Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Mg]Br.C[O:12][B:13](OC)[O:14]C.Cl>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:13]([OH:14])[OH:12]
Reactant: Cc1cccc(C)c1[Mg]Br
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 1.0 M solution of 2,6-dimethylphenylmagnesium bromide in THF (20 ml; 20 mmol) was added over 5 minutes to a solution of trimethylborate (4.5 ml; 40 mmol) in 50 ml of THF at −78° C. The reaction mixture was allowed to warm to room temperature and stir 18 hr. Mter cooling to 0° C., 50 ml of 2 N HCl was added and the resulting mixture was stirred 30 minutes at 0° C. The mixture was partitioned between water (100 ml) and CH2Cl2 (100 ml). The aqueous layer was extracted with CH2Cl2 (2×100 ml) and the combined organic layers were dried (MgSO4) and concentrated to afford a quantitative recovery of the crude title compound of this step. This material was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.C([Li])CCC.CN(C)CCN(C)C.[Br:29][C:30]1[CH:45]=[CH:44][C:33]([CH2:34][N:35]2[C:39]([CH2:40][CH2:41][CH2:42]Cl)=[CH:38][N:37]=[CH:36]2)=[CH:32][CH:31]=1>O1CCCC1>[Br:29][C:30]1[CH:45]=[CH:44][C:33]([CH:34]2[N:35]3[CH:36]=[N:37][CH:38]=[C:39]3[CH2:40][CH2:41][CH2:42]2)=[CH:32][CH:31]=1
Reactant: ClCCCc1cncn1Cc1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Brc1ccc(C2CCCc3cncn32)cc1
Reaction time: 3.5 h

Procedure:
A solution of lithium diisopropylamine, prepared at 0° from 0.12 ml of diisopropylamine and 0.33 ml of n-butyllithium (2.5M) in 2 ml of tetrahydrofuran under nitrogen, is added to a solution of 0.13 ml of N,N,N',N'-tetramethyl-ethylenediamine and 0.124 g of 1-(p-bromobenzyl)-5-(3-chloropropyl)-1H-imidazole in 2 ml of tetrahydrofuran at -78°. The reaction mixture is stirred for 3.5 h, quenched at -78° with saturated ammonium chloride solution and extracted with methylene chloride (3×10 ml). The organic extracts and dried over sodium sulfate and evaporated to yield the title compound which is purified by conversion to the hydrochloride salt, m.p. 216°.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH3:38])[CH:32]=3)=[C:25]([F:39])[CH:24]=2)=[C:13]([NH:15][CH2:16][C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH3:38])[CH:32]=3)=[C:25]([F:39])[CH:24]=1)[C:17](=[O:18])[CH2:16][NH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1cc(SCc2ccccc2)ccc1Nc1cc(F)c(-c2ccc(Cl)c(C)c2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1N1C(=O)CNc2cc(SCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a microwave vial was added, ethyl 2-((5-(benzylthio)-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)phenyl)amino)acetate (2.00 g, 3.54 mmol) followed by DCM (11.80 ml) and TFA (2.73 ml, 35.4 mmol). The vial was placed in the microwave for 30 min at 80° C. Solvent was removed in vaccuo and sodium bicarbate solution was added. The solution was extracted with DCM and organics dried over MgSO4, filtered and removed solvent in vaccuo. Used 6-(benzylthio)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (1.43 g, 2.76 mmol, 78% yield) without further purification. m/z (ESI) 520.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.I[C:28]1[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][C:35]2[CH:36]3[CH2:41][CH:38]([CH2:39][CH:40]=2)[C:37]3([CH3:43])[CH3:42])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[C:17][C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][C:35]3[CH:36]4[CH2:41][CH:38]([CH2:39][CH:40]=3)[C:37]4([CH3:43])[CH3:42])=[CH:44][CH:45]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C2CC=C(CCOc3ccc(I)cc3)C1C2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCCC3=CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Yield: 66 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 66% yield, as pale paste. 1H-NMR (CDCl3) 0.80 (s, 3H); 1.25 (s, 3H); 1.41 (s, 3H); 1.46 (s, 9H); 2.06 (d, 2H, J=5.47 Hz); 2.21 (d, 2H, J=8.44 Hz); 2.33-2.44 (m, 4H); 3.93 (tr, 2H, J=7.0 Hz); 3.98 (d, 2H, J=11.4 Hz); 4.08 (d, 2H, J=11.5 Hz); 5.18 (s, 1H); 5.32 (s, 1H); 6.76 (d, 2H, J=8.8 Hz); 7.29 (d, 2H, J=8.7 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=1)[C:7](O)=[O:8])([O-])=O.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[NH2:1][C:4]1[CH:12]=[C:11]([CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(CO)c1
Yield: 93.6 %

