Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([N:6]([C:15]([O:17]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[CH:4][CH:3]=[N:2]1.[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:15]([NH:6][C:5]4[CH:4]=[CH:3][NH:2][N:1]=4)=[O:17])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1ccn[nH]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cc[nH]n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
A mixture of bis(2,2,2-trichloroethyl) 1H-pyrazol-5-ylimidodicarbonate (264 mg, 0.609 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.106 ml, 0.609 mmol) in dimethylsulfoxide (4.0 ml) was stirred at 70° C. for 8 hours. Water was poured into the reaction mixture and the mixture 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. The residue was purified by high performance liquid chromatography (YMC HPLC column, A solution 0.1% trifluoroacetic acid solution in acetonitrile, B solution 0.1% trifluoroacetic acid solution in water, eluted with 10% A solution to 100% A solution) and aqueous saturated sodium hydrogen carbonate solution was added thereto and the mixture 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. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (22.7 mg, 10.5%) as a solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:20]([OH:39])[C@:21]4([OH:38])[C:29](=[O:30])[C:28]([C:31]([NH2:33])=[O:32])=[C:27]([OH:34])[C@@H:26]([N:35]([CH3:37])[CH3:36])[C@@H:22]4[CH2:23]3)[C:17](=[O:18])[C:14]=2[C:15]=1[OH:16])=[O:8])([CH3:4])[CH3:3].[ClH:43]>CC(C)=O>[CH3:4][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:17]([OH:18])[C:14]=2[C:15]=1[OH:16])[C:20](=[O:39])[C@@:21]1([OH:38])[C@H:22]([C@H:26]([N:35]([CH3:36])[CH3:37])[C:27]([C:28]([C:31]([NH2:33])=[O:32])=[C:29]1[OH:30])=[O:34])[CH2:23]3)=[O:8])([CH3:1])[CH3:3].[ClH:43]
Reactant: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CC(C)=O
Product: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 98 %

Procedure:
50.0 mg Tigecycline (Tygacil® 50 mg, Wyeth, powder for infusion) were dissolved in 1 ml acetone and the solution was stirred at room temperature. After about one minute an orange precipitate appeared (form VI). Afterwards 8.4 mg (1 eq) concentrated hydrochloric acid were added and the suspension was stirred at room temperature. The colour of the suspension changed after about 5 minutes from orange to yellow and the suspension was stirred for 2.5 hours at room temperature. The solid was filtered off, washed with acetone and dried under vacuum at room temperature to obtain 51.8 mg (98% yield) of crystalline form A of Tigecycline hydrochloride.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[C:15]4[O:19][CH2:18][O:17][C:16]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:26]4[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=4)[CH:14]=[C:15]4[O:19][CH2:18][O:17][C:16]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-c2cc3c(c(C45CC6CC(CC(C6)C4)C5)c2)OCO3)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 3-(1-adamantyl)-4,5-methylenedioxy-1-bromobenzene (2.00 g, 5.97 mmol), 4-formylphenylboronic acid (1.07 g, 7.16 mmol) and potassium carbonate (1.86 g, 13.42 mmol) in 1,2-dimethoxyethane (50 mL) and water (2.5 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.298 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ethyl acetate, 95:5) to give 1.82 g of 4-[3-(1-Adamantyl)-4,5-methylenedioxy phenyl]-benzaldehyde (85%). 1H NMR (500 MHz; CDCl3): δ 1.79 (s, 6H); 2.08 (s, 9H); 6.01 (s, 2H); 7.00 (d, J=2.0 Hz, 1H); 7.04 (d, J=2.0 Hz, 1H); 7.68 (d, J=8.1 Hz, 2H); 7.91 (d, J=8.1 Hz, 2H); 10.03 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([CH3:19])=[O:18])=[CH:3]1.CO.C(OCC)(=[O:24])C>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([CH3:19])(=[O:24])=[O:18])=[CH:3]1
