Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18](OCC)=[O:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH2:18][OH:19])[NH:15][C:14]=12)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
Ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Reference Example 3) (11.2 g, 29.0 mmol) was dissolved in tetrahydrofuran (150 mL) while stirring under N2 at 0° C. Lithium aluminum hydride (1.65 g, 43.4 mmol) was added in three portions, while monitoring the gas evolution and temperature. After the final addition, the reaction mixture was stirred at room temperature for 3 h and then heated at 60° C. for 3 h. The reaction mixture was cooled to 0° C. and quenched with freshly prepared hydrated sodium sulfate. The solid was removed by filtration and washed thoroughly with tetrahydrofuran. Concentration of the filtrate provided [7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (9.8 g, 99%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ4.63 (2H, s), 4.78 (4H, s), 6.26 (1H, s), 6.98 (1H, d, J=5.54 Hz), 7.27-7.38 (10H, m), 7.84 (1H, d, J=5.7 Hz), 8.27 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:13][O:14][C@@H:15]1[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:17]([C:30](OC)=[O:31])[CH2:16]1>C1COCC1>[CH3:13][O:14][C@@H:15]1[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:17]([C:30](=[O:31])[NH:1][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:16]1
Reactant: Nc1cnccn1
Reactant: COC(=O)[C@@H]1C[C@H](OC)CN1C(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](C(=O)Nc2cnccn2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of aminopyrazine (535 mg, 5.63 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M THF solution, 2.7 mL, 5.35 mmol) dropwise at 0° C. The resulting slurry was stirred at room temperature for 30 min. A solution of (2S,4S)-1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate (550 mg, 1.88 mmol) in THF (2 mL) was added to the slurry. The reaction mixture was stirred at room temperature for 4 h and quenched with methanol (3 mL). The crude product was purified by preparative HPLC to give (2S,4S)-benzyl 4-methoxy-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 18C (570 mg, 85%) as an oil. LC/MS [M+H]+: 356; Ret time (Method F): 2.32 min.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[C-:18]#[N:19].[K+]>CS(C)=O.O>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([C:18]#[N:19])=[N:3][CH:4]=1
Reactant: [C-]#N
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3.0 g, 9.54 mmol, 1.0 eq), KCN (1.24 g, 19.07 mmol, 2.0 eq) and 1,4-diazobicyclo[2,2,2]octan (DABCO.6H2O) (4.20 g, 19.07 mmol, 2.0 eq) in DMSO (50 mL) and H2O (10 mL) was stirred at 80° C. for 4 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 50:1 as eluent) to afford 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbonitrile (1.9 g, 77%) as a solid. LC-MS (m/z)=261.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:9]=2)[C:4]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:3]1
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1ccc2ccc(N3CCOCC3)cc21
Solvent: ClCCl
Product: COC(=O)C(=O)c1cn(C)c2cc(N3CCOCC3)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
1-Methyl-6-morpholin-4-yl-1H-indole (3.89 g, 18 mmol) was dissolved in CH2Cl2 (18 mL) and cooled at 0° C. Methyl chlorooxoacetate (2.4 mL, 26 mmol) was added to give a dark solution. Stirring was continued for 2 h at 0° C. and more methyl chlorooxoacetate (0.40 mL, 4.3 mmol) was added. After a further 2 h, the solvent was evaporated. The resulting solid was taken up in ether, filtered and washed well with ether to give crude methyl (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)glyoxylate (6 g).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:19][CH:18]4[O:20][CH:15]([CH2:16][CH2:17]4)[CH2:14]3)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C>[CH3:37][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:14][CH:15]5[O:20][CH:18]([CH2:17][CH2:16]5)[CH2:19]4)[N:10]=3)=[CH:22][CH:23]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CC5CCC(C4)O5)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-tolylisocyanate (60 mg, 0.45 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 228; Yield 80 mg (80%); (M+H) 502.4
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([OH:37])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C:26](=[O:37])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](OC(C)=O)[C@@H](O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](OC(C)=O)C(=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1

