Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([OH:36])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([OH:36])[CH:35]=[C:30]([Cl:29])[CH:31]=1
Reactant: OB(O)c1cc(O)cc(Cl)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(Cl)c3)n(-c3ccccc3)c(=O)c12
Yield: 13.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with (3-chloro-5-hydroxyphenyl)boronic acid (59 mg, 0.34 mmol), sodium carbonate (2M, 510 μl, 1.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) according to the method described in Example 3 to give 15 mg (32% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH:6]([S:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[ClH:2].[CH3:7][CH:6]([S:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:1][CH:3]([OH:5])[CH2:4][NH:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:8]
Reactant: CC(C)Sc1cccc(O)c1
Reactant: CCCCCCCCN
Reactant: ClCC1CO1
Product: CCCCCCCCNCC(O)COc1cccc(SC(C)C)c1
Product: Cl
Yield: 13 %

Procedure:
Reaction of the epichlorohydrin derivative of 3-(isopropylthio)phenol (4.85 g., 0.029 mole) with n-octylamine (4 g., 0.031 mole) according to the procedure of Example 2(b) and crystallization of the crude product from ethanol-ether affords a 13% yield of analytically pure 1-[3-[(1-methylethyl)thio]phenoxy]-3-(octylamino)2-propanol hydrochloride, m.p. 125°-127° (corr.).
Reaction SMILES: [CH2:1]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH3:22][SnH:23]([CH3:25])[CH3:24]>>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([S:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Sn:23]([CH3:25])([CH3:24])[CH3:22])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: C=CCCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Reactant: C[SnH](C)C
Product: Cc1ccc(S(=O)(=O)CCCCCCCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 1 was employed except that 13.1 g (42.5 mmoles) of 10-undecenyl-p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 189 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The residual oil weighed 15.5 g. One-half of the crude product was chromatographed on a column containing silica gel using toluene and 2% acetone in toluene as eluents. The product, 11-(p-tolylsulfonyl)-undecyltrimethylstannane, was obtained as an oil. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1, 1140 cm-1 (--SO2 ) and 760 cm-1 [(CH3)3Sn--]. NMR showed the following:
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][CH:23]([CH3:34])[CH2:24][CH2:25][N:26]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][CH2:24][CH:23]([CH3:34])[CH3:22])[CH:30]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC(C)CCn1cc(B(O)O)cn1
Product: CC(C)CCn1cc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cn1
Yield: 21 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (99 mg) was reacted with 1-(3-methylbutyl)-1H-pyrazole-4-boronic acid, pinacol ester as in General Procedure 4B to give the title compound as a brown solid (21% yield). M.p.=134° C., LCMS: m/z=431.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 0.96 (6H, d, J=6.6 Hz), 1.61 (1H, m), 1.80 (2H, m), 3.28 (2H, t, J=4.8 Hz), 3.51 (2H, m), 4.15 (2H, t, J=7.5 Hz), 4.50 (2H, s), 4.90 (1H, bs), 6.96 (1H, d, J=1.5 Hz), 7.02 (1H, m), 7.12 (1H, m), 7.51 (1H, s), 7.63 (2H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](O)=[N:3][CH:2]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][NH:28][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCc1ccc(OCc2ccccc2)cc1
Reactant: Oc1ncnc2nccnc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: c1ccc(COc2ccc(CCNc3ncnc4nccnc34)cc2)cc1
Temperature: 114 °C
Yield: 73.8 %

