Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.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>[CH3:9][Si:10]([C:11]#[C:12][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: Nc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(N)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-pyridin-3-ylamine and 2.3 mL (16.2 mmol) 1-trimethylsilyl-ethyne using 66 mg (0.3 mmol) CuI, 303 mg (1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl2(PPh3)2 and 19 mL (139 mmol) triethylamine in 20 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate and small amounts of cyclohexane, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. The product precipitated on the column and was subsequently extracted from the silica gel with pure MeOH. Yield: 2.0 g (91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:47])=[C:28]([N:34]2[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:45])[O:42][CH2:43][CH3:44])[C@H:36]([OH:46])[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:47][C:27]1[C:26]([NH:25][C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:45])[O:42][CH2:43][CH3:44])[C@H:36]([OH:46])[CH2:35]1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Reactant: CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(CC)Cc4ccc(OC)cc4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (42 mg, 0.123 mmol), ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (40 mg, 0.118 mmol), DPPF (4.58 mg, 8.26 umol), Cs2CO3 (65.4 mg, 0.201 mmol), Xantphos (6.83 mg, 0.012 mmol), Palladium(II)Acetate (7.95 mg, 0.035 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc and washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 25% EtOAc in DCM to afford ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (50 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 200 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A mixture of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine (7) (1.0 g, 4 mmol), 2-fluoro-4-nitrophenol (0.942 g, 6 mmol) and K2CO3 (1.1 g, 8 mmol) in Ph2O (20 mL) was stirred at 200° C. for 24 h. The cooled reaction mixture was diluted with DCM (200 mL) and extracted with 1M HCl (200 mL). The aqueous phase was filtered through paper filter, basified (pH˜10) with conc. NH4OH to produce a cloudy mixture that was extracted with DCM. The organic phase was dried over anhydrous Na2SO4 and concentrated under pressure to give title compound 8 as an orange solid (0.667 g, 45% yield). MS (m/z): 371.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CN1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Yield: 89 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (100 mg, 0.353 mmol) and 1-methylpiperazine (39.2 μL, 0.353 mmol) were combined and purified as per Preparation Hb to give 2-chloro-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (109 mg, 0.314 mmol, 89% yield). LC-MS (M+H)+=347.2.
Reaction SMILES: [NH+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1.[OH-].[Na+]>C(O)(C)C>[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc[nH+]cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: C(=Cc1ccncc1)c1ccccc1
Reaction time: 2 h

Procedure:
To 67.5 parts of the 4-picolinium quaternary salt as in Example 13 but without the acid salt was added 100 parts isopropanol, 32.5 parts benzaldehyde, and one part piperidine. The resulting solution was boiled at reflux two hours, 100 parts 40% sodium hydroxide added, and the heating continued for two hours. The cooled mixture was extracted with chloroform, and the organic phase evaporated to dryness to yield a residue that was recrystallized from methanol-water to give 21 parts 4-styrylpyridine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@:8]2([CH2:12][C:13]([OH:15])=[O:14])[CH3:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:21](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@:8]2([CH2:12][C:13]([O:15][CH3:21])=[O:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: C[C@@]1(CC(=O)O)CCc2ccc(O)cc21
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@]1(C)CCc2ccc(O)cc21
Reaction time: 3 h
Yield: 67 %

Procedure:
(S)-5-(6-Methoxy-1-methyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (290 mg, 960 μmol) was dissolved in N-methylpyrrolidinone (2 mL). Water (17.2 μL, 960 μmol) was added, and the reaction was heated and stirred at 125° C. for one hour to give the intermediate anisole carboxylic acid. The reaction was cooled and NaOH (170 mg, 4.3 mmol) and 1-dodecanethiol (0.80 mmol, 3.3 mmol) were added. The reaction was reheated to 125° C. and stirred for 2.5 days. Another 2.25 equivalents of NaOH was added along with 1.75 equivalents of the thiol. The resulting mixture was stirred at 125° C. for an additional 16 hours. The reaction was then cooled to room temperature and diluted with water (about 25 mL). The resulting mixture was extracted with diethyl ether (2×50 mL) and then the aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with EtOAc (2×75 mL). The combined EtOAc layers were washed with water (2×75 mL) and brine (1×25 mL) and dried over magnesium sulfate. The organic layer was filtered and the solvent was removed. The residue was used directly in the next step (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (370 mg, 190% yield) (contains residual NMP). The (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (197 mg, 955 mmol) was dissolved in MeOH (10 mL) and a catalytic amount of sulfuric acid was added. The mixture was heated at reflux and stirred for three hours. The reaction was cooled, basified with saturated sodium bicarbonate, and the solvent was removed. The residue was then partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (1×50 mL), and the combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. After filtration and solvent removal, the residue was purified by medium pressure chromatography (silica, 0 to 15% EtOAc:DCM) to give (S)-methyl 2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetate (141 mg, 67% yield). LCMS ESI (neg.) m/e: 219.1 (M−1)−. Chiral Analytical HPLC (ChiralPak AD-H column, 8% isopropanol:hexanes): retention time=18.1 minutes (second peak).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11].[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1>CS(C)=O.O>[CH:1]12[CH2:8][CH2:7][CH:4]([N:5]([CH2:36][CH:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:29](=[O:33])[O:30][CH2:31][C:32]=4[C:24]=3[CH3:23])[OH:35])[CH2:6]1)[CH2:3][N:2]2[CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11]
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(O)CN2CC3CCC2CN3)ccc2c1COC2=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(O)CN2CC3CCC2CN3CC(O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
In four separate reactions, isomers A-D of 5-[2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (about 100 mg, 0.33 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (95 mg, 0.50 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to it, the mixtures were diluted with water (20 mL), extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residues were purified by preparative TLC (MeOH/DCM=1:15) to obtain 5,5′-[2,5-diazabicyclo[2.2.2]octane-2,5-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one) as 4 mixtures of two isomers, which were separated by SFC chiral chromatography to obtain two single isomers for each (eight total).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:21]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:13]2[CH2:17][O:16][C:15](=[O:18])[N:14]2[CH3:21])[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC(=O)N1C
Temperature: 70 °C
Reaction time: 14 h
Yield: 85.6 %

Procedure:
To a solution of 4(S)-(1(S)-(3,4-dichlorophenyl)-3-butenyl)-2-oxazolidinone (3.25 g, 11.4 mmol) in DMF (25 mL) at room temp was added NaH (573 mg, 95%, 22.7 mmol). The mixture was stirred for 20 min whereupon MeI (3.54 mL, 57.0 mmol) freshly filtered through basic alumina was added and the resultant reaction mixture was stirred at 70° C. for 14 h. The cooled reaction mixture was diluted with H2O (250 mL) and extracted with EtOAc (3×125 mL). The combined organic extracts were washed with H2O (3×100 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, 1-5% MeOH/CH2Cl2) to afford the title compound (2.93 g, 86%) as a colorless solid and recovered starting material (382 mg, 11%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH2:12]([O:15][C:16](Cl)=[O:17])[CH2:13][CH3:14].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)N(C(=O)C)C(C(NC)=O)C1)=O)CCC>>[CH2:12]([O:15][C:16]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1)=[O:17])[CH2:13][CH3:14]
Reactant: NC1CNc2ccccc2C1
Reactant: CCCOC(=O)Cl
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NC)N(C(C)=O)c2ccccc21)NC(=O)OC(C)(C)C
Product: CCCOC(=O)NC1CNc2ccccc2C1

Procedure:
Analogously to the method described in Example 108b) from 3(R,S)-amino-1,2,3,4-tetrahydroquinoline and propylchloroformate: Rf (P)=0.84; MS: M+ =234.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36]OCC3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].Cl[C:40]1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(N2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.C(N)CC>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][NH:32][CH2:37][CH2:36][CH3:40])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Solvent: CCCN
Product: CCCNCCc1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and propylamine (0.5 mL). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([C:4]([OH:6])=[O:5])[CH3:3].[CH3:15][C@H:16](NC)[C@H](O)C1C=CC=CC=1>>[CH3:15][CH2:16][O:5][C:4]([C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Clofibric acid (1.073 g, 5 mmol) and ephedrine (0.826 g, 5 mmol) were molten in a hot mortar until a free-flowing clear liquid was obtained. The mixture solidified at room temperature and was grinded to obtain a yellow powder in quantitative yield. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=9.36 (br s, 2H), 7.30 (m, 5H), 7.19 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.75 Hz, 2H), 5.10 (s, 1H), 3.12 (m, 1H), 2.52 (s, 3H), 1.41 (s, 6H), 0.85 (d, J=6.58 Hz), 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=176.8, 155.5, 141.8, 128.5, 128.0, 126.9, 125.8, 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6. mp 131° C., T5%onset 166° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([CH3:6])[C:8]=1[N+:15]([O-:17])=[O:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(COS(C)(=O)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
At 10°-15° C., 27 g (0.23 mol) of methanesulfonyl chloride dissolved in 20 ml of CH2Cl2 is dripped into a mixture of 34 g (0.2 mol) of 3-methyl-2-nitrobenzyl alcohol and 27 g (0.27 mol) of triethylamine in 100 ml of CH2Cl2. The reaction mixture is stirred for 1 hour at room temperature and is then extracted with water. The organic phase is dried over MgSO4 and evaporated down. There is obtained as residue 48 g of the title compound as a yellow oil, containing about 10% of the corresponding benzyl chloride as impurity. The crude product is used for the next reaction without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:30])([CH3:29])[CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](O)=[O:21].C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:20](=[O:21])[CH:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18]([CH3:30])([CH3:29])[CH3:17])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 3,3-dimethyl-2-phenylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.53 (dd, J=7.4, 10.9, 1H), 7.73 (dd, J=3.3, 5.3, 2H), 7.44 (d, J=7.0, 1H), 7.41-7.24 (m, 7H), 4.41-4.30 (m, 1H), 3.62 (d, J=13.1, 0.5H), 3.53 (d, J=13.1, 0.5H), 3.45 (d, J=15.0, 0.5H), 3.35 (d, J=13.1, 0.5H), 2.90 (dd, J=3.1, 8.9, 0.5H), 2.63-2.45 (m, 2.5H), 2.44-2.36 (m, 0.5H), 2.31 (d, J=6.5, 1H), 2.28 (d, J=5.3, 1H), 2.23 (d, J=5.8, 1H), 2.15 (dd, J=5.9, 12.3, 0.5H), 1.92 (dd, J=6.1, 12.2, 0.5H), 1.84 (dd, J=8.1, 12.6, 0.5H), 1.72 (ddd, J=6.5, 12.5, 18.9, 1H), 1.46-1.25 (m, 2H), 1.14 (d, J=1.8, 9H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[O:15]=[C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[CH:24][C:23](C(O)=O)=[C:22]2[N:17]1[CH2:18][CH2:19][C:20]1[CH:38]=[CH:37][S:36][C:21]=12>C1(C)C=CC=CC=1>[F:32][C:28]1[CH:27]=[C:26]([C:25]2[C:16](=[O:15])[N:17]3[C:22](=[C:23]([C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH:24]=2)[C:21]2[S:36][CH:37]=[CH:38][C:20]=2[CH2:19][CH2:18]3)[CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2
Reaction time: 8 h

Procedure:
0.96 ml of N,N-dimethylformamide di-t-butyl acetal was added dropwise within 20 minutes to a boiling solution of 0.34 g of 4,5-dihydro-7-oxo-8-(m-fluorophenyl)-7H-thieno[2,3-a]quinolizine-10-carboxylic acid in 5 ml of toluene. The mixture was heated under reflux for an additional 30 minutes, left to stand at room temperature overnight and then washed once with water, twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate and there was obtained tert-butyl 8-(m-fluorophenyl)-4,5-dihydro-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 135°-137°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.[OH-].[K+]>>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])=[CH2:9]
Reactant: Nc1ccccc1CCO
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccccc1N
Temperature: 200 °C
Yield: 48.4 %

Procedure:
A mixture of 2-(2-aminophenyl)ethanol (5 g, 36.4 mmol) and KOH (2.0 g, 36.4 mmol) was heated to 200° C. for 4 h. After cooling, the mixture was distilled under vacuum to yield 2.1 g of product.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 2-[(aminooxy)methyl]morpholine-4-carboxylate 156 (0.317 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 157 (0.35 g, 79%) as a colorless oil.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[S:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:7]=1.[CH3:18][N:19]=[C:20]=[S:21].C(OC(C)C)(C)C.C>CCCCCC.C(#N)C.C(OCC)(=O)C.O.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:18][NH:19][C:20]([C:12]1([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)[S:17][CH2:16][CH2:15][CH2:14][O:13]1)=[S:21]
Reactant: CN=C=S
Reactant: c1cncc(C2OCCCS2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNC(=S)C1(c2cccnc2)OCCCS1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
A mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 50 cc) is added dropwise and in the course of 10 minutes to a 1.6 M solution of n-butyllithium in hexane (44 cc), kept under a nitrogen atmosphere and cooled to -70° C. A solution of 2-(pyrid-3-yl)-1,3-oxathiane (8.5 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 50 cc) is then added in the course of 25 minutes at the same temperature. After stirring for 15 minutes, a solution of methyl isothiocyanate (5.4 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 50 cc) is added in the course of 15 minutes. The reaction mixture is stirred for 45 minutes at -70° C. and then for 1 hour whilst allowing the temperature to rise gradually to about 20° C. It is then run into a stirred mixture of distilled water (300 cc) and ethyl acetate (240 cc). After decantation, the aqueous phase is extracted twice with ethyl acetate (400 cc in total). The organic phases are combined, washed three times with distilled water (600 cc in total), dried over anhydrous sodium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product obtained, to which a mixture of diisopropyl ether and ethyl acetate (90/10 by volume; 70 cc) is added, is stirred for 10 minutes at 20° C. The resulting crystals are filtered off, washed twice with diisopropyl ether (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product obtained (4.4 g) is chromatographed on neutral silica gel (40 g) contained in a column of diameter 2.6 cm. Elution is carried out with a cyclohexane/ethyl acetate mixture (40/60 by volume; 2000 cc) and then with ethyl acetate (800 cc), 200 cc fractions being collected. Fractions 4 to 14 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product obtained (3.9 g) is dissolved in boiling acetonitrile (45 cc). The solution, to which decolourising charcoal (0.2 g) is added, is filtered hot and the filtrate, after cooling, is then kept for 1 hour at 0° C. The resulting crystals are filtered off, washed twice with acetonitrile (10 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. N-Methyl-2-(pyrid-3-yl)-1,3-oxathiane-2-carbothioamide (2.9 g), melting at 194° C., is thus obtained.