Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH:12](OCC)=[O:13].C(N(CC)CC)C.O>C(OCC)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CCOC=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=CNCCc1ccc(Br)cc1
Yield: 93.1 %

Procedure:
500 g (1.78 mol) of 2-(4-Bromo-phenyl)ethylamine hydrobromide, 1 liter (12.4 mol) of ethyl formate and 248 mL (1.78 mol) of triethylamine were combined and heated to reflux for 3 hrs. The reaction was treated with 1 liter each of deionized water and ethyl acetate. The organic layer was separated and washed with 1 liter each of water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield 378 g of a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:9]([O:8][CH3:7])=[O:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1CCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
Methanesulfonyl chloride (2.3 mL, 30 mmol) was slowly added to a stirring solution of D/L-proline methyl ester hydrochloride (5.0 g, 30.2 mmol) and triethylamine (8.4 mL, 60 mmol) in anhydrous methylene chloride (75 mL). The reaction was stirred overnight at ambient temperature and then diluted with ethyl acetate. The organic layer was successively washed with water, 1N aqueous hydrochloric acid twice, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), and filtered. The solution was concentrated under reduced pressure to give the desired product as a tan liquid (4.45 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 4.53-4.49 (dd, 1H, J=8.7, 3.6 Hz), 3.75 (s, 3H), 3.57-3.54 (m, 1H), 3.52-3.42 (m, 1H), 3.01 (s, 3H), 2.32-2.22 (m, 1H), 2.11-1.98 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([Mg]Br)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Br)CC1C=CC=CC=1.[Mg].CC[O:36]CC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[O:36])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: Br[Mg]CCc1ccccc1
Agent: BrCCc1ccccc1
Agent: [Mg]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (35 g) in toluene (100 ml) was added dropwise at reflux temperature under nitrogen to a stirred solution of phenethylmagnesium bromide [prepared in the usual manner from phenethyl bromide (45.6 g) and magnesium (6.24 g)] in ether (100 ml). When the addition was completed, ether was distilled from the mixture until the internal temperature rose to 110° C., then stirring at this temperature was continued for 18 hours. The mixture was then cooled to ambient temperature, added to a mixture of ice (200 g) and concentrated hydrochloric acid (100 ml), heated at 95° C. with occasional stirring for 4 hours, and cooled to ambient temperature. The product was extracted into dichloromethane (3×200 ml), and the combined extracts were washed with water (100 ml), saturated aqueous sodium carbonate solution (2×100 ml) and water (100 ml), dried (Na2SO4), and the solvent was removed in vacuo. The residue was distilled to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one as a yellow oil (38.8 g), b.p. 178-181° C./1.3 mbar.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([OH:13])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.CCOC(C)=O.O>CN(C=O)C>[OH:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH2:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1cc(O)c2ccc(O)cc2n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)c2ccc(OCc3ccc(C#N)cc3)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of 2.05 g (10.4 mmol) of 2-methyl-quinoline-4,7-diol, 1.72 g (12.5 mmol) of potassium carbonate and 2.1 g (12.5 mmol) of 4-(bromomethyl)-benzonitrile in 100 ml of DMF were stirred at RT under an nitrogen atmosphere for 4 h until completion of the reaction according to HPLC analysis. The reaction mixture was cooled to RT and poured into EtOAc/water (300 ml/400 ml). The product that precipitated was filtered off by suction, washed with water, AcOEt and ether and dried in a high vacuum to give 2.23 g (73%) of 4-(4-hydroxy-2-methyl-quinolin-7-yloxymethyl)-benzonitrile as a white solid. ISP mass spectrum, m/e: 291.4 (M+1 calculated for C18H14N2O2: 291).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br>CN(C=O)C.O>[O:15]1[CH2:14][CH:13]1[CH2:11][O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCC1=CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=CCCC(COCC2CO2)=C1
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
(Compound No. 229) 1,3-Cyclohexadiene-1-methanol (2 g, 0.0182 mol) synthesized in Example 21 was dissolved in DMF (10 ml) and 60% sodium hydride (775 mg, 0.0194 mol) was added at 0° C. The mixture was stirred for 10 minutes and a solution of epibromohydrin (3 g, 0.022 mol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour and the reaction mixture was poured in water, extracted with ethyl acetate and the combined ethyl acetate layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (silica gel 60 g, ethyl acetate:hexane=1:10) to obtain 1-(2,3-epoxypropoxymethyl)-cyclohexa-1,3-diene (2.31 g, 76%). This compound has the following NMR spectrum.