Procedure:
85 g of 3-nitro-5-methoxycarbonylbenzoic acid was dissolved in 200 ml of THF under a flow of nitrogen, and 43.4 ml of borane dimethylsulfide complex was added with stirring under ice-cooling. After stirring for 18 hours, 200 ml of water was added, and then 96 g of potassium carbonate was added. It was extracted with ethyl acetate, and theorganic layer was washed with salt solution. After drying with magnesium sulfate, the resulting solid was dissolved in 800 ml of ethyl acetate, 750 mg of 10% Pd/C was added, and stirring was continued under the flow of hydrogen. After the reaction was completed, it was subjected to the filtration, and then the filtrate was concentrated to produce 64 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C(=C\c1ccccn1)\CC1OCCCO1
Agent: [Pd]
Product: c1ccc(CCCC2OCCCO2)nc1
Yield: 92.5 %

Procedure:
Through a suspension of 800 mg (4.2 mmol) of olefin 149 and 100 mg of 10% palladium on carbon was bubbled a steady stream of hydrogen gas for a period of 10 min. The reaction mixture was then filtered through celite and concentrated to give 805 mg of the acetal 150 as a colorless oil. 1H NMR consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:13][C:12]3=[N:14][N:15]=[C:16]([C@H:17]([NH:19]C(=O)OCC4C=CC=CC=4)[CH3:18])[N:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br>C(O)(=O)C.O>[NH2:19][C@@H:17]([C:16]1[N:11]2[C:12]([S:13][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10]2)=[N:14][N:15]=1)[CH3:18]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](N)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Temperature: 90 °C
Yield: 70.1 %

Procedure:
(Step 8-iii) To a slurry of (R)-benzyl 1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)ethylcarbamate (0.39 g, 0.92 mmol) in acetic acid (20 mL) was added 48% hydrobromic acid in water (10 mL). The mixture was heated to 90° C. for 2 hours. After cooling to room temperature, the resulting solution was concentrated to ⅓ the original volume, poured on ice and the pH adjusted to 8 with 2N sodium hydroxide. The resulting precipitate was filtered, washed with water, and dried overnight in vacuo to provide (R)-3-(1-aminoethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-amine (0.19 g): ESMS MH+=294.
Reaction SMILES: COC([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)=O.O.[Cl-].[NH4+:25]>C(Cl)Cl.[Fe]>[C:17]1([S:14]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([NH2:25])=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Fe]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Yield: 82.2 %

