Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)[NH2:2].C(N(CC)CC)C.C(O[CH:22]=[N:23][C:24]#[N:25])C>C(O)C>[NH2:25][C:24]1[N:1]([C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[N:2]=[CH:22][N:23]=1
Reactant: NNc1nc2ccccc2[nH]1
Reactant: CCOC=NC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ncnn1-c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydrazino-1H-benzimidazole (5.0 g, 33.7 mmol) in ethanol (30 ml) is added sequentially triethylamine (5 ml, 33.7 mmol) and N-cyanoformimidic acid ethyl ester (3.3 g, 33.7 mmol) with cooling. After stirring for 2 hours at 0° C. the resulting precipitate is filtered with suction and dried to give 3-amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole. 1H-NMR (400 MHz, d6-DMSO): 13.0 (s, 1H); 7.77 (s, 1H); 7.70 (m, 2H); 7.50 (m, 2H); 7.20 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:8]=2[CH:17]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:8]=2[CH:17]=1
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(N)cc2[nH]1
Reaction time: 3 h

Procedure:
A solution of 1.9 g (8.1 mmol) of ethyl 6-nitro-1H-benzimidazole-2-carboxylate in 30 ml of ethanol was hydrogenated in the presence of 190 mg of palladium (10% on activated carbon) at RT and standard pressure for 3 h. The reaction mixture was then filtered through kieselguhr and the residue was washed with ethanol. The combined filtrates were concentrated under reduced pressure. The residue was dried under reduced pressure and then purified by flash chromatography (silica gel 50, mobile phase: dichloromethane/methanol 3-5%). Yield: 640 mg (39% of theory)
Reaction SMILES: C([CH:5]([C:17]([OH:19])=[O:18])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)(C)(C)C>FC(F)(F)C(O)=O>[C:17]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)([OH:19])=[O:18]
Reactant: CC(=O)Cc1cccc(OC(C(=O)O)C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Cc1cccc(OCC(=O)O)c1
Reaction time: 0.08 h

Procedure:
To m-(t-butylcarboxymethoxy)phenyl acetone, 6.7 g, was added trifluoroacetic acid (40 ml) at room temperature under nitrogen. After five minutes, reaction was found to be completed by tlc (silica gel eluted with 1:9 parts by volume methanol:methylene chloride) and the solvent was then evaporated to dryness. The resulting brown oil showed the desired product and trace of starting material on tlc. IR showed characteristic carboxylic acid peak at 3600-2450 cm-1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:17][N:18]([CH3:20])[CH3:19])=[CH:9][C:8]=1[S:10]([N:13]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:12])=[O:11]
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)c(S(=O)(=O)N=CN(C)C)c1
Temperature: -10 °C

Procedure:
A mixture of 7.8 g (0.033 moles) of 5-acetyl 2-chlorobenzenesulfonamide [Chem. Abst., 63, 5563a (1965)] and 50 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 5 hours, then cooled at -10° C. The precipitate formed was collected, washed with 50 ml of ether and air dried. The solid was boiled up in 400 ml of ethanol, treated with activated charcoal and filtered. The filtrate was cooled at -10° C. and filtered to collect an orange-red precipitate. The solid was washed with 50 ml of ethanol and dried in vacuo at 60° C. and gave 5.2 g of N'-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]sulfonyl]-N,N-dimethylmethanimidamide, mp 204°-206° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH2:2][CH3:3].O=S(Cl)Cl.[NH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]([CH:11]=1)[C:5]([NH:21][CH2:22][CH2:23][CH3:24])=[N:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCCNC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCN=C(NCCC)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
In a sulfonation flask 32.8 g (0.125 mol) 5-chloro-2-nitrobenzoic acid propylamide are dissolved in 74.4 g (0.625 mol) SOCl2 and heated at reflux temperature for 4 hours. Then the excess SOCl2 is removed in a water jet vacuum and the crude imidoylchloride is dissolved in 30 ml of absolute THF. The resulting solution was added dropwise to a stirred solution of 15.4 g (0.26 mol) 1-aminopropane in 30 ml THF. The mixture is stirred for 5 hours at reflux temperature and then the solvent is removed in a water jet vacuum. The residue is taken up in ethylacetate and the organic phase is washed twice with water and saturated sodiumcarbonate solution. After drying of the organic phase, the solvent is removed in a water jet vacuum and the raw material purified by column chromatography over silica gel (eluant: hexane/THF=3:1). Yield: 27.8 g 5-chloro-2-nitro-N,N′-dipropylbenzamidine in the form of brown crystals; m.p. 63-64° C.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[C:42]=1[CH3:43])=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[C:42]=1[CH3:43])=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C
Temperature: 95 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
1.17 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.891 g of N-(6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 10 ml of 1-methyl-2-pyrrolidone; 0.517 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 15 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected and recrystallized with ethyl acetate-ethyl ether (1:1) to yield 0.629 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](I)[CH3:21]>>[CH3:19][N:2]([CH3:1])[C:3]([C:4]1([N:5]2[CH:9]=[C:8]([CH3:10])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:21][CH2:20][CH2:17]1)=[O:18]
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Reactant: CCI
Product: Cc1cn(C2(C(=O)N(C)C)CCC2)nc1-c1ccccc1

