Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:11]1[C:15]2([CH2:20][CH2:19][CH:18](O)[CH2:17][CH2:16]2)OCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>O1CCCC1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:18]2[CH2:19][CH2:20][C:15](=[O:11])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC(C)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
In 40 ml of anhydrous tetrahydrofuran were dissolved 4.00 g of 4-isopropylphenol, 5.10 g of 1,4-dioxaspiro[4.5]decan-8-ol and 8.47 g of triphenylphosphine. Then, 14.1 g of 40% solution of diethyl azodicarboxylate in toluene was dropwise added at 0-5° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduce pressure. Ethyl ether was added to the residue, the deposited insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue thus obtained was mixed with 60 ml of anhydrous tetrahydrofuran and 40 ml of 6 mol/L hydrochloric acid and stirred at ambient temperature for 24 hours. The reaction mixture was poured in a mixture of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=20:1, followed by hexane:ethyl acetate=20:1] gave 2.40 g of 4-(4-isopropylphenoxy)-1-cyclohexanone as a colorless oily product.
Reaction SMILES: [C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[H][H]>C(O)C.[Pd].[C]>[C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(N)cc1
Yield: 96911.8 %

Procedure:
Nα -Boc-4-Nitrophenyl-D-alanine (209 grams, 0.68 mole) was dissolved in 500 mL of ethyl alcohol and acidified with acetic acid (10 mL). To this was added 0.65 g of 10% Pd/carbon, and the mixture was hydrogenated at about room temperature using H2 at about 40 psi until the uptake of hydrogen had ceased (6 hours). The catalyst was removed by filtration, and the reaction products were concentrated under vacuum to yield a viscous oil that solidified upon trituration with petroleum ether. The amino acid was collected by filtration, washed with petroleum ether and dried to give 184 g of Nα -Boc-4-aminophenyl-D-alanine (0,659 mole, 97%) having [α]D =-40.2° (c=1.0 in EtOAc) and -23.4° (c=1.0 in MeOH); mp=128°-133° C.
Reaction SMILES: C([NH:4][C:5](C(OCC)=O)([CH2:11][C:12]1[CH:25]=[C:24]([OH:26])[C:23]2[C:22](=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[OH:28])[C:15](=[O:29])[C:14]=2[CH:13]=1)[C:6]([O:8]CC)=[O:7])(=O)C>Br>[NH2:4][CH:5]([CH2:11][C:12]1[CH:25]=[C:24]([OH:26])[C:23]2[C:22](=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[OH:28])[C:15](=[O:29])[C:14]=2[CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O)(NC(C)=O)C(=O)OCC
Agent: Br
Product: NC(Cc1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-acetamido-2-carboethoxy-3-(9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracen-2-yl)propanoate (99.7 g) and 47% hydrobromic acid (1500 ml) was stirred at reflux for 6 hours. The mixture was cooled to room temperature and filtered. The isolated solid was stirred with 1N sodium hdroxide (1600 ml) for 15 minutes and the mixture filtered. The filtrate was cooled to 10° C. and acidified using glacial acetic acid (720 ml). The mixture was stirred for 10 minutes and then filtered. The isolated solid was washed with water (1 liter), pulled dry and then dried in vacuo at 60° C., m.p. 210°-212° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:15])[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:3]1[C:16]([O:18]C(C)(C)C)=[O:17]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:23])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:15])[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:3]1[C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)Oc2ccccc2)C1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)Oc1ccccc1
Yield: 88.4 %

