Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12](#[N:16])[CH2:13][C:14]#[N:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:12]#[N:16])[C:14]#[N:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: N#CCC#N
Reactant: COc1cc(Cl)ccc1C=O
Product: COc1cc(Cl)ccc1C=C(C#N)C#N

Procedure:
By the method used for Intermediate 3,4-chloro-2-methoxybenzaldehyde from Step A was reacted with malononitrile to afford the title compound as a yellow solid. LC-MS 219 (M+1).
Reaction SMILES: Cl.COCCOC[N:8]([C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[CH3:29])[S:9]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:11])=[O:10]>C(O)C>[CH3:28][C:25]1[C:24]([CH3:29])=[C:23]([NH:8][S:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:27][N:26]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(-c2ccccc2)s1
Agent: Cl
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)s2)c1C
Yield: 41.6 %

Procedure:
HCl (3 ml of a 3 N aqueous solution) was added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide (100 mg, 0.24 mmol) in 3 ml of 95% ethanol and the resulting mixture was refluxed for 6 h. The mixture was then concentrated, diluted with 5 ml of water, neutralized with saturated aqueous sodium bicarbonate solution and acidified to pH 4 using glacial acetic acid. The mixture was extracted with ethyl acetate (2×25 ml) and the combined organic extract was washed with brine (1×5 ml), dried and evaporated. Flash chromatography of the residue on silica gel using 2% MeOH/CHCl3 and further purification by reverse phase HPLC yielded 33.4 mg (42%) of the pure sulfonamide as a white powder, m.p. 176-178° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)=[CH2:19])[CH3:22]
Reactant: Cc1cccc2c(Cl)ncnc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ncnc2c(C)cccc12
Yield: 89.1 %