Reaction SMILES: [OH:1][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:3].C1COCC1.C(N(CC)CC)C.Cl[C:29]1([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[CH3:34][C:29]1([O:3][C:2]([C:4]([F:14])([F:15])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:1])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1(Cl)CCCC1
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC1(C)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A 2 L reactor was charged under nitrogen with 7.0 g (purity 78%, 25 mmol) of methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester and 300 mL of THF (dehydrated), followed by cooling down to 0° C., adding 6.5 mL (47 mmol/1.9 equivalents) of triethylamine, and stirring at 0° C. for 10 minutes. Then, furthermore 4.7 g (40.0 mmol/1.6 equivalents) of 1-chloro-1-methylcyclopentane was added, followed by stirring at 0° C. for 20 minutes. To the reaction liquid 500 mL of water was added, followed by extraction two times with diisopropyl ether, removing water by magnesium sulfate, conducting a filtration, and distilling diisopropyl ether out, thereby obtaining 6.6 g of the target methacrylic acid 1-(1-methylcyclopentyloxycarbonyl)-1,1-difluoro-2-butyl ester. Upon this, purity was 96%, and yield was 83%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[CH:10][C:3]=12.[C:30](=[O:32])=[O:31].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:11]([N:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:30]([OH:32])=[O:31])[C:3]=2[CH:10]=[N:9]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of Isopropylmagnesium chloride-lithium chloride complex (21.99 mL of 14% w/v, 21.20 mmol) in THF (2.5 mL) was cooled to below −20° C. This was treated with 4-iodo-1-trityl-pyrazolo[5,4-b]pyridine (9.84 g, 20.19 mmol) under nitrogen and allowed to stir for 30 minutes. The reaction was then treated with 3 pellets of CO2 and allowed to warm up. After a further hour the mixture was diluted with EtOAc and acidified with saturated aqueous ammonium chloride. The layers were separated, dried (MgSO4), filtered and concentrated in vacuo. The mixture was purified by column chromatography (1:1 Petroleum ether/EtOAc moving to 10% MeOH/EtOAc) to give the product as an off-white oil (7.0 g, 86% Yield). 1H NMR (DMSO, 400 MHz) δ 7.17-7.26 (15H, m), 7.47-7.49 (1H, m), 8.18 (1H, d), 8.56-8.58 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17]>>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of p-toluidine with 2-methyl-benzenesulfonyl chloride
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].C([CH:17]([C:21]([OH:23])=O)[C:18]([OH:20])=[O:19])C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:35]2C=CC=C[C:34]=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:21]([CH2:17][C:18]([O:20][CH2:34][CH3:35])=[O:19])=[O:23]
Reactant: CCC(C(=O)O)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NCCCc1ccc2c(n1)NCCC2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC(=O)NCCCc1ccc2c(n1)NCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1-8 (0.068 g, 0.36 mmol), ethylmalonic acid (0.052 g, 0.40 mmol), BOP (0.24 g, 0.54 mmol), and NMM (0.16 mL, 1.4 mmol) in DMF (1.8 mL) was stirred at ambient temperature for 20 h. The mixture was diluted with ethyl acetate, washed with water, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed on silica gel, eluting with 15% ethanol/EtOAc to give 1-9 as a colorless glass.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16]C[O:18][C:12]=2[CH:11]=1)[CH3:2].C(=O)([O-])[O-:22].[K+].[K+]>S(=O)(=O)(O)O>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:18])[CH:11]=1)[CH3:2]
Reactant: CCN(CC)CC#CCCCc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCN(CC)CCC(=O)CCCc1ccc(O)c(O)c1

Procedure:
Add mercuric sulphate (0.27 g) to a swirled solution of 1-diethylamino-6-(3,4-methylenedioxyphenyl)hex-2-yne (3 g) in 10% aqueous sulphuric acid (15 cc) and heat the mixture for 90 minutes at 75° in an atmosphere of nitrogen. Filter the cooled reaction mixture and add solid potassium carbonate to pH 8.5. Extract the product with ether; wash and dry and evaporate the solvent to leave as residue crude 1-diethylamino-6-(3,4-dihydroxyphenyl)hexan-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(OCC)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-aminoindan (100 g), acetic anhydride (84 g), pyridine (65 g) and ethyl acetate (500 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether (800 ml). The solid was filtered off, washed with diethyl ether (500 ml) and with hexane (500 ml) and dried. There was thus obtained 5-acetamidoindan (104.5 g), m.p. 107° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[CH2:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)[CH3:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:37]1[CH2:38][CH2:39][C:33]2([O:32][CH2:31][CH2:30][N:29]([C:27]([C:25]3[N:26]=[C:22]([CH2:20][CH3:21])[S:23][CH:24]=3)=[O:28])[CH2:34]2)[CH2:35][CH2:36]1
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cccc(CCO)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-chloro-3-(2-hydroxyethyl)benzaldehyde [Aromatic Intermediate 11] (1.5 g) and (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 26, step b] (4.25 g) in tetrahydrofuran (50 mL) was added triethylamine (2.5 mL) in one portion. The mixture was stirred for 0.5 h, sodium triacetoxyborohydride (2.58 g) was then added in one portion and the resultant solution was stirred for 2 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was shaken vigorously for 10 min and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic solutions were washed with brine, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate:triethylamine as solvent. The fractions containing the product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.40 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](=[N:10][OH:11])[NH2:9])[CH:7]=1.[OH:14][CH2:15][C:16]1[CH:21]=[C:20]([C:22](O)=O)[CH:19]=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8]2[N:9]=[C:22]([C:20]3[CH:19]=[CH:18][C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:16]([CH2:15][OH:14])[CH:21]=3)[O:11][N:10]=2)[CH:7]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CO)c2)n1
Temperature: 150 °C

Procedure:
Intermediate 23 (276 mg; 1.5 mmol; 1 eq.), Intermediate 41 (436 mg; 1.8 mmol; 1.2 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (345 mg; 1.8 mmol; 1.2 eq.) were dissolved in THF (6 mL) and acetonitrile (6 mL) and the reaction mixture was stirred at room temperature for 2 hours. DIEA (0.61 mL; 3.6 mmol; 2.4 eq.) was added and the mixture was heated in the microwave at 150° C. for 30 min. The reaction mixture was then filtered through a SPE-NH2 column (2 g) and through a SPE-SCX column (2 g) and rinsed with ACN. The filtrate was evaporated and the residue washed with ACN to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[S:23][C:24]([CH3:27])=[CH:25][NH+:26]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:19][C@@H:20]([C:22]2[S:23][C:24]([CH3:27])=[CH:25][N:26]=2)[CH3:21])=[O:10])=[CH:5][CH:6]=1
Reactant: Cc1c[nH+]c([C@@H](C)[NH3+])s1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)s1
Reaction time: 24 h
Yield: 866.9 %

Procedure:
To a solution of 0.05 g (0.24 mmol) 1,1′-biphenyl-4-ylacetic acid in 0.50 ml DMF was added 0.05 g (0.24 mmol) 2-[(1R)-1-ammonioethyl]-5-methyl-1,3-thiazol-3-ium dichloride, 0.04 g (0.31 mmol) HOAT, 0.60 g (0.31 mmol) EDC, and 0.12 mL (0.71 mmol) DIEA. After 24 h at room temperature, the reaction mixture was purified by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to afford 0.70 g (86%) 2-(biphenyl-4-yl)-N-[(1R)-1-(5-methyl-1,3-thiazol-2-yl)ethyl]acetamide. 1H NMR (CDCl3, 400 MHz) 7.59 (m, 4H), 7.44 (m, 2H), 7.35 (m, 4H), 6.55 (br d, 1H, J=7.32 Hz), 5.43 (m, 1H), 3.65 (s, 2H), 2.43 (s, 3H), 1.55 (d, 3H, J=6.96 Hz). HRMS (ES) [M+1]+ calcd for C20H21N2OS: 337.1375. Found: 337.1368.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:26]2[N:35]=[CH:34][C:33]3[C:28](=[C:29]([F:40])[CH:30]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=3)[C:27]2=[O:41])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[C:15](=[O:24])[N:14]([CH3:25])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:36]([C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[C:27](=[O:41])[N:26]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[CH:22][NH:21][N:20]=4)[C:15](=[O:24])[N:14]([CH3:25])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:35]=[CH:34]2)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc[nH]n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc[nH]n2)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A mixture of 152c (100 mg, 0.18 mmol) and lithium hydroxide hydrate (84 mg, 2.0 mmol) in THF (8 mL), i-propanol (8 mL) and water (2 mL) was stirred at 40° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 152 (6.5 mg, 7%) as a pale yellow solid. MS-ESI: [M+H]+ 515.8. 