Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12](C)[C:13]=2[C:14]#[N:15])[CH:7]=1.[Sn](Cl)[Cl:21].[CH2:23](O)[CH3:24]>Cl.O>[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:14]([NH2:15])[C:13]3[CH:12]=[C:11]([CH2:23][CH3:24])[S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cc1csc(Nc2cc(F)ccc2[N+](=O)[O-])c1C#N
Reactant: Cl[Sn]Cl
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Yield: 82 %

Procedure:
Suspend 2-(5-fluoro-2-nitro-phenylamino)-methyl-thiophene-3-carbonitrile (0.7.9 g, 27 mmol) in ethanol (70 ml), add anhydrous tin(II)chloride(15 g, 79 mmol) in concentrated hydrochloric acid (60 ml) and heat the mixture under reflux for 6 hours. Dilute the mixture with water and allow to cool. Collect the precipitate formed by filtration and dry under high vacuum to give 6-fluoro-2-ethyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride as a yellow solid (6.5 g, 82%): mass spectrum (FIA) 262 (M+1).
Reaction SMILES: [CH:1]1([CH:9]=[CH:10][C:11](=[O:17])[CH2:12][C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1.Cl[C:28]1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1C=CC=CC=1.CN(C)C=O.O1CCOCC1>[CH:1]1([C:9]2[N:23]([C:22]3[CH:24]=[CH:25][C:19]([OH:18])=[CH:20][C:21]=3[CH3:26])[CH:28]=[C:12]([C:11](=[O:17])[CH:10]=2)[C:13]([OH:15])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(O)ccc1N
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: COC(=O)CC(=O)C=CC1CCCCCCC1
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCCCCCC1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
In 5 ml of benzene was dissolved 0.3 g of methyl 5-cyclooctyl-3-oxo-4-pentenoate, and 0.3 g of N,N-dimethylformamidodimethylacetal was added thereto. They were reacted at 70° C. for one hour. Then, the reaction mixture was cooled to room temperature, and 0.27 g of 4-hydroxy-2-methylaniline was added thereto. The resulting mixture was subjected to reaction at room temperature for 2 hours. After completion of this reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: toluene/ethyl acetate (50:1 by volume) mixture). The fraction containing the objective substance was concentrated, and the oily substance thus obtained was dissolved in 5 ml of N,N-dimethylformamide and the resulting mixture was refluxed for 4 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (50:1 by volume) mixture). The fraction containing the objective substance was concentrated and the oily substance thus obtained was dissolved in 5 ml of dioxane, and 0.2 g of 2,3,5,6-tetrachloro-p-benzoquinone was added thereto, and they were reacted at 80°-90° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. These crystals were dissolved in 20 ml of chloroform, and after removing the insolubles, the chloroform was removed by distillation under reduced pressure. To the residue was added 5 ml of a 1N aqueous sodium hydroxide solution and 5 ml of methanol, and they were reacted at room temperature for 30 minutes. After the methanol was removed by distillation under reduced pressure, the resulting solution was adjusted to a pH of 6.5 with 2N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.14 g of 6-cyclooctyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 118°-120° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]3[C:25]4[C:20](=[CH:21][C:22]([N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=4)[C:18](=[O:19])[O:17]3)=[CH:11][C:10]=2C2[C:4]1=[CH:5]C=CC=2)[CH3:2].[CH2:29]([N:33]([CH2:49]CCC)[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]([CH2:45]CCC)[CH2:41]CCC)[CH:35]=1)CCC>>[CH3:49][N:33]([CH3:29])[C:34]1[CH:35]=[C:36]([N:40]([CH3:41])[CH3:45])[CH:37]=[CH:38][C:39]=1[CH:16]([C:25]1[CH:24]=[CH:23][C:22]([N:26]([CH3:28])[CH3:27])=[CH:21][C:20]=1[C:18]([OH:19])=[O:17])[C:12]1[CH:13]=[CH:14][C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: CCCCN(CCCC)c1cccc(N(CCCC)CCCC)c1
Reactant: CCn1c2ccccc2c2cc(C3OC(=O)c4cc(N(C)C)ccc43)ccc21
Product: CCN(CC)c1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1

