Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH3:28][NH:29][CH3:30]>C1COCC1>[CH3:28][N:29]([CH2:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([C:8]3[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=4[F:27])=[CH:11][NH:10][N:9]=3)=[N:13][C:14]=2[CH:20]=1)[CH3:30]
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Yield: 17.3 %

Procedure:
The compound was prepared in a manner analogous to Example 22B, however using 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (57.4 mg, 0.16 mmol), dry THF (5 ml), 3 Å molecular sieves, dimethylamine (35% in EtOH) (55 μL, 0.31 mmol) and triacetoxy sodium borohydride (100 mg, 0.47 mmol) to give N-[3-(5-dimethylaminomethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (11 mg, 18%) as a yellow solid. (LC/MS: Rt 2.85, [M+H]+ 397.17).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[OH:26][C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:29]2[CH2:30][CH2:31][CH:27]([OH:26])[CH2:28]2)=[O:16])=[CH:24][CH:23]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)cnc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 286, 30 mg, 0.08 mmol) in DMF (3 mL) was added (R)-(+)-3-hydroxypyrrolidine (7.2 mg, 0.08 mmol), HOBt (11.2 mg, 0.08 mmol) and DIPEA (30.3 μL, 0.17 mmol). After 5 min, EDCI (20.7 mg, 0.11 mmol) was added and the reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and ethyl acetate (3×20 mL). The combined organic fractions were washed with 2N sodium hydroxide solution (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was triturated from methanol to give the title compound. m/z (ES+)=431 [M+H]+; RT=3.44 min.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)C>C(Cl)Cl>[F:3][C:4]([F:13])([F:14])[CH:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(O)C(F)(F)F

Procedure:
To a suspension of 91.2 g (2.4 mol) of sodium borohydride in 6 l of CH2Cl2 cooled at +2° C., are dropwise added 1473 g of ethyl 4,4,4-trifluoroacetoacetate while keeping temperature between +4° and +7° C. After the introduction, 100 ml of absolute ethanol are added while keeping temperature at +3° C. The reaction medium is washed with bicarbonated water. The organic phase is concentrated and the product is distilled at 78° C. under 10 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:19]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:12]([OH:16])(=[O:19])[CH3:13].[C:12]([OH:16])(=[O:19])[CH3:13].[CH:3]1[C:4]2[C:5](=[O:17])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:16])[C:13]=2[CH:14]=[CH:15][C:2]=1[CH:1]=[O:19]
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methylanthraquinone (16.0 g, 72.0 mmol) in a mixture of acetic acid (400 ml) and acetic anhydride (400 ml) was added concentrated sulfuric acid (16 ml) at 5° C. Chromium trioxide (18.0 g, 0.18 mmol) was added over a period of 1 hour at 5° C. The reaction mixture was then stirred at 5° C. for 4 hours, poured into ice water, and extracted with chloroform. The organic extract was dried over MgSO4 and concentrated under vacuum to give anthraquinone-2-aldehyde diacetate (16.0 g, 65%.) To a solution of the anthraquinone-2-aldehyde diacetate (16.0 g, 47.3 mmol) in acetic acid (400 ml) was added dropwise 35% aqueous hydrochloric acid (170 ml) at room temperature. The reaction mixture had been stirred while refluxing for 15 min. cooled to room temperature, filtered off with suction, and washed with water. After drying, anthraquinone-2-aldehyde (10.0 g, 89%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[CH2:20]([OH:23])[C:21]#[CH:22]>C(N(CC)CC)C.[Cu]I.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>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:22]#[C:21][CH2:20][OH:23]
Reactant: C#CCO
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OCc2ccccc2)ccc1C#CCO
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a solution of 5-Benzyloxy-2-bromo-benzoic acid methyl ester (120 g, 374 mmol) and prop-2-yn-1-ol (41.9 g, 747 mmol) in triethylamine (1 L), copper(I) iodide (0.712 g, 3.74 mmol) and bis(triphenylphosphine)palladium(II) chloride (26.2 g, 37.4 mmol) at RT under N2. The mixture was heated at 50° C. reflux under N2 for 12 hr. The reaction was cooled to room temperature, concentrated to dryness, diluted with H2O (50 mL) and extracted with ethyl acetate (500 mL*3), The organic phase was washed with saturated sodium bicarbonate solution 500 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=10:1˜4:1 to give title product (80 g, 72%) as yellow oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])=[N+]=[N-].[C:21](OC(=O)C)(=[O:23])[CH3:22]>[C].[Pd].C(O)(=O)C>[C:21]([NH:1][CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(N=[N+]=[N-])C2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(SC)c2c1CCC(NC(C)=O)C2=O
Yield: 73.8 %

