Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[C:16]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:17]=2[S:18][C:19]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)O>>[CH3:14][C:15]1[C:16]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:17]=2[S:18][C:19]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[C:3](=[O:7])[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]=1[OH:6]
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: Cc1ccc2sc(C(O)c3ccccc3)c(C)c2c1
Product: Cc1ccc2sc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)c(C)c2c1

Procedure:
23.2 Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (3,5-dimethyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 423.5 ([M−H]−).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])=[O:4].[O:27]1CC[CH2:29][CH2:28]1>CO>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]([OH:20])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:28](=[O:27])[CH3:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]=2[CH:12]=1)#[N:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C(N)c2ccccc2)[C@@H]1O
Reactant: C1CCOC1
Solvent: CO
Product: CC(=O)NC(C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O)c1ccccc1

Procedure:
To a solution containing (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)benzeneacetamide (340 mg, 0.97 mmol; isomer A of the title compound of Example 2) in tetrahydrofuran (10 mL, a few drops of methanol were added to obtain a clear solution) at room temperature was slowly added excess acetyl chloride while maintaining the reaction at pH ~8.5 by simultaneous addition of 7% sodium carbonate solution. After the completion of the reaction, it was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to provide a colorless solid (320 mg, 84.2%) which was recrystallized from hot 2-propanol to give (3S-trans)-N-[2-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl )amino]-2-oxo-1-phenylethyl]acetamide, mp 234°-236° C. Analysis calculated for C22H23N3O4.0.2H2O: C, 66.55; H, 5.94; N, 10.58. Found: C, 66.71; H, 5.58; N, 10.56. [α]D =-91.2° (c =0.5, MeOH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>C1(C)C=CC=CC=1.CN(C)C=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 83518.1 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 500 ml were charged 55.3 g (0.40 mol) of potassium carbonate, 200 ml of N,N-dimethylformamide, 54.0 g (0.40 mol) of dimethyl malonate with a purity of 98% and 32.5 g (0.20 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 70° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, 160 ml of toluene was added to the mixture, and 50 ml (0.60 mol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, this organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it was found that 45.3 g (reaction yield: 84%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])([CH3:20])[C:18]#[N:19])[C:11]=1[CH3:30]>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])([CH3:20])[C:18]#[N:19])[C:11]=1[CH3:30])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(C(C)(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(C(C)(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 145.8 %

Procedure:
To a solution of 3-pentanol (140 mg, 1.59 mmol) in 2 ml of dry THF was added sodium hydride (60% in oil, 38 mg) and the mixture was stirred at room temperature for 5 minutes. 2-(6-Chloro-2,5-dimethylpyrimidin-4-yl)-2-(2,4,6-trimethylphenyl)-propionitrile (100 mg, 0.319 mmol) was added to the reaction mixture, and the resulting mixture was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a brown oil (170 mg). The residue was purified through chromatotron using 20% ethyl acetate in hexane as eluent to give a mixture of two isomers as a yellow glass form and both having a M+ of 365 from GC/Ms. 1H NMR (CDCl3) δ 6.8 and 6.76 (s, 2H), 4.08 and 3.96 (m, 1H), 3.25 and 3.22 (s, 3H), 2.36 and 2.30 (s, 3H), 2.21, 2.20 and 2.06 (s, total of 9H), 1.5–1.7 (m, 4H), 1.04 (s, 3H), 0.96 and 0.90 (t, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9](O)[CH2:8][CH2:7][CH2:6]2>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[CH:8][CH2:7][CH2:6]2)=[CH:11][CH:12]=1
Reactant: COc1ccc2c(c1)CCCC2O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC=C2
Temperature: 115 °C
Yield: 95.5 %

Procedure:
Crude 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (10.3 g, 0.058 mol) was dissolved in 100 ml of toluene and heated in an oil bath (115° C.). P-tolylsulphonic acid (20 mg) was added to the reaction mixture and it was refluxed for about 1 h. The reaction was monitored by GC. The reaction mixture was then cooled and washed with sat. NaHCO3 solution, water and brine and organic layer was dried over Na2SO4. Concentration gave 8.87 g of light brown oil. Yield 96%.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)N.C(O)(=O)C>O>[F:7][C:8]([F:17])([F:16])[C:9]1[CH:15]=[C:14]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:13]=[CH:11][CH:10]=1
Reactant: C/C(N)=C\C#N
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Aminocrotonitrile (1.0 g, 12.2 mmol), 3-trifluoromethylaniline (2.0 g, 12.4 mmol), and acetic acid (1.23 g, 20.5 mmol) are dissolved in water (8 ml). The reaction mixture is stirred at room temperature for 30 minutes. The mixture is extracted with toluene three times and the organic phase is dried over sodium sulfate. The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([C:20]([OH:22])=[O:21])[C:6]=2[CH:23]=1.S(Cl)(Cl)=O.[CH2:28](O)[CH3:29]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[C:7]([C:20]([O:22][CH2:28][CH3:29])=[O:21])[C:6]=2[CH:23]=1
Reactant: COc1ccc(CCc2oc3ccc(Br)cc3c2C(=O)O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(CCc2ccc(OC)cc2)oc2ccc(Br)cc12