Procedure:
Employing a procedure similar to that described in Example 1, part B above, 3-(9-ethyl-3-carbazolyl)-6-dimethylaminophthalide from A is interacted with N,N,N',N'-tetrabutyl-m-phenylenediamine to obtain 2-[α-(9-ethyl-3-carbazolyl)]-α-[2,4-bis(dibutylamino)phenyl]methyl-5-dimethylaminobenzoic acid (Formula III: R=CH3 ; X=H; Y=9-C2H5 -3-carbazolyl; Z=2,4-[(C4H9)2N]2C6H3).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:43]=[CH:44][CH:45]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[CH2:42][CH2:41][CH2:40][CH2:39][C:15]=2[C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:22][CH:21]=1)=[O:18])=[O:10])([CH3:3])[CH3:2].Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:58]1[CH2:68][CH2:67][CH:61]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:60][CH2:59]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C1COCC1>[CH:1]([N:4]([CH2:5][C:6]1[CH:45]=[CH:44][CH:43]=[C:8]([C:9](=[O:10])[NH:11][C:12]2[S:13][C:14]3[CH2:42][CH2:41][CH2:40][CH2:39][C:15]=3[C:16]=2[C:17](=[O:18])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=3)=[CH:22][CH:21]=2)[CH:7]=1)[C:47]([N:58]1[CH2:59][CH2:60][CH:61]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:67][CH2:68]1)=[O:49])([CH3:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC(C)C)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)N(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 150 mg of methyl 4-{3-[4-({[2-({3-[(isopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]propyl}benzoate and 3.5 mL of THF was added 0.045 mL of triethylamine and 28 mg of triphosgene under ice cooling, followed by stirring for 3 hours at room temperature. Thereafter, 0.080 mL of ethyl isonipecotate was added to the reaction mixture, followed by stirring for 18 hours at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by stirring for 1 hour at room temperature, and then extraction was performed using chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (NH silica gel manufactured by FUJI SILYSIA CHEMICAL LTD. (amino type silica gel (treated with aminopropyl)), (hexane:ethyl acetate=1:1)), thereby obtaining 178 mg of ethyl 1-{isopropyl[3-({3-[(4-{3-[4-(methoxycarbonyl)phenyl]propyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]carbamoyl}piperidine-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16]C)=O)=[CH:11][C:10]([CH:18]3[CH2:20][CH2:19]3)=[N:9]2)=[N:6][CH:7]=1.C1(C(=O)CC(=NOC)C(OCC)=[O:28])CC1.COCCO.BrC1C=C[C:45]([NH:48][NH2:49])=NC=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:15][C:16](=[O:28])[N:48]([CH3:45])[N:49]=3)=[CH:11][C:10]([CH:18]3[CH2:20][CH2:19]3)=[N:9]2)=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CCOC(=O)C(CC(=O)C1CC1)=NOC
Reactant: CCOC(=O)c1cc(C2CC2)nn1-c1ccc(Br)cn1
Solvent: COCCO
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(C3CC3)nn2-c2ccc(Br)cn2)oc1=O
Temperature: 25 °C
Yield: 33 %

Procedure:
Step-3: Ethyl 1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazole-5-carboxylate: To a stirred solution of ethyl 4-cyclopropyl-2-(methoxyimino)-4-oxobutanoate (420 mg, 1.97 mmol) in acetic acid:2-methoxyethanol (6 mL, 2:1) was added 5-bromo-2-hydrazinylpyridine (370 mg, 1.97 mmol) at room temperature. The resulting mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexanes system) to afford 220 mg (33%) of the title compound as pale yellow syrup. 1HNMR (400 MHz, CDCl3) δ 8.49 (d, J=2.0 Hz, 1H), 7.95 (dd, J=2.0 & 8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 4.30 (q, J=7.0 Hz, 2H), 2.04-1.98 (m, 1H), 1.29 (t, J=7.0 Hz, 3H), 1.02-0.97 (m, 2H), 0.83-0.79 (m, 2H); ESI-MS (m/z) 336, 338 [(MH)+, Br79,81].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[N:36][CH:35]=1.NN>CO.O>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][CH:35]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nncc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cn1nncc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Yield: 90.5 %