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(C(F)(F)F)cc21
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
1-methyl-3-methylsulphinyl-7-trifluoromethyl-4-quinolone was oxidised in dichloromethane at 0° to give 1-methyl-3-methylsulphonyl-7-trifluoromethyl-4-quinolone, m.p. 300°-301° (from methanol:ethyl acetate)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:28](Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2noc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (220 mg), benzoyl chloride (70 μL), and triethylamine (250 μL) in tetrahydrofuran (5 mL) is stirred for 30 min at room temperature before heating to 80° C. for 15 h. The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 93:7) to afford the title compound. LC (method 3): tR=2.09 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[CH:3]=1.P(O[CH2:20][CH3:21])(OCC)(OCC)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:20]3[C:21](=[CH:7][CH:2]=[CH:3][CH:4]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: CCOP(=O)(OCC)OCC
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: Brc1ccc2c(c1)[nH]c1ccccc12

Procedure:
A 250 mL round bottom flask was charged with 4-Bromo-2-nitrobenzene (19.2 g, 69.04 mmol), and triethyl phosphate (84 mL, 483.28 mmol). Then, at 160° C. to 165° C., the mixture was heated under reflux for 14 hours. After the reaction was completed, the remaining triethyl phosphate was removed by vacuum distillation. The resultant product was diluted with a mixed solvent of MeOH:H2O=1:1, and the produced solid was filtered. The obtained solid was washed with a mixed solvent of MeOH:H2O=1:1 and petroleum ether.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH3:16].ClC(Cl)C.[Br:21]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9])=[CH:4][C:3]=1[CH2:16][Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Temperature: 47 °C
Reaction time: 0.5 h

Procedure:
(4-Bromo-3-methyl-phenoxy)-tert-butyl-dimethyl-silane (255 g, 0.846 mol), dichloroethane (2.5 L), N-bromosuccinimide (165 g, 0.927 mol) and 2,2′-azobisisobutyronitrile (19.0 g, 0.116 mol) were combined in a 5 L flask. The mixture was degassed by evacuating and purging with N2 (5×). The reaction mixture was heated to 47° C., and the heat was shut off. An exotherm to 76° C. occurred. GC analysis showed 6.5% unreacted starting material. The heat was applied again, and the reaction was held at reflux (83° C.) for 15 min. After cooling to 8° C., heptane (1.0 L) was added. The resulting slurry was stirred at 4° C. for 30 min and filtered. The filtrate was evaporated to dryness. The residue was treated with heptane (1 L), placed in the freezer overnight, and filtered. The filtrate was concentrated to the title compound (326 g, 101%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)C(OC)=O)[CH:6]=1.BrCC1C=C(C=CC=1)[C:23](OC)=[O:24].BrCC1C=CC=C(OC)C=1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:10]([O:24][CH3:23])[CH:9]=2)[CH:6]=1
Reactant: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: COc1cccc(CBr)c1
Product: COc1cccc(Cn2cc(Br)cn2)c1

Procedure:
The title compound was prepared using a procedure analogous to methyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoate except that methyl 3-(bromomethyl)benzoate was replaced with 1-(bromomethyl)-3-methoxybenzene. LCMS, [M+H]+=267.1.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([OH:42])[CH:41]=1)[C:36](O)=[O:37].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:36](=[O:37])[C:35]1[CH:34]=[C:33]([OH:32])[CH:41]=[C:40]([OH:42])[CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(O)cc(O)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 37.6 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 87 mg (0.562 mmol) of 3,5-dihydroxybenzoic acid, 143 mg (0.561 mmol)of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (99 mg, 38%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.41, FD-MS: M+ =563.