Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([OH:44])=[O:43])=[CH:38][CH:37]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[F:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[C:39]([C:42]([OH:44])=[O:43])[CH:40]=[CH:41][C:36]=2[C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:21]([F:20])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)cc1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3'-fluoro-4'-octyloxybiphenyl-4-carboxylic acid was used instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=2)=[O:14])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Product: O=C(CCCCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Yield: 43 %

Procedure:
Starting with methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate and 8-bromooctylbenzene, the title compound (28 mg, 43%) was obtained as a white solid using a procedure similar to Example 1. 1H NMR (400 MHz, CDCl3) 1.34 (m, 8H), 1.62 (quintet, J=7.3 Hz, 2H), 1.81 (quintet, J=7.3 Hz, 2H), 2.61 (dd, J=7.9, 7.6 Hz, 2H), 3.21 (t, J=7.5 Hz, 2H), 7.16-7.19 (m, 3H), 7.26-7.30 (m, 2H), 7.54 (dd, J=7.6, 4.7, Hz, 1H), 7.93 (td, J=7.6, 1.5 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.85 (d, J=4.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.6, 28.9, 29.00, 29.02, 29.2, 31.4, 35.90, 35.92, 40.1, 124.0, 125.5, 126.7, 128.2, 128.4, 137.3, 142.6, 142.8, 150.8, 161.2, 165.0, 187.2; MALDI-FTMS m/z 364.2024 (C22H25N3O2+H+ requires 364.2019).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>C(OCC)C>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCCCC
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOCC
Product: CCCCN(CCCC)C(=O)CC(C)=O
Temperature: 150 °C
Yield: 67.7 %

Procedure:
A! A mixture of ethyl acetoacetate (50 g, 0.38 mole) and dibutylamine (49.65 g, 0.38 mole) was heated to 150° C. for one day. After cooling, the reaction mixture was taken up in 500 ml of ethyl ether and washed with 200 ml of 1N HCl and 200 ml of water. The ether phase was anhydrified over sodium sulfate, and evaporated to dryness thus yielding 86.7 g of a crude which was distilled under vacuum to give 54.86 g (yield: 67%) of N,N-dibutyl-3-oxo-butanamide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At RT, 90 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 30 μl (0.37 mmol) of pyrrolidine were stirred in 2.3 ml of THF for 30 min. About 12 ml of water were added to the reaction mixture, the suspension formed was freed from THF on a rotary evaporator, and the precipitate formed was filtered off and washed with water and dried under high vacuum. This gave 78 mg (81% of theory) of the desired target compound.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Yield: 47.1 %

Procedure:
1.3 g of crude 17-difluoromethylene-3-(tetrahydro-pyran-2-yl-oxy)-estra-1,3,5(10)-trien in 30 ml of methanol and 3 ml of water are suspended with 1.3 g of oxalic acid for 1 hour at a bath temperature of 100° C. Then, it is added to water, extracted three times with dichloromethane, washed neutral, dried on sodium sulfate and evaporated to dryness in a vacuum. 1.0 g of crude 17-difluoromethylene-estra-1,3,5(10)-trien-3-ol, which is chromatographed on silica gel with hexane/ethyl acetate, is obtained. 480 mg of pure 17-difluoromethylene-estra-1,3,5(10) -trien-3-ol is obtained as colorless crystals with a melting point of 154-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=O)[S:29][CH:30]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:31]([C:28]3[S:29][CH:30]=[C:26]([O:25][CH3:24])[CH:27]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COc1csc(C=O)c1
Product: COc1csc(-c2nc3cc(Br)cc(N)n3n2)c1