Procedure:
Following the procedure of Example 95, but substituting α-(3-bromopropyl)-N,N,4-trimethyl-3-phenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and without the addition of ethyl iodide there was obtained N,N-dimethyl-1-(4-methyl-3-phenylpyrazol-1-yl)cyclobutanecarboxamide having a melting point of 87°-89° C.
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=NC=1.Cl.C([N:31]1[CH2:36][CH2:35][C@H:34]([CH:37]([NH:39][C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][N:41]=2)[CH3:38])[C@@H:33]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([C@@H:33]2[C@@H:34]([CH:37]([NH:39][C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][N:41]=3)[CH3:38])[CH2:35][CH2:36][NH:31][CH2:32]2)=[CH:49][CH:50]=1
Reactant: CC(Nc1ccc(C#N)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Product: CC(Nc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 6-{1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethylamino}-nicotinonitrile as light yellow viscous oil. MS (m/e): 341.2 [(M+H)+].
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:18][O:19][CH2:20][CH:21]=[CH2:22])[C:15]([OH:17])=[O:16])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:18][O:19][CH2:20][CH:21]=[CH2:22])[C:15]([OH:17])=[O:16])[N:10]=1
Reactant: C=CCON=C(C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: C=CCON=C(C(=O)O)c1nsc(N)n1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A solution of 570 mg (1.74 mmoles) of 2-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetic acid in 6 ml of trifluoroacetic acid was allowed to stand for 1 hour at ambient temperature. Evaporation followed by trituration with 30 ml of isopropyl ether gave 376 mg (95%) of the title compound. Mp. 109° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([S:17](C)=O)S[C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:17][C:20]=4[CH:21]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cc1cc2ncn(Cc3ccc4nc(S(C)=O)sc4c3)c2cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1C
Temperature: 130 °C
Yield: 46.9 %

Procedure:
A stirred mixture of 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (150 mg, 0.42 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol (140 mg, 1.2 mmol), DIEA (540 mg, 4.2 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (80 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.26-7.31 (m, 2H), 7.14 (m, 1H), 5.40 (s, 2H), 4.71 (d, J=3.0 Hz, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.30 (s, 6H), 2.02 (m, 1H), 1.88 (m, 1H), 1.86-1.90 (m, 2H), 1.12-1.27 (m, 4H); LCMS (ESI) m/z 407 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:52][CH:51]=2)[C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a solution of 819 mg (2.07 mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide (Step A) in 7.0 mL of dry dimethylformamide under nitrogen at 0° C. was added 83 mg (2.1 mmol) of 60% sodium hydride/oil dispersion. After stirring for 15 minutes, a solution of 810 mg (2.1 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step F) in 2.0 mL of dimethylformamide was added by cannula. The flask which originally contained the methanesulfonate ester was rinsed with 1.0 mL of dimethylformamide which was added to the reaction mixture. After stirring at 0° C. for 15 minutes, the reaction mixture was diluted with 400 mL of ethyl acetate and 50% saturated ammonium chloride. The mixture was transferred to a separatory funnel and the aqueous layer was separated. The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45) to afford 1.2 g (84%) of the product as a white foam. 1H NMR (200 MHz, CDCl3): δ 1.38 (s, 9H), 1.48 (s, 3H), 1.52 (s, 3H), 1.78 (s, 1H), 2.35-2.70 (m, 3H), 4.18 (d, 6 Hz, 2H), 4.38-4.62 (m, 2H), 4.82 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.25 (d, 16 Hz, 1H), 5.32 (s, 1H), 7.08 (d, 6 Hz, 1H), 7.12-7.43 (m, 18H). FAB-MS: calculated for C41H46N4O6 690; found 691(M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:42])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[C:27]([F:40])[CH:26]=4)[CH:18]=3)=[C:12]([CH3:41])[CH:11]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:42]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH3:41])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([F:40])[CH:26]=4)[CH:18]=3)=[C:14]([CH3:16])[CH:15]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(OCC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)OC(C)(C)C)c(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
To a solution of tert-butyl 3-{4-[({4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (0.08 g, 0.14 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (2 mL) under stirring at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.06 g, yield 78%) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][C:4]([CH3:8])([CH2:5][F:6])[C:3](=[O:9])[CH2:2][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(CF)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)Cn1cncn1
Yield: 60.5 %

