Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18](Cl)=[C:13]3[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]=O>[N:29]1([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([C:8]4[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=4)[N:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=23)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(Cl)c12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-n3ccnc3)c12
Yield: 81.4 %

Procedure:
A solution of compound (36a) (0.196 g), potassium carbonate (0.145 g), copper(II) oxide (nanopowder) (0.021 g), and imidazole (0.042 g) in DMF (2.0 mL) was stirred at 120° C. for 20 hr. The reaction solution was diluted with chloroform, and insoluble matters were filtered through celite. The solvent was distilled away, and ethyl acetate and ether were added to the residue. The precipitate was collected by filtration to obtain compound (36b) (0.173 g, 81%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].Cl[CH2:21][CH2:22][N:23]1[CH:28]([CH3:29])[CH2:27][CH2:26][CH2:25][CH:24]1[CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]1[CH:28]([CH3:29])[CH2:27][CH2:26][CH2:25][CH:24]1[CH3:30])[C:9]#[N:10]
Reactant: CC(C)N(CCC(C#N)c1ccccc1F)C(C)C
Reactant: CC1CCCC(C)N1CCCl
Product: CC(C)N(CCC(C#N)(CCN1C(C)CCCC1C)c1ccccc1F)C(C)C

Procedure:
Substitution of equivalent quantities of α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 1-(2-chloroethyl)-2,6-dimethylpiperidine in the procedure of Example 2, Method B, and substantial repetition of the procedure detailed therein, affords α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(2,6-dimethyl-1-piperidinyl)ethyl]acetonitrile, as an oil boiling at about 170°-175° C. at 0.3 mm. pressure.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=2[CH:10]=1
Reactant: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from (3-amino-2′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G10) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light green powder (30 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of 4-Bromo-2-nitroaniline (435 mg, 2 mmol) and benzaldehyde (0.204 ml, 2 mmol,) in 4 ml dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (424 mg, 2 mmol). Then acetic acid (120 μl, 2 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 276 mg (0.9 mmol, 45%) of benzyl-(4-bromo-2-nitrophenyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:46](=O)/[CH:47]=[CH:48]/N(C)C)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[NH:53]([CH:55]1[CH2:58][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:56]1)[NH2:54].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[C:5]([F:28])=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[C:46]1[N:53]([CH:55]2[CH2:56][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58]2)[N:54]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3C(=O)/C=C/N(C)C)cc2F)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 70 °C
Yield: 280.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-4-({3-[(2E)-3-(dimethylamino)prop-2-enoyl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 39, 504 mg, 0.648 mmol) in ethanol (10 mL) was slowly added a solution of tert-butyl 3-hydrazinoazetidine-1-carboxylate (Preparation 36, 536 mg, 2.86 mmol) in ethanol (10 mL) and acetic acid (0.23 mL) at 0° C. under nitrogen. The reaction was heated to 70° C. for 3 hours and then cooled to room temperature. The reaction mixture was neutralised to pH 7 with saturated aqueous sodium hydrogen carbonate solution (2 mL) and concentrated in vacuo to afford a yellow oil. The oil was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil (1.64 g). The oil was partially purified by silica gel column chromatography (0%-10% methanol in dichloromethane) to afford the title compound as a brown oil (419 mg) of 39% purity via LCMS. The compound was used without further purification in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=4[CH:30]=[CH:31][C:16]2=3)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=4[CH:30]=[CH:31][C:16]2=3)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CC(=O)N(c2cccc(OCc3ccccc3)c2)c2ccc3c(c2N1)CCCC3
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2cccc(O)c2)c2ccc3c(c2N1)CCCC3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-(3-Benzyloxyphenyl)-8,9,10,11-tetrahydronaphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (58 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL)-methanol (3 mL). To the solution was added 10% palladium-carbon (6 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to give the titled compound as slightly yellow crystal (30 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:19])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2nc(Cl)ccc2[nH]1
Yield: 59.8 %