Procedure:
4-Chloro-8-methylquinazoline (5.10 g, 25.13 mmol) is dissolved in toluene (50 mL) and tributyl(1-ethoxyvinyl)tin (9.98 g, 27.64 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.45 g, 1.26 mmol) are added to the solution and the reaction is refluxed for 3 h. Volatiles are evaporated under reduced pressure and the resulting mixture is diluted with brine and ethyl acetate. The phases separated and the organic phase washed with brine, dried and volatiles evaporated under reduced pressure. The residue is purified by flash chromatography (0-30% EtOAc in cyclohexane) to give 4-(1-ethoxy-vinyl)-8-methyl-quinazoline (4.80 g, 89%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:19]>>[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:19]
Reactant: CCc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: CCc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3-ethylaniline (18 μl, 0.144 mmol) similar to Example 92 and isolated as a yellow oil (12 mg, 36%). 1H NMR (CDCl3): 8.84-8.82 (m, 1H), 8.57-8.54 (m, 1H), 7.89-7.84 (m, 1H), 7.72 (s, 1H), 7.44-7.40 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.14-7.11 (m, 3H), 7.01 (s, 1H), 2.69 (q, J=7.8 Hz, 2H), 1.27 (t, J=7.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.Cl>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#Cc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Aminophenyl-acetylene (1.17 g, 10 mmol) was added to DCM (30 mL), and Et3N (2.8 mL, 20 mmol) was added thereto. (BOC)2O (2.3 g, 10 mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, 1N HCl was added, which was then extracted with EtOAc and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]>C1C=CC=CC=1.CCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:25])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cc(N=C=S)ccc1Cl
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Following a procedure similar to that described in Example 42 but using 2.3 g. sodium in 300 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 21.4 g. 4-chloro-3-nitrophenyl isothiocyanate (m.p. 54°-56°C., prepared from 4-chloro-3-nitroaniline) in 100 ml. dry acetone there was obtained 1-(4-chloro-3-nitrophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 92°-94°C. (from benzene-n-pentane); hydrochloride (22.5 g.), m.p. 138°-140°C. (from acetonitrile).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.CS[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2.[S:24]([O-:27])([O-])=[O:25].[Na+].[Na+]>O1CCCC1>[CH3:2][S:24]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2)(=[O:27])=[O:25]
Reactant: O=S([O-])[O-]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
36.7 g (149 mmol) of 70% pure meta-chloroperbenzoic acid were added to 12.0 g (67.7 mmol) of the compound from Example 8A in 800 ml of tetrahydrofuran at 0° C., and the mixture was stirred at RT for 15 min. Addition of 100 ml of a saturated aqueous sodium sulfite solution was followed by extraction with ethyl acetate several times. The combined organic phases were washed five times with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. 11.0 g (75% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:18].[CH3:19][NH:20][CH3:21].[CH2:22]=O.Cl>CC(O)C>[ClH:18].[CH3:19][N:20]([CH2:22][CH:3]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:1][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: C=O
Reactant: CNC
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CC1C(=O)c2ccccc2OC1c1ccccc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 44.8 g (0.2 mol) of flavanone (commercially available from Aldrich Chemical Co., Milwaukee, Wisconsin), 32.6 g (0.4 mole) of dimethylamine hydrochloride, 12.6 g (0.4 mol) of paraformaldehyde, 1 ml of concentrated HCl, and 120 ml of 2-propanol was stirred at reflux for 1 hour. The reaction was then allowed to cool to room temperature, the solvent was removed under reduced pressure and the residue partitioned between 400 ml of ether and 1 liter of 5 percent aqueous hydrochloric acid. The aqueous phase was separated, washed with 200 ml of ether, cooled and made basic with solid K2CO3. The liberated base was extracted into ether, the ether solution dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was taken up in 200 ml of ethyl acetate and treated with excess acetyl chloride and ethanol. Upon cooling, white crystals precipitated. After drying, a yield of 43.8 g of 3-dimethylaminomethyl flavanone hydrochloride, (mp 172°-174° C.) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.CCO>CCOC(C)=O>[Cl:12][C:5]1[C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]2[N:1]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCO)cc1
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCc1ccc(-n2c(-c3ccccn3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl) phenyl]amino}phenyl)ethanol (1.83 g, 5.54 mmol), 2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), and EtOH (40 ml) was refluxed for 1 hour. After cooling to room temperature, the solvent was removed. The residue was dissolved with benzene (50 ml) and treated with Pb(OAc)4 (3.38 g, 6.10 mmol) at room temperature for 1 hour. The mixture was diluted with EtOAc and the solution was washed with sat. NaHCO3 aq. and brine. The organic fraction was dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with hexane/EtOAc=5/2 to afford 1.20 g (52%) of the title compound.
Reaction SMILES: [N-:1]=[C:2]=[S:3].NC1S[CH:7]=[CH:8][N:9]=1.CCO[C:13]([CH3:15])=O.[CH3:16][N:17]([CH:19]=O)[CH3:18]>>[N-:1]=[C:2]=[S:3].[NH2:9][CH2:8][CH2:7][C:19]1[N:17]([CH3:18])[CH:16]=[CH:13][CH:15]=1
Reactant: Nc1nccs1
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Agent: [N-]=C=S
Product: Cn1cccc1CCN
Temperature: 100 °C

Procedure:
An isothiocyanate of 2-(2-aminoethyl)-1-methylpyrrole was prepared according to Ann 657, 104-107 (1962). 1H-NMR (CDCl3) δ 2.95 (t, 2H), 3.55 (s, 1H), 3.65 (t, 2H), 5.9-5.95 (m, 1H), 6.05 (t, 1H), 6.55 (t, 1H). This isothiocyanate was dissolved in DMF (4 ml). To this solution was added 200 mg (2 mmol) of 2-aminothiazole and the solution was heated at 100° C. for about 16 h. EtOAc was added and the organic phase was washed with sat. NH4Cl-solution and brine. After drying (Na2SO4), the product was purified on a silica gel column, using EtOAc/Hexane 1:1, as eluent. This gave almost pure titled product. Recrystallization from toluene/hexanes gave 150 mg of the titled product.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)([O-])=O.[C:30](=[O:33])([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:33][C:30]3[CH:26]=[CH:21][CH:22]=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=3)=[CH:3][CH:4]=2)([CH3:10])[CH3:9])=[CH:12][CH:13]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1)c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Temperature: 65 °C
Yield: 93.4 %