1H NMR (500 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 8.32 (s, 1H), 8.04 (m, 1H), 7.55-7.53 (m, 4H), 7.50-7.49 (m, 1H), 7.44 (s, 1H), 6.01 (s, 1H), 4.49-4.48 (m, 2H), 3.71 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10]([OH:15])=[N:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10](=[O:15])[N:9]([C@@H:27]2[CH2:26][CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28]2)[CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10]([O:29][C@@H:25]2[CH2:26][CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)=[N:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: Oc1nccc2cc(C3CC3)cc(F)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2nccc3cc(C4CC4)cc(F)c23)C1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2ccc3cc(C4CC4)cc(F)c3c2=O)C1
Temperature: 25 °C

Procedure:
A mixture of 6-cyclopropyl-8-fluoroisoquinolin-1-ol (500 mg, 2.46 mmol), (S)-1-BOC-3-hydroxypiperidine (1.49 g, 7.39 mmol), Ph3P (2.58 g, 9.84 mmol) in THF (20 mL) was stirred at RT into a clear solution. DIAD (1.94 mL, 9.84 mmol) was added dropwise. The mixture was stirred at RT for 48 h. The mixture was diluted with EtOAc, washed with water ×3, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0% to 5% EtOAc in DCM to afford (R)-tert-butyl 3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)piperidine-1-carboxylate (57) as minor product and (R)-tert-butyl 3-(6-cyclopropyl-8-fluoroisoquinolin-1-yloxy)piperidine-1-carboxylate as major product (58).
Reaction SMILES: O[C@H](CC1C=CC=CC=1)C(O)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[CH2:23][C@@H:24]([NH2:26])[CH2:25][C:17]=3[C:16]=2[CH:15]=1.C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>C1(C)C=CC=CC=1>[CH:40]([O:39][C:37](=[O:38])[NH:26][C@@H:24]1[CH2:23][C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][C:16]=3[C:17]=2[CH2:25]1)([CH3:42])[CH3:41]
Reactant: N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Reactant: CC(C)OC(=O)Cl
Agent: O=C(O)[C@H](O)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
(S)-7-Bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-ylamine(R)-2-hydroxy-3-phenylpropionic acid salt (60.00 g, 143.78 mmol) and diisopropylethylamine (50 mL, 296.12 mmol) are combined in toluene (165 mL). The reaction vessel is purged with nitrogen three times. The mixture is cooled to 0° C. with stirring and is held at that temperature for 30 min. A solution of isopropyl chloroformate (20.00 g, 163.20 mmol) in toluene (165 mL) is added at 0-5° C. over 10 min. The mixture is stirred at 5° C. for 10 min. HPLC shows 98.6% complete. The reaction is quenched with water (1 L) and ethyl acetate (480 mL). The mixture is filtered and the solid is washed with ethyl acetate (2×240 mL). The combined organic layer is washed with brine twice, dried (MgSO4), and filtered. The organic solvent is reduced to 50 mL. The mixture is cooled to 25° C. and tert-butyl methyl ether (50 mL) and ethyl acetate (50 mL) are added. An off-white solid is precipitated. The solid is filtered and washed with heptanes (100 mL). The solid is dried under vacuum at 50° C. for 4 h to give 44.4 g (90.3%) of a light brown solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([NH:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN2CCc3ccccc3C2C1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine hydrochloride (1.38 g), suspended in a solution of triethylamine (2 ml) in dichloromethane (10 ml) stirred at room temperature was added methane sulphonyl chloride (0.570 g) in dichloromethane (5 ml). After stirring for 18 hours, the solution was washed with water and the organic phase separated, dried and evaporated to yield the title compound (1.06 g) as an oil, which was converted in ethanolic hydrogen chloride to the hydrochloride (0.395 g) m.p. 244.8° C. C14H20N2O2S.HCl requires C, 53.06; H, 6.68; N, 8.84%. Found: C, 53.07; H, 6.77; N, 8.64%.