Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2c(Cl)cccc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2,6-dichlorophenylsulfonyl chloride (0.589 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2,6-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.658 g, 93%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14](=O)[CH3:15].[BH4-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:14][CH3:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1 eq, 5.37 mmol) in methanol (20 mL) was added acetaldehyde (0.95 eq) and the resulting mixture was heated to 80° C. and stirred for 2 h., then stirred at room temperature overnight. Sodium borohydride (0.95 eq, 5.1 mmol ) was added and reaction mixture was stirred for an additional 2 h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.05 (3H, t), 1.45 (9H, s), 1.60-1.75 (1H, m), 2.00-2.10 (1H, m), 2.68 (4H, q), 2.90-3.15 (1H, m), 3.25-3.65 (4H, m). ESI-MS m/z: 215 (M+1), UV retention time: 0.75 min.
Reaction SMILES: C(N[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:16]([CH:19]=1)[C:17]#[N:18])(=[O:11])=[O:10])C1C=CC=CC=1.[ClH:33].Cl[O-].[Na+]>ClCCl>[C:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:15]1[CH:14]=[CH:13][C:12]([S:9]([Cl:33])(=[O:11])=[O:10])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1cc(S(=O)(=O)NCc2ccccc2)ccc1Oc1ccccc1-c1ccccc1
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1

Procedure:
A mixture of 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile (Preparation 56, 6.06 g, 15.4 mmol), dichloromethane and aq HCl was stirred vigorously with cooling (ice bath). Sodium hypochlorite was added dropwise over 30 minutes and stirring continued with cooling for 1 hour. The layers were separated, the aqueous extracted with dichloromethane (2×100 ml), and the organic collected, dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Heptane 10/90 to 20/80) to furnish 4.58 g of the title compound. 1HNMR (CDCl3): δ 6.7 (m, 1H), 7.2-7.6 (m, 9H), 7.85 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:34][CH2:33][N:32]([C:25]4[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=4[O:23][CH3:22])[CH2:37][CH2:36]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: COc1ccc(N2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)c(OC)c1
Yield: 69 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2,4-dimethoxyphenyl)-piperazine. Purified by flash chromatography (ethyl acetate—heptane 1:4), yield 69%. White crystals, m.p. 98-99° C.; HPLC-MS: m/z=504 (M+1) at Rt=4.0 min.; IR (KBr): ν 1733, 1712 (C═O) cm−1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:2]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])=[CH:18][CH:17]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:25]([CH2:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=3)[C:26]2=[O:27])[CH:2]=1
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccnc1

Procedure:
The procedure of Example 1 was repeated using 2-(pyridin-3-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 3), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(pyridin-3-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 178 to 180° C./DMF-EtOH.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23]C)=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH2:25][OH:26])=[N:8]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([OH:23])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH2:25][OH:26])=[N:8]2)=[CH:4][CH:3]=1
Reactant: COc1c2n(c3c(CO)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)nc(CO)c32)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-4-(hydroxymethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (27 mg g, 70 μmol) in anhydrous dichloromethane (1 mL), a solution of boron tribromide in dichloromethane (90 μL, 90 μmol; 1 M) was added. After stirring at room temperature for one hour, the reaction mixture was treated with anhydrous methanol (2 mL), stirred for 30 minutes, and concentrated under vacuum. The procedure was repeated twice. The residue was subjected to purification on preparative reverse phase high pressure column chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[O:7][C:8]2=[O:13])([O-:3])=[O:2].[CH3:15][OH:16]>>[CH3:15][O:16][C:6](=[O:14])[C:5]1[C:9](=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]([OH:13])=[O:7]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Nitro-isobenzofuran-1,3-dione (10.0 g, 51.8 mmol) in 50 mL of anhydrous MeOH was heated to reflux under N2 overnight. The mixture was cooled to RT, poured into ice-cold water, and the precipitates were collected by filtration, then dried to give the titled compound as a white solid.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:3]([O-:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
then adding a quantity of 2M aqueous sodium hydroxide (for quantity see Table 29) at the same temperature as the stearic acid dispersion with stirring over a particular time (see Table 29 for the time of addition) thereby producing a clear solution with a pH of about 9.2 substantially containing sodium stearate;
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:20]([NH:27][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane in 10 ml of diethyl ether were added 2 g of dry silica gel and 0.1 ml of benzylamine, and the mixture was stirred for 16 hours at room temperature, then heated under reflux for 2 hours. After filtration of the silica gel, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 56 mg of (3S)-N-benzyl-3-carbobenzoxyamino-2-hydroxy-5-methylhexylamine as a colorless viscous oil. To a solution of 54 mg of the amine compound obtained in 10 ml methanol was added 0.2 ml of a 2N-hydrochloric acid. The mixture was hydrogenated over 10 mg of palladium charcoal under hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 43 mg of (3S) -N-benzyl-3-amino-2-hydroxy-5-methylhexylamine dihydrochloride.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[C:5]([N+:19]([O-])=O)[CH:4]=1)=[O:2].[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[CH:7][C:6]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]1
Reactant: COC(=O)C1CCN(c2ccc(C=O)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.8 %

Procedure:
To a mixture of 10% palladium on carbon (1.67 g, 1.57 mmol) and methyl 1-(4-formyl-2-nitrophenyl)piperidine-4-carboxylate 58 (3.435 g, 11.8 mmol) was added EtOAc (100 mL). The nitrogen atmosphere was replaced by hydrogen from a double balloon and the reaction mixture was stirred at room temperature for 4 h, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave methyl 1-(2-amino-4-formylphenyl)piperidine-4-carboxylate 59 (0.488 g, 15.8% yield) as a yellow solid. Mass spectrum: calculated for C14H18N2O3 262.1. found 263.2 (M++1).
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+]>>[CH2:13]([C:2]1[S:19][C:18]([NH2:20])=[N:17][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NC(N)=S
Reactant: CCCCC(Br)C(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCCc1sc(N)nc1-c1ccc(OC)cc1
Yield: 57.2 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-methoxy-phenyl)-hexan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 3 hours, followed by post-treatment to give a crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 1:1 (V:V) to obtain a product as a white solid in a yield of 57.2%, mp: 118-119 └. 1H-NMR (CDCl3, 400 M.Hz) δ: 0.90 (3H, t, J=7.2 Hz, CH3), 1.36 (2H, sextuple, J=7.20 Hz, CH2), 1.59 (2H, quintuple, J=7.20 Hz, CH2), 2.74 (2H, t, J=7.2 Hz, CH3), 3.83 (3H, s, OCH3), 4.93 (2H, br, NH2), 6.93 (2H, d, J=8.80 Hz, ArH), 7.45 (2H, d, J=8.80 Hz, ArH); EI-MS m/e (%): 262.0 (M+, 55), 219.0 (100), 177.0 (36); HREI-MS Calcd. for C14H18N2OS: 262.1140. found: 262.1140. Anal. Calcd. for C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. found: C, 64.19; H, 7.02; N, 10.63.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.[NH2:18][NH2:19]>CS(C)=O>[I:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:19][N:18]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1
Reactant: NN
Reactant: CN1CCC(C(=O)c2cc(I)ccc2F)CC1
Solvent: CS(C)=O
Product: CN1CCC(c2n[nH]c3ccc(I)cc23)CC1
Temperature: 100 °C
Yield: 99 %

Procedure:
A mixture of 4-(2-fluoro-5-iodobenzoyl)-1-methylpiperidine (4.20 g, 12.1 mmol), anhydrous NH2NH2 (30 mL), and DMSO (15 mL) was heated at 100° C. overnight, diluted with ice water and filtered. The filtercake was washed with water and dried in vacuo to provide the title compound (4.1 g, 99%), characterized by HNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=O)[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[S:43])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=S)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.25 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disufide; 0.21 g) in xylene (10 mL) was refluxed overnight. The mixture was cooled to about 50° C. and water (15 mL) was added and refluxed for 2 h. The mixture was stirred at room temperature overnight and evaporated. The residue was partitioned between EtOAc and water. The EtOAc layer was washed with water, dried and evaporated to yield 0.25 g of N-(2,6-dichlorothiobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 504 (MH+).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=[O:18].[N+:19]([O-])([OH:21])=[O:20]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2nc[nH]c(=O)c2cc1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To H2SO4 (98%, 15 ml) was added 6-bromo-7-methylquinazolin-4(3H)-one (1.0 g, 4.2 mmol) and the mixture was stirred at rt until dissolution was complete. The mixture was cooled to 0° C. and then nitric acid (fuming) (0.26 g, 4.2 mmol) was added dropwise at 0° C. and stirred for 10 min, and then stirred at rt for 5 h. The mixture was poured onto ice (300 g) and extracted with EtOAc (3×80 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and concentated in vacuo. The product was recrystalized from MeOH (˜15 ml). MS (M+H)+ 284, 286.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([C:12]1[CH:13]=[CH:14][C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:10][CH2:9][C:8]=2[CH:11]=1)=[O:20]
Reactant: O=C(Cl)CCCCl
Reactant: CC(=O)N1CCc2ccccc2CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(C(=O)CCCCl)cc2CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
In 30 ml of dichloromethane, was dissolved 3.79 g of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine. To the solution were added 3.38 g of 4-chlorobutyryl chloride and 4.00 g of aluminum chloride. The mixture was stirred for 2 hours at room temperature (about 20° C.). The reaction mixture was poured into 50 ml of ice-water. The organic layer was separated, which was washed successively with 50 ml of 0.5N aqueous solution of sodium hydroxide and 50 ml of pure water, then dried over anhydrous sodium sulfate. The solvent was distilled off to leave 5.40 g of an oily residue. The residue was purified by means of a silica gel column chromatography (developing solvent, ethyl acetate-dichloromethane 1:1 (V/V)) to afford 2.92 g of the title compound as colorless crystals, m.p.103°-106° C.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:6])C([O-])=O.[Na+].[C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:11])[CH3:10].O>COCCOCCOC>[C:9]([O:12][CH2:13][C@H:14]1[C@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1([Cl:6])[Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC/C=C/c1ccccc1
Reactant: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of sodium trichloroacetate (27.8 g, 150 mmol) in diglyme (20 ml) was added dropwise over 1 hour to a solution of trans-cinnamyl acetate (8.81 g, 50 mmol) in diglyme (80 ml) at 120° C. to 135° C. and the reaction mixture was heated at 120° C. to 125° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into water (300 ml), extracted with n-hexane (300 ml+3×50 ml) and dried over MgSO4. The solvent was removed and the residue was distilled under vacuum affording the title compound (11.0 g, 76% yield, b.p. 104-105° C. (0.15 mmHg)).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1>>[F:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([F:34])[CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1cc(F)cc(OCCCBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)cc(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.820 g of 1-(3-bromopropoxy)-3,5-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.39.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:10](=[O:13])[C:11]=1I.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[Sn]>CN(C)C=O.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:10](=[O:13])[C:11]=1[CH:30]=[CH2:31]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(I)c2=O)c1
Agent: [Pd]
Agent: [Sn]
Solvent: CN(C)C=O
Product: C=Cc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)OC)ccc2C)c1=O
Temperature: 60 °C

Procedure:
A round bottom flask containing methyl 3-[4-[(2,4-difluorobenzyl)oxy]-5-iodo-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (2.50 g, 4.88 mmol) in N,N-dimethylformamide was evacuated and flushed with argon. Tributyl(vinyl)tin (2.3 g, 7.3 mmol) and dichlorobis(triphenylphosphine) palladium (II) (0.34 g, 0.49 mmol) were added in the nitrogen atmosphere of a glove box. Heated at 60° C. under argon overnight. Added additional tin (0.7 mL) and palladium (0.17 g) reagents and continued over weekend. No progress observed. Distilled DMF, washed crude product with ethyl acetate, and filtered through celite. The filtrate was concentrated and purified by flash column using 25% ethyl acetate in hexane as eluent. Used without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][C:15]=1[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:9].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:10]1[CH:11]=[N:12][C:13]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:14][C:15]=1[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:9]
Reactant: Cc1ncccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
In accordance with process variant a) a mixture of 6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide and 1-methylpiperazine is heated at about 120° C. for 2 h. After cooling to room temperature, the mixture is diluted with dichloromethane and washed with water. The aqueous layer is worked up in conventional manner to give the compound 2-methyl-6′-(4-methyl-piperazin-1-yl)-[3,4′]bipyridinyl-3′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide of formula I-1.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([OH:10])=[CH:4][C:3]=1[F:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:6][C:5]([O:10][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][C:3]=1[F:11]
Reactant: C1=COCCC1
Reactant: OCc1cc(O)cc(F)c1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Fc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of 4-bromo-3-fluoro-5-(hydroxymethyl)phenol (5.64 g, 25.5 mmol), 3,4-dihydro-2H-pyran (5.8 mL, 64 mmol), and dl-camphorsulfonic acid (118 mg, 2 mol %) in dichloromethane (150 mL) was stirred at room temperature for overnight. The mixture was washed with saturated aqueous sodium bicarbonate and brine, and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (9:1 hexane/ethyl acetate) to give 2-(4-bromo-3-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (9.14 g, 92%).