Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])=[CH:4][C:3]=1[N+:18]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1ccc(F)c(N)c1
Yield: 60.8 %

Procedure:
A mixture of N-[(4-fluoro-3-nitrophenyl)carbamoyl]glycine, ethyl ester (8 g, 0.029 mol) and 5% platinum on activated carbon (0.5 g) in ethyl acetate is hydrogenated at 50 psi until hydrogen uptake is complete. The reaction mixture is then filtered and cooled in an ice-bath until a solid forms. The solid is collected by filtration and air-dried to give the title product as a white solid (4.5 g, mp 152°-153° C.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]=[O:8])[CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]=[O:8])[CH2:3]1
Reactant: O=CN1CC[C@@H](O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=CN1CCC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The (R)-3-hydroxypyrrolidine-1-carbaldehyde (31 g) was treated with dihydropyran (36.8 ml) and p-toluenesulphonic acid (1 g). The mixture was stirred at room temperature for approximately one hour, during which time the colour changed from yellow to dark purple. GC analysis showed the reaction was complete. The reaction was quenched by addition of saturated sodium bicarbonate solution (90 ml). The aqueous phase was extracted with DCM (3×90 ml). The combined organic phase was washed with saturated sodium chloride solution (90 ml), then dried over MgSO4 and concentrated at below 30° C. The product, 3-(tetrahydropyran-2-yloxy)pyrrolidine-1-carbaldehyde, was obtained in 100% yield, 54.5 g. GC analysis showed two adjacent peaks, RT 14.45 and 14.83 min, 49.7 and 47.1% respectively. δH (CDCl3) 8.22 and 8.27 (1H, 2×s), 4.60-4.75 (1H, m), 4.35-4.50 (1H, m), 3.80-3.95 (1H, m), 3.40-3.70 (5H, m), 1.40-2.20 (8H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:12])[CH2:10][CH3:11]>>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Cl
Reactant: O=c1cc(O)cc[nH]1
Product: CCC(=O)Oc1cc[nH]c(=O)c1
Yield: 23 %

