Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21](Cl)(=O)[O:22]CC.C1C=CC=CC=1>C(N(CC)CC)C>[F:1][C:2]([F:19])([F:20])[CH2:3][N:4]1[C:5]2[C:6](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:14][C:21]1=[O:22]
Reactant: CCOC(=O)Cl
Reactant: N=C(c1ccccc1)c1ccccc1NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=c1nc(-c2ccccc2)c2ccccc2n1CC(F)(F)F

Procedure:
To a mixture of 2.8 g of 2-(2,2,2-trifluoroethylamino)-benzophenonimine, 2 ml. of ethyl chlorocarbonate and 20 ml. of benzene was added dropwise 2.0 g of triethylamine, and the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was absorbed on a silica gel column, eluted with chloroform to obtain 1-(2,2,2-trifluoroethyl)-4-phenyl-2(1H)-quinazolinone, which was recrystallized from ethanol to give colorless crystals, m.p. 181.5°-182.0° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[CH3:1][C:2]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=[S:36]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)CN1C(=O)C(C)(CC(=O)OCC)c2c1cccc2[N+](=O)[O-]
Product: CCOC(=O)CN1C(=S)C(C)(CC(=O)OCC)c2c1cccc2[N+](=O)[O-]

Procedure:
A mixture of (±)-diethyl 2,2′-(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step B (2.30 g, 6.31 mmol) and Lawesson's reagent (1.53 g, 3.79 mmol) was heated at 150° C. in xylenes (120 mL) for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=381 (M+1).
Reaction SMILES: [CH3:1][O-:2].[K+].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[N:9][C:10]=1F>[Cl-].[NH4+]>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[N:9][C:10]=1[O:2][CH3:1]
Reactant: CN(C)c1ccc(Br)c(F)n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: COc1nc(N(C)C)ccc1Br
Temperature: 25 °C

Procedure:
To a solution of potassium methoxide (25% in methanol, 74.2 mL, 251 mmol) was added Intermediate (5-bromo-6-fluoro-pyridin-2-yl)-dimethyl-amine (18.36 g, 83.8 mmol). The reaction was stirred at reflux for 3 h before cooling to room temperature. The contents were poured into a solution of saturated ammonium chloride (500 mL) and this was extracted with ethyl acetate (3×300 mL). The combined organics were washed with brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford desired product as an oil that solidified upon standing to give an off white/yellow solid (18.3 g, 95% yield). 1H NMR (CDCl3, 400 MHz) 5=7.49 (d, J=8.59 Hz, 1 H) 5.95 (d, J=8.59 Hz, 1 H) 3.96 (s, 3 H) 3.05 (s, 6 H); MS (FID)=230.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].C([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])C.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([OH:28])=[O:26])=[CH:30][CH:31]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)N2CCCC2C#Cc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 8 h

Procedure:
A mixture of 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (255 mg, 0.8 mmol), 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (195 mg, 0.8 mmol), EDC (230 mg, 1.2 mmol), DMAP (98 mg, 0.8 mmol) in DMF (20 mL) was stirred overnight. The reaction mixture was poured into 1 N HCl and the resulting precipitate was collected with suction and dissolve in CHCl3. The solution was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (100:1, v/v) as eluent to give the desired compound, which was dissolved in THF (8 mL). 0.25 N NaOH (8 mL) was added to this solution and the resulting mixture was stirred overnight. The mixture was poured into 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was recrystallized from CHCl3-n-hexane to give 144 mg (37%) 33 as a pale yellow crystalline powder. mp 152–155 (d); 1H-NMR (DMSO-d6) δ 1.92–2.27 (4 H, m), 2.50 (2 H, s), 3.33–3.78 (2 H, m), 3.80 and 3.82 (total 3 H, s, each), 4.88–5.12 (1 H, m), 6.77–7.24 and 7.99–8.20 (total 7 H, m), 7.48 and 7.52 (2 H, d, J=8.3 Hz, each), 7.91 (2H, d, J=8.3 Hz), 8.72 (1H, s), 9.18 (1H, s), 13.11 (1H, br-s); MS (FAB) m/z 516 (M++1); Anal. Calcd for C29H26N3O5F.2H2O: C, 63.15; H, 5.48; N, 7.62. Found: C, 63.58; H, 5.15; N, 7.22.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OCC)[CH2:21][CH3:22])#[N:18]>C(O)C>[C:17]([N:19]=[C:20]([NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])[CH2:21][CH3:22])#[N:18]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(CC)=NC#N
Solvent: CCO
Product: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 47 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (4.37 g) and ethyl N-cyanopropionimidate (2.65 g) in ethanol (22 ml) was refluxed for 10 hours. The mixture was cooled and concentrated under reduced pressure. The residue was pulverized with ethanol and recrystallized from ethanol to give trans-4-[N-[1-(cyanoimino)propyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (2.81 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.Cl.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(Nc2cc(-c3cc(Cl)ccc3C)nc(N)n2)cc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a stirred suspension of the hydrochloride salt of 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine (0.01 g, 0.0344 mmol) in ethanol (5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.01 ml) followed by p-tolylamine (0.074 g, 0.068 mmol). The mixture was heated under reflux for 75 minutes. After evaporation of volatiles under reduced pressure, the residue was treated 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. After filtration the solid was dissolved in methanol (5 ml) and treated with a solution of sodium carbonate in water (1.0 M, 1.0 ml). After stirring for 30 minutes volatiles were evaporated under reduced pressure. The residue was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.011 g, 98% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.27 (s, 3H, CH3), 2.34 (s, 3H, CH3), 6.07 (s, 1H, Ar), 6.33 (s, 2H, NH2), 7.10 (d, 2H, J=8.3 Hz, Ar), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.35-7.40 (m, 2H, Ar), 7.61 (d, 1H, J=8.4 Hz, Ar), 9.09 (s, 1H, NH).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH3:34])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCNC1CCCC1C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(CC)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Ethylamino-cyclopentanecarboxylic acid ethyl ester (0.0926 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{ethyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C20H28N4O7S2 500.14, found 501.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].[CH3:17]I>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:17])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: CI
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(C2CCC2)c2cc(Br)ccc21
Yield: 70.3 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 59 using the 5-bromo-3-cyclobutyl-1H-indazole intermediate (427 mg, 1.70 mmol), NaH (97.5 mg, 2.25 mmol), and methyl iodide (294 mg, 2.06 mmol) to afford titled compound as a colorless oil (317 mg, 71%). 1H NMR (CDCl3) 7.82 (s, 1H), 7.41 (d, J=8.8, 1H), 7.21 (d, J=8.8, 1H), 3.90 (s, 3H), 3.88 (pent, J=9.2, 1H), 2.51-2.43 (m, 4H), 2.18-2.13 (m, 1H), 2.01 (m, 1H). LC/MS (Method B) 4.05 min, [M+1]+ 265/267.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+:22]>O1CCCC1.CO>[Na+:22].[N:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([O-:20])=[O:2])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(SCCCc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1ccc(SCCCc2ccncc2)cc1
Yield: 100.7 %