Procedure:
A mixture of ethyl 5-azido-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (3.62 g), palladium-carbon (5%, 50% wet, 4.0 g), acetic acid (70 ml) and acetic anhydride (35 ml) was subjected to a catalytic reduction reaction at room temperature under 1 atm. The insoluble substances were filtered off; the filtrate was concentrated under reduced pressure; the residue was dissolved in ethyl acetate-tetrahydrofuran (3:1, v/v). This solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.81 g, 73.8%), which was then recrystallized from chloroform-ethanol. Colorless needles. Melting point 215-216° C.
Reaction SMILES: [O:1]=[C:2]([CH3:22])[CH2:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1.[CH3:23][Mg]I.CCOCC>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[N:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1
Reactant: CCOC(=O)c1cc(CC(C)=O)n(COCC[Si](C)(C)C)n1
Reactant: C[Mg]I
Solvent: CCOCC
Product: CCOC(=O)c1cc(CC(C)(C)O)n(COCC[Si](C)(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 2(d) starting from ethyl 5-(2-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (5.24 mmol, 1.7 g) and 3 M solution of MeMgI in ether (6.78 mmol, 2.2 ml). Yield 301 mg. 1H-NMR (400 MHz; CDCl3): δ −0.05 (s, 9H), 0.89 (t, 2H), 1.24 (s, 6H), 1.38 (t, 3H), 2.76 (s, 2H), 3.57 (t, 2H), 4.34 (q, 2H), 5.81 (s, 2H), 6.76 (s, 1H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[I:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>CCOCC.C1COCC1>[OH:22][C:15]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([I:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: COc1ccccc1[Mg]Br
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccc(I)cc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3M 2-methoxyphenylmagnesium bromide (0.92 mL, 2.747 mmol) in Et2O is added drop wise to a suspension of 5-iodoisatin (300 mg, 1.099 mmol) in THF whilst cooling in ice. The mixture is then stirred at room temperature for 1 hour. The reaction mixture is quenched by adding ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases are washed several times with water, dried over MgSO4 and concentrated under reduced pressure. The precipitate is filtered off with suction, washed with very small amounts of ethyl acetate and dried. This afforded the desired product as a light yellow solid.
Reaction SMILES: [S:1]([O:5][C@H:6]1[C@@H:12]([CH2:13][O:14][C:15]([O:17][CH3:18])=[O:16])[O:11][CH:8]([O:9][CH3:10])[C@@H:7]1[OH:19])([CH3:4])(=[O:3])=[O:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>N1C=CC=CC=1>[S:1]([O:5][C@H:6]1[C@@H:12]([CH2:13][O:14][C:15]([O:17][CH3:18])=[O:16])[O:11][CH:8]([O:9][CH3:10])[C@@H:7]1[O:19][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: COC(=O)OC[C@H]1OC(OC)[C@H](O)[C@H]1OS(C)(=O)=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COC(=O)OC[C@H]1OC(OC)[C@H](OC(=O)c2cccc(C(F)(F)F)c2)[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
A flame dried 250 ml flask equipped with an addition funnel, magnetic stirrer and nitrogen inlet was charged with methyl 3-O-mesyl-5-O-(methoxycarbonyl)-D-xylofuranoside (5.84 g, 19.4 mmoles) (C. D. Anderson, L. Goodman and B. R. Baker, J. Am. Chem. Soc. 1958, 80, 5247) and anhydrous pyridine. The solution was cooled in an ice bath and 3-(trifluoromethyl)-benzoyl chloride (5.27 g, 25.3 mmoles) was added dropwise over 10 min. After the addition was complete the ice bath was removed and the reaction was continued 24 hours at ambient temperature. The mixture was poured into ice water (400 mL) and the aqueous solution extracted with ether (2×250 mL). The combined ether extracts were washed with 400 mL. of 1.2NHCl and 400 mL of 10% aqueous NaHCO3. The solvent was removed by rotary evaporation and the residual oil was purified by flash chromatography (3-inch diameter column containing 18 inches of flash silica gel). The column was eluted with 1:1/ethyl acetate:hexanes while collecting 200 mL fractions. Fractions 12-15 contained pure product and these fractions were concentrated in vacuo to afford 8.92 g (97.3%) of methyl 3-O-mesyl-5-O-(methoxycarbonyl)-2-O-(m-trifluoromethylbenzoyl)-D-xylofuranoside as a colourless oil containing an approximately equal mixture of α and β anomers. 1H NMR (CDCl3) δ3.09 and 3.19(s, 3H, OCH3), 3.34 and 3.37(s, 3H, SO2CH3), 3.79(s, 3H, OCO2CH3), 4.4-4.9(m, 3H, C-4H and C-5H), 5.1-5.6(m, 3H, C-1H, C-2H and C-3H) and 7.5-8.5 (m, 4H, ArH); TLC Rf =0.77 and 0.84, silica gel, CHCl3 :CH3OH/90:10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH2:13](O)[CH3:14]>>[CH2:13]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCO
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(N)cc1