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(O[Na])=O>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.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CCc1nnc(Nc2cc(Br)cn(C)c2=O)s1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CCc1nnc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)s1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 332a (200 mg, 0.63 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (754 mg, 1.89 mmol), PdCl2(dppf) (51 mg, 0.063 mmol), K3PO4 (267 mg, 1.26 mmol), CH3COONa (103 mg, 1.26 mmol), acetonitrile (15 mL), and water (0.5 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, it was heated at 100° C. under a nitrogen atmosphere for 2 h. The resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 332b as a brown solid (178 mg, 48%). MS-ESI: [M+H]+ 588.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:23](OC)=[O:24])=[C:4]([NH:27][C:28](=[O:36])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:23]([OH:24])=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:28](=[O:36])[NH:27]2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[OH:22])=[CH:10][CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(OC)c3O)cc2)c(Cl)cc1NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(-c3cc4c(O)c(-c5ccccc5)c(=O)[nH]c4cc3Cl)cc2)c1O
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a solution of methyl 6-chloro-2″-hydroxy-3″-methoxy-4-(2-phenylacetamido)-[1,1′:4′,1″-terphenyl]-3-carboxylate (Intermediate 58) (340 mg, 0.677 mmol) in tetrahydrofuran (100 mL) at 60° C. was added dropwise KHMDS 0.5M/THF (5.42 mL, 2.71 mmol). The reaction mixture was stirred for 2 h after the end of addition. After cooling, the reaction mixture was acidified with 1N HCl and extracted with dichloromethane. The organic layer was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in acetonitrile, filtered and was washed with acetonitrile and diisopropylether to give the title compound 7-chloro-4-hydroxy-6-[2′-hydroxy-3′-(methyloxy)-4-biphenylyl]-3-phenyl-2(1H)-quinolinone (175 mg, 0.372 mmol, 55% yield) as a light brown powder. LCMS: (M+H)+=470; Rt=2.99 min. HRMS: calculated for C28H19ClNO4 (M−H)+: 468.1003. found: 468.0962.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH3:8])=[CH:5][CH:6]=1.C([Li])CCC.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:15][CH:14]([C:2]1[S:3][C:4]([S:7][CH3:8])=[CH:5][CH:6]=1)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CSc1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
1.2 g of 2-bromo-5-(methylsulfanyl)thiophen (compound in Production Example 45) was dissolved in 20 mL anhydrous tetrahydrofuran, and 3.72 mL solution of 1.59 M n-butyl lithium in hexane was added dropwise there to at −70° C. After the mixture was stirred for 1 hour, 6 ml solution of 1.2 g t-butyl 4-formyl-piperidine-1-carboxylate in anhydrous tetrahydrofuran was added dropwise thereto and stirred at −70° C. for 2 hours. The temperature of the reaction solution was gradually increased to 0° C., water and an ammonium chloride solution were added thereto, and the reaction solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate and purified by silica gel column chromatography (ethyl acetate/hexane), to give 1.41 g of the title compound as pale pink crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[N:21]1([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:29][C:27]([N:21]1[CH2:26][CH2:25][N:24]([C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:23][CH2:22]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with benzyl piperazine-1-carboxylate (31166-44-6) in the presence of TBTU and DIEA to obtain the title compound as light brown oil; MS (EI): m/e=487.5 [MH+].