Procedure:
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid 11-b (25.20 g, 128.18 mmol) was added to a refluxing mixture of sulfuric acid (20 ml) and methanol (400 ml). The mixture was refluxed overnight. The mixture was then evaporated and a cold NaHCO3 solution was added until basic pH. The precipitate was filtered off and dried, yielding 16.15 g of the desired product (59.8%). m/z=211.17 (M+H)+, Cl pattern.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[O:5][N:4]=1)[CH3:2].[CH2:13]([N:16]=C=O)[CH2:14][CH3:15].COC1C=C[N+]([O-])=CC=1.O>C1(C)C=CC=CC=1.C(N1C=CN=C1)=C>[CH2:13]([NH:16][C:9](=[O:11])[CH:8]([C:6]1[O:5][N:4]=[C:3]([CH2:1][CH3:2])[N:7]=1)[CH3:12])[CH2:14][CH3:15]
Reactant: CCCN=C=O
Reactant: CCc1noc(C(C)C(=O)O)n1
Agent: C=Cn1ccnc1
Agent: COc1cc[n+]([O-])cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCNC(=O)C(C)c1nc(CC)no1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 47.3 %

Procedure:
Employing anhydrous conditions, 17 mmol of about 90% pure α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionic acid (=3 ethyl-α-methyl-1,2,4-oxadiazol-5-yl-acetic acid) were dissolved in 40 ml of toluene and about 20.5 mmol of n-propyl-isocyanate and about 60 mg of the catalyst (a saturated solution of 4-methoxy-pyridine-1-oxide.1 H2O in N-vinyl-imidazole) were added to the solution. While a slow stream of nitrogen was continuously passed over the surface, the reaction mixture was stirred for 5.5 hours at room temperature and the reaction mixture was evaporated in vacuo. The residue was dissolved in 100 ml of a 1:1 mixture of ethyl acetate and diethyl ether and this solution was extracted 4 times at pH 2.0 with 10 ml of water. The combined acid washings were extracted once with 10 ml of ethyl acetate and discarded. The two organic layers were combined and extracted 3 times at pH 7.0 with 10 ml of water. The combined washings were extracted once with 10 ml of ethyl acetate and discarded. The combined organic layers were treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was stirred in 20 ml of n-hexane, whereupon diethyl ether was added slowly till the solid was almost completely dissolved. After filtration, the solution was gradually cooled to -18° C. and the crystalline precipitate was collected by filtration, washed repeatedly with n-hexane and with very cold diethyl ether to obtain 1.7 g (about 50% yield) of N-propyl-α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionamide with a purity of about 95% (according to TLC and PMR spectrum) and a m.p. of 52°-53° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:26](OC)(OC)OC.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:12]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:26]1
Reactant: Nc1cnc2ccccc2c1NCCCCCC(=O)c1ccccc1
Reactant: COC(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCn1cnc2cnc3ccccc3c21)c1ccccc1

Procedure:
By the general method described in Step 6 of Example 4, a solution of 6-(3-aminoquinolin-4-ylamino)-1-phenylhexan-1-one (2.76 g, 8.25 mmol), trimethyl orthoformate (1.5 g, 9.9 mmol), and pyridine hydrochloride (95 mg, 0.83 mmol) in toluene (26 mL) was heated at reflux under a Dean-Stark trap for 2 hours, then concentrated under reduced pressure to provide 6-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(OC1C=CC=C(C(C)(C)C=CCCCCC)C=1)C1C=CC=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC(C)(C)c1cccc(O)c1
Agent: CCCCCC=CC(C)(C)c1cccc(OCc2ccccc2)c1
Product: CCCCCCC(C)(C)c1cccc(O)c1

Procedure:
In like manner, 2-(3-hydroxyphenyl)-2-methylnonane is prepared in 82% (7.8 g.) yield from 13.0 g. (0.0406 mol.) of 1-benzyloxy-3-(1,1-dimethyl-oct-2-enyl)benzene. It is obtained as an oil having the characteristics:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C@@H:4]1[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:15])([CH3:1])[C@H:3]1[OH:14])[C:21](=[O:26])[C:20]2=[O:27]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2C(=O)C(=O)c3cc(Cl)ccc32)[C@@H]1O