Procedure:
A 1 l glass reaction vessel was charged with 85.6 grams (0.375 mol) of 2,2-bis(4-hydroxyphenyl)propane, 151.2 grams (0.9 mol) of m-dinitrobenzene, 124.6 grams of potassium carbonate and 660 ml of N,N-dimethyl formamide. The mixture was reacted for 10 hours at a temperature for 140°-150° C. After completing the reaction, the resultant mixture was cooled and filtered to remove potassium nitrite. The solvent was distilled off from the filtrate under reduced pressure. The residue was cooled to 65° C., added with 450 ml of methanol and stirred for an hour. The resulted crystals were filtered, washed with water, washed with methanol, and dried to obtain 164.8 grams (93.5% yield) of 2,2-bis[4-(3-nitrophenoxy)phenyl]propane as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), and anhydrous tetrahydrofuran (250 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 2 hrs. The nitrogen flow was stopped and a solution of 3-dimethylaminopropylamine (2.04 g, 0.020 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stoppered and stirred at room temperature over the weekend. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (100 ml) and 5% potassium hydroxide (50 ml). The layers were separated and the aqueous portion washed with ethyl acetate (50 ml). The combined organic portions were washed with 5% potassium hydroxide solution (25 ml), water (25 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The solid residue was converted to the dihydrochloride salt and crystallized from acetone-ethanol-tetrahydrofuran to give 3.23 g (36%) of a white granular solid, mp. 203°-209° C. with decomposition.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:12]([CH2:28][CH3:29])=[N:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([CH2:28][CH3:29])=[N:11]2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CCc1nn(Cc2ccc(S(C)(=O)=O)cc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2ccc(S(C)(=O)=O)cc2)cc1C1CCNCC1

Procedure:
4-((1-(4-Methylsulfonylbenzyl)-3-ethyl)-(1H)-pyrazol-4-yl)-N-t-butoxylcarbonylpiperidine from Step C was treated with TFA for 1 h and evaporated to afford the title compound as the TFA salt.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:20])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:17])=[CH:13][CH:12]=[C:11]([CH3:18])[C:10]=2[C:9](=O)[CH2:8]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:20])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:17])=[CH:13][CH:12]=[C:11]([CH3:18])[C:10]=2[C:9](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:8]1
Reactant: Cc1cc[n+]([O-])c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cc[n+]([O-])c2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Temperature: 105 °C
Reaction time: 2 h
Yield: 175.8 %

Procedure:
To a mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (426 mg) and aminoguanidine hydrochloride (159 mg) were added ethanol (8 ml) and concentrated hydrochloric acid (0.15 ml), and the mixture was stirred at 105° C. for 2 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline-1-oxide hydrochloride (Compound 158) (480 mg) as colorless crystals.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH:14]1([N:20]=[N:21][C:22]2(Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CO>[CH:22]1([N:21]=[N:20][C:14]2([S:13][C:10]3[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: ClC1(N=NC2CCCCC2)CCCCC1
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(SC2(N=NC3CCCCC3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4.96 grams (.062 moles) of 50% sodium hydroxide in 100 ml of methanol in a 250 ml erlenmeyer flask was added 10.45 grams (.063 moles) of para-(t-butyl)thiophenol and the solution stirred for 15 minutes at room temperature. The solution was cooled to 5° C. and 13.7 grams (.06 moles) of 1-cyclohexylazo-1-chlorocyclohexane (from Example 3-11) was added dropwise over 20 minutes while holding the reaction temperature at 5° to 10° C. with a cold water bath. After the addition was complete the bath was removed and the reaction stirred for an additional 60 minutes at room temperature. A 1.0 gram portion of 50% sodium hydroxide was then added to react with any excess thiophenol, the reaction mixture poured into 300 ml water and the product extracted into 100 ml of pentane. The pentane solution was separated and successively washed with 50 ml portions of water, 10% HCl, water, 5% sodium hydroxide and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid that weighed 14.0 grams (63% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-cyclohexylazo-1-[para-(t-butyl)-thiophenoxy] cyclohexane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].[Cl:30][C:31]1[C:36]([CH2:37]O)=[CH:35][CH:34]=[CH:33][N:32]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:30][C:31]1[C:36]([CH2:37][O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: OCc1cccnc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCc2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of triphenylphosphine (2740 mg), 4-isopropylphenol (1138 mg), (2-chloropyridin-3-yl)methanol (1000 mg) and dehydrated THF (20 mL) was added DEAD (40% toluene solution, 4549 mg) at room temperature over 30 min. The reaction mixture was stirred at room temperature for 2 hr, DEAD (40% toluene solution, 919 mg) was added at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1623 mg) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccccc1Br

