Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=CC1C=CC=CC=1.[N+](=CC(OCC)=O)=[N-].[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)CCC(C(C)C)C(O)C1.C1([C@@H]2C[C@H]2C([O-])=O)C=CC=CC=1>ClCCl>[C:17]1([CH:23]2[CH2:25][CH:24]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccccc1

Procedure:
To a mixture of styrene (2.15g, 20.7 mmol) and Rh2(4S-BNOX)4 (0.0113 g, 0.0131 mmol) in 5.0 mL of anhydrous dichloromethane was added, by syringe at room temperature, ethyl diazoacetate (0298 g, 2.62 mmol) in 3.0 mL of dichloromethane under nitrogen and at an addition rate of 0.8 mL/h (syringe pump). After addition was complete, the dichloromethane solution was passed through a plug of neutral alumina to separate the catalyst, and solvent and excess styrene were removed under reduced pressure Gas chromatographic separation of the trans-isomer produced a material whose specific rotation was −6.4° which corresponded to an enantiomeric excess of the ethyl (1R,2R)-2-phenylcyclopropanecarboxylate. Conversion of the ethyl esters to the 1-menthyl esters by base hydrolysis, acid chloride formation, and esterification with (−)-menthol provided a gas chromatographically separable mixture that showed 25% enantiomeric excess for the (1R,2R)-enantiomer of the trans-2-phenylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CC#N>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12]([O:14][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCC2
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.10 g, 3.74 mmol), NaI (841 mg, 5.61 mmol) and triethylamine (1.56 mL, 11.22 mmol) in CH3CN (15 mL), is added trimethylsilyl chloride (0.707 mL, 5.61 mmol) via syringe. The reaction mixture is stirred at room temperature for 15 h., 30 mL of ethyl acetate/hexanes (1:1 with a few drops of triethylamine) is added to dilute the solution. Saturated sodium bicarbonate solution (20 mL) is added. The layers are separated and the aqueous phase is extracted with ethyl acetate/hexanes (1:1) (3×10 mL). The combined organic layers are dried (Na2SO4) and evaporated to provide 4-trimethylsilanyloxy-6,7-dihydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.3 g, 100%) as a viscous red oil. 1H NMR (400 MHz, CDCl3) δ0.180 (9H, s), 1.576 (9H, s), 2.343 (2H, m), 2.930 (2H, t), 3.781 (3H, s), 4.826 (1H, t), 7.580 (1H, s). MS (ES+) 366 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([OH:43])[CH:25]=[CH:26][C:27]=1[CH:28]([CH3:42])[C:29]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=1)([OH:34])[C:30]([F:33])([F:32])[F:31]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:43][C:24]2[CH:25]=[CH:26][C:27]([CH:28]([CH3:42])[C:29]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[C:22]([Cl:21])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 8 h

Procedure:
Copper(II)acetate (30 mg), (4-methoxycarbonylphenyl)boronic acid (CAS Reg. No. 99768-12-4, 30 mg), and triethylamine (22 mg) were added to a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19 step 5, 20 mg) in DCM (2 ml). The mixture was stirred with molecular sieves under air atmosphere overnight and then concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (15 mg) as a white solid. MS (m/e)=500.1 [M+H+].
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+:5].[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1>O.C(O)C>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([S:1]([O-:3])(=[O:2])=[O:4])[NH:13]2)=[CH:9][CH:8]=1.[Na+:5]
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1cc2ccc(F)cc2[nH]1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a solution of 23.4 g sodium bisulfite in 80 ml water a solution of 13.5 g 6-fluoro indole in ethanol is added drop wise. The obtained suspension is stirred at room temperature over night. The precipitate is filtered and washed with cold water, cold methanol and diethyl ether. 7.0 g (29%) of the title compound are obtained as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Br)ccc2ccsc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)ccc2ccsc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
The product from Step G (1.08 g, 4.7 mmol) was dissolved in acetone (10 mL) and potassium carbonate (1.30 g, 9.4 mmol) and dimethyl sulfate (0.9 mL, 9.4 mmol) were added and the mixture was stirred at 50° C. for 24 hours. The mixture was cooled to room temperature and filtered over sodium sulfate. The reaction mixture was then concentrated to an oil and redissolved in methanol (10 mL), and sodium hydroxide (1.5 g) was added to decompose excess dimethyl sulfate. The mixture was stirred for 1 hour. Methanol was removed and the residue was dissolved in water (5 mL) and extracted (2×30 mL) with diethyl ether. The combined organic extract was dried over sodium sulfate, filtered and concentrated to an oil. The oil was purified on column chromatography (silica gel, 0-100% ethyl acetate/hexanes as an eluent) to give 6-bromo-7-methoxy-benzothiophene (0.96 g, 84%): 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.32 (d, J=5.4 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C@H:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C@@H:6]([CH2:5][NH:4][S:45]([C:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([CH3:26])[CH:36]=4)=[CH:40][CH:41]=3)(=[O:46])=[O:47])[C:7]([O:9][CH3:10])=[O:8])[CH2:16][CH2:15]2)=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H](CN)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(Cc2ccc(F)cc2)CC1
Yield: 44.5 %

