Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1CBr
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.51 g, 7.8 mmol), N-bromosuccinimide (1.53 g, 8.6 mmol), and benzoyl peroxide (189 mg, 0.78 mmol) in CCl4 (60 mL) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated in vacuo, and the residue was chromatographed (0-20% EtOAc/hexanes) to give 2.82 g of the title compound. MS: (+) m/z 402.06 (M+1)
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23]>>[NH2:24][C:22]1[S:23][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: CCOC(=O)/C(=N\OC1CCCCCCC1)C(=O)CBr
Reactant: NC(N)=S
Product: CCOC(=O)/C(=N\OC1CCCCCCC1)c1csc(N)n1
Yield: 72 %

Procedure:
Ethyl 4-bromo-(Z)-2-(cyclooctyloxyimino)-3-oxobutyrate (2.8 g) was treated with thiourea as described in Example 4d. Crystallisation from cyclohexane gave the title compound as colourless needles (1.9 g, 72%), m.p. 117°-8° C. [Found, C: 55.66, H: 7.16, N: 12.45. C15H23N3O3S requires C: 55.36, H: 7.12, N: 12.91%]. νmax (KBr) 3428, 2926, 1718, 1610, 1541 cm-1 : δH (CDCl3) 1.35 (3H, t) 1.4-2.0 (14H, m), 4.36 (3H, q+m) 5.65 (2H, br s, exch D2O), 6.66 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:23](=[O:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:23](=[O:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Product: CC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 0 °C

Procedure:
1.3 g (4.4 mmol) of 1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine were stirred at 20°-25° C. with 5 ml of acetic anhydride for one hour, then the yellow solution was poured into 100 g of ice-water and stirred until the decomposition of the excess anhydride became complete. The precipitate formed was filtered, washed with 3×10 ml of distilled water and dried to give 1.6 g of raw product. After recrystallization from 20 ml of benzene 1.50 g (89.85%) of the aimed product were obtained, m.p.: 158°-160° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[OH:24])[N:7]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=2[F:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cncc(C2=C(c3cc(C)ccc3O)CCC2)n1
Product: CCOC(=O)c1cncc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3F)CCC2)n1

Procedure:
Prepared by general procedure F(iii) but using 6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyrazine-2-carboxylic acid ethyl ester instead of 6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic acid ethyl ester and 2,4-difluorobenzyl bromide instead of 4-fluorobenzyl bromide.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Temperature: 20 °C
Yield: 44.4 %

Procedure:
To 7.5 g (165 mmole) of anhydrous dimethylamine in 50 ml of methylene chloride and cooled to -30° C. was added a solution of 20 g (664 mmole) of 2-bromo-4'-difluoromethoxyacetophenone in 50 ml of methylene chloride. After the addition was complete the reaction was allowed to warm to 20° C. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous sodium hydroxide, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo yielded 16.8 g of 2-dimethylamino-4'-difluoromethoxyacetophenone, an oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:14]([CH2:21][C:22](O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][C:22]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)COc1ccccc1
Product: c1ccc(OCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from Benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and Phenoxyacetic acid (153 mg; 1 mmol) as described in method 2 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; yield: 0.049 g (16.8%); MS m/z: 293.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): □5.48 (s, 2H); 7.00-7.03 (m, 1H); 7.11-7.13 (m, 2H); 7.32-7.36 (m, 2H); 7.78 (d, 1H, 3J=8.3 Hz); 7.86 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.20 (br s, 1H); 8.40 (s, 1H); 12.82 (br s, 1H); HPLC (METHOD [A]): rt 11.29 min (100%)
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([F:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:9][C:6]1[CH:5]=[C:4]([Cl:10])[CH:3]=[C:2]([CH:11]2[CH2:13][CH2:12]2)[C:7]=1[NH2:8]
Reactant: Nc1c(F)cc(Cl)cc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c(F)cc(Cl)cc1C1CC1
Temperature: 90 °C