Procedure:
A mixture of 3.3 g of the product of Step B, 35 ml of toluene and 100 mg of monohydrated p-toluene sulfonic acid was refluxed until gas evolution ceased and then was evaporated to dryness under reduced pressure. The 3.4 g residue were chromatographed over silica gel and eluted with a 70-30-1 cyclohexane-ethyl acetate acetic acid mixture to obtain 2.4 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-phenoxyl-propenyl]-cyclopropane-carboxylic acid melting at 57° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH3:28][C:29]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:32]([O:5][CH2:4][C@@H:3]([NH2:2])[CH2:6][NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]3)[CH2:16]1)[CH2:10]2)([C:29]([CH3:31])([CH3:30])[CH3:28])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@H](CO)CNCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC[C@@H](N)CNCC12CC3CC(CC(C3)C1)C2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a solution of (S)-2-amino-3-((1-adamantylmethyl)amino)propan-1-ol HCl salt (1.2 g, 3.8 mmol) in anhydrous CH2Cl2 (20 mL) were added DIEA (1.9 g, 15.2 mmol), DMAP (2.3 mg, 0.02 mmol) and TBDPSCl (1.2 g, 4.2 mmol) at 0° C. The mixture was stirred at rt for 2 h. The reaction solution was extracted with CH2Cl2 (100 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, and concentrated to give the crude product, which was purified by preparative TLC (PE:EtOAc 10/1) to afford (S)-3-(tert-butyldiphenylsilyloxy)-N1-(1-adamantylmethyl)propane-1,2-diamine (620 mg, 29%) 1H NMR: (CDCl3, 400 MHz): δ=1.05 (s, 9H), 1.54 (s, 6H), 1.62-1.73 (m, 6H), 1.98 (s, 3H), 2.32 (d, 1H), 2.45 (d, 1H), 2.56 (d, 1H), 2.85 (d, 1H), 3.15 (m, 4H), 3.65 (m, 2H), 7.4 (m, 6H), 7.62 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])#[N:20]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Reactant: CC(C)(C)CC(C)(N)C#N
Product: CC(C)(C)CC(C)(C#N)NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d) and 2-amino-2,4,4-trimethylpentanenitrile (CAN 65260-84-6) as starting materials and isolated (643 mg, 87%) as a yellow oil; MS (ESI, m/z): 422.3 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A suspension of 0.32 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) in 5 ml acetonitrile was treated successively with 0.32 mmol 4-phenylbutyric acid, 1.61 mmol DIPEA and 0.35 mmol TBTU. The reaction mixture was stirred for 1 hour at room temperature and concentrated. Chromatography (SiO2; dichloromethane/methanol) gave the title compound as a colorless solid. Yield=71%. MS (m/e): 419.3 (MH−, 100%).
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH:29]1[CH2:32][CH2:31][CH2:30]1)[C:5](=[O:28])[NH:6]2.N(OCCC(C)C)=O.C(=O)([O-])O.[Na+]>O1CCCC1.[Cu](Cl)Cl>[CH:29]1([N:4]2[C:3]3[C:7](=[N:8][C:9]([C:11]4[C:19]5[C:14](=[N:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[F:27])[N:12]=4)=[N:10][CH:2]=3)[NH:6][C:5]2=[O:28])[CH2:32][CH2:31][CH2:30]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C3CCC3)c12
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.12 mmol) of the compound from example 121 were initially charged in tetrahydrofuran (5 ml), then 0.11 ml (0.81 mmol) of isoamyl nitrite and 3 mg (0.02 mmol) of copper(II) chloride were added, and the mixture was stirred at RT overnight. The reaction mixture was admixed with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 7 mg (13% of theory) of the title compound in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.B(O)(O)[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 49.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(4-methylbenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.071 g; 0.204 mmol), p-tolylboronic acid (0.029 g; 0.217 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g; 0.011 mmol), sodium carbonate (0.045 g; 0.423 mmol), sodium iodide (0.064 g; 0.423 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.041 g (50%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([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)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[S:42](N)([NH2:45])(=[O:44])=[O:43]>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH:18]=[CH:19][N:20]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:21]=[CH:22]2)=[CH:5][N:4]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3C=CN(S(N)(=O)=O)C=C3)c2c1
Yield: 73.1 %

Procedure:
A mixture of 54 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187, 96 mg sulfamide, and 5 mL dioxane was heated for 4 hours under reflux. The reaction solution was evaporated, then ethyl acetate and water were added to the residue, and the organic layer was separated, then washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 45 mg of the title compound as a white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=O.[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:17](=[O:19])[CH2:16][CH2:15][CH:14]([CH3:13])[CH3:20]
Reactant: Cc1ccccc1N
Reactant: CC(C)CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)CCC(C)C

Procedure:
Carbonyldiimidazole (65 g) was mixed with 500 ml of dry dichloromethane in a 2-L round bottom flask and stirred magnetically. A solution of 4-methylvaleric acid in 200 ml of dichloromethane was added dropwise over 45 minutes and the mixture was stirred for another 1.25 hours. o-Toluidine (45 g) in 100 ml of dichloromethane was then added over about 20 minutes. After stirring for 2 hours the mixture was washed with water and then the solvent was stripped on a rotary evaporator. The residue was mixed with 150 ml of methanol and 75 ml of water and put in the freezer. Filtration of the precipitate, dilution of the filtrate with water and refiltration of the precipitate gave 75 g (94%) of vacuum dried N-(2-methylphenyl)-4-methylvaleramide which was used without further treatment in the next step:
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C@@H:6]([NH:16][C:17](=[O:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1>O1CCCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@H:6]([NH:16][C:17](=[O:19])[CH3:18])[CH2:5][S:2][CH3:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(C[C@@H](CCl)NC(C)=O)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H](CSC)NC(C)=O)cc1
Yield: 96.8 %