Procedure:
Using 1.00 g of 4-hydroxy-2-pyridone and 0.94 ml of propanoyl chloride and following the general procedure of Example 12, 350 mg of the title compound was obtained in a yield of 23%.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[C:6]([Cl:11])=[C:5]([Cl:12])[C:4]=1[Cl:13])[CH3:2].[Cl:14]Cl>>[Cl:14][CH:1]([C:3]1[C:4]([Cl:13])=[C:5]([Cl:12])[C:6]([Cl:11])=[C:7]([Cl:10])[C:8]=1[Cl:9])[CH3:2]
Reactant: ClCl
Reactant: CCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Product: CC(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In U.S. Pat. No. 2,193,823, a method is taught for low yield α-chlorination of ethylpentachlorobenzene by contacting the same in the liquid phase at elevated temperature with chlorine gas in the presence of the light of an ordinary electric light bulb to produce α-chloroethylpentachlorobenzene. The desired product must be separated from the reaction mixture by treating the mixture chemically to remove residual chlorine, followed by two vacuum distillation steps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([NH:20][OH:21])=[NH:19])[N:9]=2)=[CH:4][CH:3]=1.[S:22]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=O)(=[O:25])(=[O:24])[NH2:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]3[N:19]=[C:29]([C:28]4[CH:27]=[C:26]([S:22]([NH2:23])(=[O:25])=[O:24])[CH:34]=[CH:33][CH:32]=4)[O:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Product: NS(=O)(=O)c1cccc(-c2nc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)no2)c1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16 g, 0.5 mmol) and commercially available 3-sulfamoyl-benzoic acid (0.1 g, 0.5 mmol) according to the general procedure VI. Obtained as a white solid (0.1 g, 43%). MS (ISP) 482.1 [(M+H)+]; mp 273° C.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][O:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:32]4[CH:33]=[N:34][O:35][CH:36]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cnoc3)sc2n1
Temperature: 100 °C
Yield: 6 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (80 mg, 0.185 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (36.1 mg, 0.185 mmol), bis(triphenylphosphine)palladium(II) chloride (13.01 mg, 0.019 mmol), and potassium carbonate (90 mg, 0.649 mmol) and the reaction mixture heated at 100° C. using a microwave reactor for 1.5 h. The reaction mixture was then filtered through celite, washing with DCM (30 mL) and the filtrate evaporated to dryness. The resulting material was then purified by MDAP (acidic conditions), to afford the title compound (4.67 mg). LCMS (A) m/z: 420 [M+1]+, Rt 1.09 min (acidic).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[C:29]([O:33][C:34](=[O:49])[NH:35][C:36]([CH3:48])([CH3:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:35][C:36]([CH3:48])([CH3:47])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:43][CH:44]=1)=[O:49])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Yield: 91.8 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (58 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (222 mg) according to an analogous synthetic method to Example 212, the title compound (92 mg) was obtained.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[Na+].O.S(OCC)(O[CH2:17][CH3:18])(=O)=O>O1CCCC1>[CH2:17]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH3:18]
Reactant: CCOS(=O)(=O)OCC
Reactant: c1ccc2[nH]cnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc2ccccc21
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a flask were added 100 g benzimidazole, 44 g Sodium hydroxide, 320 ml water and 480 ml tetrahydrofuran and the mixture was stirred under nitrogen. 157 g Diethyl sulfate were added slowly, maintaining a temperature of 40 C. After 2 hrs at 40 C, the reaction was quenched with slow addition of 100 ml concentrated hydrochloric acid. After washing with 150 ml hexane, the mixture was basified with 50 g Sodium hydroxide and extracted with 275 ml ethyl acetate, then 225 ml ethyl acetate. The solvent was removed, leaving an orange oil, which was distilled under full vacuum to give 109.4 g clear colorless oil.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH:18]([CH2:24][C:25]([NH2:27])=[O:26])[C:19](OCC)=[O:20]>C(O)C>[C:2]([NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:24]1[CH2:18][C:19](=[O:20])[NH:27][C:25]1=[O:26])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(Br)CC(N)=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C1CC(=O)NC1=O

Procedure:
In 100 ml of ethanol was dissolved 3.4 g of sodium, and following addition of 32 g of diethyl acetylaminomalonate, the mixture was refluxed for 2 hours. To the reaction mixture was added dropwise a solution of 16.5 g of ethyl 2-bromosuccinamate in ethanol (40 ml) and under stirring the mixture was refluxed for 30 minutes. This reaction mixture was concentrated under reduced pressure, followed by addition of ethyl acetate and water, and stirred. The aqueous layer was separated and the ethyl acetate layer was extracted with water. These aqueous extracts were combined, washed with ethyl acetate, adjusted to pH 1.5 with conc. hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added ethyl ether and the mixture was allowed to stand in a refrigerator, whereupon crystals separated out. Yield 7.3 g.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)[CH3:2].Br[CH:14]([CH3:19])[C:15]([O:17]C)=[O:16]>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)Br
Reactant: COc1ccc2c(c1)CCC2=O
Product: COc1ccc2c(c1)CC=C2C(C)C(=O)O

Procedure:
This substrate was prepared using the same procedures as described for Examples 1 and 2a, starting with 5-methoxyl-1-indanone and methyl 2-bromopropionate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4](N)[CH:3]=1.[C:10](O)(C(F)(F)F)=[O:11].N(OC(C)(C)C)=O>CO>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: Nc1cc(Cl)c(I)cn1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: CO
Product: COc1cc(Cl)c(I)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-5-iodo-pyridin-2-ylamine (64.2 g, 0.25 mol) in methanol (1.1 L) and TFA (93.7 mL, 1.26 mol) was added tert-butyl nitrite (150 mL, 1.26 mol) so as to maintain temperature less than 3° C. The resultant mixture was stirred at RT for 1 h then allowed to warm to RT and stirred for 16 h. The reaction was quenched by the careful addition of water then concentrated in vacuo to ¼ volume. The resultant residue was treated with water (1 L) and the precipitate formed collected by filtration and dried in vacuo at 35° C. to give the title compound (62.3 g, 92%). Contains 16% impurity. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1 H, s), 7.20 (1 H, s), 3.86 (3 H, s).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][NH2:18])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[CH3:19][C:20]([CH3:22])=O.C([BH3-])#N.[Na+].N#N>>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][NH:18][CH:20]([CH3:22])[CH3:19])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: NCCNc1ccc2ncc(Br)n2n1
Reactant: CC(C)=O
Agent: N#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)NCCNc1ccc2ncc(Br)n2n1

Procedure:
Glacial acetic acid [64-19-7] (1.6 mL, 28.0 mmol) was added to a stirred suspension of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)ethane-1,2-diamine (7.0 g, 27.2 mmol), acetone [67-64-1] (2.4 mL, 32.6 mmol), sodium cyanoborohydride [25895-80-7] (1.8 g, 27.2 mmol) and powdered, activated 4 Angstrom molecular sieve (4 g). The flask was N2 blanketed, closed with a septum, and the mixture allowed to stir at ambient temperature for 3d, then filtered. The filtrate was evaporated, and the residue partitioned between 10% (w/v) aqueous NaHCO3 and ethyl acetate. The extract was dried (CaSO4), and evaporated to afford a clear orange oil. This oil was triturated in heptane to precipitate N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N2-isopropylethane-1,2-diamine as 2.3 g of yellow powder, mp. 87-88° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.32 Hz, 5H) 1.60 (br. s., 1H) 2.71-2.81 (m, 3H) 3.34 (q, J=6.32 Hz, 2H) 6.73 (d, J=9.85 Hz, 1H) 7.07 (t, J=5.31 Hz, 1H) 7.47 (s, 1H) 7.68 (d, J=9.60 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 22.92, 41.48, 45.29, 47.81, 98.98, 112.99, 125.26, 130.24, 136.53, 154.24. LRMS (ESI) m/z 297.9/299.9 [(M+H)]+, calc'd for C11H16BrN5. 289.19.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:23]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][C:14]1[CH:15]=[CH:16][C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[N:6]=3)[NH:12][C:11]=2[CH:13]=1
Reactant: Cc1ccc2nc(-c3nc(C4=CCN(C(=O)OC(C)(C)C)CC4)cnc3N)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(-c3nc(C4=CCNCC4)cnc3N)[nH]c2c1

Procedure:
Tert-butyl 4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (620 mg, 1.525 mmol) was stirred in DCM (20 mL) with TFA (4 mL) for 2 hours. The solvent was removed in vacuo and the residue taken up in EtOAc and washed with saturated aqueous Na2CO3. DCM was added and the resultant solid was collected by filtration and taken through to the next stage. MS (ES+) 307
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1.[BH4-].[Na+].Cl>CO>[CH3:28][C:2]([CH3:1])([CH3:29])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1
Reactant: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)C2CCC(=O)CC2)[C@@H](C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)[C@H]2CC[C@H](O)CC2)[C@@H](C)C1
Reaction time: 0.5 h

Procedure:
(1S,6S)-4,6-Dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(4-oxo-cyclohexyl)-amide (2.0 g, 4.9 mmol) in MeOH (100 mL) was treated with sodium borohydride (230 mg, 6.0 mmol) at 0° C. After stirring for 30 min, 4M HCl (6 mL) was added and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers washed with saturated NaHCO3(aq), brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (20-60% ethyl acetate/hexanes) gave the desired (1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(trans-4-hydroxy-cyclohexyl)-amide (1.74 g, 4.2 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:33](O)[CH3:34]>>[CH2:33]([O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:10]=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:34]
Reactant: O=C(O)Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Yield: 89 %

Procedure:
A mixture of (1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetic acid (3.70 g), concentrated sulfuric acid (0.5 ml), and ethanol (200 ml) was refluxed for 5 hours. The reaction mixture was alkalinized with saturated aqueous sodium bicarbonate, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl(1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetate (3.62 g, yield: 89%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:6, volume ratio).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]1([C:50]2[NH:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:55]([C:53]2[NH:54][C:50]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:51][CH:52]=2)=[O:56])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Reactant: CC(C)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NC(=O)c2ccc(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-isopropyl-piperidin-4-ylamine (350 mg) in DCM (15 mL) was added DIEA (1.67 mL), followed by HATU (935 mg) and 5-phenyl-1H-pyrrole-2-carboxylic acid (461 mg). The mixture was stirred for 1 h at RT whereupon it was washed two times with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated to give crude 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide which was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:23][C:24]#[C:25]C>>[CH2:20]([O:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21])[C:23]#[C:24][CH3:25]
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: CC#CCBr
Product: CC#CCOc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-butyne by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])C.O.[NH2:20]N>C(O)(=O)C>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[N:5]=[CH:4][NH:2][N:20]=2)[CH:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(-c2nc[nH]n2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 3.75 h
Yield: 51.9 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 0.309 mmol scale) is treated with glacial acetic acid (1 mL) followed by hydrazine hydrate (16.5 μL, 0.340 mmol). The resulting mixture is stirred at 90° C. for 3.75 hr. The reaction mixture is evaporated, then partitioned between water and dichloromethane and the pH adjusted to 6-7 by treating with solid sodium bicarbonate. The aqueous layer is separated and then further extracted with five portions of dichloromethane. The combined extract is dried over magnesium sulfate, filtered and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-3-yl)-pyridine (35 mg, 52% yield, 2 steps) as a white solid. MS: m/e=219 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 11.52 (1H, s), 8.18 (1H, s), 7.78 (1H, s), 3.98 (3H, s), 2.68 (3H, s), 2.57 (2H, q), 1.19 (3H, t).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]2[N:18]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19](=[S:21])[NH:20][C:16]=2[CH:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([N:18]2[C:17]3[CH:28]=[CH:29][C:14]([Cl:13])=[CH:15][C:16]=3[NH:20][C:19]2=[S:21])[CH2:27][CH2:26]1
Reactant: BrCC1COc2ccccc2O1
Reactant: S=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: S=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2COc3ccccc3O2)CC1

Procedure:
2.3 g of 2-bromomethyl-1,4-benzodioxane, 2.35 g of 4-(5-chlorobenzimidazole-2-thion-1-yl)-piperidine, 1.4 ml of triethylamine and 0.3 g of sodium iodide were warmed at 60° C. in 25 ml of anhydrous dimethylformamide for 60 hours, and the mixture was then poured onto ice-water. The precipitate which had separated out was filtered off with suction, washed with water and dried.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:20][C:19]3[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH3:16])[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1Cn1nnc2c(-c3ccco3)nc(N)nc21
Reaction time: 1 h
Yield: 25.3 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (606 mg, 3 mmol) in DMF (5 mL) at 0° C., was treated with CsCO3 (977 mg, 3 mmol), stirred for 1 h, treated with 2-methoxy-5-nitrobenzyl bromide (738 mg, 3 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (10 mL), filtered and the resulting solid purified by chromatography [SiO2; EtOAc:Heptane (2:1)] to give the title compound (279 mg, 25%) as a yellow solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:24])[C:6]1[CH:15]=[C:14]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.Cl>O.CCO>[N:21]1[CH:20]=[CH:19][C:18]([CH:17]=[CH:16][C:14]2[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[C:6]([CH:15]=2)[C:5]([OH:24])=[O:4])=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(C=Cc2ccncc2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(C=Cc2ccncc2)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of LiOH (2.5 mmol) in water (1 ml) was added to 5-(2-pyridin-4-yl-vinyl)-isophthalic acid dimethylester (297 mg, 1 mmol) suspended in 5 ml EtOH. The mixture was stirred at room temperature. The reaction was monitored by TLC until completion. 2.5 ml 1 M HCl solution was then added and the mixture was evaporated to dryness. The product was used in next step without further purification.