Procedure:
197 g (1 mole) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone were slowly added dropwise to a boiling solution of 77 g (1.1 mols) of 1,2,4-triazole and 210 g (1.5 moles) of potassium carbonate in 500 ml of acetone such that, after removing the heating bath, the exothermic reaction kept the solution simmering. The mixture was then kept under reflux for a further 3 hours, the inorganic salts were filtered off and the filtrate was concentrated in vacuo. The residue was taken up in chloroform/water and the organic phase was separated off and evaporated. The residue which remained was distilled in vacuo and the distillate was crystallized with cyclohexane. 112 g (55% of theory) of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 59° C. were obtained. ##STR15##
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[C:10](=[O:16])[C:9](=[N:17]O)[CH2:8]2.C1(C)C=CC(S(Cl)(=O)=[O:26])=CC=1>O>[C:9]([CH2:8][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[C:10]([OH:16])=[O:26])#[N:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=NO)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CC#N)c(C(=O)O)c(OC)c1
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of NaOH (3.4 g, 85 mmol) in H2O (50 ml) was added of 5,7-Dimethoxy-indan-1,2-dione 2-oxime (5.0 g, 22.6 mmol). The mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (5.7 g, 30 mmol) was added in portions to the mixture. The mixture was heated at 80° C. for 15 min. After cooling carefully to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and precipitate was formed. The precipitate was collected and dried to give product (3.5 g, 70%). LC-MS: m/e 220 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](SC)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl.Cl.[NH2:19][CH:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.C(N(CC)CC)C>O1CCCC1>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[CH:20]([NH:19][C:13]([NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])=[NH:14])[CH2:21]2
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CN2CCC1CC2
Temperature: 80 °C
Yield: 15.1 %

Procedure:
3,5-Diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide (Intermediate 3, 250 mg, 0.88 mmol) is dissolved in tetrahydrofuran (20 mL) and to the solution 3-amino-quinuclidine dihydrochloride (211 mg, 1.06 mmol) and triethylamine (0.61 mL, 4.41 mmol) are added. The mixture is heated at 80° C. for 24 hours. The solid is removed by filtration and the is filtrate evaporated and purified by preparative HPLC (5 mM ammonium formate in H2O: CH3CN gradient) obtaining the title compound (45 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)([C:17](OCC)=[O:18])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:30]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)([C:17](=[O:18])[NH2:30])[CH3:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: N
Reactant: CCOC(=O)C(C)(NC(=O)C1CCCN1C(=O)OC(C)(C)C)c1ccc(Br)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NC(C)(C(N)=O)c1ccc(Br)cc1
Reaction time: 72 h
Yield: 64 %

Procedure:
To a stirred solution of 2-[1-(4-bromo-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 0.6 mmol) in ethanol (8 mL) was bubbled through NH3 gas for 5 minutes at −78° C. The solution was stirred at ambient for 3 days in a sealed tube. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a colorless oil (169 mg, 64%). m/z 439.8, 441.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5]([SH:8])=[N:6][CH:7]=1.Br[CH:12]([CH3:14])[CH3:13]>>[CH:12]([S:8][C:5]1[C:4]([C:9]#[N:10])=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)([CH3:14])[CH3:13]
Reactant: Cc1cnc(S)c(C#N)c1
Reactant: CC(C)Br
Product: Cc1cnc(SC(C)C)c(C#N)c1
Yield: 70 %

Procedure:
5-Methyl-2-sulfanyl-pyridine-3-carbonitrile (0.2 g, 1.3 mmol) and 2-bromopropane were reacted in the same manner as in Step A of Preparation Example 5 to obtain the title compound (0.18 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:16][NH2:17])=[O:15])[NH:12][N:13]=1.[OH:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>C(O)C>[OH:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[N:17][NH:16][C:14]([C:11]1[NH:12][N:13]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:10]=1)=[O:15]
Reactant: NNC(=O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCO
Product: O=C(NN=Cc1ccc(O)cc1O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 66 %

Procedure:
In ethanol (30 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide (136 mg) prepared in the Step 21-1-1 and 2,4-dihydroxybenzaldehyde (69 mg) was heated under reflux for 29 hours. Crystal appeared as the mixture was concentrated under a reduced pressure, the resulting crystal was separated by filtration, washed with ethanol, washed with ethyl acetate, and dried to give the title compound (129 mg, 66%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])C1C=CC=CC=1>C(Cl)Cl.B(Br)(Br)Br>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Clc1ccccc1CCCCc1ccccc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CCCCc1ccccc1Cl
Yield: 94 %

Procedure:
Finally, following a procedure similar to that described in the final part of Preparation 15, the whole of this 1-(2-benzyloxyphenyl)-4-(2-chlorophenyl)butane was dissolved in 18 ml of methylene chloride and debenzylated by means of 8.15 ml of a 1M solution of boron tribromide in methylene chloride. The crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.0 g (yield 94%) of the title compound as a colorless solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[ClH:1].[NH:37]([C:38]([NH:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 50.9 mg (0.43 mmol) of phenyl isocyanate. After 16 h at room temperature, the reaction mixture is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 35 mg (35.8% of theory) of the title compound are obtained.