Procedure:
(3β,5α,11α,12β,25R)3,11-di(acetoxy)spirostan-12-ol was oxidized with chromium trioxide and pyridine in methylene chloride according to the procedure described in Org. Syn., 1976, 55, 84 to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH2:13][CH3:14]>C1C=CC=CC=1>[C:12]([NH:11][C:10]1[CH:9]=[C:8]([CH:18]=[CH:17][CH:16]=1)[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Nc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CCC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
42 g of diketene were added to a solution of 82.1 g of m-aminopropionanilide in 400 ml of benzene and the mixture was stirred for 41/2 hours and then was vacuum filtered. The recovered precipitate was washed with benzene, then isopropyl ether and dried to obtain 118 g of m-propionamido-acetylacetanilide melting at 70° C. which was used as is for the next step.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:32](Br)[CH:33]=[CH2:34]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[C@@H:15]([CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:34][CH:33]=[CH2:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](CCC(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred −78° C. solution of Example 8B (15.65 g, 54.2 mmol) in THF (160 mL) was added sodium bis(trimethylsilyl)amide (55 mL, 1M in THF). The reaction mixture was stirred for 45 minutes and allyl bromide (5.3 mL, 60.9 mmol) was added. The reaction mixture was stirred for 90 minutes, warmed to 0° C., and stirred an additional 90 minutes. The reaction was quenched with saturated ammonium chloride, concentrated, and partitioned between water and ethyl acetate. The organic layer was washed sequentially with water, 1M sodium bicarbonate, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 330 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:15]([CH2:17][C:18](=[C:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]([O:36][CH3:37])=[C:34]3[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]3[CH:38]3[CH2:40][CH2:39]3)=[CH:28][C:27]=2[F:45])[CH2:22][CH2:21]1)Cl)C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:38]1([N:33]2[C:34]3[C:29](=[CH:28][C:27]([F:45])=[C:26]([N:23]4[CH2:24][CH2:25][C:20](=[CH:18][CH2:17][NH:15][CH3:8])[CH2:21][CH2:22]4)[C:35]=3[O:36][CH3:37])[C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32]2)[CH2:39][CH2:40]1
Reactant: COc1c(N2CCC(=C(Cl)CN(C)Cc3ccccc3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: CNCC=C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1
Reaction time: 3 h
Yield: 14.3 %

Procedure:
A solution of 161 (70 mg, 0.11 mmol) in methanol/formic acid (v/v=20/1) (14 mL) was treated with 10% Pd/C (35 mg, 7.3 mmol) under nitrogen at rt and stirred for 3 h. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by HPLC (reverse phase C-18 column, 35-90% acetonitrile/water containing 0.1% trifluoroacetic acid) to afford the trifluoroacetic acid salt of 221 (8.3 mg, 15%) as a yellow solid. MS 416 (M+H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]([CH2:23][CH3:24])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.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>[C:1]1([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)[CH:6]=[CH:5][C:4]([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(B(O)O)cc1
Reactant: CCn1nc(Br)c2ncccc21
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc(-c2ccc(-c3nn(CC)c4cccnc34)cc2)c2ncccc21
Yield: 7.3 %

Procedure:
A mixture of 1,4-phenylenediboronic acid (37.0 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (101 mg), Pd(PPh3)4 (25.8 mg) and Cs2CO3 (0.280 g) in DME/water (3/1, 4 mL) was exposed to microwave irradiation (120° C., 40 min), treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). Crystallization from AcOEt/hexane gave the title compound (6.00 mg).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[C:32]([O:39][CH3:40])(=[O:38])[C:33]#[C:34][CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:16]1[N:15]2[N:14]=[C:34]([CH2:35][CH2:36][CH3:37])[C:33]([C:32]([O:39][CH3:40])=[O:38])=[C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=1
Reactant: CCCC#CC(=O)OC
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nn2c(OCc3c(F)cccc3F)cc(C)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
0.50 g (1.01 mmol) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 3.3 ml of DMF, and 229 mg (1.82 mmol) of methyl hex-2-ynoate were added. 251 mg (1.82 mmol) of potassium carbonate were added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 24 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 169 mg of the title compound were obtained (42% of theory; 95% purity).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:21])[C:5](=[O:20])[C:6]=1[Sn](CCCC)(CCCC)CCCC.I[C:23]1[CH:24]=[C:25]([NH:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[NH:37][CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[O:31])[CH:26]=[CH:27][CH:28]=1.CCOC(C)=O>[Cu](I)I.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:21])[C:5](=[O:20])[C:6]=1[C:27]1[CH:26]=[C:25]([NH:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[NH:37][CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[O:31])[CH:24]=[CH:23][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC)c(=O)c1=O
Reactant: O=C(Nc1cccc(I)c1)c1sccc1NCc1ccnc2ccccc12
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(-c2cccc(NC(=O)c3sccc3NCc3ccnc4ccccc34)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitrogen was bubbled through a solution containing 3-methoxy-4-tributylstannanylcyclobut-3-ene-1,2-dione (0.40 g, 1.0 mmol) and 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid (3-iodophenyl)amide (0.54 g, 1.1 mmol) for 5 min, then benzylchlorobis(triphenyl phosphine)Pd(II) (45 mg, 0.06 mmol) and copper iodide (17 mg, 0.09 mmol) were added. The mixture stirred at rt for 1 h. EtOAc (50 mL) was added and the mixture was filtered, partitioned over saturated aqueous NH4Cl, and then washed with 10% aqueous KF solution. The aqueous layer was back-extracted with EtOAc (3×50 mL) and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The mixture purified by silica gel chromatography (100% EtOAc) to yield a yellow oil. CH2Cl2 was added and the solution was sonicated. Title compound 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid [3-(2-methoxy-3,4-dioxocyclobut-1-enyl)phenyl]amide precipitated out as a yellow solid and was filtered. MS (ES): m/z 470.0 [M+1]. 1H NMR (DMSO-d6, 400 MHz): δ=4.54 (s, 3H), 5.10 (d, J=6.4 Hz, 2H), 6.80 (d, J=3.2 Hz, 1H), 7.40 (d, J=4.0 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.60-7.64 (m, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.08-8.12 (m, 1H), 8.32 (s, 1H), 8.85 (d, J=4.0 Hz, 1H), 9.75 (s, 1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15]Cl>C1COCC1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:2]([CH2:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CC(=O)OC
Reactant: ClCc1cccs1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccs1)(Cc1cccs1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.3 %

Procedure:
87.8 g of dimethyl malonate and 41.0 g of potassium t-butylate are dissolved in 1.1 l of THF (anhydrous) while cooling in ice, and, under argon, 44.1 g of 2-thienylmethylchloride in 500 ml of THF are added dropwise. The mixture is stirred at R.T. for 3 h, the KCL is removed by filtration, the solvent is removed in vacuo, and the residue is chromatographed. 33.8 g of the title compound (I) are obtained as a colorless oil, in addition to 8.8 g of dimethyl bis-(2-thienylmethyl)malonate (II)
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:11](C([O-])=O)=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[OH2:28].[OH-].[Na+]>CO>[OH:28][C:11]1[C:10]([C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([OH:22])=[O:21])[CH:17]=2)[CH:12]=1
Reactant: COC(=O)c1ccc2cc(C(=O)[O-])c(C(=O)Nc3ccccc3)cc2c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Reaction time: 8 h
Yield: 85 %

Procedure:
Sodium 3-phenylaminocarbonyl-6-methoxycarbonyl-2-naphthoate (0.081 g) obtained in Example 29 was suspended in methanol (8.10 g) and deionized water (8.13 g) and 1N-sodium hydroxide (4.0 g) was added dropwise under ice-cooling, followed by stirring overnight. The reaction solution was freeze-dried and the resultant solid was dissolved in water. The solution was acidified with diluted hydrochloric acid and the deposited crystal was filtered. The crystal was dried under reduced pressure to obtain 0.057 g of 2-hydroxy-3-phenylaminocarbonyl-6-hydroxycarbonylnaphthalene.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH3:10][CH:11]1[CH2:13][NH:12]1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:12]1[CH2:13][CH:11]1[CH3:10])[CH2:7][CH2:8][CH3:9]
Reactant: C=CC(=O)OCCCC
Reactant: CC1CN1
Product: CCCCOC(=O)CCN1CC1C
Reaction time: 20 h

Procedure:
To 25.6 g (0.20 mol) of n-butyl acrylate (Aldrich) was added 19.0 g (0.30 mol) of 2-methylaziridine (Aldrich, 90%) to cause a mildly exothermic reaction. The reaction mixture was allowed to stand at room temperature for 20 hours. At that time analysis of the reaction mixture by NMR spectroscopy indicated complete absence of vinylic protons of the starting n-butyl acrylate and formation of the title compound. The excess 2-methylaziridine was removed at reduced pressure to leave 37.1 g (100%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21].C([O-])(O)=O.[Na+:27]>C(O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O-:22])=[O:21].[Na+:27]
Reactant: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)[O-]
Temperature: 60 °C
Yield: 99.7 %

Procedure:
To a solution of 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example 36, 1.0 g, 3.33 mmol) in ethanol (20 mL) was added a solution of NaHCO3 (294 mg, 3.50 mmol) in water (15 mL). The mixture was stirred and warmed up to 60° C. until the solution become clear then evaporated to dryness to provide sodium 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (1.07 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.45 (m, 3H), 1.50-1.70 (m, 5H), 1.53-1.72 (m, 5H), 1.98-2.00 (m, 2H), 2.64 (s, 3H), 4.59-4.63 (m, 1H), 6.87-6.89 (d, J=7.6 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H). MS 301 (MH++H-Na).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN.C1COCC1.Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.[Cl-].[NH4+]>ClCCl>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:39][CH3:37])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18])[CH3:10])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(CC(=O)O)c1
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Cc1cccc(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)c1
Yield: 72.5 %

Procedure:
To a solution of (3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)acetic acid (2.62 g) prepared in reference example 16, 4-dimethylaminopyridine (78 mg) and 2.0M methylamine/THF (3.3 ml) in dichloromethane (25 ml) was added at 0° C. 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (1.24 g) and the mixture was stirred for 6 hours. Further, 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (0.13 g) and 2.0M methylamine/THF (0.33 ml) were added thereto and the mixture was reacted overnight. To the mixture was added an aqueous saturated ammonium chloride solution (50 ml) and the mixture was extracted with ethyl acetate.(100 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (2×50 ml), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give 2-(3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)-N-methylacetamide (1.96 g).
Reaction SMILES: O(C([NH:8][C@@H:9]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=O)C(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][C@@H:9]([C@H:18]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11]
Reactant: C[C@@H](c1ccc(F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccc(F)cc1)[C@H](N)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step A in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. After stirring at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 269.0 (M+1).