[N:36]N)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN1CCOCC1>[C:23](=[N:36][NH:12][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[NH:8][C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc2c(F)cc(N)cc2[nH]1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN1CCOCC1
Product: Cc1nc2cc(NN=C(c3ccccc3)c3ccccc3)cc(F)c2[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a separate reaction container, 7-fluoro-2-methyl-3H-benzimidazol-5-yl amine (100 mg, 0.44 mmol), lithium bis(trimethylsilyl) amide (190 mg, 1.1 mmol), and benzophenone hydrazone (94.3 mg, 0.48 mmol) were dissolved in N-methyl-morpholine (0.5 ml) under a nitrogen atmosphere. Then, the prepared solution containing the catalyst was added thereto. After deaeration, this was heated and stirred at 100° C. under a nitrogen atmosphere for two hours. The reaction mixture was cooled to room temperature, and then an aqueous solution of 6 M hydrochloric acid (0.5 ml) was added thereto. The organic layer was isolated, and concentrated under reduced pressure. Thus, crude N-benzhydrylidene-N′-(7-fluoro-2-methyl-1H-benzimidazol-5-yl)-hydrazine was obtained. The obtained crude product was used in subsequent reactions without being purified.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.B.O1CCCC1>CO>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(-n2cccn2)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(-n2cccn2)cc1
Yield: 83 %

Procedure:
To 4-(pyrazol-1-yl)benzonitrile (see WO 2005/095343A) (1.46 g, 8.63 mmol) was added a solution of 1M borane.tetrahydrofuran complex in tetrahydrofuran (93 ml, 93 mmol), followed by heating to reflux for 16 hours. After completion of the reaction, methanol (14 ml) was added to the reaction solution, followed by concentration under reduced pressure. 6N Hydrochloric acid (265 ml) was added to the residue, followed by further heating to reflux for 3 hours. After this solution was concentrated under reduced pressure, a small amount of water was added. The resulting solution was adjusted to pH 11 with a 30% aqueous sodium hydroxide solution under ice cooling, followed by extraction with methylene chloride. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=90:10:1 (V/V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.24 g) as a pale yellow solid. (Yield: 83%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH2:13][CH3:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)O1>>[CH2:13]([C:4]1[CH:3]=[C:2]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH3:14]
Reactant: CCc1cc(Br)ccc1CC(=O)OC
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CCc1cc(-c2ccc(O)cc2)ccc1CC(=O)OC
Yield: 84 %

Procedure:
According to a method similar to Example (26-3), from methyl (4-bromo-2-ethylphenyl)acetate (138 mg, 0.537 mmol) synthesized in Example (85-3) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (142 mg, 0.644 mmol), methyl (3-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate was obtained (122 mg, yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:16][CH:17]=[CH:18][C:7]=4[C:6]=2[CH:19]=1)[NH:10][CH:11]=3.[H-].[Na+].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:16][CH:17]=[CH:18][C:7]=4[C:6]=2[CH:19]=1)[N:10]([S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH:11]=3
Reactant: CN1Cc2c[nH]c3nccc(c23)-c2cc(F)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Reaction time: 0.5 h

Procedure:
To a solution of Example 41B (18.49 g, 73.0 mmol) in N,N-dimethylformamide (146 mL) at room temperature under nitrogen was added sodium hydride (4.38 g, 110 mmol) in portions. The mixture was stirred for 30 minutes and p-toluenesulfonyl chloride (15.31 g, 80 mmol) was added in portions over 10 minutes. The mixture was stirred overnight at room temperature, poured into water and filtered. The solid was washed with heptanes and placed in a vacuum oven overnight at 50° C. The residue was taken up in dichloromethane/methanol and concentrated to give a solid containing ˜10% unreacted starting material. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=5.3 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.76 (d, J=10.4 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=5.5 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.31-7.25 (m, 2H), 4.10 (s, 2H), 2.89 (s, 3H), 2.33 (s, 3H). MS (ESI+) m/z 408.5 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][S:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:14])=[O:13])[CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)CCCCCCCCCCBr
Reactant: NC1CC1
Product: O=S(=O)(CCCCCCCCCCBr)NC1CC1
Yield: 97.3 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 3 except for using 10-bromodecanesulfonyl chloride (450 mg, 1.41 mmol) in place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (177 mg, 3.10 mmol), to give N-cyclopropyl-10-bromodecanesulfonamide (467 mg) as colorless crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]([NH2:10])=[NH:9])[CH:7]=1.C[O-].[Na+].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>CCO>[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:10]=[C:17]([OH:16])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:9]=2)[CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)n1cc(F)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-n2cc(F)cn2)nc1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a solution of 28-e (2 g, 12 mmol) in EtOH was added sodium methoxide (1 g, 18 mmol) and diethyl ethoxymethylenemalonate (2.64 g, 12 mmol). The reaction was cooled to room temperature, filtered and washed with EtOH and Et2O to afford the title product, 28-f, (1.9 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)[O:24][C:23]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:22][C:21](=O)[O:20]1>>[C:28]([C:27]1[CH:26]=[C:25]([C:23](=[O:24])[CH2:22][C:21]([NH:1][C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[O:20])[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: Nc1cc(-n2ccc(CO)c2)ccc1[N+](=O)[O-]
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(CO)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from [1-(3-amino-4-nitro-phenyl)-1H-pyrrol-3-yl]-methanol (Example F5) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange solid (77 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>>[C:16]([NH:12][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:8][C:9]([OH:11])=[O:10])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A 0° C. slurry of 50.0 g (300 mmole) of DL-3-amino-3phenyl propionic acid in 300 mL of 1N aq NaOH (300 mmole) was treated simultaneously with 48.0 mL (340 mmole) of benzyl chloroformate and 300 mL of 1N aq NaOH (300 mole). The reaction was stirred at ambient temperature for 18 h at which time the reaction was acidified to pH 2 with conc. aq HCl and extracted with EtOAc (4×200 mL). The combined organic fractions were dried over Na2SO4 and evaporated in vacuo to give 73.4 g (250 mmol; 82%) of N-Cbz-3-amino-3-phenyl propionic acid as an off white solid.