Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]1[C@H:30]2[C@H:26]([O:27][CH2:28][CH2:29]2)[O:25][CH2:24]1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]([O:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:10][C@@H:9]([OH:19])[C@@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]3[C@H:30]4[C@H:26]([O:27][CH2:28][CH2:29]4)[O:25][CH2:24]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230), 1,3-benzodioxole-5-sulfonyl chloride (Eur. Pat. Appl. 583960, Feb 23, 1994, 56 mg, 0.253 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,3-benzodioxole-5-sulfonyl chloride (11 mg, 0.050 mmol) was added and the reaction was heated for an additional hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride : methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (123 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.32 (m, 6H), 1.70 (m, 5H), 2.14 (m, 2H), 3.00 (m, 4H), 3.18 (b, 1H), 3.74 (m, 2H), 3.97 (m, 4H), 4.27 (m, 1H), 4.90 (m, 1H), 5.07 (m, 1H), 5.70 (d, 1H), 6.15 (s, 2H), 6.95 (d, 1H), 7.30 (m, 7H). MS(ESI): 641(M+Na).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[C:33](C1C=CC(OCC2C=CC(C(OC)C3C=C(C=CC=3)C#N)=CC=2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([O:26][CH3:33])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(OC)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(OC)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared essentially as described for 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid employing 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrile to give a white solid, 82%. 1H NMR (DMSO-d6) δ 13.00 (bs, 1H), 12.85 (s, 1H), 7.96 (s, 1H), 7.79-7.85 (m, 2H), 7.63 (d, 1H), 7.40-7.48 (m, 5H), 6.72 (d, 1H), 5.50 (s, 1H), 5.24 (s, 2H), 3.30 (s, 3H), 2.58-2.61 (m, 5H), 1.44-1.52 (m, 2H), 0.84-0.88 (m, 3H). LCMS M+1 449.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.C1[C:35]2[C:34](=[O:36])[C:33]3C(=CC=CC=3)C=2C(C(Cl)=O)=CC=1>ClCCl>[CH:34]([O:36][CH:12]([CH3:11])[CH3:13])([CH3:35])[CH3:33].[NH2:15][C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[CH:12][C:11]=1[NH-:14]
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Product: CN1CCN(c2ccc([NH-])c(N)c2)CC1
Yield: 390.3 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 2.06 g of 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine, 2.85 ml of triethylamine and 2.43 g of 9H-fluoren-9-one-4-carboxylic acid chloride in 50 ml of dichloromethane, for 20 hours at room temperature. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (95/5 by volume), and then formation of a paste with diisopropyl ether, in this way we obtain 4 g of [2-amino-4-(4-methylpiperazin-1-yl)phenyl]amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:56](Cl)(=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:58][C:57]([CH3:60])([CH3:59])[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)=[O:61]
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(C(=O)C(C)(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 38.9 %

Procedure:
Using a procedure analogous to Example 26, the product from Example 14 (120 mg, 0.150 mmol) was treated with pivaloyl chloride (21.7 mg, 1.2 eq) to provide the title barbituric acid (45.0 mg, 40%). MS found: (M+H)+=544.
Reaction SMILES: ClCC1(COC2C=CC(Cl)=CC=2Cl)CO1.[Cl:16][C:17]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:18]=1[O:19][CH2:20][C:21]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[CH2:23][O:22]1.[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][C:17]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:18]=1[O:19][CH2:20][C:21]([OH:22])([CH2:23][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33]
Reactant: Clc1ccc(OCC2(COc3ccc(Cl)cc3Cl)CO2)c(Cl)c1
Reactant: c1nc[nH]n1
Agent: ClCC1(COc2ccc(Cl)cc2Cl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(COc1ccc(Cl)cc1Cl)(COc1ccc(Cl)cc1Cl)Cn1cncn1