Procedure:
To a mixture of pteridin-4-ol (282 mg, 1.9 mmol) and 2-(4-benzyloxyphenyl)-ethylamine (476 mg, 2.1 mmol) and hexamethyldisilazane (5 mL) in a 25 mL round bottom flask, equipped with reflux condenser, drying tube and magnetic stir bar, was added ammonium sulfate (100 mg, 0.76 mmol). The mixture was heated to 114° C. overnight and then the solvent was removed in vacuo. The residue was suspended in H2O and filtered. The filter cake was dissolved in CH2Cl2, dried with Na2SO4, filtered, and concentrated in vacuo to provide [2-(4-benzyloxyphenyl)-ethyl]-pteridin-4-yl-amine as a white solid (501 mg): 1H NMR (300 MHz) δ 9.01 (d, J=1.9 Hz, 1H), 8.81 (s, 1H), 8.61 (d, J=1.9 Hz, 1H), 7.49-7.29 (m, 6H), 7.25-7.15 (m, 3H), 6.96 (dd, J=6.8, 4.8 Hz, 2H), 5.06 (s, 2H), 3.93 (dd, J=13.2, 6.9 Hz, 2H), 3.00 (t, J=7.0 Hz, 2H); ESIMS m/z 358.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2](=[CH2:11])[C:3]([O:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[O:4].[NH2:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:28])=[C:23]([Cl:36])[CH:22]=1.O.CCOC(C)=O>N1C=CC=CC=1>[CH3:11][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:28])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[C:23]([Cl:36])[CH:22]=1)=[O:10])=[O:4]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2N)cc1Cl
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1cc(Br)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Isocyanatoethyl 2-methylacrylate (0.31 g, 2.2 mmol) was slowly added to a solution of {4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl}(2-methylphenyl)methanone (0.60 g, 1.44 mmol)(disclosed in WO 01/05744) in dry pyridine (3.00 mL). The solution was stirred at room temperature for 6 h after which it was poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/EtOAc 4:1 as the eluent to afford the title compound as a light brown solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:23])=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:23][CH2:3][C:2]#[CH:1])=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1
Reactant: C#CCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Product: C#CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
This was prepared as for Example 24 but using propargyl bromide (0.48 g, 0.0044 mol) and 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g, 0.0018 mol) and recrystallising the product from ethanol/water; yield=210 mg as a white crystalline solid, mp=183°-185° C. Found: C, 69.21; H, 3.68; N, 4.34. C18H12ClNO2 +0.1 H2O requires C, 69.39; H, 3.95; N, 4.50. δ (360 MHz, DMSO-d6), 3.50 (1H, t, J=2.3 Hz, CCH), 4.26 (2H, d, J=2.5 Hz, OCH2C), 7.28 (1H, dd, J=8.5 and 1.9 Hz, H6), 7.32-7.48 (6H, m, aromatics), 7.86 (1H, d, J=8.6 Hz, H5), 11.96 (1H, s, br, NH). MS (CI) m/z=310 [MH]+.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:28][CH2:29][CH2:30][Cl:31])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCCBr
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Yield: 27 %

Procedure:
6-(3-Chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime was prepared in 27% yield using the method described in example 85A, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 1-bromo-3-chloropropane in dimethylformamide. The title compound was isolated as a yellow solid.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:70]([CH3:71])[N:69]=[N:68][N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:70]([CH3:71])[N:69]=[N:68][N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1nnnc1SCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: Cn1nnnc1SCC1=C(C(O)=S)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-(1-methyl-5-tetrazolyl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (576 mg: 0.555 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) cooling at -30° to -40° C. is added a solution of aluminum chloride (591 mg: 4.44 mMol.) in anisole (2 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (5 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove the organic solvents, and purified by styrene-divinylbenzene copolymer chromatography (methanol: water=4:1). The resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl]amino-3-(1-methyl-5-tetrazolyl)thiomethylthio-3-cephem-4-carboxylic acid as yellow powder (200 mg). Yield: 68%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[N:22]=[CH:23][NH:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[N:22]1[C:21]2[CH:25]=[CH:26][C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)=[CH:19][C:20]=2[NH:24][CH:23]=1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4nc[nH]c4c3)n2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5nc[nH]c5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(3H-benzoimidazol-5-yl)-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(3H-benzoimidazol-5-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-tert-butyl-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid methyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2 mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E88); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.O.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]#[N:17])=[CH:3][C:4]=1[O:10][C:11]([F:14])([F:13])[F:12])=[O:7]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(C=O)c(OC(F)(F)F)c1

Procedure:
10.63 g (39.51 mmol) of 4-bromo-2-(trifluoromethoxy)benzaldehyde, 3.43 g (29.24 mmol) of zinc cyanide and 1.37 g (1.19 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 80 ml of DMF. The reaction mixture is then reacted in several portions in a single mode microwave (Emrys Optimizer, 5 min at 220° C.). The combined mixtures are mixed with water and extracted twice with toluene. The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and then the solvent is removed in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 10:1). 3.32 g (78% of theory) of the title compound are obtained with a purity of 80% (according to LC-MS).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH3:20])([CH:17]=[CH:18][CH3:19])[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:21]([Br:25])[CH:22]=[CH:23][CH3:24].C(OCC)(=[O:28])C>>[Br-:25].[C:21]([N+:12]1([CH2:11][C:10]([CH3:20])([CH:17]=[CH:18][CH3:19])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:28])/[CH:22]=[CH:23]/[CH3:24]
Reactant: CC=CCBr
Reactant: CC=CC(C)(Cc1ccc(Cl)cc1Cl)CN1CCCC1
Reactant: CCOC(C)=O
Product: CC=CC(C)(Cc1ccc(Cl)cc1Cl)C[N+]1(C(=O)/C=C/C)CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 31.2 g of N-[3-(2,4-dichlorophenyl)-2-methyl-2-prop-1-en-1-yl-propyl]-pyrrolidine and 27 g of crotyl bromide in 250 ml of ethyl acetate is refluxed for 5 hours. The mixture is then stirred for 15 hours at room temperature and the crystalline product which is obtained is filtered off, washed with ether and dried in vacuo. 15 g of the desired product is obtained; m.p.: 128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37])[CH3:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:37][CH2:36][C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH2:31][CH3:32])=[O:29]
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: CCOc1ccccc1CN
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2[C@@H]1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=1.C(Cl)(Cl)Cl>[O-2].[O-2].[Mn+4].O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(-c2ccco2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(-c2ccco2)n1
Yield: 73.4 %

Procedure:
8 g of manganese dioxide are added to a solution of 2 g of (6-furan-2-yl-pyridin-2-yl)methanol (11.4 mmol) and 50 ml of chloroform. The reaction mixture is heated under reflux for 1 hour 30 minutes with removal of the water formed continuously. The solid in suspension is removed by filtration on celite and then the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform). 1.45 g of a yellow solid are recovered.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[C:29](O)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2.C(C=P(CCCC)(CCCC)CCCC)#N.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:20][C:21]1[C:29]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2
Reactant: COc1c(O)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 65.8 %

Procedure:
Under nitrogen, the 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.23 g, 5.01 mmol) obtained in Example 385, (b), the 4-methoxy-1H-indazol-5-ol (0.906 g, 5.52 mmol) obtained in Example 469 and 90%-cyanomethylenetri-n-butylphosphorane (161 g, 6.02 mmol) were dissolved in toluene (20 ml), and the resulting solution was heated under reflux for 5 hours. The reaction solution was cooled to room temperature and water and a 1N-aqueous sodium hydroxide solution were added thereto. The resulting solution was separated by the addition of toluene and the desired compound was extracted from the aqueous layer with toluene. The combined toluene layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the concentration residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, 1/1) to obtain 2-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione (1.29 g, yield 66%).
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[O:39]([Si](C)(C)C)[K]>C1COCC1.CO>[C:2]([O:7][C:6]1[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[CH2:13][NH:14][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:24][CH:25]=2)=[CH:11][C:5]=1[CH2:4][OH:3])(=[O:39])[CH3:1]
Reactant: C[Si](C)(C)O[K]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(F)c5)cc4)C(=O)O3)ccc2O1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc([C@@H](O)CNCCc2ccc(OCCOCc3cccc(F)c3)cc2)cc1CO
Temperature: 75 °C

Procedure:
(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-(2-[(3-fluorobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one (125 mg) in THF (1 mL) was treated with KOSiMe3 and the resulting solution was heated at 75° C. for 2 h. The solution was then diluted in MeOH, passed down an SCX-2 cartridge (10 g) and then concentrated in vacuo. The residue was purified by chromatography (SPE, 5 g) eluting with CH2Cl2-MeOH-2M NH3 in MeOH (98:1:1) and then CH2Cl2-MeOH-2M NH3 in MeOH (95:4:1) to give the free base of the title compound. This was converted to the acetate salt using acetic acid to give the title compound (38 mg). LCMS RT=2.56 min. ES+ve 456 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][N:28]=[C:27]([CH3:32])[C:26]=2[CH:33]=1.CN1CCCN(C)C1=O>O1CCCC1>[OH:11][C:10]([C:13]([F:16])([F:15])[F:14])([CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17])[CH2:12][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][N:28]=[C:27]([CH3:32])[C:26]=2[CH:33]=1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccc2c(=O)onc(C)c2c1)C(F)(F)F

Procedure:
584 mg of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl-oxiran, 282 mg of 6-amino-4-methyl-2,3-benzoxazin-1-one and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2[1H]-pyrimidinone are heated to 120° C. for 6 hours. After 1 ml of tetrahydrofuran is added, it is chromatographed on silica gel, and the title compound is eluted with hexane/ethyl acetate/tetrahydrofuran (55:40:5), flash point 178-179° C.