Procedure:
1H-NMR (DMSO-d6) δ: 3.00 (2H, m), 3.35 (2H, m), 3.69 (3H, s), 6.80 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz), 7.50 (1H, dd), 7.55 (1H, d), 8.00 (1H, d) d) 64.2 g of 5-bromo-2-[2-(4-methoxyphenyl)-ethyl]-3-benzofurancarboxylic acid obtained in the above step c) was suspended in 900 ml of ethanol. 30 ml of thionyl chloride was added dropwise to the above suspension with ice cooling. After refluxing under heating for 5 hours, 50 ml of thionyl chloride was further added dropwise to the resulting reaction mixture, followed by additional refluxing under heating for 3 hours. The reaction solution thus obtained was concentrated to dryness, and the resulting residue was mixed with water to collect insoluble materials by filtration. The thus collected insoluble materials were dissolved in ethyl acetate and washed with a saturated sodium bicarbonate aqueous solution, water, a saturated sodium chloride aqueous solution in that order, followed by drying to distill off the solvent. Thereafter, the resulting residue was suspended in ethanol and then collected by filtration to obtain 59.23 g of ethyl 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzofurancarboxylate.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]=1[CH2:23][CH3:24].[NH2:26][NH2:27]>>[CH2:23]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:5]=1[CH2:4][C:3]([NH:26][NH2:27])=[O:2])=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH3:24]
Reactant: NN
Reactant: CCc1c(CC(=O)OC)c2cc(OC)ccc2n1Cc1ccccc1
Product: CCc1c(CC(=O)NN)c2cc(OC)ccc2n1Cc1ccccc1
Yield: 74 %

Procedure:
Using the method described in Example 3, Part C, 748 mg 2.2 mmol) of 2-ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester was reacted with 2.2 mL of hydrazine to give 552 mg (74% yield) of 2-ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide, that crystallized out of the reaction mixture on cooling (melting point, 138-140° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:48](=[O:50])[CH3:49])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (0.0551 g, 0.097 mmol) and pyridine (0.05 mL, 0.618 mmol) in DMF (2 mL) was treated dropwise with acetic anhydride (Aldrich) (10.0 μl, 0.107 mmol) at 0° C. The orange solution was stirred at rt overnight. The mixture was concentrated in vacuo to reduce the solvent volume to about 1 mL. Water (2 mL) and brine (20 mL) were added and the aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)acetamide (0.060 g, 100% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H); 8.75 (d, J=2.19 Hz, 1H); 8.47 (s, 1H); 8.24 (d, J=2.34 Hz, 1H); 8.06-8.16 (m, 1H); 7.86-7.95 (m, 1H); 7.83 (br. s., 1H); 7.19 (t, J=8.48 Hz, 4H); 6.87 (d, J=6.58 Hz, 4H); 4.84 (d, J=10.96 Hz, 4H); 3.80 (d, J=4.09 Hz, 6H); 2.59 (s, 3H); 2.20 (s, 3H). m/z (ESI, +ve ion) 611.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[CH:23]>>[NH2:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([C:22]#[C:23][C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:9]=2[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]3)=[CH:25][CH:26]=1)(=[O:31])=[O:32]
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3ccc(S(N)(=O)=O)cc3)c2OC1C(F)(F)F

Procedure:
Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in U.S. Pat. No. 6,271,253 B1 Example 73, Step 2 was reacted with 4-ethynylbenzene sulfonamide prepared as in Step 2 via a method similar to that described in Example 21f, Step 1 to give the product: ESHRMS m/z 503.0686 (M+NH4, C21H15ClF3O5SNH4, Calc'd 503.0655).
Reaction SMILES: C[N:2]1[C:6]([C:7]2[N:8]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:9]3[C:14]([CH:15]=2)=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:12]=[CH:11][CH:10]=3)=CC(O)=N1.[N-:38]=[N+:39]=[N-:40].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[C:7]([C:6]1[NH:2][N:40]=[N:39][N:38]=1)[N:8]2[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1-c1cccc2c1cc(-c1cc(O)nn1C)n2CCCOc1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cccc2c1cc(-c1nnn[nH]1)n2CCCOc1cccc2ccccc12

