Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)[C:10]([F:13])([F:12])[F:11].[F:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[C:41]([O:43][CH3:44])=[O:42].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:44][O:43][C:41]([C:40]1[CH:39]=[CH:38][C:37]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:23]=[CH:22][CH:21]=[C:16]4[C:15]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[C:10]([F:12])([F:13])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:36][C:35]=1[F:34])=[O:42]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cccc4cnccc34)C(F)(F)F)c(Cl)c2)cc1F
Temperature: 80 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
To a suspension of trifluoromethanesulfonic acid 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenyl ester (86 mg), 3-fluoro-4-methoxycarbonylphenyl-boronic acid (50 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloromethane adduct (7 mg) in dioxane (0.5 ml) under argon were added water (0.4 ml) and a 2 M aqueous sodium carbonate solution (0.25 ml). The mixture was stirred at 80° C. for 5 h. The mixture was filtered and to the filtrate was added water. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>2:3) to give the title compound (12 mg) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20]>>[C:1]([C:3]1[S:7][C:6]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:14][CH2:15][CH2:16][CH2:17]3)[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N=C2NC3(CCCC3)CS2)s1
Reactant: CC(C)CBr
Product: CC(C)CN1C(=Nc2ccc(C#N)s2)SCC12CCCC2

Procedure:
2-Cyano-5-nitrothiophene was reduced to 2-amino-5-cyanothiophene according to Method A1a. The aminothiophene was converted to 5-cyano-1-thiophene isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 5-cyano-1-thiophene isothiocyanate according to Method C1e to give 2-(5-cyanothienylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2-(5-cyanothienylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][N:19]1[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:23]3[N:19]([CH3:18])[N:20]=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: Cn1nc(C(F)(F)F)cc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OC[C@@H]2F)c1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (CAS 128694-63-3) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=418.3 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:21][CH:22]1[C:23]([O:61]C(OCC)C)([CH3:60])[CH2:24][CH2:25][CH:26]([OH:59])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:58])=[CH:37]/[CH:38]=[CH:39]/[CH:40]([CH3:57])[CH2:41][CH:42]2[O:56][CH:43]2[CH:44]([CH3:55])[CH:45]([O:48][C:49](=[O:54])[CH2:50][O:51][CH2:52][CH3:53])[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[CH3:19]>CO.C(OCC)(=O)C>[C:18]([O:21][CH:22]1[C:23]([OH:61])([CH3:60])[CH2:24][CH2:25][CH:26]([OH:59])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:58])=[CH:37]/[CH:38]=[CH:39]/[CH:40]([CH3:57])[CH2:41][CH:42]2[O:56][CH:43]2[CH:44]([CH3:55])[CH:45]([O:48][C:49](=[O:54])[CH2:50][O:51][CH2:52][CH3:53])[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[CH3:19]
Reactant: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Reaction time: 1 h

Procedure:
Pyridinium p-toluenesulfonate (29 mg, 0.12 mmol) was added to a solution of (8E,12E,14E)-7-acetoxy-21-ethoxyacetoxy-6-(1-ethoxyethoxy)-3-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (8.0 mg, 0.012 mmol) in methanol (1.0 mL) at room temperature, followed by stirring at the same temperature for one hour. After the reaction mixture was diluted with ethyl acetate, it was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by thin layer chromatography (MERCK Silicagel 60 F254, 0.25 mm, developing solution; hexane:ethyl acetate=1:2) to obtain the title compound (4.0 mg, 56%) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].[C:20](OCC)(=[O:22])[CH3:21]>C1COCC1.CCCCCC>[C:20]([CH:16]1[CH2:17][CH2:18][N:14]([CH3:13])[C:15]1=[O:19])(=[O:22])[CH3:21]
Reactant: CN1CCCC1=O
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
20.40 g (0.20 mol) of diisopropylamine were placed in 200 ml dry THF under nitrogen and 80 ml n-butyl lithium in hexane (2.5 M) were added dropwise. It was allowed to stir for 20 minutes and then 20.00 g (0.20 mol) of 1-methyl-2-pyrrolidinone were added dropwise at −78° C. After stirring the reaction mixture for 1 hour 17.64 g (0.20 mol) of dry ethyl acetate were added at −78° C. The reaction mixture was warmed to room temperature and stirred for 14 hours. The THF was removed on a rotary evaporator under reduced pressure and the residue was taken up in 80 ml of 6 N HCl. The acidic aqueous phase was saturated with NaCl and extracted 5 times with 300 ml ethyl acetate. The combined organic layers were dried over Na2SO4, and the solvent was removed on a rotary evaporator. The remaining yellow oil was purified by column chromatography. This gave 5.10 g product as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:25])[CH2:12][C:13]([C:15]1[C:16]([C:21]([F:24])([F:23])[F:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=O.Cl>CC(O)=O>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:13]([C:15]1[C:16]([C:21]([F:22])([F:24])[F:23])=[N:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]2=[O:25])([O-:10])=[O:9]
Reactant: O=C(CC(=O)c1cccc([N+](=O)[O-])c1O)c1cccnc1C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2cccnc2C(F)(F)F)oc2c([N+](=O)[O-])cccc12
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)pyridin-3-yl)propane-1,3-dione 26 (135 mg, 0.38 mmol), conc. HCl (0.2 ml) and AcOH (5 ml) was stirred at 100° C. for 3.5 h. The reaction mixture was concentrated and sat. aq Na2CO3 was added. The resulting solid was collected by filtration to give 27 as a yellow solid, which was used for the next step without other treatment.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[C:4]([F:21])[C:3]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[C:29]1([C:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][C:48]=3[O:55][CH:56]([CH3:58])[CH3:57])[N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:29]1([C:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53][N:8]([S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]4[CH:5]=[C:4]([F:21])[C:3]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:2]([F:1])[CH:7]=4)=[CH:49][C:48]=3[O:55][CH:56]([CH3:58])[CH3:57])[N:36]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CCc1c(F)cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CC(C)Oc1cc(CO)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(F)cc(N(Cc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reaction time: 16 h

Procedure:
A solution of ethyl 3-(2,6-difluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.425 g, 1.03 mmol), {4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxyphenyl}methanol (0.315 g, 0.790 mmol) and triphenylphosphine (0.312 g, 1.19 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature, diethyl azodicarboxylate (40% toluene solution, 0.540 mL, 1.19 mmol) was added and the mixture was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give ethyl 3-(4-{{4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl}[(2-nitrophenyl)sulfonyl]amino}-2,6-difluorophenyl)propanoate as a yellow oil. To a solution of the obtained oil and mercaptoacetic acid (0.169 g, 1.84 mmol) in N,N-dimethylformamide (15 mL) was added lithium hydroxide monohydrate (0.154 g, 3.68 mmol), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (0.431 g, yield 90%, 2 steps) as a yellow oil.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[Cl:33][C:34]1[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4Cl)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4Cl)cc3)cc2C1=O
Yield: 70 %

Procedure:
The compound of example 134 was prepared analogous to compound of example 98 by hydrolysis of compound of example 133.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-methylpiperazine (10.0 mg, 0.1 mmol). The title compound was obtained as a solid (26.5 mg, 61% yield). MS m/z: 433 [M+H]+.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]1=[O:17].C(=O)([O-])O.[Na+]>[Pd].C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[CH2:2][C:3]2=[O:17])[CH:12]=1
Reactant: O=C1N(c2cccnc2)c2ncccc2C1(Br)Br
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1Cc2cccnc2N1c1cccnc1
Reaction time: 19 h
Yield: 31.3 %

Procedure:
3,3-dibromo-1-pyridin-3-yl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (crude, 2.12 g) and 10% by weight palladium on activated charcoal (750 mg) are suspended in absolute ethanol (85 mL). This mixture is allowed to stir under a hydrogen atmosphere at atmospheric pressure for 19 hours. The reaction mixture is filtered through a pad of hyflo, washing the cake well with copious amounts of boiling ethanol. Concentration of the filtrate gives crude 1-pyridin-3-yl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as an sticky brown solid. Saturated aqueous sodium hydrogen carbonate (30 mL) is added and the mixture extracted with 8 portions of dichloromethane. The combined extracts are dried over magnesium sulfate, filtered and evaporated to give a brown residue. The crude material is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1). Fractions containing the product are combined and evaporated to give 380 mg of 1-pyridin-3-yl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (47% yield starting from 3-bromopyridine). MS: m/e 212 (M+H). 1H NMR (300 MHz, CDCl3): 8.90 (1H, d), 8.62 (1H, dd), 8.19 (1H, d), 7.96 (1H, dt), 7.61 (1H, d), 7.47 (1H, dd), 7.08 (1H, dd), 3.78 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C@@H:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=2)[CH3:15])[CH:9]=1)=[O:6].ClCCOCCCl.C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]([CH3:48])[CH:46]=O>>[Cl:23][C:19]1[N:18]=[C:17]([NH:16][C@H:14]([C:10]2[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[C:2](/[N:1]=[CH:44]\[N:45]([CH3:48])[CH3:46])[CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[CH3:15])[CH:22]=[N:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cc(N)cc(C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCOCCCl
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cc(/N=C\N(C)C)cc(C(F)(F)F)c2)c1
Temperature: 180 °C
Yield: 16 %

Procedure:
A mixture of (S)-3-amino-N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-5-(trifluoromethyl)benzamide (38 mg, 0.09 mmol), 2-chloroethyl ether (0.012 mL, 0.1 mmol) and potassium carbonate (30 mg, 0.21 mmol) in N,N-dimethyl formamide (1 mL) was heated in a microwave reactor at 180° C. for 40 minutes. After this time the mixture was allowed to cool to room temperature and was filtered through cotton wool, diluted with ethyl acetate (15 mL), washed with saturated aqueous sodium hydrogen carbonate (2×10 mL), water (2×10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, ethyl acetate/methanol) followed by passage through a column of Sephadex with methanol as eluant to give the byproduct (S,Z)-N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-3-((dimethylamino)methyleneamino)-5-(trifluoromethyl)benzamide (7 mg, 16%) as a yellow oil.
Reaction SMILES: [NH:1]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]([C:15]([OH:17])=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].ClC(OCC(C)C)=O.[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH:34][C:15]([C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[C:5]([NH:1][C:2]([CH3:4])=[O:3])=[CH:6][CH:7]=1)=[O:17])[CH3:27]
Reactant: CCN1CCCC1CN
Reactant: CC(=O)Nc1ccc(C(=O)O)c2c1OCCO2
Agent: CC(C)COC(=O)Cl
Product: CCN1CCCC1CNC(=O)c1ccc(NC(C)=O)c2c1OCCO2