Procedure:
A solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide (700 mg, 1.22 mmol) and hydrazine (0.19 mL, 6.1 mmol) in 5 mL of MeOH was stirred at rt overnight, diluted with 200 ml of H2O and extracted with DCM (100 ml×2). The combined organic layers were concentrated and the resulting solid was dissolved in 6N HCl (50 ml). The aqueous layer was washed with DCM (50 ml×2). The organic layers were discarded and the remaining aqueous solution was concentrated to give the product as an HCl salt (490 mg, 75%): LCMS (ES) m/z 444.0 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) δppm 8.10 (m, 1H), 7.92 (m, 1H), 7.73 (m, 1H), 7.57 (m, 1H), 7.44 (m, 1H), 4.65 (m, 1H), 4.17 (s, 3H), 3.25-3.11 (m, 4H).
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[I:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1>CN(C)C=O>[I:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: OCc1cccs1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(I)cn1Cc1cccs1
Temperature: 80 °C

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.5 ml) was added to a stirred suspension of 5-iodopyrimidin-2-one (777 mg) and 2-hydroxymethyl thiophene (0.62 ml) in dry N,N-dimethylformamide (8 ml) under nitrogen and the mixture was then heated at 80° C. After 13/4 h the reaction mixture was evaporated to a brown solid which was crystallised twice from ethyl acetate to give the title pyrimidinone (540 mg), m.p. 207°-209° C., λmax (EtOH) 232.5 nm (ε 21,820), 341.5 nm (ε 2,420).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N+]([O-])=O)=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22].NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C([N+]([O-])=O)=CC=1C(Cl)=O.C(O)CCCC.C(=O)([O-])[O-].[K+].[K+].[CH3:64][C:65]1[CH:70]=[CH:69][C:68]([SH:71])=[CH:67][CH:66]=1>O.CN1CCCC1=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([S:71][C:68]2[CH:69]=[CH:70][C:65]([CH3:64])=[CH:66][CH:67]=2)=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22]
Reactant: CCCCCOC(=O)c1cc([N+](=O)[O-])c2c(c1N)C(=O)c1ccccc1C2=O
Reactant: Cc1ccc(S)cc1
Agent: Nc1c(C(=O)Cl)cc([N+](=O)[O-])c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCCCCO
Product: CCCCCOC(=O)c1cc(Sc2ccc(C)cc2)c2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
7.7 g of pentyl 1-amino-4-nitroanthraquinone-2-carboxylate, prepared from 1-amino-4-nitroanthraquinone-2-carboxylic acid chloride and n-pentanol, 2.7 g of anhydrous potassium carbonate and 2.7 g of 4-methylthiophenol are introduced into 50 cc of N-methylpyrrolidone, and the mixture is heated to 125°-130° C. in the course of 1 hour and is stirred at this temperature until, after about 1.5 hours, complete reaction has been achieved. The reaction mixture is allowed to cool and is diluted at 40° C. with 20 cc of water. When the mixture has cooled completely, the dyestuff which has been precipitated is filtered off with suction and washed with a mixture of N-methylpyrrolidone and water and then with hot water. After drying at 60° C., 6.7 g of n-pentyl 1-amino-4-(4-methylphenylmercapto)-anthraquinone-2-carboxylate are obtained, corresponding to a yield of 72% of theory. The dyestuff can be purified by recrystallisation from dimethylformamide.
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:9][C:10]1[C:11]([C:2]#[C:1][C:3]2([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: C#CC1(O)CCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclopentanol (35.8 mg, 0.33 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and CuI (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 5 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(1-hydroxy-cyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 32 mg, 67%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:27]1([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:37]5[CH2:36][CH2:35][NH:34][CH:33]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:38]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 71.8 %