Procedure:
To the suspension of 2 (1.16 g, 3.84 mmol) in WA (38 mL) and water (9 mL), iron (0.64 g, 11.51 mmol) and ammonium chloride (0.41 g, 7.67 mmol) were added and refluxed overnight. After the reaction was filtrated with celite, the solvent was concentrated under reduced pressure to give a brown residue, which was dissolved in CH2Cl2 and quenched with water, followed by extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a brown residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:2:1% NH3(aq)) to afford 27 (0.86 g). 1H NMR (500 MHz, CD3OD): δ 3.60 (s, 2H), 6.48 (d, J=3.6 Hz, 1H), 6.69 (dd, J=8.7, 2.1 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 7.39-7.42 (m, 2H), 7.44 (d, J=3.5 Hz, 1H), 7.49-7.51 (m, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 2H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C@@:11]12[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][CH2:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10].CN(C=O)C.C([O-])(O)=O.[Na+]>CC#N.O.CCOC(C)=O>[Br:8][C:24]1[C:23]2[N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:21]=[CH:20][C:19]=2[CH:18]=[C:17]2[C@:11]3([CH2:9][CH3:10])[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]3[CH2:13][CH2:14][CH2:15][C:16]=12
Reactant: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
NBS (0.052 g, 0.29 mmol) was added in one portion to a solution of (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.100 g, 0.224 mmol) and DMF (2.20 mL) under a nitrogen atmosphere. The solution was warmed to about 60° C. for about 2 h. A solution of NBS (0.0040 g, 0.022 mmol) and DMF (0.10 mL) was added. After about 1 h, a solution of NBS (0.0040 g, 0.022 mmol) and DMF (0.10 mL) was added. After about 30 min, the light yellow solution was allowed to cool to rt. Sat. aq. NaHCO3 (5 mL), water (5 mL), and EtOAc (10 mL) were added. The layers were separated and the organics were washed with water (10 mL) and sat. aq. NaCl (10 mL). The aqueous layers were extracted with EtOAc (10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (12 g) using a gradient of 0-7% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford a sticky ivory solid. The residue was dissolved in MeCN, treated with water, and concentrated under reduced pressure to remove MeCN. The mixture was frozen then lyophilized to afford (3R,4aR,12bR)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (58, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0809 g, 69% yield) as a fluffy white solid. LC/MS, method 2, Rt=3.00 min, MS m/z 525 and 527 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.91 (s, 1H), 7.55-7.48 (m, 2H), 7.37-7.29 (m, 2H), 5.87 (s, 1H), 3.73-3.63 (m, 1H), 3.04-2.90 (m, 1H), 2.42-2.27 (m, 1H), 2.22-1.52 (m, 11H), 1.29-1.10 (m, 1H), 0.46 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(OC[N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:28])=[CH:18][N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[CH:12]=[N:11]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:28][C:17]1[C:14]2[C:15](=[O:16])[NH:10][N:11]=[CH:12][C:13]=2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=1
Reactant: [H][H]
Reactant: Cc1cn(COCC[Si](C)(C)C)c2cnn(COCc3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To 380 ml of ethanol solution containing 25.3 g (65 mmol) of 5-benzyloxymethyl-3-methyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(c) was added 25 g of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 2.5 hours. After completion of the reaction, insoluble material was removed from the reaction suspension by filtration, 100 ml of 28% aqueous ammonia was added to the obtained filtrate, and the mixture was stirred at room temperature for 5 hours. Then, the solution was concentrated under reduced pressure, 500 ml of water was added to the obtained concentrate, and precipitated solid was collected by filtration. The obtained solid was washed with water, and dried under reduced pressure to obtain 14.3 g of the title compound as a pale yellowish solid. (Yield: 79%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH:14]([C:17]1[CH:23]=[CH:22][C:20](N)=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C1C2C(CCCC2)CCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:20]2[CH:22]=[CH:23][C:17]([CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[CH:3]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCC2CCCCC2C1
Product: CC(C)c1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Yield: 60.5 %