Procedure:
In 15% hydrogen chloride-ethanol, p-aminophenylacetic acid was refluxed. After removal of ethanol by distillation, the residue was extracted with ethyl acetate and the extract was washed successively with water, saturated sodium bicarbonate solution and water and dried. The ethyl acetate was then distilled off to give p-aminophenylacetic acid ethyl ester.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[K+].C(OCC)(=O)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2.5 h

Procedure:
4-Piperidone hydrochloride hydrate (50.0 g, 325 mmol) and potassium bicarbonate (181.9 g, 1.82 mol) were combined in a two phase mixture of ethyl acetate (750 mL) and water (75 mL). Benzyl chloroformate (49 mL, 343 mmol) was added dropwise to the stirred mixture over 10 minutes. The mixture was stirred 2.5 hours, then it was diluted with water (700 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated to a light yellow oil (76.75 g, 100%). The material was found to be analytically pure and suitable for further transformation without further workup. Analysis calculated for C13H15NO3 : C, 66.94; H, 6.48; N, 6.00. Found: C, 66.67; H, 6.48; N, 5.90.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13](OCC)=[O:14])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[NH3:23]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([NH2:23])=[O:14])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: N
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(N)=O)C1

Procedure:
Ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (0.1 g, 0.315 mmol) was taken in 4 ml aqueous ammonia and microwaved at 120° C. for 5 minutes. The solid product precipitated out after the reaction was filtered through Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash to obtain 1.25 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.85 (bs, 1H), 7.5-7.6 (m, 2H), 7.4 (s, 1H), 7.2 (d, 1H), 6.85 (s, 1H), 4.6-4.7 (m, 2H), 4.4 (t, 2H), 3.7-3.8 (m, 2H), 3.1-3.2 (m, 4H), 3.0 (s, 3H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([O:12][CH:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:14]=[O:15])[CH2:9][CH2:10][CH3:11]>C(O)CCC>[CH2:17]([O:16][CH:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH:14]([OH:15])[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3])[CH2:18][CH2:19][CH3:20]
Reactant: C=CC(=O)OCC
Reactant: CCCCOC(C=O)OCCCC
Solvent: CCCCO
Product: C=C(C(=O)OCC)C(O)C(OCCCC)OCCCC

Procedure:
400 mmoles ethyl acrylate and 70 g (355 mmoles) of 95.5% by weight dibutoxyethanal in butanol were reacted using the method of example 1 to form 4,4-dibutoxy-2-ethoxycarbonyl-3-hydroxy-1-butene as a liquid which distilled at 120° C. under 0.4 mbar.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[OH:12][C:13]1[CH:14]=[C:15]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[OH:19]>>[CH3:1][O:24][C:23]([C:20]1([C:15]2[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([OH:12])[CH:14]=2)[CH2:22][CH2:21]1)=[O:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Product: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 775.8 %