Procedure:
43.0 g (0.2 mol) of DL-2-bromo-phenylacetic acid are dissolved in 400 ml of ethanol at ambient temperature with stirring. At 5°-10° C. 11.8 g (0.2 mol) of thionylchloride are slowly added dropwise whilst cooling with ice. After 12 hours at ambient temperature the solvent is distilled off and the residue is taken up in ethyl acetate. After extraction with saturated sodium bicarbonate solution and saturated saline solution the product is dried over sodium sulphate and evaporated down.
Reaction SMILES: [Li+].[Cl-].[C:3]([N:6]1[CH2:11][CH:10]=[C:9]([Sn](CCCC)(CCCC)CCCC)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>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>[C:3]([N:6]1[CH2:11][CH:10]=[C:9]([C:3]2[C:4]3[CH:30]=[CH:29][O:28][C:27]=3[CH:26]=[CH:7][N:6]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: C1COCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Product: CC(=O)N1CC=C(c2nccc3occc23)CC1
Temperature: 100 °C

Procedure:
7 equivalents of LiCl, and then 0.03 equivalents of Pd(PPh3)4 are added, under a stream of argon, to a solution of 52.3 mmol of the product of Preparation 1 and 1.2 equivalents of the product obtained in Step B in 800 ml of dioxane. The reaction mixture is heated to 100° C. and 0.03 equivalent of Pd(PPh3)4 is added in succession, after reaction for 12 hours, 24 hours and 48 hours, and the reaction mixture is maintained at 100° C. for an additional 24 hours. After cooling, filtration over Celite and concentration under reduced pressure, chromatography of the residue on silica gel (dichloromethane/ethanol: 97/3) enables the expected product to be isolated; the product is then crystallised in pentane.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(OCC)(=O)C>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](=[O:29])[CH2:18][NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccccc1F
Yield: 64.1 %

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (1.09 g, 4 mmol) in methylene chloride (25 mL) and add triethylamine (0.578 mL, 4 mmol) followed by o-fluorobenzoyl chloride (1 g, 4 mmol). Stir the reaction for 1 hour at room temperature. Add an additional amount of methylene chloride(25 mL) and stir overnight. Dilute the reaction with ethyl acetate (100 mL), wash with water (100 mL) and dry the organic phase. Concentrate in vacuo and recrystallize the residue from ethyl acetate/hexane to yield thetitle compound (1.05 g, 67%); mp >290° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[CH2:32]([N:35]([CH2:44][CH2:45][CH3:46])[C:36](=[O:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH3:34]>>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([F:30])[CH:27]=1)[CH2:23][C@H:9]([NH:8][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][C:36]([N:35]([CH2:32][CH2:33][CH3:34])[CH2:44][CH2:45][CH3:46])=[O:43])[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: CCCN(CCC)C(=O)CCCC(=O)O
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)CCCC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(OC)c1

Procedure:
Following the general procedure of EXAMPLEs 6 and making non-critical variations and using (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 5) with 5-(dipropylamino)-5-oxopentanoic acid (DX), the title compound is obtained, MH+=534.2.