Procedure:
Heat a stirring solution of 4-(3-pyridin-4-yl-propylsulfanyl)-benzoic acid methyl ester (174 mg, 0.605 mmol) (Intermediate 10) and 2N sodium hydroxide (0.42 mL, 0.848 mmol) in 1:1 tetrahydrofuran/methanol (4 ml) to reflux temperature for 18 h. The reaction is allowed to cool and then concentrated in vacuo to obtain 180 mg (99%) of the title compound. MS (ES+) m/e 274.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(N(CC)CC)C>C(O)CCC>[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-aminoindole (6.23 g, 47 mmol), bis(2-chloroethyl)amine hydrochloride (16.8 g, 96 mmol) and triethylamine (19 mL, 141 mmol) in butanol is heated at 100° C. for 8 hours, cooled to room temperature and concentrated in vacuo to give 9.46 g of 5-piperazin-1-yl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:10]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH2:12][CH2:13][CH:8]1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Clc1cccnc1C1CCCC(c2ncccc2Cl)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2Cl)CCCC1c1ncccc1Cl
Yield: 82.3 %

Procedure:
Using General Procedure A: 3,3″-dichloro-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (304 mg, 0.987 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (351 mg, 1.38 mmol), KI (32.7 mg, 0.197 mmol), DIPEA (0.34 mL, 1.97 mmol), and DMF (5 mL) were stirred at 60° C. for 3 h. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded 5-cyano-2-(3,3″-dichloro-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (391 mg, 82%) as a yellow oil. 1H NMR (CDCl3) δ 1.63-1.78 (m, 3H), 2.01-2.14 (m, 1H), 2.18-2.38 (m, 2H), 3.87 (s, 3H), 3.95 (s, 2H), 4.52 (dd, 2H, J=11.4, 1.6 Hz), 6.89 (dd, 2H, J=8.4, 4.9 Hz), 7.38-7.48 (m, 3H), 7.57 (d, 1H, J=1.7 Hz), 8.22-8.32 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1B(O)O)=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1C=CC=CC=1.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:12]1([C:7]2[CH:6]=[CH:5][S:4][C:3]=2[CH:1]=[O:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1sccc1B(O)O
Reactant: Brc1ccccc1
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: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: O=Cc1sccc1-c1ccccc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
2-Formylthiophen-3-boronic acid (4) (0.89 g, 5.7 mmol) dissolved in 96% ethanol (15 ml) was added dropwise to a mixture of 2-bromobenzene (0.66 ml, 6.2 mmol) in benzene (12 ml), (Ph3P)4Pd (197 mg, 0.15 mmol) and an aqueous solution of 2M Na2CO3 (6.3 ml). The reaction mixture was then refluxed for 6 hrs. Then the mixture was cooled to room temperature, the solvent was partially removed under reduced pressure and the resulting mixture was extracted with ethyl ether (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was chromatographed using 95/5 petroleum ether/ethyl acetate, thus giving the derivative (5) (0.575 g, [lacuna] mmol, 53% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: OCc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(CO)c4C3)c(F)cc2c1=O
Yield: 41.3 %

Procedure:
283 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 170 mg of the target compound.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[C:14]([CH3:20])[CH:13]=1.CN(/[CH:24]=[C:25](/[C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33])\[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>C(O)C>[C:32]([C:31]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:20])[N:19]=[CH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(C)(C)C
Reactant: Cc1cc(Cl)ccc1NN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C)c1C(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
N-Ethyldiisopropylamine (1.553 mL, 8.97 mmol) was added to (4-chloro-2-methylphenyl)hydrazine hydrochloride (1.733 g, 8.97 mmol) and (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate#83) (2.04 g, 8.97 mmol) in ethanol (30 mL). The resulting solution was stirred at 90° C. for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with water (2×10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate (0.891 g, 30.9%) as a orange oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2.N1CCCCC1>CO>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:20]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])/[C:33](=[O:39])[NH:34]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 57 %

Procedure:
3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (40 mg, 0.134 mmol) and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 were dissolved in 0.3 ml of methanol under stirring, and added with piperidine (0.03 ml, 0.3 mmol) to the solution. Upon the completion of the addition, the mixture was stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 28 (40 mg, yield 57%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[N+:11]([O-])([OH:13])=[O:12].C(OCC)C>C(O)(=O)CC>[N+:11]([C:7]1[C:2]([OH:1])=[C:3]2[S:10][CH:9]=[CH:8][C:4]2=[N:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2ccsc12
Solvent: CCOCC
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2ccsc2c1O
Temperature: 110 °C

Procedure:
Commercially available 7-hydroxythieno[3,2-b]pyridine (9.9 g, 65.5 mmol) was dissolved in propionic acid (200 mL) and heated to 110° C., behind a bomb shield. 4.85 mL of fuming nitric acid (90%) was added over 2 minutes, during which time a copius precipitate formed. The thick suspension was brought to reflux (oil bath temperature ˜150° C.) for 1 h during which time an orange gas evolved (Caution: procedure should only be performed in a well ventilated hood). The reaction mixture was allowed to cool to room temperature and 200 mL of diethyl ether was added. The product was collected by filtration, washed with ˜400 mL of water, 300 mL of 1:1 diethyl ether/methanol, and dried to yield 9.5 g, (74%) of A2.1 as a tan powder. M.S. 197 (M+H)+ 100%.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.CC([O-])=O.C([BH3-])#N.[Na+]>CO>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][CH2:1][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(CNc2ccc(Cl)cc2)cc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
4-Formylbenzoic acid (15 g, 100 mmol) was suspended in methanol (500 mL) and 4-chloroaniline (12.7 g, 100 mmol) was added. The resulting suspension was heated at reflux temperature for 30 minutes and subsequently cooled to approximately 35° C. Acetic cid glacial (50 mL) was added followed by sodium cyanoborohydride (4.96 g, 80 mmol) in portions. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to approximately 150 mL by rotary evaporation. Water (150 mL) was added and the resulting suspension was stirred at room temperature for 16 hours. Filtration, washing with water and drying afforded 26.8 g (100%) 4-[(4-chlorophenylamino)-methyl]benzoic acid as a solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2OC(=O)N[C@@H:10]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)[CH:6]=[CH:7][CH:8]=1.Br[C:30]1[CH:31]=[C:32]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[O:39][C:38](=[O:48])[NH:37]2)[CH:33]=[N:34][CH:35]=1.C1(C#C)C=CC=CC=1>>[F:47][C:43]1[CH:42]=[C:41]([C@H:40]2[O:39][C:38](=[O:48])[NH:37][C@@H:36]2[C:32]2[CH:33]=[N:34][CH:35]=[C:30]([C:10]#[C:9][C:5]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=3)[CH:31]=2)[CH:46]=[CH:45][CH:44]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cccc(F)c2)O1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2cncc(C#Cc3ccccc3)c2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromopyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one and phenylacetylene. 1H-NMR (CDCl3, 500 MHz) δ 8.78 (bs, 1H), 8.42 (bs, 1H), 7.90 (m, 1H), 7.57 (m, 2H), 7.35-7.45 (m, 4H), 7.02-7.17 (m, 3H), 6.83 (bs, 1H), 5.30 (d, J=7.3, 1H), 4.83 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 164.2, 162.2, 158.6, 152.9, 146.9, 139.1 (d, J=7.7), 136.4, 133.7 (br), 131.9, 131.1 (d, J=8.6), 129.3, 128.7, 122.1, 121.6 (d, J=2.9), 116.6 (d, J=21), 113.0 (d, J=23), 94.2, 85.2, 84.9, 62.5. Mass spec.: 359.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH2:18][OH:19])[N:15]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH:18]=[O:19])[N:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)Nc1nc(/C=C/CO)cs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C/C=C/c1csc(NC(=O)Nc2ccc(Br)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 49, the desired compound was prepared from 0.84 g of (E)-3-[2-(3-p-bromophenylureido)thiazol-4-yl]allyl alcohol, 1.13 g of a sulfur trioxide pyridine complex, 0.72 g of triethylamine and 20 ml of dimethyl sulfoxide. The resulting product was a pale brown powder having the following physical properties.