Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>CN(C=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17][CH2:16]1)=[O:19])[CH3:22]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3o2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-benzooxazole (8.00 g, 52.1 mmol, 1.0 equiv) and ethyl 4-amino-1-piperidine carboxylate (10.78 g, 62.5 mmol, 1.2 equiv) in anhydrous DMF (50 mL) was stirred at rt. A precipitate formed over night which was filtered off, the volume of the filtrate reduced and the residue taken up in ethyl acetate (10 mL). Precipitation of this solution from hexane provided an additional batch of the title compound as a white solid. Combined yield: 6.8 g (45%). 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J=7.2 Hz, 3H), 1.48-1.52 (m, 2H), 2.14-2.18 (m, 2H), 3.09 (br t, 2H), 3.81-3.95 (m, 1H), 4.12-4.18 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 5.64 (br d, J=7.8 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.93, 32.53, 42.85, 50.66, 61.72, 109.00, 116.62, 121.24, 124.24, 143.10, 148.66, 155.72, 161.32. MS (ISP): 290.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH:2]=[CH2:3].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: C=CCNC(N)=S
Solvent: CCO
Product: C=CCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 42 was repeated but using 20 g of allylthiourea, 37 g of ethyl bromopyruvate and 200 ml of ethanol, giving the title compound as a pale yellow powder.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](OCC)=[O:10].[H-].[Na+]>C1COCC1>[CH:9]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[I:1])=[O:10]
Reactant: CCOC=O
Reactant: Nc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CNc1ccccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.1 %

Procedure:
A solution of 2-iodaniline (6.0 g, 27.4 mmol) and ethyl formate (11.1 mL, 137.4 mmol) in 200 mL of THF was added dropwise to a suspension of sodium hydride (1.4 g, 34.2 mmol) in 250 mL of THF. The mixture was stirred at room temperature for 24 hours, quenched with water and extracted into ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated to give 6.3 g of crude N-formyl-2-iodoaniline as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH:19]=[CH:20][C:21]([OH:23])=[O:22]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:15])([F:16])[F:17])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=CC(=O)O
Solvent: CCO
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CCC(=O)O
Yield: 80.9 %

Procedure:
To 100 ml of ethanol are added 8.8 g (0.025 mole) of 3-{2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-2-propenoic acid to produce a solution which is added to a pressure bottle and flushed with nitrogen. To the solution is added 1 g of 10% palladium on carbon. The pressure bottle is placed in a hydrogenation apparatus and pressurized to 1384 g/cm2 (50 lbs/in.2) with hydrogen. The pressure bottle is shaken until the pressure ceases dropping. The resulting solution is vented, filtered and evaporated at reduced pressure to obtain a residual solid which is recrystallized from chlorobutane o give 7.0 gm of 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid having a melting point of 116°-117°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[CH2:25]([O:27][C:28](=[O:33])[CH2:29]C([O-])=O)[CH3:26].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:9])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 178.7 %

Procedure:
To a solution of 4-methoxybenzoic acid (26.2 g, 172 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (30.7 g, 189 mmol) and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added monoethyl-malonate magnesium salt (27.1 g, 94.7 mmol) was added and the mixture was stirred at 60° C. for 2 hrs. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(4-methoxyphenyl)-3-oxopropionate (37.6 g, 94% w/w,. 92%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C[O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20](OC)O1>N1C=CC=CC=1.C(O)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]1[CH:20]=[CH:21][C:22]([CH:18]=[O:17])=[CH:23]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1n1ccc(C=O)c1
Yield: 61.1 %