Procedure:
Following the procedure described in the Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-1H-indole-2,3-dione as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=O)[CH3:4].Cl.[CH3:16][C:17]([CH3:19])=[O:18]>C(O)C.O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:16][C:17](=[O:18])[CH3:19])[CH:11]=[CH:12][C:13]=1[OH:14])[CH3:4]
Reactant: CC(C)=O
Reactant: CCOc1cc(C=O)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C=CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
10% sodium hydroxide aqueous solution (80 ml) was added under stirring to a solution of 3-ethoxy-4-hydroxybenzaldehyde (16.6 g, 100 mmol) in acetone (50 ml), 95% ethanol (50 ml) and water (400 ml). The reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0, the precipitated yellow solid was collected by filtration, washed with water and ethanol successively, dried, and then recrystallized from 95% ethanol to give 14.5 g of a yellow crystal, mp: 98-100° C., yield 70.4%.
Reaction SMILES: NC1[C:7]([CH2:8][CH2:9][C:10]2[NH:19][C:13]3=[N:14][CH:15]=[C:16](Br)[CH:17]=[C:12]3[N:11]=2)=[C:6](C)[CH:5]=[CH:4]N=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:21][C:22]1[CH:23]=[C:24]([C:16]2[CH:17]=[C:12]3[N:11]=[C:10]([CH2:9][CH2:8][C:7]4[N:11]=[C:10]([NH2:19])[CH:9]=[C:5]([CH3:4])[CH:6]=4)[NH:19][C:13]3=[N:14][CH:15]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1ccnc(N)c1CCc1nc2cc(Br)cnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cc(Cl)cc(Cl)c4)cnc3[nH]2)c1
Yield: 61.7 %

Procedure:
The title compound is synthesized according to General Procedure A. 100 mg of 2-[2-(2-amino-4-methylpyridin-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 5.0 ml dioxane, 903 μl Na2CO3 solution, 65 mg of 3,5-dichlorophenylboronic acid, 13 mg of PdCl2(PCy3)2, 120° C. for 64 h. During extraction with 20 ml of CH2Cl2/H2O the title compound starts precipitating in the organic layer. Subsequently, 37 mg of the pure title compound can be obtained as a colorless powder after filtration and lyophilization from 2.0 ml dioxane and 1.0 ml water. M.p. 224° C. ESI-MS: 398.3, 400.2, 402.3 (MH+; 100%, 65%, 13%). TLC: Rf=0.24 (dichloromethane/methanol 10:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: ClC1CCCC1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(OC2CCCC2)cn1
Temperature: 65 °C
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyrimidin-5-ol (1 g, 7.66 mmol), chlorocyclopentane (2.39 mL, 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) in N,N-dimethylformamide were heated at 65° C. for 16 h at ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to afford 2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6% yield) as a white solid. MS (LC/MS) R.T.=2.32; [M+H]+=199.23.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:24]=[CH2:25].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:18]=3[C:17]([F:27])([F:16])[F:26])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnccc2C(F)(F)F)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [BrH:1].[NH2:2][NH:3][C:4]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)=[NH:5].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[BrH:1].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:2][NH:3][C:4]([NH:6][N:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[NH:5])=[CH:20][CH:19]=1
Reactant: N=C(NN)NN=Cc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Br
Product: N=C(NN=Cc1ccc(Cl)cc1)NN=Cc1ccc(Cl)c(Cl)c1

Procedure:
In a similar manner the reaction of 1-amino-3-(4-bromobenzylideneamino)guanidine methosulfate with 4-chlorobenzaldehyde gives the methosulfate salt of the subject compound. The reaction of 1-amino-3-(4-cyanobenzylideneamino)guanidine hydroiodide with 4-chlorobenzaldehyde gives 1-(4-chlorobenzylideneamino)-3-(4-cyanobenzylideneamino)guanidine hydroiodide; the reaction of 1-amino-3-(4-chlorobenzylideneamino)guanidinehydrochloride with 4-cyanobenzaldehyde affords the corresponding hydrochloride salt which melts at 297°-298° C. The reaction of 1-amino-3-(3,4-dichlorobenzylideneamino)guanidine hydrobromide and 4-chlorobenzaldehyde gives 1-(4-chlorobenzylidene-amino)-3-(3,4-dichlorobenzylideneamino)guanidine hydrobromide; the reaction of 1-amino-3-(4-chlorobenzylideneamino)guanidine hydrochloride with 3,4-dichlorobenzaldehyde gives the corresponding hydrochloride salt which melts at 288° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1C2C(CO[C:47]([NH:49][C@H:50]([C:67]([O:69][CH3:70])=[O:68])[CH2:51][S:52][CH2:53][CH:54]([C:59](=[O:66])[C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)[CH2:55][C:56]([OH:58])=[O:57])=[O:48])C3C(=CC=CC=3)C=2C=CC=1.[Cl:71][C:72]1[CH:77]=[CH:76][C:75]([N:78]=C=O)=[CH:74][CH:73]=1>C1COCC1.ClCCl>[Cl:71][C:72]1[CH:77]=[CH:76][C:75]([NH:78][C:47]([NH:49][C@H:50]([C:67]([O:69][CH3:70])=[O:68])[CH2:51][S:52][CH2:53][CH:54]([C:59](=[O:66])[C:60]2[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=2)[CH2:55][C:56]([OH:58])=[O:57])=[O:48])=[CH:74][CH:73]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1ccc(Cl)cc1
Yield: 12 %

