Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18]O)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][Cl:24])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Product: ClCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1

Procedure:
3-[N,N-bis-(4-chlorobenzyl)amino]propyl chloride was prepared by halogenating 3-[N,N-bis-(4-chlorobenzyl)amino]propanol using thionyl chloride.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30](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>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:29]#[N:30])=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: CN(C)C=O
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]
Product: N#Cc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Temperature: 80 °C

Procedure:
A mixture of compound 31b (200 mg, 0.450 mmol), zinc cyanide (106 mg, 0.910 mmol), Pd(PPh3)4 (105 mg, 0.910 mmol) in DMF (5 mL) was heated to 80° C. for 4 h. The reaction was cooled to rt, filtered through a diatomaceous earth cartridge (2.5 g), and the filter cake was rinsed with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was recrystallized with hot EtOAc, collected by filtration, and dried to give compound 55a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H18N6O2: 387.2 [M+H]. found 387.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH:11]1[S:15][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][C:12]1=[O:23]>CC(O)=O>[NH:16]([C:14]1[S:15][CH:11]([CH2:10][C:9]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[C:12](=[O:23])[N:13]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1NC(=O)CC1SC(Nc2ccccc2)=NC1=O
Solvent: CC(=O)O
Product: O=C1N=C(Nc2ccccc2)SC1Cc1nc2ccccc2[nH]1
Reaction time: 0.17 h

Procedure:
N-(2-Aminophenyl)-2-(2-anilino-4-oxo-4,5-dihydro-1,3-thiazol-5-yl)acetamide (40.8 mg, 1 eq) was taken up in HOAc (2 mL), transferred to a micro-tube and run at 100° C. for 600 s. The reaction mixture was evaporated to give 42 mg, as a crude brown oil. Purified by HP-LCMS, to the pooled fractions was added NaOH (1M) to pH=14, the MeCN was evaporated and the aqueous layer extracted with DCM/H2O (9:1), dried and evaporated to give the title compound as an off-white powder: HPLC 99%, RT=2.02 min (System A, 10-97% MeCN over 3 min), 99%, RT=0.96 min (System B, 2-95% MeCN over 2 min); 1H NMR (400 MHz, METHANOL-D4) δ ppm 3.23 (m, 1 H) 3.80 (m, 1 H) 4.70 (m, 1 H) 7.02 (m, 1 H) 7.17 (m, 3 H) 7.32 (m, 2 H) 7.50 (m, 2 H) 7.62 (m, 1 H); MS [M+H]+ m/z=323.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=4)=[CH:14][N:15]3[C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[CH:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>[Ni].CO.CN(C=O)C>[NH2:32][C:28]1[CH:27]=[C:26]([C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[N:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[CH:19]=3)[CH:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CNc1cc(-n2cc(-c3cccc([N+](=O)[O-])c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1cc(-n2cc(-c3cccc(N)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Methanol/DMF (2:1, 20 mL) was added to 6-(6-(4-methoxyphenyl)-3-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (70 mg, 0.16 mmol) and Raney nickel (Raney Ni; about 50 mg). The mixture was stirred at room temperature for 12 hours under hydrogen gas (1 atm). The reaction solution was filtered using a diatomite pad and concentrated under reduced pressure. The target compound (60 mg) was obtained as brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:18][CH:19]([N+:30]#[C-:31])S(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[C:19]([CH3:18])[NH:30][CH:31]=1)=[O:17])[CH3:2]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(C)c1-c1cccc2ccccc12
Yield: 66 %

Procedure:
4.3 g(18.9 mmol) of 3-(naphthalen-1-yl)-acrylic acid ethylester prepared in Preparation 6-1) and 3.95 g(18.9 mmol) of α -methyltosylmethylisocyanide disclosed in A. M. van Leusen, et al., Tetrahedron Letter, 1975, 40, 3487 were dissoved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) of potassium t-butoxide dissolved in 100 ml of tetrahydrofuran was slowly added thereto, which was then refluxed for 30 minutes. To the reaction solution was added 100 ml of water to stop the reaction and the solvent was removed under reduced pressure. The residue was extracted with diethylether, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography using a solvent mixture of ethyl acetate/n-hexane(1/3, v/v) as an eluent to give 3.50 g(12.5 mmol, Yield 66%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)#[CH:18]>CCOC(C)=O.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-Ethynyl-4-methoxy-benzene (86 mg, 0.65 mmol) was then added, and the resulting solution was stirred for 3 h at 100° C. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 163 (101 mg, 71% yield) as a white solid. LC-MS (M+H=327, obsd.=327).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 mL of morpholine is stirred at 120° C. for 6 hours. To the reaction mixture 150 mL of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 15 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 4.2 g of the title compound. Mp.: 172° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[N:15]=[N:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH2:26](O)[CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:19][C:18](=[O:20])[CH2:17][N:16]1[C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)=[N:13][N:14]=[N:15]1
Reactant: CCCCOc1ccc(-c2nnnn2CC(=O)O)cc1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: CCCCOc1ccc(-c2nnnn2CC(=O)OCCO)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
To a solution of 0.5 g (1.81 mM) of [5-(4-butoxyphenyl) tetrazol-1-yl] acetic acid in 3 ml of ethylene glycol was added 0.3 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=20/1) for separation and purification, to give 400 mg (yield 69%) of [5-(4-butoxyphenyl) tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: C([O-])(O)=O.[Na+].[Br:6][C:7]1[CH:8]=[C:9]([N+:21]([O-])=O)[C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][CH:12]=1.Cl>CCOC(C)=O.O>[Br:6][C:7]1[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1NCCN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cnc1NCCN1CCCC1

Procedure:
2.44 g (10.8 mmol) Zinn(II)chloride dihydrate and 2.20 g (26.2 mmol) NaHCO3 are added to a solution of 680 mg (2.16 mmol) (5-bromo-3-nitro-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine in 40 mL EtOAc at RT. The reaction is refluxed for 1.5 h and then diluted with 20 mL water. The aqueous phase is acidified with 1 M HCl and separated off from the organic phase. The aqueous phase is made alkaline with saturated K2CO3 solution and extracted twice with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: C1(OC2C=C(C=CC=2OC)C[C:11]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:24])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])CCCC1.C1OCCOCCOCCOCCOCCOC1.[OH-].[K+].Cl>C1C=CC=CC=1.C(O)C>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:23](=[O:24])[CH2:22][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)(Cc1ccc(OC)c(OC2CCCC2)c1)C(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
2.43 g (4.7 mmol) of diethyl α-(3-cyclopentyloxy-4-methoxybenzyl)-α-(4-methoxyphenacyl)malonate [prepared as described in step (ii) above] and 1.26 g (4.7 mmol) of 18-crown-6 were dissolved in 50 ml of benzene, and 4.70 ml (4.7 mmol) of a 1.1M solution of potassium hydroxide in ethanol were added to the resulting solution. The mixture was then stirred for 30 minutes, after which the ethanol in the reaction mixture was removed by distillation under reduced pressure. The remaining reaction solution was heated under reflux for 14 hours and then the reaction mixture was cooled to room temperature. The mixture was then acidified by the addition of 3N aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 1.68 g of the title compound as slightly yellow crystals (yield 81%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].CO.[H][H]>CO.O1CCCC1.C(C1C=C(C(C)(C)C)C2OP([C-]3C=CC=C3)OC3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C=2C=1)(C)(C)C.[C-]1(P2OC3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C3C=C(C(C)(C)C)C=C(C(C)(C)C)C=3O2)C=CC=C1.[Fe+2]>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Fe+2]
Agent: CC(C)(C)c1cc(C(C)(C)C)c2op(-[c-]3cccc3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(C)C(=O)OC
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 33 mg (0.031 mmol) of the ferrocenyl bis(phosphonite) prepared in Example 1 and 12 mg (0.031 mmol) of bis(bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) perchlorate in 2 mL of methanol/tetrahydrofuran (1:1) solution is stirred for two hours. Then, to the resultant solution of rhodium complex is added a solution of 490 mg (3.1 mmol) of dimethyl itaconate and 13 mL of methanol in a pressure reactor. The reactor is then pressurized to 1018 psi with hydrogen and the reaction is stirred at ambient temperature for 88 hours. 1H nmr analysis of the reaction mixtures shows a 100% conversion of dimethyl itaconate starting material to product. Workup of the reaction mixture gives 492 mg (99% yield) of desired dimethyl 2-methylsuccinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].O1CCCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C(OCC)(=O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:31])[CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(NC(C)=O)ccc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(C)=S)ccc1OC
Reaction time: 18 h

Procedure:
Combine methyl 2-methoxy-5-acetamidobenzoate (2.23 g, 10 mmol) and tetrahydrofuran (1000 mL). Add Lawesson's reagent (2.02 g, 5 mmol). After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 12% ethyl acetate/dichloromethane to give methyl 2-methoxy-5-thioacetamidobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:12].[BH4-].[Na+].BrC1C=C2C(=CC=1)SCCC2O.N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CO.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:12][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37]
Reactant: O=C1CCSc2ccc(Br)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: OC1CCSc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCSc2ccc(Br)cc21

Procedure:
6-Bromo-thiochroman-4-one (Intermediate-K2) (prepared according to the procedures found in Johnson, A. T. et al Bioorg Med. Chem. 1999, 7, 1321. incorporated herein by reference) (1.11 g, 4.6 mmol) in MeOH (46 mL) was treated with sodium borohydride (0.14 g, 4.6 mmol) at 0° C. for 30 m. The mixture was subjected to a standard aqueous work-up and the alcohol, 6-bromo-thiochroman-4-ol, was used in the next step without further purification. 6-Bromo-thiochroman-4-ol (˜4.5 mmol) in DMF (20 mL) was treated with imidazole (0.31 g) and TBSCl (0.69 g) at rt for 16 h. After an aqueous work-up the residue was purified by chromatography on silica gel with 10% EtOAc:hexanes to afford (6-bromo-thiochroman-4-yl-oxy)-tert-butyl-dimethyl-silane (Intermediate-K3) as a yellow oil, 1.06 g.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][NH2:36]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:36]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=465.1 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]C)=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][N+:22]([O-])=O)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]2[C:3]3=[CH:2][NH:1][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=43)[C:10](=[O:12])[NH:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Product: COc1ccc(C2CNC(=O)c3cccc4[nH]cc2c34)cc1

Procedure:
In a manner similar to that described for the preparation of Example Q, methyl indole-4-carboxylate and p-methoxy nitrostyrene were condensed and the resulting nitro alkane was reduced/cyclized to give, after recrystallization (CH2Cl2/MeOH/hexanes), (rac)-3-(4-methoxyphenyl)-3,4,5,6-tetrahydro-1H-axepino[5,4,3-cd]indol-6-one, 16.9 mh (50%) as a white solid: m.p. 221-223° C.; 1H NMR (300 MHz, d4—MeOH) δ 3.57 (br m, 5H), 5.15 (br s, 1H) 6.62 (m, 2H), 6.86 (m, 2H), 7.08 (app t, J=7.8 Hz, 1H), 7.11 (s, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H). Anal. (C19H16N2O20.25 H2O) C, H, N.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=1)[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=1)[CH:7]=[O:8]
Reactant: CCOC(=O)C(CCCCCl)c1cccc(-c2cccnc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: O=CC(CCCCCl)c1cccc(-c2cccnc2)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.54 g (1.6 mmol) ethyl 6-chloro-2[m-(3-pyridyl)phenyl]hexanoate in 10 mL methylene chloride at -78° C. is added slowly 2.2 mL (3.4 mmol) of a 1.5 M solution of diisobutylaluminum hydride in hexanes. The reaction is stirred at -78° C. for 5 minutes and 1.6 mL methanol is added followed by 50 mL ether. The mixture is warmed to 0° C. and 1.6 mL brine and 1.11 g finely powdered sodium sulfate are added. The mixture is stirred and then filtered. The filter cake is washed with methylene chloride and combined organic layer is evaporated to give 6-chloro-2-[m-(3-pyridyl)phenyl]hexanal as an oil; IR (CH2Cl2): 1724, 1682 cm-1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11]C)[CH:10]=1)[CH:6]=[O:7].C[C:14]1[N:19]=[C:18]([C:20](O)=O)[CH:17]=[CH:16][CH:15]=1>>[CH3:20][C:18]1[N:19]=[C:14]([C:6]([C:5]2[CH:8]=[C:9]([OH:11])[CH:10]=[C:3]([OH:2])[CH:4]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Cc1cccc(C(=O)O)n1
Product: Cc1cccc(C(=O)c2cc(O)cc(O)c2)n1

Procedure:
3,5-Dihydroxyphenyl 6-methyl-2-pyridyl ketone is prepared according to example 1 from 3,5-dimethoxybenzaldehyde and 6-methyl picolinic acid. This intermediate is then reacted according to example 2 and purified to yield pure erythro-α-(3,5-dihydroxyphenyl)-α-(6-phenethyl-2-piperidinyl)methanol hydrochloride, m.p. 285°C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:36]([CH2:35][CH:34]([OH:38])[C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[CH3:37])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccc(OC)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.20 mmol), 1-(4-methoxyphenyl)-2-(methylamino)ethanol (Tetrahedron 1999, 55, 4831-4842) (58 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 16 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid.
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[F:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([O:26][CH2:25][CH2:24][O:23][C:22]3[CH:27]=[CH:28][C:19]([F:18])=[CH:20][CH:21]=3)[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: OCCOc1ccc(F)cc1
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Product: CCc1cc(CC)n2nc(OCCOc3ccc(F)cc3)nc2n1
Yield: 70 %

Procedure:
The title compound was prepared according to the experimentals described for Example 14 above from 2-methanesulfonyl-5,7-diethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 2-(4-fluorophenoxy)ethan-1-ol in 70% yield. EM (calc.): 330.1; MS (ESI) m/e: 331.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I.O>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(I)cc2)C1
Reactant: Oc1ccccc1Cl
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(Oc3ccccc3Cl)cc2)C1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
To a degassed solution of 3-[2-(4-iodo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.40 g; 0.92 mmol), and 2-chlorophenol (0.28 g; 2.22 mmol) in DMSO, was added picolinic acid (22.7 mg; 0.18 mmol), CuI (17.6 mg; 0.09 mmol) and K3PO4 (0.78 g; 3.69 mmol). The resulting mixture was heated overnight, at 90° C. After cooling to RT, water was added and the mixture extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:2) to afford 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-thiomorpholin-4-yl}-propionic acid tert-butyl ester (0.15 g).