Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH3:14][N:15]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]=2[CH:17]=[CH:16]1.CCN(C(C)C)C(C)C.O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][N:15]3[CH3:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: Cn1ccc2c(N)cccc21
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1Nc1cccc2c1ccn2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (328 mg, 1.48 mmol) and 1-methyl-1H-indol-4-amine (260 mg, 1.78 mmol) in CH3CN (6 mL) at room temperature, DIEA (0.4 mL, 2.22 mmol) was added. The mixture was stirred at room temperature for 24 h. Water (15 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxylate as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:17])[C:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[C:12]([O:11][C:10](=[O:16])[NH:9][CH2:8][C:5]1[C:4]([F:17])=[CH:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=2[C:27]([F:28])([F:29])[F:30])=[CH:7][N:6]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCc1ncc(Br)cc1F
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Product: COc1ccc(Nc2cnc(CNC(=O)OC(C)(C)C)c(F)c2)c(C(F)(F)F)c1
Yield: 26 %

Procedure:
Analogously to Example 1a), tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate (0.55 mmol) was reacted with 4-methoxy-2-trifluoromethyl-aniline. The crude product was purified by chromatography (column: Varian Pursuit XRS C18; 10 μM; 41.4×250 mm, gradient: acetonitrile/water/CF3COOH: 10/90/0.1→100/0/0.1). The product was thus obtained in a yield of 26% of theory.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=3)=[O:24])=[N:21][CH:22]=2)[CH:19]=1.C(=O)(O)[O-].[Na+]>ClCCCl.O>[CH3:35][O:34][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[N+:31]([O-:33])=[O:32])[C:23]([C:20]1[N:18]2[CH:19]=[C:14]([NH:13][C:8](=[O:10])[CH3:9])[CH:15]=[CH:16][C:17]2=[CH:22][N:21]=1)=[O:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: COc1cc(C(=O)c2ncc3ccc(NC(C)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
1.29 ml (9.29 mmol) of triethylamine and then 0.51 ml (7.15 mmol) of acetyl chloride are added to 0.50 g (1.43 mmol) of (6-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone hydrochloride in 25 ml of 1,2-dichloroethane cooled to 5° C. and then the mixture is allowed to return to ambient temperature and is stirred for 18 hours. The medium is taken up in water, basified with a sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The product is purified by column chromatography on silica gel, elution being carried out with a mixture of dichloromethane and acetone (90/10). 316 mg of a yellow solid are obtained. Melting point: 257° C.; 1H NMR (d6-DMSO): 2.15 (3H, s), 4.01 (3H, s), 7.45 (1H, d), 7.92 (1H, s), 8.00-8.06 (3H, m), 8.13 (1H, s), 10.62 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14](I)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27](C)[CH:28]=[O:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:28]([NH2:27])=[O:29])[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)OCCn1cc(I)nc1-2
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Temperature: 70 °C

Procedure:
A mixture of 10-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (2056 mg, 5.916 mmol), bis(triphenylphosphine)palladium(II) chloride (2.10E2 mg, 0.300 mmol) and hexamethyldisilazane (7.488 mL, 35.50 mmol) in 60 ml of N,N-Dimethylformamide was subjected to carbonylation at 1 atm with CO from balloon. The reaction mixture was heated at 70° C. for 1 h. The mixture was concentrated in vacuum, the residue partitioned between ethyl acetate and 1 M aqueous sodium carbonate. The organic extracts were washed with water, brine, dried over magnesium sulfate, concentrated in vacuum and purified on a 12 g silica column eluting with 0-5% MeOH in DCM to give 1300 mg (83%). MS(ESI+): 265.0. 1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.25 (s, 1H), 4.56 (s, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:33])[O:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[O:33])[CH2:14][CH2:15]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A mixture comprising of tert-butyl(2-(piperidin-4-yl)ethyl)carbamate (1.85 g, 8.10 mmol) in DCM (80 ml), sat. aqueous sodium bicarbonate solution (20 ml, 8.10 mmol) and 3,5-dichlorobenzyl carbonochloridate (prepared according to Bioorganic & Medicinal Chemistry Letters, 21(21), 6608-6612; 2011, Intermediate 33) (1.940 g, 8.10 mmol) was stirred at room temperature for 3 hours. The resulting mixture was treated with 2M NaOH soln. (50 ml). The organics were separated, dried (MgSO4) and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li+].CC([N-]C(C)C)C.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([NH:23][C:24]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[Br:7])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1csc(Br)n1
Reactant: O=C=NCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1sc(Br)nc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a stirred solution of 2,4-dibromo-thiazole (4.95 g, 20.4 mmol) in THF at −78° C. was added LDA (1.8M in THF/hexanes, 13.6 ml, 24.5 mmol) slowly. The reaction was then stirred at −78° C. for 30 min., when benzylisocyanate (3.8 ml, 30.6 mmol) was added slowly. The mixture was then stirred at −78° C. for 30 min. before it was slowly warmed up to RT. Water was then added carefully to quench the reaction. The mixture was extracted with EtOAc and the combined extracts were dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (10% EtOAc/hexanes) to give 2,4-dibromo-thiazole-5-carboxylic acid benzylamide 26B as a white solid (5.05 g, 13.43 mmol, 66%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:49])[N:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[C:43]1([S:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][CH2:31][N:29]([CH3:30])[C:28](=[O:49])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:42])=[O:41])[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(=O)(=O)c1ccccc1
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was given to a solution of N-((1R)-1-{N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (647 mg, 1.08 mmol) in dichloromethane (4 ml). The reaction mixture was stirred for 2.5 h at. 0° C. It was diluted with dichloromethane (15 ml). A saturated aqueous solution of sodium hydrogen carbonate (15 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×15 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (20 g), using dichloromethane/methanol/25% aqueous ammonia 200:10:1 as eluent to give 434 mg of (2R)-N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[C:8]([CH3:10])([CH3:9])[CH:7]1[C:11]#[N:12])=[O:5])[CH3:2].O.CN(C)C=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[C:8]([CH3:9])([CH3:10])[CH:7]1[C:11]#[N:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C#N)C1(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(C#N)C1(C)C
Yield: 61 %

Procedure:
A mixture of 71.7 g (0.3 mol) of 3,3-dimethyl-2-cyano-cyclopropane-1,1-dicarboxylic acid diethyl ester, 6 ml of water and 100 ml of dimethylformamide was heated to the boiling point under reflux for 20 hours. For working up, the mixture was diluted with toluene, washed twice with 300 ml of water each time, dried and distilled. 30.6 g (61% of theory) of 3,3-dimethyl-2-cyano-cyclopropane-1-carboxylic acid ethyl ester of boiling point 87°-95° C./2 mbar were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[S-2:16].[Na+].[Na+].Cl>CN(C=O)C>[SH:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(-c2ccncc2F)cc1
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccncc2S)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 4-(3-fluoropyridin-4-yl)benzonitrile (1.08 g, 5.4 mmol) and sodium sulfide (0.84 g, 10.8 mmol) in DMF (20 mL) was stirred at 130° C. for 0.5 hours. While the reaction was cooled in ice water bath, aqueous HCl (6N, 2.5 mL) was added drop wise with rigorous stirring. The resulting yellow paste was concentrated using rotary evaporation on a water bath (80° C.) to dryness. The resulting yellow solid was extracted with methanol (4×20 mL). The combined extracts were concentrated to dryness to give a yellow solid (1.1 g, 96%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[NH:12][C:11]=2[N:10]=[C:9]1[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])(=O)=O>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:11]=2[N:10]=[C:9]1[C:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)[nH]c2nc(C(C)(C)C)n(Cc3ccccc3)c2c1=O
Reactant: COC(=O)CCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(C(C)(C)C)n2Cc2ccccc2)n(CCC(=O)OC)c1=O
Temperature: 95 °C

Procedure:
5.0 g (14.7 mmol) of 7-benzyl-8-(tert.-butyl)-1-n-propyl-xanthine are dissolved in 200 ml of dimethylformamide. After the addition of 5.36 g of K2CO3, 19.6 mmol of methyl 3-methanesulphonylpropionate are added at ambient temperature and the mixture is then heated to 90-100° C. After about 20 hours at constant temperature the solvent is distilled off in vacuo and the residue remaining is taken up in dichloromethane. The organic phase is washed with water, dried over MgSO4 and the solvent is distilled off in vacuo. The crude product remaining is purified by chromatography on silica gel (dichloromethane:methanol 97:3).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.O1CCC[CH2:12]1.C(NC(C)C)(C)C.[Li].CI>C1COCC1.C1CCCCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:12]
Reactant: Brc1csc2ncccc12
Reactant: C1CCOC1
Agent: [Li]
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Product: Cc1sc2ncccc2c1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
500 mg of 3-Bromo-thieno[2,3-b]pyridine (3.70 mmol) is dissolved in 3 ml of dry THF and cooled to −78° C. 2.71 ml of lithium diisopropylamine mono (tetrahydrofuran) 1.5 M solution in cyclohexane (4.07) is added to the mixture at −78° C. and stirred at −78° C. for 20 min. 0.25 ml of methyl iodide (43.7 mmol) is added to the mixture and stirred at −78° C.→room temperature for 1 h. The reaction mixture is quenched with sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 382 mg of the title compound. Yield 45%. mass spectrum (m/e): 230 (M+1); 1H-NMR (CDCl3): 8.56 (dd, 1H, J=4.7 Hz, 1.5 Hz), 7.97 (dd, 1H, J=8.5 Hz, 1.5 Hz), 7.37 (dd, 1H, J=8.5 Hz, 4.7 Hz), 2.62 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[Cl:57][C:58]1[CH:73]=[CH:72][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[O:65])=[CH:60][CH:59]=1>>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][N:69]([C:15]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[S:18][C:11]=4[N:12]=[C:13]([CH3:17])[N:14]=3)[CH2:68][CH2:67]2)=[O:65])=[CH:72][CH:73]=1
Reactant: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (40 mg, 0.15 mmol) and BOP (88 mg, 0.20 mmol) in CH3ON (1 ml) was added DBU (34 μl, 0.23 mmol). After stirring for 10 minutes at room temperature, 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (59 mg, 0.23 mmol) was added. The reaction was stirred at room temperature overnight and then heated at 60° C. for 4 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (66 mg, 86%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][C:9]=1[OH:16]>C(O)C>[CH3:1][N:2]([CH2:4][C:10]1[CH:11]=[C:12]([CH:13]=[C:8]([O:7][CH3:6])[C:9]=1[OH:16])[CH:14]=[O:15])[CH3:3]
Reactant: C=O
Reactant: COc1cc(C=O)ccc1O
Reactant: CNC
Solvent: CCO
Product: COc1cc(C=O)cc(CN(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
18.0 g (0.15 mol) of a 40% aqueous dimethylamine solution were added to 12.0 g (0.15 mol) of a 37% aqueous formaldehyde solution in 90 ml of ethanol. Then 15.2 g (0.10 mol) of 4-hydroxy-3-methoxybenzaldehyde (vanillin) were added. The reaction mixture was refluxed for 30 minutes and stirred for a further 24 hours at room temperature. Then the reaction mixture was left to stand overnight in the refrigerator at 0 to 5° C. The precipitated solid was filtered out, washed with ice-cold acetone and dried. The result was a white powder.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CN1C(=O)N(C)CCC1.[O:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]([OH:29])=[O:28].IC>C1COCC1>[CH3:1][C:23]1([C:27]([OH:29])=[O:28])[CH2:24][CH2:25][CH2:26][O:22]1
Reactant: O=C(O)C1CCCO1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of N,N-diisopropylamine (15 ml, 106 mmol) in THF (40 ml) at 0° C. was added n-BuLi (99 mmol, 1.6 M/Hex). After stirring the mixture for 30 min. DMPU (12 ml, 99 mmol) and tetrahydro-2-furoic acid (4.2 ml, 44 mmol) were added at 0° C. After 1 hr at 0° C., iodomethane (5.4 ml, 88 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was partitioned between ethyl acetate and 1N HCl. The aqueous layer was extracted with ethyl acetate (2×500 ml) and chloroform (500 ml). The extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography with methylene chloride/methanol/acetic acid=97:3:0.5 to afford the desired product as an oil (2.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH3:36])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH3:36])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(Nc3cc(N)ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Yield: 42.5 %

Procedure:
A solution of the product from Example 63C (0.150 g, 0.303 mmole), iron powder (0.10 g, 1.86 mmol) and ammonium chloride (0.10 g, 1.98 mmol) in a methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.06 g, 42%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>C1COCC1.C(O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCC(=O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
200 mg of ethyl 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-4-oxobutanoate was dissolved in 2.0 ml of THF and 2.0 ml of ethanol, and 1.3 ml of aqueous 1M sodium hydroxide solution was added, followed by stirring at room temperature for 4 hours. After adding 1 M hydrochloric acid and water thereto, the insoluble materials were collected by filtration to obtain 180 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-4-oxobutanoic acid.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5].[CH2:11]([O:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=O)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([N:2]([C@@H:3]([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5])[CH3:1])=[O:21])[CH3:12]
Reactant: C=CC[C@H](NC)C(=O)OC
Reactant: CCOc1ccsc1C(=O)O
Product: C=CC[C@@H](C(=O)OC)N(C)C(=O)c1sccc1OCC

Procedure:
Step N (1): (S)-Methyl 2-(methylamino)pent-4-enoate from Step G (1) and 3-ethoxythiophene-2-carboxylic acid were coupled according to the procedure outlined in Step A (1). The product was purified using silica gel column chromatography to provide 80 mg (quantitative yield) of (S)-methyl 2-(3-ethoxy-N-methylthiophene-2-carboxamido)pent-4-enoate. LC-MS (M+H)+=298.29; 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (t, J=6.77 Hz, 3H) 2.48-2.64 (m, 1H) 2.68-2.82 (m, 1H) 3.01 (s, 3H) 3.72 (s, 3H) 4.06 (q, J=6.83 Hz, 2H) 5.00-5.20 (m, 3H) 5.63-5.84 (m, 1H) 6.70 (d, J=5.49 Hz, 1H) 7.29 (d, J=5.49 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.O[C@H]1CCNC1.Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([C:25]([NH:27][CH2:28][C@:29]3([OH:36])[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]3)=[O:26])=[C:20]([Cl:37])[CH:19]=[CH:18][C:17]=2[N:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:37][C:20]1[CH:19]=[CH:18][C:17]2[N:16]=[C:15]([N:1]3[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]3)[CH:24]=[CH:23][C:22]=2[C:21]=1[C:25]([NH:27][CH2:28][C@:29]1([OH:36])[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]1)=[O:26]
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: OC1CCNCC1
Agent: O[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(O)CC4)ccc23)C1

Procedure:
The title compound was prepared by the method of Example 1, step e) by reacting piperidin-4-ol (28 mg) (instead of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.10 g) and diisopropylethylamine (0.11 g) in acetonitrile (2 ml) to afford the title compound as a white solid (99 mg). m.p. 120° C. dec.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20].C(O)CO.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.[Cu]I>[F:22][C:13]([F:12])([F:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Ic1cnc2ccccc2c1
Reactant: FC(F)(F)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: FC(F)(F)c1ccccc1Sc1cnc2ccccc2c1
Yield: 112.9 %

Procedure:
A mixture of 3-iodoquinoline (6 g, 23.5 mmol), 2-trifluoromethyl benzenethiol (5 g, 28 mmol), CuI (225 mg, 3.89 mmol), ethylene glycol (3.5 g, 56.4 mmol), K2CO3 (8 g, 58 mmol) in isopropanol (20 mL) was refluxed under N2 for 12 h. The reaction mixture was filtered through a short pad of silica gel and the filtrate was concentrated in vacuo to dryness. The product was purified by flash column chromatography on silica gel to give the product 3-(2-trifluoromethyl-phenylsulfanyl)-quinoline (8.1 g, 95%)
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9].[NH2:10][NH2:11]>C(O)(=O)C>[CH3:4][C:3]1[C:2]([O:9][C:5]2[CH:6]=[CH:7][C:2]([C:1]#[N:8])=[CH:3][CH:4]=2)=[C:7]([CH3:6])[NH:11][N:10]=1
Reactant: NN
Reactant: O
Reactant: N#Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1n[nH]c(C)c1Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
The benzonitrile of Preparation 1 (7.2 g, 33 mmol) was dissolved in acetic acid (70 ml). Hydrazine hydrate (1.9 ml, 39.7 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour, under nitrogen. It was then concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with dichloromethane:ethyl acetate (3:1 then 1:1, by volume) to provide the title compound (4.09 g, 88%) as a pale yellow solid.