Procedure:
To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (4.5 g) MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). The stirring was continued at 50° C. overnight before the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (2.1 g). 1H NMR (DMSO 300 MHz) δ 8.81 (brs, 2H), 6.66 (d, J=2.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.53 (dd, J=2.1, 8.1 Hz, 1H), 3.51 (s, 3H), 1.38-1.35 (m, 2H), 1.07-1.03 (m, 2H).
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[NH2:10][CH2:11][C@H:12]([OH:14])[CH3:13]>O1CCOCC1>[CH2:7]([O:6][C:4]([NH:10][CH2:11][C@H:12]([OH:14])[CH3:13])=[O:5])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)NC[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an amount of 246 mg of (R)-1-amino-2-propanol was dissolved in 5 ml of 1,4-dioxane, added with 722 ml of 5 N aqueous sodium hydroxide, then added with 345 μl of ethyl chloroformate, and stirred at room temperature for 30 minutes. The reaction mixture was added with water, and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 465 mg of (R)-1-ethoxycarbonylamino-2-propanol. Physicochemical Properties of this Compound
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4].[OH-].[Na+]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:12]=1[Br:1])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Bromine (3.6 ml, 0.07 mol) was added to a solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-2c, 3.6 g, 0.01 mol) in glacial acetic acid (50 ml) at room temperature. The reaction mixture was stirred for 17 hours, poured over ice-water, and treated with 25% aq. NaOH until the orange solution turned a yellow color. The aqueous solution was extracted with CH2Cl2 (3×) and the combined extracts were dried and concentrated in vacuo to give the desired compound I-2d as an oil (4.7 g): +APCI MS (M+1) 441.1; 1H NMR (CD3Cl) δ 1.41 (3H, t), 4.43 (2H, q), 7.08–7.12 (2H, m), 7.20–7.40 (7H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:18][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Yield: 99.7 %

Procedure:
A solution of 3′-methyl-[1.1′-biphenyl]-4-carboxylic acid ethyl ester of Step A (3.3 g, 13.7 mmol) in tetrahydrofuran (40 mL) and 1 N sodium hydroxide (27.5 mL, 27.5 mmol) was heated at reflux overnight. After cooling, the reaction was concentrated in vacuo. The residue was acidified with 2N hydrochloric acid to yield a white solid which was collected by filtration and dried under vacuum to provide the title compound (2.9 g, 99.7%) as a white solid, m.p. 198-200° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][NH:17][CH3:18])[CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:18])[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCc1csc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1csc(Br)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
1.6 ml (13 mmol) of benzoyl chloride are added dropwise to a solution of 2.3 g (11 mmol) of (5-bromothiophen-3-ylmethyl)methylamine and 3 ml (22 mmol) of triethylamine in 30 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 1 hour, filtered, diluted with ethyl acetate and washed with water. The organic phase obtained is dried over sodium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 3.1 g (80%) of N-(5-bromothiophen-3-ylmethyl)-N-methylbenzamide are obtained.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH:45]([CH3:48])[CH:46]=O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH:45]([CH3:48])[CH:46]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:42][CH:43]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C=CCc1ccccc1)Cc1ccc(C(C)(C)C)cc1
Yield: 68.8 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.00 g, 6.71 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.2 mL, 6.71 mmol, 1.0 equiv.) and 3-(4-tert-butylphenyl)-2-methylpropanal (2.05 g, 10.1 mmol, 1.5 equiv.), 1.35 g (69%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:43])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:30][CH2:29][C:28]=2[CH:42]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:43][C:25]2[C:24]([O:23][CH3:22])=[CH:42][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCN1CCOCC1)CC2
Yield: 28 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product isolated as a white foam (30 mg, 28%). MS (ESI+): 616 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.50 (s, 1H), 7.26 (m, 1H), 6.66 (s, 1H), 3.89 (s, 3H), 3.74 (s, 4H), 2.88 (s, 2H), 2.76-7.70 (m, 14H), 2.69-2.52 (m, 6H).