Procedure:
To a mixture of EXAMPLE 168B (416 mg) in N,N-dimethylformamide (10 ml) was added NaN3 (281 mg) and NH4Cl (231 mg). The mixture was stirred at reflux overnight. After this time the mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (200 ml) and water (60 ml). The organic phase was washed with brine and dried over Na2SO4. After concentration of solvent, the residue was dissolved in dimethylsulfoxide/methanol(1:1, 2 ml) and purified via RPHPLC. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (m, 1H), 7.88 (m, 1H), 7.54 (m, 3H), 7.47 (d, 1H), 7.40 (d, 1H), 7.30 (m, 5H), 7.14 (t, 1H), 6.88 (d, 2H), 6.23 (s, 1H), 5.70 (s, 1H), 4.91 (m, 2H), 4.21 (m, 2H), 3.51 (m, 3H), 2.36 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3cccc(C(=O)OCc4ccccc4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (3.00 g) in N,N-dimethylformamide (16.8 mL) were added potassium carbonate (1.39 g) and benzyl bromide (0.996 mL) successively, and this mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (3.06 g). 1H-NMR (CDCl3) δ ppm: 3.85 (3H, s), 4.54 (2H, s), 5.48 (2H, s), 6.72 (1H, dd, J=2.2, 8.5 Hz), 6.91 (1H, d, J=2.2 Hz), 7.16-7.23 (1H, m), 7.27-7.44 (7H, m), 7.47-7.57 (4H, m), 7.60 (1H, t, J=7.8 Hz), 7.90-7.97 (1H, m), 8.10 (1H, br s).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1>C(OCC)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:13]([F:19])=[CH:14][C:15]([CH3:18])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(F)c1
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S(=O)(=O)Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 2.91 g (25 mmol) of chlorosulfonic acid and then 1.3 g (5 mmol) of 4-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-3-fluorotoluene. The mixture was stirred at 80° C. for 3 hours and cooled to room temperature. The mixture was added onto ice in small portions, and 30 ml of ethyl acetate was added to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to vacuum distillation to distill off ethyl acetate, to obtain a title compound as 1.66 g of a crystal. Yield: 93%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. The di-n-propylamine (3.04 g, 0.03 mole) was added and the reaction mixture was heated at reflux for (65° C.) for 8-9 hrs. The reaction mixture was filtered and the filtrate was evaporated to an oil, which was placed under high vacuum for 3 hrs. The solid residue was treated with water, collected by filtration, washed with water, and dried under high vacuum. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum to give 3.2 g (52%), mp 125°-27° C.
Reaction SMILES: C(NC(=O)C(N[C:13]([C:15]1[N:16]([CH3:44])[C:17]2[C:22]([C:23]=1[Cl:24])=[CH:21][C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])=[CH:19][CH:18]=2)=[O:14])C1C=CC=CC=1)C.CC(C[AlH]CC(C)C)C>C1COCC1.OS([O-])(=O)=O.[Na+].CCOC(C)=O>[Cl:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:25][C:26]([C:28]3[C:29]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][CH:35]=4)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])[CH:21]=2)[N:16]([CH3:44])[C:15]=1[CH:13]=[O:14]
Reactant: CCNC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C=O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: -78 °C
Reaction time: 6 h
Yield: 51.2 %

Procedure:
To a solution of the product from step (a) (1.56 g, 3.02 mmol) in THF (25 ml) at −78° C. was added DIBAL in THF (1.0 M, 12 ml), and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was diluted with NaHSO4 (0.25 M, 86 ml) and EtOAc (115 ml), and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to about 30 ml in volume. The product was purified by flash chromatography using 1:1 EtOAc/hexane to afford 0.706 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[Br:12][CH:13](C)[C:14](C1C=CC(Br)=CC=1C)=O>>[Br:12][CH:13]([CH3:14])[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:11])=[O:8]
Reactant: Cc1cc(Br)ccc1C(=O)C(C)Br
Reactant: O=C(O)c1ccc(Br)cc1Cl
Product: CC(Br)C(=O)c1ccc(Br)cc1Cl

Procedure:
This compound is prepared from 4-bromo-2-chloro-benzoic acid analgously to 2-bromo-1-(4-bromo-2-methyl-phenyl)-propan-1-one (Intermediate MA). 1H NMR (400 MHz, CDCl3) δ 1.90 (2H, d), 5.21 (1H, q), 7.40 (1H, d), 7.50 (1H, d), 7.62 (1H, s).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH:35]([CH3:36])[CH3:37])=[C:28]([F:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(OC(C)C)c(F)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-4-(1-methyl-ethoxy)phenylboronic acid, 5-[3-fluoro-4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=82%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:7]2.C1(C)C(S(O[CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:12]([CH2:13][CH2:14][CH3:15])[CH2:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH2:7]2
Reactant: CCCNC1CCc2c(O)cccc2C1
Reactant: Cc1ccccc1S(=O)(=O)OCCc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCc1cccs1)C1CCc2c(O)cccc2C1

Procedure:
13.1 kg (63.9 mol) (−)-5-hydroxy-N-n-propyl-2-aminotetralin, 51.6 kg (182 mol) 2-(2-thienyl)ethanol toluenesulfonate, and 4.1 kg (38.6 mol) sodium carbonate (0.6 molar ratio Na2CO3/amine starting material) were mixed in a reactor under a nitrogen atmosphere using xylenes (150 kg) as a solvent with vigorous agitation and heated to a temperature of 120° C. to 125° C. for a period of 32 hours. HPLC analysis of the reaction mixture showed less than 2% of the starting material remaining, and the reaction was halted. The product, (−)-5-hydroxy-2-[N-n-propyl-N-2-(2-thienyl)ethylamino]tetralin, was isolated in the usual manner well known to those skilled in the art without chromatographic purification to yield product that was converted to its hydrochloride salt form, with a yield of 13.2 kg (59%).