Procedure:
In a manner analogous to example 3.6, using 1.5 g (3.7 mmol) of methyl (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate trihydrochloride and 1.6 g (4.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in 17.2), 1.0 g (46%) of methyl (S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate is obtained in the form of a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.CCN(CC)CC.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][N:10]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:24])=[N:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ncc(Br)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Yield: 50.8 %

Procedure:
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added Et3N (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:19])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>ClCCl>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:19][S:1](=[O:2])[O:5][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: NC(CC1=Cc2ccccc2CC1)=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1NC(CC2=Cc3ccccc3CC2)=NO1
Yield: 14.3 %

Procedure:
Thionyl chloride (2.55 ml, 0.035 mol) was added dropwise to a mixture of N'-hydroxy-(3,4-dihydro-2-naphthalenyl)ethanimidamide (6.5 g, 0.032 mol) and pyridine (5.18 ml, 0.064 mol) in dry dichloromethane (100 ml) at 0° C. Upon completion of the addition, the reaction mixture was concentrated under reduced pressure, placed in an ice bath, diluted with deionized water (50 ml), extracted with diethyl ether (3×50 ml), filtered, dried over MgSO4 and concentrated under reduced pressure to give the crude title compound as a red-brown solid. The solid was triturated with diethyl ether (3×50 ml), dissolved in boiling diethyl ether (100 ml), vacuum filtered and recrystallized from diethyl ether (75 ml) to yield 1.14 g (14.4% yield) of pure product, m.p. 118°-120.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[C:8]#[CH:9]>ClCCl.CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1]/[CH:9]=[CH:8]/[C:7]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C#CC(=O)OCC
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/Nc1nccs1
Yield: 51 %

Procedure:
A solution of 2.3 g of 2-aminothiazole and 1.55 ml of ethyl propiolate in 10 ml of dichloromethane and 5 ml of dimethylformamide was stirred at ambient temperature for 3 days. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using first 20% then 40% ethyl acetate in hexane to provide 1.54 g (51%) of the desired compound. 1H NMR (CDCl3) δ1.30 (t, J=7 Hz, 3H), 4.22 (q, J=7 Hz, 2H), 5.79 (d, J=15 Hz, 1H), 6.03 (d, J=5 Hz, 1H), 6.68 (d, J=5 Hz, 1H), 7.47 (br, 1H), 8.17 (d, J=15 Hz, 1H). Mass spectrum: (M+H)+ =199.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][N:23]=[C:22]2[N:26]=[CH:27][CH:28]=[C:29]([CH:30]=O)[C:21]=12>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:29]4[C:21]5[C:22](=[N:23][CH:24]=[CH:25][N:20]=5)[N:26]=[CH:27][CH:28]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: O=Cc1ccnc2nccnc12
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccnc5nccnc45)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and pyrido[2,3-b]pyrazine-8-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.00 (brs, 1H), 9.16-9.10 (m, 3H), 8.00 (s, 1H), 7.78 (m, 1H), 5.00-4.97 (m, 1H), 4.63-4.58 (m, 1H), 4.34-4.18 (m, 1H), 3.30 (m, 1H), 3.27 (m, 1H), 2.92-2.77 (m, 2H), 2.49-2.38 (m, 1H), 2.09-1.97 (m, 1H), 1.48 (dd, J=10.8, 6.6 Hz, 6H), 1.20 (d, J=6.6 Hz, 3H). MS: (M+H m/z 405.2).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1>CO>[CH2:1]([NH:4][C:12](=[O:13])[CH2:11][O:10][C:9]1[CH:16]=[CH:17][C:6]([OH:5])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: COC(=O)COc1ccc(O)cc1
Solvent: CO
Product: CCCNC(=O)COc1ccc(O)cc1
Reaction time: 72 h

Procedure:
A solution of 1-propylamine (4.1 ml) and methyl 4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) was left to stand for 72 hours at ambient temperature. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml), then dried (MgSO4) and the solvent evaporated to give N-(1-propyl)-4-hydroxyphenoxyacetamide as a red oil, NMR: 0.95 (t, 3H, CH3), 1.55 (m, 2H, CH2) 3.3 (q 2H, CH2N), 4.4 (s, 2H, CH2O) 6.5-6.7 (broad s, 1H, OH), 6.8 (s, 4H, phenyl-H); m/e 227 (M+NH4)+, 210 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:6]=[C:7]([B:13]2[O:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=[C:9]([CH2:11][Br:12])[CH:10]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22]>C(#N)C>[Br:12][CH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([B:13]2[O:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=1)[CH2:4][O:22][CH2:21][CH2:20][CH2:19][OH:23]
Reactant: OCCCO
Reactant: BrCc1cc(CBr)cc(B2OCCCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OCCCOCc1cc(CBr)cc(B2OCCCO2)c1
Temperature: 25 °C