Procedure:
A mixture of 15 g of 4-chloro-1,2-dinitrobenzene, 10 g of 4-isopropylaniline and 25 ml of Decaline® is refluxed for 15 hours. The reaction mixture is concentrated under 0.01 mm Hg, the residue is taken up with water, extracted with ether, washed with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using iso ether as the eluent to give 13 g of the expected product, which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[I:11]I.[OH-].[K+]>CN(C)C=O>[I:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Cc1ccc2cn[nH]c2n1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(I)n[nH]c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 6-methyl-1H-pyrazolo[3,4-b]pyridine (4.44 g) and iodine (16.9 g) in N,N-dimethylformamide (100 mL) was added potassium hydroxide (7.48 g) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, and the precipitate was filtered. The filtrate was extracted with ethyl acetate, washed with saturated saline, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was combined with the above-mentioned precipitate and purified by silica gel column chromatography (eluent: chloroform→chloroform/methanol=19/1) to give 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine [REx(104-2)] (6.48 g) as a brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([N:32]([O:33][CH3:34])[CH3:31])=[O:7])=[CH:3][C:2]=1[OH:1]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a 5 L four necked round bottom flask was added 3-hydroxy-4-fluorobenzoic acid (100 g, 0.64 mol) and CH2Cl2 (2.3 L). Triethylamine (107 mL, 0.768 mol) was then added to the suspension. The solution was cooled to ±78° C., and EDCI (184.2 g, 0.961 mol) was added portion wise followed by the addition of N,O-dimethylhydroxyamine hydrochloride (93.6 g, 0.96 mol). The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to 0° C. over a period of 2 h. The reaction mixture was transferred to a separatory funnel and washed water (2×1.2 L). The organic portion was dried over Na2SO4, filtered and concentrated in vacuo to give 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide as a white solid (94.4 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH:28]([C:30](O)=[O:31])[O:27][C:26]2=[O:33])=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH:28]([C:30]([NH:8][C@H:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])=[O:31])[O:27][C:26]2=[O:33])=[CH:23][CH:24]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: N#Cc1ccc(N2CC(C(=O)O)OC2=O)cc1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C#N)cc2)C(=O)O1

Procedure:
In analogy to Example 4, reaction of phenylalanine tert-butyl ester and 3-(4-cyanophenyl)-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 1] gives tert-butyl (2R)-2-[3-(4-cyanophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate, m.p. 72°.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C1CCCCC1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCCCC1
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in cyclohexane (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in cyclohexane was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1>CO>[Br:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:14])[OH:15])=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(CCCBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(CCCBr)cc1

Procedure:
Also disclosed herein is a method of making 4-vinylbenzenepropanethiol. The method includes providing 1-bromo-3-phenylpropane, adding acetic anhydride and aluminum chloride, incubating the mixture at from about −20 to about 20 degrees Celsius for from about 1 hour to about 12 hours, isolating the resulting p-(3-bromopropyl)acetophenone, adding sodium borohydride to the p-(3-bromopropyl)acetophenone solution in methanol, incubating the mixture at about 0 degrees Celsius for about 2 hours, isolating the resulting p-(3-bromopropyl)-α-methylbenzenemethanol, adding toluensulfonic acid to the solution of p-(3-bromopropyl)-α-methylbenzenemethanol in toluene, refluxing the mixture under inert atmosphere for about 4 hours, isolating the resulting p-(3-Bromopropyl)styrene, adding thiourea to the p-(3-Bromopropyl)styrene, gently refluxing the mixture for about 16 hours, adding sodium hydroxide, and gently refluxing the mixture for about 4 hours.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[OH:23][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3cccc(OC)c3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of 7-hydroxy-2-(3-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (129 mg, 0.39 mmole) and glycine (588 mg, 7.83 mmole) in 0.5 M sodium methoxide/methanol (14.8 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (50 ml) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (122 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.48 (br s, 1H), 8.89 (s, 1H), 7.69 (m, 2H), 7.51 (m, 1H), 7.22 (m, 1H). 4.02 (d, J=6.2 Hz, 2H), 3.86 (s, 3H); MS: (+) m/z 359.90 (M+1); (−) m/z 357.92 (M−1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[C:17]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)([O:19][CH2:20][CH3:21])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:17]([C:22]1[CH:27]=[CH:26][C:25]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:24][CH:23]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C1=Cc2ccccc2C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 5.52 g (20 mmole) of para-carbethoxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 mnl of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 3.1 g (59%) of 2-(4-carbethoxy-phenyl)-indene.