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([CH:9]1[CH2:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:14][CH2:15][CH2:16][C:17]=3[CH:18]=2)[C:10]1=[O:21])[CH:6]([CH3:8])[CH3:7].[Br:22]Br>ClCCl>[CH2:5]([CH:9]1[CH2:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:14][CH2:15][CH2:16][C:17]=3[C:18]=2[Br:22])[C:10]1=[O:21])[CH:6]([CH3:8])[CH3:7]
Reactant: BrBr
Reactant: CC(C)CC1Cc2cc3c(cc2C1=O)CCC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)CC1Cc2c(cc3c(c2Br)CCC3)C1=O
Temperature: 0 °C
Yield: 69.9 %

Procedure:
To a suspension of 14.6 g (110 mmol) of AlCl3 in 40 ml of dichloromethane a solution of 10.0 g (43.8 mmol) of 2-isobutyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one in 25 ml of dichloromethane was added dropwise by vigorous stirring at 0° C. Further on, 7.71 g (48.2 mmol) of bromine was added dropwise at this temperature. The resulting mixture was stirred overnight at room temperature and then poured on 500 cm3 of ice. The product was extracted by 3×200 ml of dichloromethane. The combined organic extract was washed by water, aqueous NaHCO3, dried over Na2SO4, and evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-dichloromethane=3:1, vol.). Yield 9.40 g (70%) of the title product.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH:24]([C:28](O)=[O:29])[C:25](O)=[O:26])[CH2:15][CH3:16]>>[OH:29][C:28]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:25](=[O:26])[C:24]=1[S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:14][CH2:15][CH3:16]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: CCCc1ccccc1SC(C(=O)O)C(=O)O
Product: CCCc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol) and diethyl ester of [(2-propylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol). m.p. 158°-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.972 (t, 3H), 1.64 (m, 2H), 2.71 (t, 2H), 6.87 (s, 1H), 6.92 (m, 1H), 7.06 (m, 2H), 7.16 (m, 1H), 7.55 (m, 3H), 7.85 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH:11]([OH:13])[CH3:12])=[N:8][C:7]=2[CH:14]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[S:18]([O:13][CH:11]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:14][C:7]=2[N:8]=1)[CH3:12])(=[O:20])(=[O:19])[CH3:17]
Reactant: CC(O)c1nc2cc(C(F)(F)F)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(OS(C)(=O)=O)c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 1-(5-trifluoromethyl-2-benzothiazolyl)ethanol (m.p. 93°-94° C., 4.94 g) in dry pyridine was added methanesulfonyl chloride (4.58 g) and the resulting solution stirred at 0° C. for 1 hour. It was poured onto water, extracted with ether and the ether layer washed with 10% hydrochloric acid (2×20 ml). The organic extract was dried, evaporated and the residue triturated with hexane to obtain the desired compound as solid, m.p. 89° C. (5.89 g).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:5]1)#[N:2].[Na]>CO>[C:1]([CH:3]1[C:6](=[O:7])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:5])#[N:2]
Reactant: N#CC=C1OC(=O)c2ccccc21
Agent: [Na]
Solvent: CO
Product: N#CC1C(=O)c2ccccc2C1=O

Procedure:
3-Cyanomethylene phthalide (6.0 g.; 0.035 mole) was added to a solution of sodium (0.8 g.) in methanol (35 ml) and the red solution refluxed for 20 mins. On cooling and acidification with one-third of its bulk of concentrated hydrochloric acid the indandione separated as a copious yellow solid, m.p. 204°-207° C. (d) (lit. m.p. 201°-202° C.).
Reaction SMILES: [CH2:1]([C@H:4]([C@H:8]([OH:10])[CH3:9])[C:5]([OH:7])=O)[C:2]#[CH:3].[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH2:18].C(Cl)CCl>ClCCl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH:18][C:5](=[O:7])[C@H:4]([CH2:1][C:2]#[CH:3])[C@H:8]([OH:10])[CH3:9]
Reactant: C#CC[C@@H](C(=O)O)[C@@H](C)O
Reactant: NOC1CCCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: C#CC[C@@H](C(=O)NOC1CCCCO1)[C@@H](C)O
Temperature: 23 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
To a solution of (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid (3.0 g, 21.13 mmol) in dichloromethane (50 mL) is added 2-tetrahydropyranyloxyamine (3.0 g, 25.35 mmol) and EDC (4.5 g, 23.24 mmol). The resulting solution is stirred at 23° C. for 4 h, then diluted with dichloromethane (100 mL) and washed with 1 M hydrochloric acid. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (1.9 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ8.82 (bs, 1H), 4.96 (m, 1H), 3.94 (m, 2H), 3.62 (m, 1H), 2.64 (m, 1H), 2.56 (m, 1H), 2.23 (m, 1H), 2.04 (m, 1H), 1.82 (m, 2H), 1.61 (m, 4H), 1.23 (d, 3H) ppm.