Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16](Cl)[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)c(N[C@@H]2CCN(Cc3ccccc3)C2)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(F)c1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate (500 mg) in ethanol (20 mL) were added ammonium formate (584 mg) and 10% Pd/C (300 mg) at 25° C. and the mixture was heated to reflux with stirring for 1 hour. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2(30 ml), ethanol (7 mL), and benzaldehyde (140 mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride (280 mg) was 3 hours, and then poured into a mixture of CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (11 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (302 mg, 66%) was obtained as colorless syrup.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:41])[CH:25]([CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:26][NH:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:41])[CH:25]([CH2:35][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:26][N:27]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH:1]=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1OCC(Cc2ccccc2)N1C(=O)C(CNOC1CCCCO1)CC1CCCC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CN(CC(CC1CCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)OC1CCCCO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of formic acid (45.0 mL, 1193 mmol) and acetic anhydride (90.0 mL, 952 mmol) is stirred at 50° C. for one hour under nitrogen. A second flask is charged with 4-benzyl-3-[2-cyclopentylmethyl-3-(tetrahydro-pyran-2-yloxyamino)-propionyl]-oxazolidin-2-one (21.62 g, 50.2 mmol), Et3N (170.0 mL, 1220 mmol), and anhydrous DCM (450 mL). This second mixture is cooled to 4° C. under nitrogen, and the mixed acid solution is slowly added to the second flask, while maintaining 10° C. The combined mixture is stirred for 30 minutes at 10° C., quenched with saturated, washed with aqueous NaHCO3 solution, and extracted with DCM. The DCM layers are combined, dried over Na2SO4, and concentrated. The crude product is purified by flash chromatography (SiO2, 50% EtOAc in hexane), which gives N-[3-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclopentylmethyl-3-oxo-propyl]-N-(tetrahydro-pyran-2-yloxy)-formamide (20.10 g, 87% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N+:11]([C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:15](=[O:14])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1

Procedure:
To the mixture of 37 g of 2-amino-5-nitrobenzoic acid in 500 mL of dioxane, under stirring 24.5 mL of diphosgene was added dropwise. The mixture was heated under reflux conditions for 6 hours then it was evaporated to dryness. The residue was suspended in 100 mL of diethyl ether and filtered off to give 41.4 g of the title product as HCl salt, m.p.: 256-259° C. LC-MS: MH+ 209; Ret. time: 5 minutes.
Reaction SMILES: [Br-].[Na+].[C:3]([O-:6])(=[O:5])[CH3:4].[Na+].Cl[CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1>CN(C)C=O>[C:3]([O:6][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)(=[O:5])[CH3:4]
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: CC(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1COC(C)(C)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
Sodium bromide (57.93 g, 0.563 mol) and sodium acetate (46.18 g, 0.563 mol) were added to a mixture of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (84.76 g, 0.563 mol) prepared by the same manner as Example 3 and N,N-dimethylformamide (800 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 60.81 g of (R)-4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (yield 62%, b.p. 78° C. at 10 mmHg).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:32]([NH2:34])=[NH:33]>COCCO>[CH2:21]([O:20][C:8]1[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:33][CH:32]=[N:34]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Yield: 89.5 %

Procedure:
A mixture of methyl 2-amino-4,6-dibenzyloxybenzoate (7.7 g), formamidine acetate (7.2 g) and 2-methoxyethanol (100 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (60 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dibenzyloxy-3,4-dihydroquinazolin-4-one (6.8 g); NMR Spectrum: (DMSOd6) 5.24 (s, 4H), 6.75 (s, 1H), 6.8 (s, 1H), 7.3-7.7 (m, 10H), 7.95 (s, 1H), 11.75 (br s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[N:23]=[CH:22][NH:21][N:20]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1nc[nH]n1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3nc[nH]n3)ccc2n1
Yield: 19.1 %

Procedure:
250 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 8 mL of N,N-dimethylformamide, 7.7 mg of palladium acetate, 197 mg of cuprous iodide and 71.3 mg of 1,2,4-triazole are placed in a microwave tube. The reaction mixture is heated for 2.5 hours in a microwave machine set at 200° C. The cooled reaction mixture is filtered, the insoluble matter is rinsed with N,N-dimethylformamide, dichloromethane and methanol and the combined filtrates are concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a 90/10 mixture of dichloromethane and methanol. The fractions containing the pure expected product are combined and evaporated to dryness under reduced pressure to give 40 mg of N-phenyl-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Nc1cc(Br)c2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)c2cc[nH]c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
4-Bromo-6-amino indole (100 mg, 0.47 mmol) and triethylamine (0.1 ml, 0.71 mmol) were stirred together in pyridine at 0° C. Benzene sulphonyl chloride (84 mg, 0.47 mmol) was then added and the mixture stirred for 1 hour, then allowed to warm to room temperature. The mixture was loaded directly onto an aminopropyl cartridge (10 g) and eluted with methanol. Solvent was evaporated to afford the title compound as an orange/brown gum (90 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]O)[CH:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Cl:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1Cl
Solvent: ClCCl
Product: ClCc1cc(Br)ccc1Cl

Procedure:
A solution of 4-bromo-1-chloro-2-hydroxymethyl-benzene (40.0 g) and thionyl chloride (60 mL) in dichloromethane (150 mL) is stirred at 45-50° C. for 5 h. Then the solvent and the excess reagent is removed in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19](=[O:24])/[CH:20]=[CH:21]/CBr.O.[C:26](O)(=O)C>[Zn].II.CCOCC>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])([CH3:26])[CH2:14][CH:21]=[CH:20][C:19]([OH:24])=[O:18])=[CH:11][CH:12]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/CBr
Reactant: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C(C)(O)CC=CC(=O)O)cc1
Temperature: 70 °C

Procedure:
To a suspension obtained by adding a solution of 4-acetylbenzoic acid tert-butyl ester (7.82 g) in benzene-ether-tetrahydrofuran (3:3:2, 80 ml) to 4.64 g (71 mmol) of zinc, were added gradually under heating and stirring 4-bromocrotonic acid methyl ester (6.36 g) and iodine (20 mg). After reflux under heating in an oil bath at 70° C. for 1 hour, methyl 4-bromocrotonate (2.13 g) and zinc (1.55 g) were added, followed by reflux under heating for 30 minutes. The temperature was cooled down to room temperature, and the reaction mixture was poured into water (300 ml) and adjusted to pH 5 with acetic acid. The organic layer obtained by extraction with ether was washed with 5% aqueous ammonia and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography (support; silica gel, 200 g, developing agent; ethyl acetate:hexane=1:4), to obtain the object compound (9.2 g).
Reaction SMILES: Cl[O-:2].[Na+].[C:4]([C:7]1[C:8]([CH3:22])=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13](=[O:18])(=[O:17])[CH2:12][C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])(=[O:6])C>O1CCOCC1.O>[C:4]([C:7]1[C:8]([CH3:22])=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13](=[O:17])(=[O:18])[CH2:12][C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])([OH:6])=[O:2]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)ccc2c1C(=O)C(C)(C)CS2(=O)=O
Temperature: 28 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
11.6 Grams (about 9.8 mmol) of a 6.3 wt % sodium hypochlorite aqueous solution was placed in a 50-ml three-necked round-bottomed flask, and cooled to 15~20° C., and then a solution of 0.83 g (2.96 mmol) of 6-acetyl-3,3,5-trimethylthiochroman-4-one-1,1-dioxide in 5 ml of dioxane was gradually added. The mixture was stirred at 15~20° C. for 30 minutes, and then stirred at room temperature (temperature-increased to 28° C.) for 3 hours, and the reaction mixture was diluted with about 50 ml of water and washed with chloroform twice. A sodium sulfite aqueous solution was added to an aqueous layer to decompose excess hypochlorite, and then the mixture was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution to give a white solid. The solid was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, to give 0.68 g (yield 81%) of 6-carboxy-3,3,5-trimethylthiochroman-4-one-1,1-dioxide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][N:52]([CH3:62])[C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[CH:56]([OH:58])[CH3:57]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([N:52]([CH3:51])[CH3:62])[CH:54]=2)[CH3:57])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CC(O)c1cccc(N(C)C)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(N(C)C)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 58.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (83 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-dimethylamino-α-methylbenzyl alcohol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 55%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C(Cl)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:33]([N:35]1[C:47]2[CH:46]=[CH:45][C:44]([NH2:48])=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH3:34]>>[C:27]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:48][C:44]2[CH:45]=[CH:46][C:47]3[N:35]([CH2:33][CH3:34])[C:36]4[C:41]([C:42]=3[CH:43]=2)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:12])=[O:7])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=514.4.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+].O>CS(C)=O>[CH3:10][O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccnc1OC
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-3-methoxy-pyridine (110 g) in DMSO (1 L) was added sodium methoxide (124 g). The reaction mixture was heated to 80° C. overnight. The reaction mixture was poured into 3 L water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:15].Cl.[CH:17]([CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:52]([N:55]2[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]2)=[CH:51][C:48]=1[CH:49]=O>ClCCl.C(O)(=O)C>[ClH:15].[ClH:15].[CH:17]([CH:30]1[NH:31][CH2:32][CH2:33][N:34]([CH2:49][C:48]2[CH:51]=[C:52]([N:55]3[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]3)[CH:53]=[CH:54][C:47]=2[O:46][CH3:45])[CH2:35]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Sodium triacetoxyborohydride (127 mg) was added portionwise to a mixture of 2-benzhydrylpiperazine dihydrochloride (97.6 mg), N,N-diisopropylethylamine (0.104 ml) and 2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (61.2 mg) in a mixture of dichloromethane (5 ml) and acetic acid (1 drop) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (70:1). The fractions containing the objective compound were collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 3-benzhydryl-1-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]piperazine dihydrochloride (74 mg) as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(NC1C=CC(S(=O)(=O)N)=CC=1)=S)[CH2:9][C:10]([OH:12])=[O:11].C(OC(NCCCCCCCCN(CC1C=CC=CN=1)CC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: NS(=O)(=O)c1ccc(NC(=S)NCCCCCCCCN(CC(=O)O)Cc2ccccn2)cc1
Agent: CC(C)(C)OC(=O)CN(CCCCCCCCNC(=O)OC(C)(C)C)Cc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCCCN(CC(=O)O)Cc1ccccn1

Procedure:
2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid. A solution of tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridin-2-ylmethyl)amino)acetate (0.449 g, 1.0 mmol) in DCM (4 mL) and TFA (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to afford 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid. A solution of the above product 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid, 4-isothiocyanatobenzenesulfonamide (0.278 g, 1.3 mmol) in CH3CN (40 mL) and DIPEA (3.0 mL) was stirred at 50° C. under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by Amberchrom™ eluting with acetonitrile/water to give 2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid (0.500 g) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.11 (s, 1H), 7.94 (td, J=7.6, 1.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.50-7.47 (m, 1H), 7.26 (s, 2H), 4.53 (s, 2H), 4.14 (s, 2H), 3.44-3.40 (m, 2H), 3.14-3.08 (m, 2H), 1.64-1.24 (m, 1 H); ESMS m/z: 508.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[CH:21][C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propan-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give (6-{3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propoxy}-indol-1-yl)-acetic acid ethyl ester as colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20]C.Br[C:23]1[CH:24]=[C:25]([NH2:30])[CH:26]=[N:27][C:28]=1[CH3:29]>[Cu](I)I.O.CC(N(C)C)=O>[CH3:19][C:18]1[N:13]=[CH:14][C:15]([NH2:20])=[CH:16][C:17]=1[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1.[CH3:29][C:28]1[N:27]=[CH:26][C:25]([NH2:30])=[CH:24][C:23]=1[N:1]1[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: c1c[nH]nn1
Reactant: Cc1ncc(N)cc1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ncc(N)cc1-n1ccnn1
Product: Cc1ncc(N)cc1-n1nccn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1,2,3-Triazole (45 mg), cesium carbonate (260 mg), trans-N,N′-dimethylcyclohexan-1,2-diamine (76 mg), and copper iodide (50 mg) were added to a DMAc (2 ml) solution containing 5-bromo-6-methylpyridin-3-amine (100 mg) in a nitrogen atmosphere, followed by stirring in a sealed tube at 110° C. for 8 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate and washing with saturated saline. The organic layers were dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (chloroform:MeOH=1:0 to 20:1). A white solid of 6-methyl-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (12.8 mg) and brown oily matter of 6-methyl-5-(1H-1,2,3-triazol-1-yl)pyridin-3-amine (6.7 mg) were thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].P(OCC)(OCC)OCC.C[O-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29]([CH:30]=O)=[CH:28][NH:27][CH:26]=1>CN(C)C=O.O>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29](/[CH:30]=[CH:2]\[C:3]#[N:4])=[CH:28][NH:27][CH:26]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29](/[CH:30]=[CH:2]/[C:3]#[N:4])=[CH:28][NH:27][CH:26]=1
Reactant: N#CCCl
Reactant: Cc1ccccc1-c1c[nH]cc1C=O
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1c[nH]cc1/C=C/C#N
Product: Cc1ccccc1-c1c[nH]cc1/C=C\C#N
Yield: 36 %
Yield: 15 %

Procedure:
2.5 g (0.0326 mol) of chloroacetonitrile and 5.4 g (0.0326 mol) of triethyl phosphite are heated to 200° C. until the evolution of gas has ended. 30 ml of dimethylformamide and 1.8 g (0.034 mol) of sodium methylate are added to the cooled mixture and 3.0 g (0.0162 mol) of 3-(2-methylphenyl)-pyrrole-4-aldehyde in 5 ml of dimethylformamide are then added dropwise at 0° C. with stirring. After completion of the addition, the reaction mixture is stirred for 16 hours at room temperature and then added to water, the mixture is extracted with ethyl acetate, washed using water, dried over sodium sulphate and concentrated in vacuo, and the residue is purified by chromatography on silica gel (eluant ethyl acetate/cyclohexane 5 : 1). 0.5 g (15% of theory) of (Z)-β-[3-(2-methylphenyl)pyrrol -4-yl]-acrylonitrile of melting point 74° C.-75° C. and 1.2 g (36% of theory) of (E)-β-[3-(2-methylphenyl)pyrrol -4-yl]-acrylonitrile of melting point 152° C.-154° C. are obtained.