Procedure:
Wang resin (100-200 mesh, 0.66 mmol/g, 70 mg) was treated with triphenylphosphine (34.5 mg), diethyl azodicarboxylate (20.8 μL) and 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid (72.3 mg) in THF (0.5 mL) at room temperature for 3 days. The resin was filtered, washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 20% piperidine-dichloromethane (1 mL) solution for 1 h. The resin was filtered, and washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 10 eq of 4-chlorophenyl isocyanate in dichloromethane (6 mL) for two days. The resin was washed with washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 20% trifluoroacetic acid in dichloromethane (5 mL). The solution was filtered, concentrated and purified on HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 12% of the title compound; ESMS, (M+1)+480.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1>[C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(=O)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCCC(O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 3-(5-bromothiophen-2-yl)-3-oxopropyl acetate (2.4 g, 8.8 mmol, 1 eq) in THF (150 ml) was stirred at 0° C., and NaBH4 (401.2 mg, 10.6 mmol, 2 eq) was added slowly and the reaction was stirred at 23° C. After 1 hour, Na2CO3.H2O was added. After 30 min the mixture was filtered and extracted with EtOAc (3×50 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EtOAc=5:1 as eluant) to give 3-(5-bromothiophen-2-yl)-3-hydroxypropyl acetate (1.92 g, 78.2%) as white solid. LC-MS (m/z)=279.1 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[OH-:14].[Na+].Cl>O1CCOCC1>[Cl:13][C:4]1[NH:3][C:2](=[O:14])[C:7]2[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=2[CH:5]=1
Reactant: [OH-]
Reactant: CCn1ccc2c(Cl)nc(Cl)cc21
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1ccc2c(=O)[nH]c(Cl)cc21
Temperature: 160 °C
Yield: 32.8 %

Procedure:
A microwave reaction vial was charged with 4,6-dichloro-1-ethyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 0.930 mmol), a 2M aqueous sodium hydroxide solution (10 mL) and 1,4-dioxane (3 mL). The vial was sealed and then heated in the microwave at 160° C. for 30 min. At this time, the resulting mixture was acidified to pH 6.5 with a 4M aqueous hydrochloric acid solution and then concentrated in vacuo. The residue was diluted with ethanol. The solids were removed by filtration, and the filtrate was concentrated in vacuo. Flash chromatography (10/1 methylene chloride/methanol) afforded 6-chloro-1-ethyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (60 mg, 32.8%). LC-MS calcd. for C9H9ClN2O [(M)+] 196, obsd. 196.9.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([O:5][CH2:6][O:7][C:8](SCC)=[O:9])=[O:4].S(Cl)([Cl:17])(=O)=O>>[CH3:1][CH:2]([CH3:13])[C:3]([O:5][CH2:6][O:7][C:8]([Cl:17])=[O:9])=[O:4]
Reactant: CCSC(=O)OCOC(=O)C(C)C
Reactant: O=S(=O)(Cl)Cl
Product: CC(C)C(=O)OCOC(=O)Cl
Reaction time: 0.33 h

Procedure:
The compound (400 mg) obtained in Step 2 of this Example was cooled to −30° C. Sulfuryl chloride (159 μL) was added thereto, and the mixture was stirred at the same temperature for 20 minutes. The mixture was in turn stirred for 20 minutes in an ice bath and further at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dried to obtain a crude product of the title compound.