Procedure:
6-Bromo-4-chloro-2-fluoroaniline (2.0 g, 8.91 mmol), cyclopropylboronic acid (1.53 g, 17.8 mmol), K3PO4 (6.61 g, 31.2 mmol) and tricyclohexyl phosphine (0.249 g, 0.89 mmol) are dissolved in toluene (31 mL) and water (10 mL). The solution is degassed with N2, heated to 90° C., and Pd(OAc)2 (0.25 g, 1.16 mmol) is added. The reaction mixture is heated at 100° C. for 18 hours, cooled over 48 hours and loaded directly on a column of silica gel for purification by column chromatography (EtOAc/hexanes) to give 2-fluoro-4-chloro-6-cyclopropylaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.N1CCCC1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:19]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(=O)C2Cc1ccccc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 51 g (0.289 mol) of 6-methoxy-2-tetralone of formula A-1 wherein D is C, R10 is methoxy; R14, R15 and R16 are each H, and 24.2 mL (0.289 mol) of pyrrolidine in 1.5 L of toluene was heated to reflux, over a Dean-Stark trap, overnight. After removal of the azeotroped water, the reaction mixture was cooled to RT, concentrated to an oil, and dissolved in 725 mL of dioxane. To this solution was added 52 mL (0.434 mol) of benzyl bromide and the resulting solution was heated to reflux overnight. Water (100 mL) was added to the solution the resultant mixture was heated to reflux for an additional 2 h. The mixture was cooled to room temperature and poured into a solution of 1 N HCl and extracted 3 times with EtOAc. The organic layers were washed with H2O and saturated NaHCO3, then dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by flash chromatography over SiO2 using 10% EtOAc to 15% EtOAc in hexanes as the gradient eluant to give 65.2 g of the title product of this preparation as a yellow oil (85%). IR (neat) 2937, 1712, 1500 cm−1; 1H NMR (400 MHz, CDCl3) δ2.41-2.59 (m, 3H), 2.76 (dt, 1H, J=5.4, 15.5), 3.15-3.70 (m, 2H), 3.67 (t, 1H, J=6.3), 3.77 (s, 3H), 6.67-6.70 (m, 2H), 6.81 (d, 1H, J=8.1), 6.87-6.89 (m, 2H), 7.13-7.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ27.44, 38.19, 39.19, 54.13, 55.14, 112.11, 112.96, 126.30, 128.07, 128.26, 129.35, 129.53, 138.05, 138.20, 158.30, 212.41; MS m/z 267 (M+H)+.
Reaction SMILES: C(O[CH2:5][CH2:6][C:7](=O)[CH3:8])(=O)C.[CH3:10][O-:11].[Na+]>CO>[CH3:5][C:6]1[C:10](=[O:11])[CH:7]([CH3:8])[CH2:6][CH2:5][C:7]=1[CH3:8]
Reactant: CC(=O)CCOC(C)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C)C(=O)C(C)CC1

Procedure:
130 g of 1-acetoxybutan-3-one and sodium methylate solution in methanol are dripped in the course of one hour from separate supply vessels while stirring into 400 g of boiling diethyl ketone at such a rate that the reaction mixture remains constantly alkaline. A total of 190 g of a 30% by weight sodium methylate solution is used up in this way. The whole is then heated under reflux for another hour and then neutralized with glacial acetic acid. Deposited sodium acetate is filtered off and the filtrate is subjected to fractional distillation. 81 g of 2,3,6-trimethyl-2-cyclohexen-1-one is obtained as well as traces of 4-methyl-3-ethyl-2-cyclohexen-1-one. The yield with reference to 1-acetoxybutan-3-one is 59%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[Br:20])=[O:5])[CH3:2].[Cl-].[Li+].O>CS(C)=O>[Br:20][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(Br)cnc2c([N+](=O)[O-])cccc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(Br)cnc2c([N+](=O)[O-])cccc12
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
A mixture of 4-[bis(ethoxycarbonyl)methyl]-3-bromo-8-nitroquinoline (316 mg), lithium chloride (65.1 mg), water (13.8 mg) in dimethyl sulfoxide was stirred for 20 minutes at 130° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 3-bromo-4-ethoxycarbonylmethyl-8-nitroquinoline (236.8 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=1)[CH2:2][CH3:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(Cl)Cl>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.O>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: C#Cc1ccccc1
Reactant: CCCNC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CCCNC(=O)c1cccc(C#Cc2ccccc2)c1
Temperature: 70 °C

Procedure:
A mixture of N-n-propyl-3-iodobenzamide, phenylacetylene (1.5 eq.) and Pd(PPh3)2Cl2 (5 mol %) in piperidine (3 eq.) was heated at 70° C. for 30 minutes in a sealed tube. The solidified residue was dissolved with CH2Cl2 and water and poured onto HCl 2N. The acidic phase was extracted three times with CH2Cl2. The combined organic layers were washed once with HC 2N, twice with saturated NaHCO3, once with water and once with brine. The organic layer was then dried over MgSO4 and concentrated. The resulting residue was purified using SiO2 with CH2Cl2/petroleum ether 80:20 to CH2Cl2 100% to give N-n-propyl-3-phenylethynyl-benzamide as a yellow solid (Quantitative yield). NMR 1H (ppm, CDCl3): 7.88 (s, 1H), 7.74-7.68 (m, 1H), 7.63-7.60 (m, 1H), 7.53-7.50 (m, 2H), 7.42-7.33 (m, 4H), 6.22 (br. s., 1H), 3.44-3.38 (m, 2H), 1.64 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:33](=[O:35])[CH3:34])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CC(=O)Cl
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(C)=O
Yield: 73 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.40 g (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.17 g (2.2 mmol) of acetyl chloride as a reaction reagent (XII) were added. The resultant mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate, and its organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=1:2) to give 0.33 g (yield 73%) of 4-methoxy-5-methyl-6-(1-ethyl-5-acetoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51) as an end compound which comes under the general formula (XI). Table 18 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:21])[C:7]=1[F:24])C.[Li+].[OH-].Cl>CO>[F:23][C:14]([F:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])[CH2:13][NH:12][C:8]1[C:7]([F:24])=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)Cc1ccnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 0.064 g (0.18 mmol) ethyl(2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-fluoropyridin-4-yl)acetate 30-2 in 1 mL MeOH was added 198 uL (0.198 mmol, 1M aqueous solution) LiOH. The reaction was stirred at room temperature for 19 h. To the mixture was added 36 uL (0.036 mmol, 1M aqueous solution). After an additional 24 h, 54 uL (0.054 mmol, 1M aqueous solution) more LiOH was added. After an another 4 h at room temperature, 23.8 uL (0.288 mmol, 12M aqueous solution) HCl was added. The reaction was stirred for 5 min and then concentrated in vacuo to give (2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-fluoropyridin-4-yl)acetic acid 30-3. 1H NMR (CD3OD, 400 MHz) δ8.426 (d, 1H, J=5.86 Hz, ArH); 7.765 (dd, 1H, J=2.34 Hz, 7.37 Hz, ArH); 7.628-7.565 (m, 3H, ArH); 6.646 (t, 1H, J=5.36 Hz, ArH); 4.636 (t, 2H, J=13.60 Hz, CH2); 3.659 (s, 2H, CH2); MS (Electrospray): m/z 328.0 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[CH3:25][O:24][C:22](=[O:23])[NH:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(N2CCOCC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of Intermediate 5 (0.3 g) in dichloromethane (30 ml) was added triethylamine (0.3 ml) and methyl chloroformate (0.15 ml). After 3 h, the dichloromethane was removed in vacuo, and the resulting slurry dissolved in ethyl acetate (20 ml), washed with aqueous citric acid (10%, 15 ml), saturated aqueous sodium bicarbonate (15 ml) and brine (15 ml). The organic solvent was dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield the title compound as a yellow oil (0.26 g).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4]
Reactant: CN(C)CCN
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCN(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 54 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-(dimethylamino)ethylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 54%. Melting point: 133-134° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30]([NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:31])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1
Reactant: O=C(O)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNC(=O)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 11.1 %

Procedure:
[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetic acid (149.3 mg) was dissolved in N,N-dimethylformamide (1.6 mL), 2-(methylsulfonyl)ethanamine (60.3 mg), 1H-1,2,3-benzotriazol-1-ol (67.8 mg), triethylamine (0.15 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (93.0 mg) were added, and the mixture was stirred at room temperature for 17 hrs. Moreover, 2-(methylsulfonyl)ethanamine (120.6 mg), 1H-1,2,3-benzotriazol-1-ol (134.6 mg), triethylamine (0.3 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (181.4 mg) were added, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→90:10), and basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67→0:100→ethyl acetate:methanol=90:10) to give the title compound (20.3 mg) as a white powder.
Reaction SMILES: [S:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[CH:6][CH:5]=1)C#N.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>C(O)C>[SH:1][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[CH:6][CH:5]=1
Reactant: N#CSc1ccc(O)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Oc1ccc(S)cc1-c1ccccc1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
To a solution of 5-thiocyanato-biphenyl-2-ol (160 mg, 0.97 mmol) in absolute ethanol (8 mL) under nitrogen, sodium sulfide nonahydrate (298 mg, 1.1 6 mmol) was added. The resulting mixture was stirred at 85° C. for 20 min. The mixture was cooled down, made acidic with 10% aqueous HCl and extracted with ethyl acetate (×2). The combined organic layers were dried on MgSO4 and concentrated in vacuo to give the title compound as a yellow solid (105 mg, 95%) which was quickly submitted to the next reaction without further purification.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:22])([F:21])[C:5]1[N:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[CH2:12][CH2:13][C:8]2=[N:7][N:6]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>CO>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH2:12][CH2:13][C:8]4[N:9]([C:5]([C:4]([F:22])([F:21])[F:3])=[N:6][N:7]=4)[N:10]=3)[CH2:15][CH:16]=2)=[CH:24]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1nnc2n1N=C(N1CC=C(c3c[nH]c4ccccc34)CC1)CC2
Temperature: 65 °C
Reaction time: 20 h
Yield: 39.6 %

Procedure:
Potassium hydroxide (156 mg, 2.79 mmol) was added to 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (200 mg, 0.70 mmol) and 1H-indole (90 mg, 0.77 mmol) in MeOH (3 mL). The resulting mixture was stirred at 65° C. for 20 hours. The reaction mixture was evaporated to dryness then quenched with saturated aqueous ammonium chloride (0.5 mL), diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (25 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-(1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (107 mg, 40%) as a solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[C:36]([N:41]=[C:42]=[S:43])(=[O:40])[O:37][CH2:38][CH3:39]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([NH:28][C:42]([NH:41][C:36](=[O:40])[O:37][CH2:38][CH3:39])=[S:43])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(COc2ccc(CNc3ncc(I)cc3N)cc2OC)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1cc(I)cnc1NCc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a stirred solution of 5-iodo-N2-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine (Example 3-16-2) (2.00 g, 4.07 mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) in tetrahydrofuran (20 mL) was added O-ethyl carbonisothiocyanatidate (1.07 g, 8.20 mmol). The reaction mixture was allowed to stir at room temperature. After 3 h, the mixture was filtered, and the filtrate was concentrated to provide 2.30 g of ethyl N-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate as a yellow oil.