Procedure:
According to the method described in Example 31, the 8-acetamino-1,4-benzodioxane-5-carboxylic acid was treated with isobutyl chloroformate and 1-ethyl-2-aminomethylpyrrolidine. N-(1-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide was obtained. The structure was confirmed by nuclear magnetic resonance analysis.
Reaction SMILES: [Cl-].[Li+].C[Si](C[Mg]Cl)(C)C.[CH:10]([Mg]Br)([CH3:12])[CH3:11].[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]1[C:25]([CH:40]=[O:41])=[CH:26][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:26][C:25]=1[CH:40]([OH:41])[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Reactant: CC(C)[Mg]Br
Agent: C[Si](C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)C(C)C)c2)cc1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, to a solution of zinc chloride (35.9 mg) and lithium chloride (61.4 mg) in THF (976 μL) was added a 1 mol/L solution (527 μL) of trimethylsilylmethylmagnesium chloride in THF at room temperature, and the mixture was stirred for 15 min. To the reaction mixture was added a 1 mol/L solution (1449 μL) of isopropylmagnesium bromide in THF at room temperature, and the mixture was stirred for 45 min. Furthermore, to the reaction mixture was added dropwise a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-carbaldehyde (160.9 mg) in THF (1952 μL) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added, at 0° C., saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (112 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -74 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A stirred solution of (S)-4-benzyl-3-(3-(biphenyl-4-yl)propanoyl)oxazolidin-2-one (intermediate 12: 5.01 g, 13.00 mmol) in THF (180 mL) is cooled to −73.8° C., and 1M THF solution of sodium hexamethyldisilylamide (14.30 mL, 14.30 mmol) is added during 5 minutes. After 30 minutes, a solution of tert-butyl bromoacetate (2.495 mL, 16.90 mmol) in THF (20 mL) is added dropwise during 5 minutes. The solution is stirred at −74° C. for 1 hour, and the reaction is quenched with saturated aqueous NH4Cl (100 mL), and warmed up to ambient temperature. The precipitated solid is filtered off and washed with ethyl acetate (50 mL). The organic phase is separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The obtained residue is suspended in MeOH (70 mL) and then filtered to collect the solid (5.9 g) as a mixture of the desired product and the starting material. The mixture is purified by flash column chromatography on 120 g of silica gel (heptane/EtOAc=90:10 to 50:50) to give (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutanoate (2.40 g, 37%). HPLC retention time=1.74 minutes (condition B); MS=499.4 (m+); 443.4 (m-tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 2.42 (dd, J=16.67, 4.04 Hz, 1 H) 2.71 (ddd, J=16.55, 13.26, 9.60 Hz, 2 H) 2.87 (dd, J=16.93, 10.86 Hz, 1 H) 3.04 (dd, J=13.14, 6.32 Hz, 1 H) 3.32 (dd, J=13.39, 3.03 Hz, 1 H) 3.92 (t, J=8.34 Hz, 1 H) 4.07 (dd, J=8.97, 2.15 Hz, 1 H) 4.48-4.58 (m, 2 H) 7.20-7.30 (m, 3 H) 7.30-7.36 (m, 5 H) 7.42 (t, J=7.58 Hz, 2 H) 7.52 (d, J=8.1 Hz, 2 H) 7.56 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.[C:12](=[O:14])=[O:13]>C1COCC1.CCCCCC>[CH3:1][N:2]1[C:6]([C:12]([OH:14])=[O:13])=[N:5][CH:4]=[N:3]1
Reactant: O=C=O
Reactant: Cn1cncn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
1-Methyl-1H-1,2,4-triazole (1.19 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6M solution of butyllithium in hexane (9.4 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml) and the solvent was decanted off. To the residue was added ethyl acetate (20 ml) and water (20 ml). The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1 day (50° C.) to give the title compound (1.61 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S([O-])(=O)=O.[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:21]1([CH:20]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Product: CC(c1ccccc1)c1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
A 5 liter separable flask equipped with a stirrer, reflux condenser and dropping funnel was fed with 1340 g (10 moles) of tert-butylbenzene and 3 ml of trifluoromethane sulfonate, and the contents were maintained at 50° C. to 60° C. While stirring, 104 g (1 mole) of styrene was then added dropwise for 2 hours and, after the addition, the stirring was continued for further 30 minutes. After the reaction, the catalyst was deactivated with water and, through neutralization, water rinsing, drying and distillation, 1-phenyl-1-(4'-tert-butylphenyl)ethane was obtained.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)=[N:5][N:4]=1)[CH3:2].[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])=[N:5][N:4]=1)[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CCc1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCc1nnc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)o1

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-ethyl-1,3,4-oxadiazol-2-yl)carbamate (213 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was poured to the residue, and 140 mg (49.1%) of the desired product as a solid was separated by filtration.