Procedure:
23.5 g of a mixture of 2-chloromethyl-2-(2,4-dichlorophenoxymethyl)-oxirane and 2,2-bis(2,4-dichlorophenoxymethyl)-oxirane are added dropwise to a solution of 20.7 g (0.3 mol) of 1,2,4-triazole and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of acetone. The reaction mixture is stirred under reflux for 20 hours. Thereafter, the mixture is filtered cold and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and the solution is washed with water, dried over sodium sulphate and purified and separated by chromatography (silica gel 60 Merck). The column is first eluted with chloroform. The eluate thereby obtained is concentrated by distilling off the solvent, and the residue is stirred with diethyl ether. 4.8 g of 1,3-bis-(2,4-dichlorophenoxy)-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-propane (Example 5) of melting point 136° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C:28]([F:41])([F:40])[C@:29]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[C:34](Br)[N:33]=3)([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[NH3:42].C(O)CO.CO>C(OCC)(=O)C>[NH2:42][C:34]1[N:33]=[C:32]([C@:29]2([CH3:31])[C:28]([F:41])([F:40])[CH2:27][O:26][C:25]([NH:24][C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:30]2)[C:37]([F:38])=[CH:36][CH:35]=1
Reactant: N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: OCCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(N)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 43 h
Yield: 25 %

Procedure:
To a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (23.4 g, 28.8 mmol) in ammonia (173 ml, 1.21 mol, 7M in methanol) in a microwave vial was added ethylene glycol (240 ml) and methanol (240 ml). Copper oxide Cu2O (1.21 g, 8.46 mmol) was added and the vial was sealed. The reaction mixture was stirred at 80° C. for 43 hours. The cold reaction mixture was diluted with ethyl acetate and washed with water, aqueous ammonia and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was chromatographed over silica gel (400 g, dichloromethane/methanol 98:2+0.2% ammonia) to give the title compound: 4.29 g (25% yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[CH:20]([CH3:24])[C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCCCCC.O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:24])[C:21]([NH2:23])=[O:22])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Cl)C(N)=O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(N)=O

Procedure:
A mixture containing 10.0 g (0.039 mole) of 4-(4-trifluoromethylphenoxy)phenol, 5.0 g (0.039 mole) of 2-chloropropanamide, 6.9 g (0.05 mole) of anhydrous potassium carbonate, and 50 ml of dimethylsulfoxide is stirred at 90° until reaction is complete, as indicated by vpc techniques. The resultant slurry is cooled, poured into 600 ml of water, and tested with 1:1 hexane/tolune, and the product is isolated by filtration, mp 147°-149° . Recrystallization from hexane affords highly pure product, mp 149°-151°.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH2:21][C:22]#[N:23])[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[N:10]=[CH:9][CH:8]=1.Cl>CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH2:21][C:22]([NH2:2])=[NH:23])[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[N:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: N#CCc1ccc2c(c1)Nc1nccnc1S2
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: N=C(N)Cc1ccc2c(c1)Nc1nccnc1S2
Yield: 38.6 %