Procedure:
(RS)-1-Cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 19, but starting with 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) and (RS)-2-phenylpiperazine (3.2 g). After recrystallization in a mixture of dimethylformamide (5 cc) and ethanol (40 cc), (RS)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) is obtained in the form of a yellow solid, m.p. 242° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7](/[C:10](=[N:13]\[S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])/[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH:13][S:14]([C:16]([CH3:17])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CC/C(=N/S(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](NS(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-methanesulfonyl-thiazol-5-yl)-prop-(Z)-ylidene]-amide (93 mg, 0.29 mmol) in THF (5 mL) is added a 1 M solution of lithium tri-sec-butylborohydride (L-Selectride) (0.58 mL, 0.58 mmol) in THF dropwise. After 2.5 hours, the reaction mixture is quenched with saturated aqueous ammonium chloride solution (100 mL), and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2×10 mL). The combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting using a gradient of 0-100% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-thiazol-5-yl)-propyl]-amide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=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>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[OH:12])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)c(O)c1
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (2.1 g, 9.0 mmol), 4-fluorophenyl-boronic acid (2.52 g, 18 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.45 mmol), and 2M aqueous sodium carbonate solution (11 ml) in ethanol/toluene (1:5, 30 ml) were heated at reflux overnight. After cooling the solvent was removed in vacuo and the residue dissolved in EtOAc then washed with sat. aq. sodium bicarbonate and dried over MgSO4. The crude product was purified by column chromatography eluting with 1% MeOH/DCM giving the title compound as a solid (1.9 g). MS(ES): MH+ 247, M-H+ 245.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.Cl.[CH2:25]([NH:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CC(O)=O>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:32]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:33][C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: NNCc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(=O)[nH]n(Cc4ccccc4)c(=O)c3cc2C1

Procedure:
Using procedure 51, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.349 g, 1 mmol) was treated with benzylhydrazine dihydrochloride (0.27 g, 1.4 mmol) in HOAc (20 mL) Purification using silica gel, eluting with 19:1 CH2Cl2 /MeOH, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 135 as a white solid (m.p. 219-220° C.).
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:9]
Reactant: C=C(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
A mixture of 2-phenylprop-1-ene (14.16 g, 0.12 mol), N-bromosuccinimide (13.5 g, 72 mmol) and α,α'-azoisobutyronitrile (1.5 mg) in carbon tetrachloride (7.5 mL) was placed in a pre-heated oil bath at 170° C. (the internal temperature rose to 110° C.). The slurry was stirred vigorously at this temperature for 2 h. and was then allowed to cool to ambient temperature. The mixture was filtered, washing with carbon tetrachloride, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane to give the title compound as an oil (320 mg). 1H NMR (250 MHz, CDCl3) δ(7.85-7.81 (2 H, m), 7.75-7.63 (3 H, m), 5.89 (1 H, s), 5.82 (1 H, s), and 4.72 (2 H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][N:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)nc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 4.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.24 g, 1 mmol), then reacted with 6-aminonicotinonitrile (Oakwood) (0.09 g, 0.8°mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-pyridin-2-yl)-amide as a yellow solid (Yield 12 mg, 4%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH2:17]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:18]1C=CC=CC=1.C(=O)([O-])[O-:33].[K+].[K+]>CN(C=O)C.CO>[O:12]=[C:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[O:31][C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:17](=[O:33])[CH3:18])=[CH:26][CH:27]=2)[NH:7]1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(NCc2ccccc2)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (30 mg, 0.13 mmol), 4-(benzylamino)phenol (78 mg, 0.39 mmol), and potassium carbonate (90 mg, 0.65 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, and filtered through a membrane. The crude product was purified via prep-LC-MS to provide 136 (8 mg, 20% yield) as a solid. LC-MS (M+H=304, obsd.=304). 1H NMR (400 MHz, d6-DMSO): δ 12.06 (s, 1H), 9.11 (d, 1H), 8.42 (dd, 1H), 8.26 (d, 1H), 7.82 (d, 1H), 6.99 (d, 2H), 6.70 (m, 3H), 6.48 (d, 1H), 6.42 (s, 2H).