Procedure:
An oven-dried, 250-mL round bottom flask equipped with a magnetic stirring bar and reflux condenser was cooled under argon and charged with NaH (0.800 g of 60% in mineral oil, 20 mmols). The powder was washed with pentane (3×100 mL) and dried in vacuum. Acetonitrile (50 mL) was added by syringe and the mixture stirred at room temperature. 1,3-Propane diol (10 mL) was added dropwise over ten min. to form a white insoluble precipitate. The suspension was vigorously stirred for one hour at which time 20 mL was taken up by syringe and added dropwide to a 250-mL round bottom flask charged with 2-(3,5-Bis-bromomethyl-phenyl)-(1,3,2)dioxaborinane (2.865 g, 8.2 mmols) and acetonitrile (50 mL). The mixture was stirred for 12 hr at room temperature. A reflux condenser was attached along with a vacuum adapter and the reaction mixture was heated to reflux under argon for two hours. The acetonitrile was removed in vacuo and the residue purified by flash chromatography (EtOAc:hexane, 2:1). Removal of solvents gave a suspension of white solids in a yellow oil, which when analyzed by thin layer chromatography showed no starting material. The crude mixture containing 1,3-propane diol was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.Cl.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.O>[CH:17]1([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[O:21])[CH2:19][CH2:18]1
Reactant: COC(=O)c1cnc2ccc(N)cc2c1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cnc2ccc(NC(=O)C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of methyl 6-aminoquinoline-3-carboxylate.2 HCl (Int-3, 0.125 g, 0.524 mmol) and cyclopropanecarboxylic acid (45.7 μL, 0.576 mmol) in pyridine (1.98 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.301 g, 1.57 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexanes to 40/60 hexanes/ethyl acetate gradient) to afford Int-4 (0.071 g, 50%). LC-MS: (FA) ES+ 271; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.65 (s, 1H), 9.17 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.98 (dd, J=9.1, 2.3 Hz, 1H), 3.93 (s, 3H), 1.86 (tt, J=7.1, 7.1, 5.3, 5.3 Hz, 1H), 0.90-0.80 (m, 4H).
Reaction SMILES: [CH2:1](C1C=CC(C(O)=O)=CC=1C=O)[CH3:2].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1O)=[O:15].C([Zn]CC)C>>[CH2:1]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:16]=1[CH:14]=[O:15])[C:20]([OH:22])=[O:21])[CH3:2]
Reactant: O=Cc1ccc(C(=O)O)cc1O
Reactant: CCc1ccc(C(=O)O)cc1C=O
Agent: CC[Zn]CC
Product: CCc1cc(C(=O)O)ccc1C=O

Procedure:
The title compound was prepared in analogy to 4-ethyl-3-formyl benzoic acid starting from 4-formyl-3-hydroxy-benzoic acid and using diethyl zinc in step b). LC-MS*: tR=0.38 min, [M−H]−=177.28; 1H NMR (D6-DMSO): δ 1.21 (t, J=7.5 Hz, 3H), 3.10 (q, J=7.3 Hz, 2H), 7.93 (s, 1H), 7.94 (s, 2H), 10.34 (s, 1H), 13.36 (br s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].C([O:41][C:42](=[O:45])[CH2:43]Br)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([O:20][CH2:43][C:42]([OH:45])=[O:41])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(OCC(=O)O)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
200 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol were dissolved in 20 ml dimethylformamide and 300 mg cesium carbonate and 180 mg tert.-butylbromoacetate were added. The reaction mixture was stirred at room temperature for one hour then 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was dissolved in 10 ml dichloromethane and 4 ml trifluoroacetic acid were added. The reaction mixture was stirred at room temperature for three hours then 100 ml toluene were added and the solvents removed under reduced pressure. The residue was purified by RP-HPLC to provide 155 mg {1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-acetic acid as lyophilisate.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.[BH4-].[Na+]>C1COCC1.CO>[N:1]1[N:2]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(-n2nccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(-n2nccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 42.26 g (244 mmol) of 4-[1,2,3]-triazol-2-yl-benzaldehyde in 140 ml of THF and 420 ml of MeOH, 9.23 g (244 mmol) of NaBH4 are added portionwise at 0-5° C. and the mixture is stirred for 30 min. at the same temperature. The reaction is quenched with sat. NH4Cl at 0-5° C. and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid.