Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([CH2:55][S:56](Cl)(=[O:58])=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[CH2:55]([S:56]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])=[C:5]([NH:27][CH2:28][CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:4]=1)(=[O:58])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (120 mg, 0.21 mmol) and triethylamine (0.04 ml, 0.29 mmol) in anhydrous dichloromethane (2 ml) was treated with phenylmethylsulphonyl chloride (45 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in ethanol (1 ml). Hydrochloric acid (1M, 1 ml) was added to the solution and the mixture was heated at 60° C. for 8 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane methanol (95:5 by volume) gradually changing to dichloromethane: methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a white solid (92 mg).
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([NH:22][N:23]=[C:2]([CH3:13])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)COc1ccc(C#N)cc1
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: CC(COc1ccc(C#N)cc1)=NNc1ccc(C(F)(F)F)cc1

Procedure:
The sub-title compound was prepared by the method of example 20 step (ii), using the product from step (i) (3.8 g) and 4-(trifluoromethyl)phenylhydrazine (3.7 g). Yield 2.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of methyl 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionate (2.50 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propan-1-ol (2.03 g, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.82–1.98 (2H, m), 2.70–2.82 (2H, m), 3.66–3.78 (2H, m), 3.86 (3H, s), 6.95–7.06 (2H, m), 7.62–7.73 (2H, m), 8.18 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.Br[CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and (3-bromopropoxy)-tert-butyldimethylsilane. The desired product was obtained in a yield of 65% as colorless oil. MS (m/e): 670.5 (M+H, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[OH:13])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH:1]=[O:2])[C:7]([O:9][CH3:10])=[O:8])[CH:21]=[CH2:20]
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OC)ccc1C=O
Temperature: 48 °C
Yield: 94.1 %

Procedure:
To a stirred solution of methyl 4-formyl-3-hydroxybenzoate [see: Harayama, Chem. Pharm. Bull. 1994, 2170] (0.8 g, 4.1 mmol) and anhydrous K2CO3 (1.1 g, 8.0 mmol) in acetone (12 mL) is added allyl bromide (0.70 mL, 8.1 mmol). The mixture is heated in a 48° C. oil bath for 2 h. The reaction mixture is cooled to rt and filtered. The mother liquor is concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (85:15) gives 0.85 g (49%) of methyl 3-(allyloxy)-4-formylbenzoate as a clear solid: 1H NMR (400 MHz, CDCl3) δ 10.6, 7.9, 7.7, 6.1, 5.5, 5.4, 4.8, 4.0.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][S:64]([C:67]1[CH:73]=[CH:72][C:70]([NH2:71])=[CH:69][CH:68]=1)(=[O:66])=[O:65]>>[CH3:63][S:64]([C:67]1[CH:73]=[CH:72][C:70]([NH:71][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:69][CH:68]=1)(=[O:65])=[O:66]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(S(C)(=O)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.59 g, 4.6 mmol), diphenylphosphinic chloride (0.54 g, 2.3 mmol), then reacted with 4-(methylsulfonyl)aniline (Oakwood) (0.098 g, 0.57 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-methanesulfonyl-phenyl)-amide as a off white foam (Yield 0.11 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) and isonicotinoyl chloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-isonicotinamide (65.5 mg, 77.9%) as a white solid: mp 225-230° C.; FAB-HRMS m/e calcd :for C23H24N4O2S (M+H)+ 421.1698, found 421.1698.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH2:14][CH2:15][CH:16]=[CH2:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1cc(=O)oc2ccccc12
Temperature: 55 °C

Procedure:
4-Hydroxycoumarin (10.93 mmol, 1.77 g), 4-bromo-1-butene (10.93 mmol, 1.48 g) and K2CO3 (33 mmol, 4.55 g) is suspended in 50 mL of acetone, and the reaction is heated to 55° C. for 2.5 days the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. A small amount of the resulting solid is purified by column chromatography to afford an analytically pure sample of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 7.78 (1H, dd, J=1.5, 7.75 Hz), 7.66 (1H, m), 7.38 (2H, m), 5.93 (1H, m), 5.92 (1H, s), 5.20 (2H, m), 2.59 (2H, m), 2.50 (2H, m); MS (ESI, Pos.) calcd for C13H12O3 m/z [M+H]=217.1, found 217.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH2:58][CH2:59][NH2:60])=[CH:53][CH:52]=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([NH:60][CH2:59][CH2:58][NH:57][C:54]1[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=1)=[O:8]
Reactant: NCCNc1ccc(F)cc1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](CC(=O)NCCNc1ccc(F)cc1)CC1CCCCC1
Reaction time: 5 h

Procedure:
(R)-2-(Cyclohexylmethyl)succinic acid-1-methyl ester (211 mg, 0.93 mmol) from Acros Organics was treated with (500 μL, 2.87 mmol, 3.1 eq.) of diisopropylethylamine, HATU (360 mg, 1.096 mmol, 1.2 eq.) and (N-(4-Fluoro-phenyl)-ethane-1,2-diamine) (210 mg, 0.93 mmol, 1 eq.). The reagents were dissolved in dry dichloromethane (5 mL). The reaction was allowed to stir for 5 hours and monitored by LC/MS. Volatiles were removed and the reaction directly purified by automated normal-phase chromatography (0-100% ethyl acetate in hexanes gradient). (R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid methyl ester was obtained as clear oil (220 mg, 0.60 mmol, 65%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)CCC.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:6]3[CH:7]=[CH:8][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:13])=[O:14])=[CH:10][CH:11]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 72.7 %

Procedure:
(4-Tributylstannylphenyl)(3-benzyloxypropyl)sulfone (5.78 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (2.13 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.58 g) in xylene in nitrogen atmosphere for 7 hr. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate and adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(3-benzyloxypropyl)sulfonylphenyl]isoquinoline (2.56 g) as a pale brown amorphous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]([OH:12])[CH:10]=[CH2:11])[CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=CC(O)CCc1cccnc1
Reactant: O=S(=O)(Oc1ccc(-c2cccc(Cl)c2)cc1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(-c2cccc(Cl)c2)cc1)CCc1cccnc1
Yield: 28.7 %

Procedure:
Prepared according to the method described in Example 7b) from (±)-5-(3-pyridyl)-1-penten-3-ol (Example 7a, 0.66 g), 3'-chloro-4-trifluoromethanesulfonyloxybiphenyl (1.34 g), palladium(II) acetate (0.09 g), tri-o-tolylphosphine (5 ml) and triethylamine (1 ml) at 80° C. for 5 hours. Work up and purification by column chromatography over silica eluting with dichloromethane:methanol (19:1) gave (±)-1-(3'-chlorobiphenyl-4-yl)-5-(3-pyridyl)-3-pentanone (0.4 g). The latter was immediately dissolved in methanol (10 ml), cooled to 0° C. and sodium borohydride (0.043 g) added. The reaction mixture was stirred at 25° C. for 2 hours and was then concentrated under reduced pressure. Water was added to the residue and the mixture extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate. Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a solid (0.094 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:29]=[CH:30][C:31]6[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=6)[N:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: OB(O)c1ccc2ccccc2n1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6ccccc6n5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and quinoline-2-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.86 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][CH2:18][C:17]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][CH2:18][C:17]=3[CH:23]=2)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccc(OCCCCSc3ccccc3)cc2CO1
Reactant: OO
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-(4-phenylmercapto-butoxy)-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-quinoline.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=O)[CH:17]=[CH:18][C:19]=1[Cl:20].[C:25]1([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH:34]([CH2:38][OH:39])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:33][CH:34]2[CH2:38][OH:39])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: OCC1CN(Cc2ccccc2)CCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1,1'-Carbonyldiimidazole (236 mg) was added to a stirred solution of 3,4-dichlorophenylacetic acid (314 mg) in dry dichloromethane (6 ml) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 1 h and added dropwise to a cooled solution of 4-(phenylmethyl)-2-piperazinemethanol (300 mg) in dry dichloromethane (3 ml) and stirred at room temperature for 19 h. The reaction mixture was diluted with dichloromethane (5 ml) and washed with 2N sodium carbonate solution (3×10 ml). The organic layer was dried and evaporated to give an oil which was purified by flash column chromatography using gradient elution with dichloromethane:ethyl acetate (2:1), dichloromethane:ethyl acetate (1:1) and dichloromethane:methanol (9:1) to give the title compound as a solid (200 mg). m.p. 148°-150°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].I([Cl:13])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[Cl:13][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Product: O=C(CCl)c1ccccc1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
To a solution of acetophenone (5.00 g, 41.6 mmol) in DCM (42 ml), was added benzyltrimethylammonium tetrachloroiodate (28.8 g, 83.0 mmol). The reaction was heated at 60° C. for 1 hour, then the solvent was evaporated under vacuum. The residue was portioned between DCM (300 ml) and water (300 ml). The organic phase was washed sequentially with aqueous Na2S2O5 and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was triturated with petroleum ether to obtain 2-chloro-1-phenylethanone (4.90 g, 76.2% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
4-Nitrophenol (8 gm, 56 mmol) in 100 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (6.2 g, 61 mmol) followed by the dropwise addition of bromoisobutyryl bromide (14.1 g, 61 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 16 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 13.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[N:22]1([CH2:31][C:32](O)=[O:33])[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:22]3[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc(Cl)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 94.1 %

Procedure:
The title compound (1.60 g, 94%) was synthesized by reaction of 1-(4-chloro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.25 g, 3.5 mmol) with (thymin-1-yl)-acetic acid (0.64 g, 3.5 mmol) as per the procedure of example 64.
Reaction SMILES: C([N:8]1[CH2:15][C:14]2([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:11][CH2:12][O:13]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:21]([O:20][C:18]([NH:17][CH2:16][C:14]12[CH2:15][NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][O:13]2)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC12CN(Cc3ccccc3)CC1CCO2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC12CNCC1CCO2

Procedure:
12.2 g (34.5 mmol) of 7-benzyl-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo[3.3.0]octane are hydrogenated in 200 ml of ethanol on 7 g of palladium-active charcoal (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated and distilled.