Procedure:
A solution of trans-(2-amino-cyclohexyl)-carbamic acid tert-butyl ester (Tetrahedron Lett. 2000, 41, 9607; 400 mg, 1.87 mmol) and 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (365 mg, 2.05 mmol) in pyridine (0.5 mL) and acetic acid (0.82 mL) was heated at 100° C. for 4.5 h. After cooling, the reaction mixture was partitioned between ethyl acetate and 10% aq. citric acid solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) yielded the title compound (334 mg, 61%). Off-white solid, MS (ISP) 293.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 290 mg (0.90 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclopentanecarboxamide, 140 mg (0.90 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:39]2[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=2)[CH:15]=1)[C:4]([OH:34])=[O:3]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3,5-bis-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.94-1.01 (m, 6H), 1.54-1.65 (m, 1H), 1.79 (ddd, J=13.82, 7.09, 6.97 Hz, 1H), 2.04-2.15 (m, 1H), 3.85 (t, J=7.70 Hz, 1H), 7.56 (d, J=1.71 Hz, 1H), 7.64 (s, 1H), 7.67 (t, J=1.59 Hz, 1H), 7.73 (s, 4H), 7.90 (s, 1H), 8.02 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[C:11]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH2:16]([NH2:18])[CH3:17]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([NH:18][CH2:16][CH3:17])=[N:6][N:5]2[C:11]=1[S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Reactant: CCN
Solvent: CC#N
Product: CCNc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (2.00 g, 7.50 mmol) and ethylamine (50%, 10.0 ml) were stirred in acetonitrile (100 ml) at 70° C. for 8 hours. The reaction mixture was concentrated to dryness, dissolved in ice-water (50.0 ml), and adjusted to pH 6 with conc. hydrochloric acid. The precipitated crystals were filtered and washed with water to give the title compound as pale yellow crystals. The yield was 1.10 g (53.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][N:15]=[C:16](Br)[C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2].[CH2:22]([N:24]([CH2:27][CH3:28])[C:25]#[N:26])[CH3:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:22]([N:24]([C:25]1[N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:15]=[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:26]=1)[CH2:27][CH3:28])[CH3:23]
Reactant: CC(C)(C)C(Br)=NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCN(C#N)CC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
7.4 g (0.02 mol) of 2,2-dimethylpropionyl bromide 2-nitro-4-trifluoromethylphenylhydrazone and 2.0 g (0.02 mol) of N,N-diethylcyanamide were added to 100 ml of toluene. Then, 2.2 g (0.022 mol) of triethylamine was dropwise added under stirring at room temperature. After completion of the dropwise addition, stirring was continued at room temperature for further 1 hour. Then, 100 ml of toluene was added and washed with water. The organic layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 6.5 g (yield: 84.4%) of the desired compound as a pale yellow liquid. Refractive index nD20 : 1.4911.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([N:29]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:32]4[CH:31]=[CH:30]3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([N:29]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:32]4[CH:31]=[CH:30]3)[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Yield: 62.5 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (403) (900 mg. 1.8 mmol) in a mixture of tetrahydrofuran:water (2:1) (30 mL) was added lithium hydroxide monohydrate (756 g, 18.0 mmol) and the mixture was refluxed for 24 h (TLC, ethyl acetate, Rf=0.1). After completion of reaction, volatiles were evaporated and the aqueous part was washed with ethyl acetate (3×30 mL). The aqueous layer was acidified with HCl (6N) to pH 3 and extracted with ethyl acetate (3×50 mL). The organic phase was thereafter dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl methyl)-pyrimidine-4-carboxylic acid (404) (500 mg, 62%) as an off-white sticky solid.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C([BH3-])#N.[Na+].[CH2:13]([CH:20]1[C:24]2[CH:25]=[C:26]([CH:29]=O)[CH:27]=[CH:28][C:23]=2[O:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([CH:20]1[C:24]2[CH:25]=[C:26]([CH2:29][NH:6][CH:5]([CH3:7])[C:4]([NH:3][CH3:2])=[O:8])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNC(=O)[C@H](C)N
Reactant: O=Cc1ccc2c(c1)C(Cc1ccccc1)CO2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(C)NCc1ccc2c(c1)C(Cc1ccccc1)CO2
Reaction time: 12 h
Yield: 49.7 %

Procedure:
To a solution of (S)-N-methyl-alaninamide hydrochloride (0.50 g, 3.6 mmol) in methanol (10 ml), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.44 g, 6.9 mmol) and a solution of 3-benzyl-2,3-dihydro-1-benzofuran-5-carbaldehyde (0.75 g, 3.6 mmol) in methanol (10 ml) were added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (ethyl acetate) affording 0.58 g of title compound (50% yield).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](OCC)[O:32]CC)[CH:26]=2)[CH:8]=[CH:9][CH:10]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][CH:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])[CH:12]([C:25]4[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=4)[CH:31]=[O:32])[C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C=O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for 3 hr. The mixture was then adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,9-diyl)dibenzaldehyde (160 mg, yield 88%) as a light yellow solid. LC-MS (ESI) m/z: 396 (M+1)+.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[C:14]2[NH:15][CH:16]=[CH:17][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C([C:20]([O-:22])=[O:21])C>C(O)C.O>[O:4]=[C:5]1[C:14]2[NH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: CCC(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 101.1 %

Procedure:
1.64 g (39 mmol) of lithium hydroxide monohydrate is added to 1 g (3.9 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 1) suspended in 45 mL of ethanol and 45 mL of water, and the solution is stirred for 17 h at 70° C. then 5 h at 100° C. The ethanol is evaporated under vacuum and distilled water is added. The aqueous solution is washed with ethyl acetate then acidified with acetic acid to pH 4-5. The precipitate that forms is filtered then dried under vacuum at 55° C. to give 0.9 g (100%) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 49.6 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (49 mg, 50% over 2 steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.22 (m, 2H), 8.12 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.70 (dd, J=9.2, 2.7 Hz, 1H), 7.34 (s, 2H), 7.13 (d, J=9.3 Hz, 1H), 4.52 (s, 1H), 4.02 (dt, J=13.0, 4.1 Hz, 1H), 3.35 (m, 2H), 2.85 (tt, J=7.8, 4.5 Hz, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.73 (q, J=9.8 Hz, 2H), 1.22 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 99.6% (AUC), tR=10.95 min.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:61])[C:51]4[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=4)=[CH:45][CH:44]=3)[CH:41]=2)[CH2:36][N:35]1[C:62]1([C:66]([O:68]C)=[O:67])[CH2:65][CH2:64][CH2:63]1>>[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:61])[C:51]4[CH:56]=[CH:55][C:54]([C:57]([F:59])([F:58])[F:60])=[CH:53][CH:52]=4)=[CH:47][CH:48]=3)[CH:41]=2)[CH2:36][N:35]1[C:62]1([C:66]([OH:68])=[O:67])[CH2:65][CH2:64][CH2:63]1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4)cc3C2=O)CCC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CCC2)C3)cc1)c1ccc(C(F)(F)F)cc1
Yield: 96 %

Procedure:
The compound of example 580 was prepared analogous to compound of example 98 by hydrolysis of compound of example 579.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)[CH3:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][C:1](=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])[CH3:2]
Reactant: CC(=O)C1CC(C)(C)CCC1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)=C1CC(C)(C)CCC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
At 0° C., a solution of 2-acetyl-4,4-dimethyl-cyclohexanone (5.00 g, 29.7 mmol) in chloroform (15 mL) is treated with oxalyl chloride (7.54 g, 59.4 mmol). The mixture is heated to 60° C. and stirred for 15 min before it is poured onto water. The organic phase is separated, washed with sat. aq. NaHCO3 solution and brine, dried over MgSO4 and evaporated to dryness to give crude 2-(1-chloro-ethylidene)-4,4-dimethyl-cyclohexanone (3.2 g, containing regio-isomer) as a brown oil, LC-MS: tR=1.00 min.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].CN(C)C=O.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>ClCCl>[Si:12]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(O)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 10 h
Yield: 44.1 %

Procedure:
A 50 mL round bottom flask was charged with (±)-1,2-butanediol (1 g, 11.09 mmol) and to it was added dimethylformamide (8 mL) followed by tert-butyldimethylsilyl chloride (2.5 g, 16.64 mmol) and imidazole (1.88 g, 27.7 mmol). The reaction mixture was stirred for 10 hours after which it was diluted with dichloromethane and poured into a separatory funnel and washed with water (80 mL) and brine and dried over magnesium sulfate. After filtration and concentration the crude oil was purified by silica gel flash chromatography (hexanes:ethylacetate) to obtain 1 gm of pure desired product in 45% yield. 1H (CDCl3) δ(ppm): 3.6 (m, 1H). 3.5 (m, 1H), 3.4 (m, 1H), 2.4 (s, 1H), 1.44 (m, 2H), 0.99 (t, 3H), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].C(O)(=O)C.C(O)(=O)C.[CH3:24][N:25]([CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:26]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([CH2:27][N:25]([CH3:26])[CH3:24])[CH2:29][CH2:30]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Solvent: CC(=O)O
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (360 mg, 1.5 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (500 mg, 1.8 mmol) to afford the desired product (340 mg, 63%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.89 (s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 5.16-4.96 (m, 1H), 2.67 (s, 3H), 2.34-2.24 (m, 2H), 2.22 (s, 6H), 2.14 (d, J=7.1 Hz, 2H), 1.98-1.89 (m, 2H), 1.56-1.47 (m, 1H), 1.41-1.32 (m, 2H), 1.28-1.10 (m, 2H); ESI MS m/z 361 [M+H]+; HPLC 98.8% (AUC), tR=8.42 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].O>CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: O
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 35 %

Procedure:
20 g of 2,6-diacetylpyridine (0.123 mol), 19.08 g of 2-chloro-4,6-dimethylaniline (0.123 mol) and 0.5 g of p-toluenesulfonic acid were heated under reflux on a water separator in 500 ml of heptane for 75 min. The insoluble solid was filtered off. The solvent was distilled off from the filtrate down to 150 ml, and the remaining filtrate was cooled to room temperature, while stirring. 25.3 g of a yellow solid precipitated out. This was filtered off and recrystallized from 60 ml of hot isopropanol. A total of 12.9 g (0.043 mol) of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-pyridin-2-yl}ethanone were obtained in a yield of 35%.
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=[C:9]=[S:10].[CH3:23][C:24]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)([CH3:27])[C:25]#[N:26].ClCCl.CC(C)=O>C1COCC1>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([N:28]2[C:24]([CH3:23])([CH3:27])[C:25](=[NH:26])[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:22])[F:21])[CH:12]=3)[C:9]2=[S:10])=[CH:34][CH:33]=1
Reactant: Cc1ccc(NC(C)(C)C#N)cc1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C2(C)C)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
Triethylamine (0.101 g, 1 mmol) was added to a solution of 1a (0.456 g, 2 mmol) and 5a (0.348 g, 2 mmol) in dry THF (3 ml). The reaction mixture was stirred at 0° C. for 2 days and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 95:5) to afford 4-[3-(4-methylphenyl)-5-imino-4,4-dimethyl-2 -thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 5b (0.136 g, 0.34 mmol, 17%).