Procedure:
2.68 g of ammonium chloride was added to 20 ml of dry toluene in a nitrogen atmosphere. Then 36.5 ml of a 15% solution of trimethylaluminum in n-hexane was added thereto under stirring and ice-cooling. The reaction mixture was brought back to room temperature and 70 ml of dry toluene was further added. The resulting mixture was subjected to ultrasonication until the ammonium chloride disappeared completely. A 60 ml portion of the solution thus obtained was taken and 1.5 g of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile was added thereto. The obtained mixture was heated under reflux for 18 hours. After bringing back to room temperature, the reaction mixture was distributed into ethyl acetate and dilute hydrochloric acid and repeatedly extracted with water. The aqueous layer was washed with methylene chloride and the solvent contained in the solution was eliminated under reduced pressure. The obtained residue was purified by High-porous gel column chromatography (CHP20, mfd. by Mitsubishi Chemical Industries, Ltd., 75-15μ) (eluted with water/methanol) to thereby give 620 mg of the title compound as yellow crystals.
Reaction SMILES: [Na].Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.Cl.[NH2:20][C:21]([NH2:23])=[NH:22]>C(O)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[N:20]=[C:21]([NH2:23])[N:22]=[C:10]([NH2:11])[C:9]=1[C:6]1[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=1
Reactant: N=C(N)N
Reactant: N#CCc1ccncc1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(N)c(-c2ccncc2)c(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
After sodium (3.2 g, 139 mmol) was dissolved in anhydrous ethanol (200 mL), 4-pyridyl acetonitrile hydrochloride (10.0 g, 64 mmol) and 2-furaldehyde (6.1 mL, 73.6 mmol) and guanidine hydrochloride (7.0 g, 73.3 mmol) were successively added thereto. After stirring at room temperature for 1 hour, it was heated under reflux for 7 hours. After cooling as it was, the insoluble matters were filtered off, washed with tetrahydrofuran, and the solvent was removed from the filtrate. Tetrahydrofuran (200 mL) and activated manganese dioxide (30.0 g) were added to the residue, followed by heating under reflux for 2.5 hours. After cooling as it was, the manganese dioxide was filtered through Celite, and washed with tetrahydrofuran. The collected filtrate was concentrated, and then methanol was added to the residues. The resulting precipitates were collected by filtration and washed with methanol, to give the title compound (3.48 g, 21%) as a pale brown solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)(OCC)=O)C.CN(C=O)C.[H-].[Na+].[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[C:39]3[N:40]([CH:44]=[C:45]([CH:47]=O)[N:46]=3)[CH:41]=[CH:42][N:43]=2)[CH2:34][CH2:33]1.CC(O)=O.Cl>C1COCC1>[O:32]1[CH2:33][CH2:34][N:35]([C:38]2[C:39]3[N:40]([CH:44]=[C:45](/[CH:47]=[CH:9]/[C:10]4[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:11]=4)[N:46]=3)[CH:41]=[CH:42][N:43]=2)[CH2:36][CH2:37]1
Reactant: O=Cc1cn2ccnc(N3CCOCC3)c2n1
Reactant: CCOC(=O)c1cc(CP(=O)(OCC)OCC)nc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1cc(/C=C/c2cn3ccnc(N4CCOCC4)c3n2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of compound 45a (124 mg, 0.353 mmol) in DMF (3.5 mmol) was treated with 60% NaH (42.3 mg, 1.05 mmol) at 0° C. The resulting mixture was stirred at rt for 15 min, cooled to 0° C. and treated with compound 45b (90.2 mmol, 0.388 mmol) in THF (2 mL). The resulting mixture was stirred for 30 min, cooled in a dry ice/acetone bath and treated with HOAc (0.060 mL, 1.05 mmol). The reaction mixture was then allowed to warm to rt and the pH was adjusted to about 5 with concentrated HCl. The precipitate formed was collected by filtration and dried under reduced pressure to obtain (E)-2-(2-(8-morpholinoimidazo[1,2-a]pyrazin-2-yl)vinyl)quinoline-4-carboxylic acid.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1CN([P+](O[N:37]2N=[N:44][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.CCN(CC)CC>CN(C=O)C>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[NH2:44])=[O:17])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoic acid (0.1 mmol) in DMF (1 mL) was sequentially treated with PyBOP (0.12 mmol), 1,2-phenylenediamine (0.12 mmol) and Et3N (0.3 mmol). After stirring at 23° C. for 4 h, the reaction was filtered and the crude material was purified by HPLC to yield 4-((1H-benzo[d]imidazol-1-yl)methyl)-N-(2-aminophenyl)benzamide. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.88 (s, 2H), 5.60 (s, 2H), 6.54-6.61 (m, 1H), 6.76 (d, J=8.08 Hz, 1H), 6.93-6.98 (m, 1H), 7.13 (d, J=7.58 Hz, 1H), 7.18-7.23 (m, 2H), 7.43 (d, J=8.34 Hz, 2H), 7.48-7.54 (m, 1H), 7.65-7.70 (m, 1H), 7.93 (d, J=8.08 Hz, 2H), 8.46 (s, 1H), 9.60 (s, 1H). ESI-MS: m/z 343.3 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:24])([CH3:23])[C:13](=O)[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:12]([CH3:11])([CH3:23])[CH3:24])=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(C)(C)C)n(-c2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A solution of 3-bromophenylhydrazine hydrochloride (0.5 g, 2.2 mmol) and ethyl 5,5-dimethyl-2,4-dioxohexanoate (0.54 g, 2.68 mmol) in acetic acid (10 ml) was refluxed for 16 hours. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated bicarbonate and brine, and dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (4.8:0.2 hexanes/ethyl acetate) to give ethyl 1-(3-bromophenyl)-5-tert-butyl-1H-pyrazole-3-carboxylate (0.59 g, 74%) as a syrup.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)([CH2:6][CH3:7])[C:4]#[N:5])[CH3:2].O.O.NN>C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]([C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[C:4]#[N:5])[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(C#N)(CC)c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(C#N)(CC)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A solution of 3.2 g (14.7 mmol) of 2-ethyl-2-(3-nitro-phenyl)-butyronitrile in 50 ml of ethanol was treated with 350 mg of water-wet Raney nickel and the mixture heated to 60° C. 10 ml of hydrazine hydrate was added dropwise over 20 minutes and the reaction stirred for a further 1 hour at 60° C. The cooled mixture was filtered through hyflo filter aid and evaporated to give 2.5 g (90%) of 2-(3-amino-phenyl)-2-ethyl-butyronitrile as an orange oil. [Mass spectrum (ESI) MH+ =189].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[NH2:33]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C@@H:29]4[CH2:30][CH2:31][CH2:32][C@@H:28]4[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COC[C@H]1CCC[C@H]1N
Product: COC[C@H]1CCC[C@H]1NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1R,2S)-2-(methoxymethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.60 (m, 2H) 1.60-1.83 (m, 3H) 1.84-2.01 (m, 1H) 2.20-2.37 (m, 1H) 2.44 (s, 3H) 3.19 (s, 3H) 3.20-3.27 (m, 1H) 3.40 (dd, J=9.35, 6.06 Hz, 2H) 4.43 (t, J=7.45 Hz, 1H) 7.67 (d, J=7.58 Hz, 1H) 7.74 (br. s., 1H) 7.81 (d, J=18.69 Hz, 1H) 8.24-8.70 (m, 3H) 8.88 (d, J=1.77 Hz, 1H) 13.24 (br. s., 1H). MS m/z [M+H]+ 432.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Reactant: c1c[nH]cn1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCn1ccnc1)\c1nc2ccccc2s1
Yield: 46 %

Procedure:
The named compound was prepared as described in Example 38 starting with (H) of Example 38 (3.0 g, 8.7 mmol) and using imidazole in place of dipropylamine to produce 1.5 g (46% yield) of the named compound as the HCl salt, mp 214°-217° C. IR(KBr): 3400, 1595 cm-1. MS: 376(MH+). 1H NMR (CD3OD): δ 9.01 (s, 1H), 7.88-6.91 (m, 12H), 4.21 (t, J=5.2 Hz, 2H), 3.34 (t, J=5.2 Hz, 2H), 2.25 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[Cu](C#N)[C:14]#[N:15].C(OCC)(=O)C.CCCCCC>CN(C=O)C.[Hg]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:14]#[N:15]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: N#C[Cu]C#N
Agent: [Hg]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Temperature: 100 °C
Yield: 105 %

Procedure:
In a 2-liter flask equipped with a septum inlet, magnetic stirring bar, and condenser leading to a mercury bubbler was placed 100 g (0.348 mol) of 4-amino-3-iodobenzotrifluoride in 1 liter DMF. To this reaction flask with stirring was added 37.4 g (0.416 mol) of copper cyanide and the contents were heated to 100° C. under nitrogen for fourteen hours. Afterwards, TLC analysis revealed minor starting material (20/80) ethyl acetate/hexane. The contents were cooled to 40° C. and filtered through a pad of Celite. The solids were washed with ether and the filtrate transferred to a separatory funnel and washed with about 5% aqueous ammonium hydroxide. The aqueous layer was back-extracted with ether and the organics were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated to yield a black oil. The oil was chromatographed on a Biotage 75L cartridge with ethyl acetate/hexane to obtain 68 g 2-amino-5-(trifluoromethyl)benzonitrile as a black solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(CNCc1ccc(Br)cc1)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
50 g (270.2 mmol) 4-bromobenzaldehyde were dissolved in 200 ml toluene and 28.4 g (270.2 mmol) aminoacetaldehyde dimethylacetal were added. After the addition of 5.1 g (27.0 mmol) p-toluenesulfonic acid monohydrate, the reaction mixture was heated under reflux in a Dean Stark apparatus. After 4 h, the reaction was cooled to room temperature and washed with saturated NaHCO3-solution (2×) and H2O. The combined aqueous layers were extracted with toluene and the combined organic layers were dried with MgSO4 and evaporated. The residue was dissolved in 200 ml ethanol and 5.11 g (135.1 mmol) sodium borohydride were added in small portions. After stirring for 2 h at room temperature and standing overnight, 5.0 ml acetic acid were added and the solvent was removed i. vac. The residue was taken up in dichloromethane and washed (2×) with H2O. After drying with MgSO4 and evaporation, 60.5 g of the title compound were obtained, which were used without further purification. Rt=0.80 min (Method C). Detected mass: 274.1/276.1 (M+H+).