Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]=1[NH2:15])#[N:2].C(N(CC)CC)C.Cl[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:5][C:4]=1[N:15]1[CH2:24][CH2:25][CH2:26][C:27]1=[O:28])#[N:2]
Reactant: Cc1c(-c2ccccc2)[nH]c(N)c1C#N
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)[nH]c(N2CCCC2=O)c1C#N
Temperature: -50 °C
Yield: 22.8 %

Procedure:
To a solution of 3-cyano-4-methyl-2-amino-5-phenylpyrrole (4.9 g) in THF (80 ml) was added triethylamine (2.5 g) and while the mixture was stirred at −50° C., 4-chlorobutyryl chloride (3.5 g) was added. This reaction mixture was then stirred at room temperature for 1.5 hours, after which the insoluble matter was filtered off. The filtrate was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous solution of sodium hydrogen carbonate, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from benzene/n-hexane. The crystals were suspended in ethanol (40 ml), and potassium tert-butoxide (1.32 g) was added thereto. The mixture was stirred at room temperature overnight and the resulting crystals were collected by filtration, washed with water, and air-dried. The crude crystals thus obtained were recrystallized from ethanol to provide the title compound as light-yellow needles (1.5 g). m.p. 140-141° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=2.[Si]([O:31][CH2:32][CH2:33][CH2:34]Br)(C(C)(C)C)(C)C.[C:36]1(=[O:42])[NH:40][C:39](=[O:41])[CH:38]=[CH:37]1>CO.Cl.O>[OH:31][CH2:32][CH2:33][CH2:34][N:14]1[C:13]2[CH:12]=[C:11]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:37]3[C:36](=[O:42])[NH:40][C:39](=[O:41])[C:38]=3[C:21]=2[C:20]2[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]1=2
Reactant: COc1ccc2[nH]c(/C=C/c3ccc([N+](=O)[O-])cc3Br)cc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=C1C=CC(=O)N1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4)cc1n2CCCO)C(=O)NC3=O
Yield: 23 %

Procedure:
5-Methoxy-2-[(E,Z)-2-phenylethenyl]-1H-indole (II; Ar=phenyl) (6.85 g, 27.5 mmol) was reacted with with 3-bromopropyl tert-butyl(dimethyl)silyl ether using the procedure described in example 38. The product isolated was reacted directly with maleimide (5.2 g) using the procedure described in example 68. Aromatisation of the crude Diels-Alder adduct using the procedure described in example 79 gave crude material that was then dissolved in methanol (300 mL) to which 1N hydrochloric acid (50 mL) was added. This solution was stirred at rt for 3h before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The residue was adsorbed onto silica and chromatographed eluting with dichloromethane to ethyl acetate/dichloromethane (7:3). Trituration with diethyl ether gave alcohol (202) as a yellow powder (2.55 g, 23%), mp 241–243° C. 1H NMR δ [(CD3)2SO] 11.10 (br s, 1H), 8.56 (d, J=2.6 Hz, 1H), 7.82 (s, 1H), 7.67 (m, 3H), 7.47 (m, 3H), 7.30 (dd. J=9.0, 2.6 Hz, 1H), 4.66 (t, J=4.9 Hz, 1H), 4.55 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.39 (m. 2H), 1.93 (m, 2H). Found: C, 71.95; H, 5.09; N, 6.93. C24H20N2O4 requires: C, 71.99; H. 5.03; N. 6.99.
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.Cl.[O:22]=[S:23]1(=[O:31])[CH2:27][CH:26]([C:28]([NH2:30])=[O:29])[NH:25][CH2:24]1.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH:26]([C:28]([NH2:30])=[O:29])[CH2:27][S:23](=[O:31])(=[O:22])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CS(=O)(=O)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CC[n+]1ccccc1Br
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)C1CS(=O)(=O)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 20.8 %

Procedure:
A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 200 mg, 704 μmol), 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 169 mg, 844 μmol), 2-bromo-1-ethylpyridinium tetrafluoroborate (212 mg, 774 μmol) and DIEA (273 mg, 361 μL, 2.11 mmol) in THF (20 mL) was stirred for 24 h at ambient temperature. The solvent was removed under reduced pressure, ice/sat. aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (75 mL). The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL). The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the title compound (63 mg, 21%) as colorless oil, MS (EI): m/e=431.3 [MH+].
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>O1CCOCC1.O.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>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)=[C:3]([CH3:17])[CH:4]=2)[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(N2CCN(C(C)C)CC2)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(-c2cnc(N3CCN(C(C)C)CC3)cc2C)c1
Temperature: 100 °C

Procedure:
To a solution of 1-(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine (0.59 g, 2 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added 3-acetylamino-phenylboronic acid (430 mg, 2.4 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and TEA (404 mg, 4 mmol). The resulting mixture was degassed and heated at 100° C. for 4 h under a nitrogen atmosphere. The mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with CH2Cl2/MeOH (100:1). This afforded 138 mg (15%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:10]2[C:11](=[O:15])[C:12]([CH3:14])([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][CH:6]=3)[C:9]2=[S:28])=[CH:17][C:18]=1[C:24]([F:26])([F:27])[F:25])#[N:21]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
A mixture of 4-[3-(4-aminophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (2d) (0.02 g, 0.05 mmol), methanesulfonyl chloride (0.009 g, 0.075 mmol) and pyridine (0.006 g, 0.075 mmol) in dichloromethane (1 ml) was stirred at room temperature for 15 hours. The medium was washed with water (2 ml) and extracted with ethyl acetate (5 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (HPLC, alumina column) to yield N-{4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]phenyl}methanesulfonamide (47a) [RD150] (0.009 g, 0.018 mmol, 36%), the structure of which is illustrated in Formula 2, as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][N:14]=[C:13]([CH3:19])[N:12]=1>O>[NH2:10][C:11]1[C:16]([CH2:17][N:18]2[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:9])=[CH:15][N:14]=[C:13]([CH3:19])[N:12]=1
Reactant: Cc1ncc(CN)c(N)n1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1ncc(Cn2c(C)cc(O)cc2=O)c(N)n1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (0.9 g, 0.007 mol) and 4-amino-5-aminomethyl-2-methylpyrimidine (1.0 g, 0.007 mol) in water (10.0 ml) was heated at 100° C. for 1 h under argon atmosphere. The reaction mixture was cooled, and filtered the yellow precipitate. It was washed successively with cold water, ethanol, and dried in vacuo to afford the title compound (1.01 g, 51%) as a pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ7.62 (s, 1H), 7.04 (s, 1H), 5.83 (d, 1H, J=2.0 Hz), 5.58 (d, 1H, J=2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ES-HRMS m/z 325.0304 (M+H C12H14N4O2Br requires 325.0295).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH:12]=[O:13].P(O)(O)([O-])=[O:15].[Na+].Cl([O-])=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]([OH:15])=[O:13]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccnc2c(Br)cccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccnc2c(Br)cccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
As shown in step 9-iv of Scheme 9, to a stirred suspension of 8-bromoquinoline-4-carbaldehyde (531.4 g, 2.25 mol) in THF (4.8 L) was added water (4.8 L) and monosodium phosphate (491.1 g, 4.05 mol). The mixture was cooled to 5° C. and, keeping the reaction temperature below 15° C., sodium chlorite (534.4 g, 4.727 mol) was slowly added portionwise as a solid over about 1 hour. After addition was complete the reaction mixture was stirred at 10° C. for 1 hour followed by the portionwise addition of 1N Na2S2O3 (1.18 L) whilst keeping the temperature below 20° C. The reaction mixture was stirred at RT followed by the removal of the THF under reduced pressure. The resulting aqueous solution containing a precipitate was treated with sat'd NaHCO3 (about 1 L) until a pH of 3 to 4 was achieved. This mixture was stirred an additional 15 minutes and the solid was collected by filtration, washed with water (2×1 L), washed with tert butyl methyl ether (2×500 mL), and dried in a convection oven at 60° C. for 48 hours. Additional drying under high vacuum provided 8-bromoquinoline-4-carboxylic acid (compound 2032, 530.7 g, 94% yield from compound 1030) as a yellowish tan solid: LC-MS=252.34 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 14.09 (s, 1H), 9.16 (d, J=4.4 Hz, 1H), 8.71 (dd, J=8.6, 1.2 Hz, 1H), 8.25 (dd, J=7.5, 1.2 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H), 7.64 (dd, J=8.6, 7.5 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:33][CH2:32]2)[CH2:26][NH:27][CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].C(N(CC)CC)C>CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:35][CH2:36]2)[CH2:26][N:27]([CH3:28])[C:14]([C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1CCCC2
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc([N+](=O)[O-])cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
3-Nitro-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride [from 3-nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.150 g , 6.78 mmol) and PCl5 (0.190 g, 8.48 mmol) in EtOAc (1.5 mL) as described in T. Nakayama, T. Okutome, R. Matsui, M. Kurumi, Y. Sakurai, T. Aoyama, S. Fujii, Chem. Pharm. Bull. 32(10) 3968 (1984)] was dissolved in EtOAc (2 mL) and added to a stirred solution of N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.3075 g, 0.678 mmol), triethylamine (0.124 mL, 0.892 mmol) and EtOAc (3.1 mL) and the mixture stirred overnight at ambient temperature. The reaction mixture was washed with 10% aqueous HCl, 5% aqueous NaOH and brine solutions, dried (MgSO4) and the solvent removed in vacuo to yield the title compound (0.168 g, 38%) which was converted to the citrate salt MS: m/z 656 (M+H). Analysis for C34H39Cl2N3O4S.C6H8O7.2.0H2O: calculated: C, 54.30; H, 5.81; N, 4.75; found: C, 54.10; H, 5.55; N, 4.55.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-methylaniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, 3,4-difluoro-2-[2-fluoro-4-methylanilino]benzoic acid was isolated as a crude pale brown solid which was reacted directly with 2-(aminooxy)ethanol and DMT-MM by the general procedure of Example 6, Step B below, then purified by column chromatography on silica gel (100% EtOAc as eluant) to give 3,4-difluoro-2-(2-fluoro-4-methylanilino)-N-(2-hydroxyethoxy)benzamide as a white solid (44%); m.p. (EtOAc/hexane) 134-139° C. 1H NMR [400 MHz, (CD3)2SO] □ 11.82 (v br s, 1 H), 8.77 (br s, 1 H), 7.41 (ddd, J=8.1, 5.7, 1.6 Hz, 1 H), 7.13-7.00 (m, 2 H), 6.88 (dd, J=8.3, 1.1 Hz, 1 H), 6.82 (ddd, J=8.5, 8.5, 4.2 Hz, 1 H), 4.76 (v br s, 1 H), 3.86 (t, J=5.0 Hz, 2 H), 3.58 (J=5.0 Hz, 2 H), 2.25 (s, 3 H). Anal. calcd. for C16H15F3N2O3: C 56.5; H, 4.4; N, 8.2. Found C, 56.3; H, 4.5; N, 8.2.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](Cl)=[CH:11][C:10]=1[Cl:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[Cl:8][C:9]1[C:10]([Cl:19])=[CH:11][C:12]([NH:2][CH:3]2[CH2:7][CH2:6][CH:5]=[CH:4]2)=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: NC1C=CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1C=CCC1

Procedure:
3-Aminocyclopentene hydrochloride (R. Vince and S. Daluge, J. Med. Chem. 1974, 17,578) (5.10 g, 42.8 mmol), 1,2,4-trichloro-5-nitrobenzene (Aldrich, 10.0 g, 42.8 mmol), and potassium carbonate (98%, Aldrich, 15.00 g, 107 mmol) were refluxed in t-butyl alcohol (100 mL) under nitrogen for 24 hours. Volatiles were evaporated in vacuo and the residue chromatographed on silica gel. Title compound was eluted with 20-30% chloroform-hexanes as an orange powder (5.14 g, 44%), m.p. 85°-86° C.; 1H-NMR(DMSO-d6) δ: 8.27 (s, 1, aromatic CH), 7.88 (d, J=7.3 Hz, 1, NH), 7.48 (s, 1, aromatic CH), 6.2-6.0 (m, 1, =CH), 6.0-5.8 (m, 1, =CH), 5.0- 4.7 (m, 1, NCH), 2.6-2.2 (m overlapping solvent, 3 CH), 1.8-1.5 (m, 1, 1/2CH2); mass spectrum(CI): 273 (M+1).
Reaction SMILES: ClC1[C:7](=[O:8])[C:6]([C:9]#N)=[C:5](C#N)[C:4](=O)C=1Cl.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCOC[CH2:23]1>>[CH3:21][C:15]1[CH:20]=[CH:19][C:18]([CH3:23])=[C:17]2[C:16]=1[CH:4]=[CH:5][C:6]([CH:7]=[O:8])=[CH:9]2
Reactant: C1COCCO1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccccc1
Product: Cc1ccc(C)c2cc(C=O)ccc12
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere, the obtained aldehyde (20.9 g) was dissolved in dioxane (300 ml). After adding dichlorodicyanobenzoquinone (50.9 g), the resultant mixture was heated under ref lux for 1.5 hr. Then, it was cooled to room temperature by allowing to stand followed by the addition of toluene (500 ml). The resulting precipitate was collected by filtration and washed with toluene several times. The filtrate was concentrated and the resulting crude product was purified by silica gel column chromatography to give 5,8-dimethyl-2-naphtaldehyde (10.3 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[C:11]([C:15]#[N:16])[C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH:2]=[CH2:3].[CH3:25][O:26][C:27]1[CH:47]=[CH:46][C:30]([CH2:31][N:32]([C:36]2[CH:41]=[C:40]([Sn](C)(C)C)[CH:39]=[CH:38][N:37]=2)[C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.O1CCOCC1>CCOC(C)=O.C(Cl)Cl.[Cu]I.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>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:40]2[CH:39]=[CH:38][N:37]=[C:36]([N:32]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:47][CH:46]=3)[C:33](=[O:35])[CH3:34])[CH:41]=2)=[C:11]([C:15]#[N:16])[C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(Br)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: COc1ccc(CN(C(C)=O)c2cc([Sn](C)(C)C)ccn2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCn1ccnc1-c1sc(-c2ccnc(N(Cc3ccc(OC)cc3)C(C)=O)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
The mixture of 5-(1-allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)thiophene-3-carbonitrile (0.840 g, 1.91 mmol), N-(4-methoxybenzyl)-N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.992 g, 2.37 mmol) Lithium chloride (0.232 g, 5.46 mmol), Copper(I) iodide (0.104 g, 0.546 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.210 g, 0.182 mmol) in dry 1,4-Dioxane (50 mL, 600 mmol) was heated under N2 to reflux for 1 hour. The mixture was cooled to r.t., evaporated in rotavapor. The residue was quenched with aqueous saturated NaHCO3, extracted with DCM (2×150 mL), washed with water, brine, dried over Na2SO4, filtered, evaporated in rotavapor to give a brown solid. The solid was heated in EtOAc/DCM (50 mL/15 mL) to reflux for 15 min, cooled to r.t., filtered and washed with small amount of EtOAc. The filtrate was purified on a silica column using hexane as solvent A and hexane:concentrated aqueous NH4OH:MeOH:DCM (67%:0.5%:10.5%:22%) as solvent B (A/B from 100/0 to 0/100 in 5 min then 100% B for 10 min) to give a solid product (1.32 g, 75% pure by LCMS, yield 84.2%). LCMS: (AA) ES+, 614, 616. The product was used for next step without further purification.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([N+:33]([O-:35])=[O:34])=[C:12]2[C:17](=[C:18]([O:21][CH3:22])[C:19]=1[F:20])[N:16]([C@@H:23]1[CH2:25][C@@H:24]1[F:26])[CH:15]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]2=[O:32].O>CN(C)C=O>[F:20][C:19]1[C:18]([O:21][CH3:22])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15][N:16]2[C@@H:23]2[CH2:25][C@@H:24]2[F:26])=[C:11]([N+:33]([O-:35])=[O:34])[CH:10]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)c(N)c([N+](=O)[O-])c2c1=O
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc([N+](=O)[O-])c2c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
Isoamyl nitrite (3.81 g, 32.5 mmol) was added to dimethylformamide (60 ml), and while stirring at 70° C., a solution, wherein ethyl 6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (8.90 g, 23.2 mmol) was dissolved in dimethylformamide (120 ml), was added dropwise thereto over a period of 3 hours. After completion of dripping, the reaction solution was stirred at 70° C. for 1 hour, allowed to cool, and then poured into water (500 ml). After extraction with ethyl acetate (300 ml×3), the organic layers combined were washed with 1 mol/l hydrochloric acid (300 ml) and saturated saline solution (200 ml×2) in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and the crude crystals obtained were recrystallized in ethanol and then dried under a reduced pressure. 3.81 g (45%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[C:21]3[CH:20]=[C:19]([C:22]([C:30]4[CH:35]=[CH:34][C:33](Cl)=[CH:32][CH:31]=4)(C4N(C)C=NC=4)[OH:23])[CH:18]=[CH:17][C:16]=3[NH:15]C3=NN=NN23)[CH:9]=[CH:10][CH:11]=1.[OH2:40].C[CH2:42][OH:43]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[O:40][N:15]=[C:16]3[CH:17]=[CH:18][C:19]([C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:43][CH3:42])=[CH:32][CH:31]=4)=[O:23])=[CH:20][C:21]=23)[CH:9]=[CH:10][CH:11]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)n1nnnc1N2
Reactant: CCO
Reactant: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
Thionyl chloride (0.1 ml) was added at room temperature to a mixture of compound 1 (0.0002 mol) in EtOH (2 ml). The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was taken up in DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.15 g) was purified by column chromatography over kromasil® (10 μm) (eluent: DCM/MeOH 98/2). The pure fractions were collected and the solvent was evaporated. The residue (0.03 g) was taken up in DCM and evaporated till dryness, yielding 0.023 g (17%) of compound 10.