Procedure:
4 g of sodium thiomethoxide are added at 0-5° C. to a solution of 13.8 g of N-[(1S)-2-chloro-1-(4-methoxybenzyl)ethyl]acetamide in 60 ml of tetra-hydrofuran. After returning to ambient temperature, the suspension is filtered and the solid is washed with 2×10 ml of tetrahydrofuran. The filtrate is concentrated to dryness, providing 14 g of N-[(1S)-1-(4-methoxybenzyl)-2-(methylthio)ethyl]acetamide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:20]=[CH2:21]
Reactant: C=CCNCC=C
Reactant: Cc1csc2c(NC3CCCCC3)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCN(CC=C)c1nc(NC2CCCCC2)c2scc(C)c2n1
Yield: 72.5 %

Procedure:
In a sealed tube were heated 338 mg (1.2 mmol) of 2-chloro-4-cyclohexylamino-7-methylthieno[3,2-d]pyrimidine and 1.87 g (19.2 mmol) of diallylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 298 mg (yield: 72.7%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.[S:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>CO.C(Cl)Cl>[C:18]1([C:4]2[CH:3]=[C:2]([C:27]3([OH:30])[CH2:28][CH2:29][S:24][CH2:25][CH2:26]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Reactant: O=C1CCSCC1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(O)CCSCC3)cc2C2=CCCCC2)n1
Yield: 62 %

Procedure:
The title compound was prepared by the procedure of Example 11 using 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 120 mg, 0.323 mmol) and tetrahydro-thiopyran-4-one (188 mg, 1.62 mmol). Silica gel chromatography (1-3% MeOH/DCM) afforded the title compound (82.3 mg, 62%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.56 (s, 1H), 9.66 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.74 (d, 1H, J=2.5 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.86 (m, 1H), 3.22 (m, 2H), 2.46-2.54 (m, 2H), 2.22-2.33 (m, 4H), 2.16-2.22 (m, 2H), 2.01-2.09 (m, 2H), 1.73-1.89 (m, 5H). Mass spectrum (ESI, m/z): Calcd. for C22H24N4O2S, 409.2 (M+H). found 409.1.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]([CH3:34])[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]([CH3:34])[CH2:13][CH:14]=[CH:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(OC)c(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(OC)c(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(2,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(2,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-benzenesulfonamide was synthesized (76%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (br s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.70-7.65 (m, 2H), 7.54 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.20 (s, 2H), 4.48 (s, 2H). MS (EI): m/z 509 (M−H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:33]=[C:34]([N:36]2[CH2:40][CH2:39][CH2:38][C:37]2=[O:41])[CH:35]=1)[C:8]([NH:10][C@@H:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:12]([OH:25])[CH2:13][C@H:14]([C:16](=[O:24])[NH:17][CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:15])=[O:9])[CH:2]=[CH2:3]>CO.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O>[CH2:26]([C@H:11]([NH:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:35]=[C:34]([N:36]2[CH2:40][CH2:39][CH2:38][C:37]2=[O:41])[CH:33]=1)[C@@H:12]([OH:25])[CH2:13][C@H:14]([C:16](=[O:24])[NH:17][CH2:18][CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH3:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)cc(N2CCCC2=O)c1
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)cc(N2CCCC2=O)c1

Procedure:
The allyl compound of E3 (0.042 g) was hydrogenated in methanol (5 ml) in the presence of 5% palladium-barium sulfate (0.020 g) for 3 hrs. The mixture was filtered through celite and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH:12][CH:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)COCc1ccccc1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COCc1ccccc1
Yield: 11.7 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 545 mg of 3-benzyloxy-2-hydroxypropylamine (prepared as described in Preparation 48), 700 mg of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione, 470 mg of sodium cyanoborohydride and 60 ml of anhydrous methanol were used. The resulting crude product was applied to a silica gel chromatography column, and eluted using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 10:1 to 5:1 by volume as the eluent. The resulting product was further purified by reverse phase preparative high performance liquid chromatography [YMC-Pack ODS-A (trade name, manufactured by YMC Co.), using a 50:50:1:1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent], to give 130 mg of the title compound as a pale yellow glassy solid having an Rf value of 0.16 (on silica gel thin layer chromatography, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).