Procedure:
The title compound, MS m/e (%): 325 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 4-methoxy-thiophene-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C.CO>[NH2:34][C:35]1[C:36]([C:43]([N:45]=[C:46]([NH2:49])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]3[NH:21][CH:20]=[CH:19][N:18]=3)=[O:15])=[CH:10][CH:9]=2)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1
Reactant: NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamide dihydrochloride 35 (99 mg, 0.27 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) in absolute ethanol (4 mL) and anhydrous methanol (3 mL) was stirred at 70° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (130 mg, 0.34 mmol) was added in one portion. The reaction mixture was stirred for 3 h and then cooled to room temperature. The yellow insolubles were removed by suction filtration and the liquid filtrate was concentrated by rotary evaporation. The crude residue was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, 150:10:1, and 100:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamide as a yellow solid (44 mg, 29% yield). The free base thus obtained was dissolved in methanol and treated with 4 drops of 4 N aqueous HCl. The solution was concentrated under reduced pressure and further dried under vacuum to give the final compound 36. mp 172–174° C. 1H NMR (300 MHz, CD3OD) δ 1.61–1.77 (m, 4H), 2.58–2.70 (m, 2H), 3.32-3.40 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.20 (s, 2H). m/z (ESI): 501 [C21H25ClN10O3+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:19]([NH:21][CH3:22])=[O:20]>>[CH2:23]([C:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:16])([C:19](=[O:20])[NH:21][CH3:22])[CH2:25][CH3:26])[CH3:24]
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1cccc(-c2ccc(Cl)cc2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=360.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].Cl.Cl.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:15][C:11]2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Agent: Cl
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(N(C)C)cc1

Procedure:
The title compound was prepared as a white solid (0.160 g, 23% for two steps) from 6-methoxy-5-formyl-2-naphthoic acid methyl ester using p-dimethylamino-benzyl amine dihydrochloride and a procedure similar to steps 3-4 of Example 1, mp >215° C. (decomp.); 1H NMR (DMSO-d6) δ2.97 (s, 6H), 3.94 (s, 3H), 4.14-4.23 (m, 2H), 4.39-4.48 (m, 2H), 6.88-7.14 (bs, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.59 (d, J=9.3 Hz, 1H), 7.97 (dd, J=1.7, 8.9 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.59 (d, J=1.6 Hz, 1H), 9.05-9.24 (bs, 2H), 11.90-13.75 (bs, 1H); IR (neat) 3320, 2330-3130, 1705, 1670, 1625, 1580, 1515, 1485, 1460, 1430, 1280, 1260, 1220, 1200, 1175, and 1100 cm−1; mass spectrum [(+) ESI], m/z 365 (M +H)+ and [(−) ESI], m/z 363 (M−H)−; Anal. Calcd. for C22H24N2O3. 2HCl.1.25H2O: C, 57.46; H, 6.25; N, 6.09, Found: C, 57.25; H, 6.37; N, 5.93.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C@H:3]([NH:6][CH3:7])[CH2:4][OH:5].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[CH3:19].O>C(Cl)Cl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:6]([C@@H:3]([CH:2]([CH3:8])[CH3:1])[CH2:4][OH:5])[CH3:7])=[O:15])=[CH:12][C:11]=1[CH3:19]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN[C@H](CO)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](CO)C(C)C)ccc1F
Reaction time: 3 h
Yield: 83.5 %

Procedure:
TEA (1.774 mL, 12.80 mmol) was added to (S)-3-methyl-2-(methylamino)butan-1-ol (Compound B2.1) (0.5 g, 4.3 mmol) in DCM (5 mL). The mixture was cooled on an ice-bath and 4-fluoro-3-methylbenzoyl chloride (1.27 mL, 8.96 mmol) in DCM (5 mL) was dropwise (over 5 min) added. The resultant mixture was stirred at rt over night. Additional TEA (0.414 mL, 2.99 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.368 g, 2.13 mmol) was added and the stirring was continued for 3 h. Water (12 mL) was added to the mixture. The organic layer was dried though a phase separator and concentrated. THF (15 mL) and NaOH was added to the residue and the resulting mixture was stirred over night. The mixture was neutralized by the addition of acetic acid. The solvent was removed and DCM (50 mL) was added. The organic phase was washed with Na2CO3 (saturated, 2×30 mL) and brine (30 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.91 g, 85%). The obtained crude product was used without further purification. Mixture of rotamers: (600 MHz, CD3OD) δ 0.77-0.82, 0.95, 1.02, 1.74-1.83, 1.89-1.97, 2.23-2.31, 2.83, 2.92, 3.37-3.44, 3.58-3.74, 3.79-3.86, 4.23-4.31, 7.01-7.11, 7.18-7.36. Ratio major:minor:1:0.6. Total no of protons: 19.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br[CH2:12][CH:13]=[CH:14][CH2:15][CH3:16]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH:13]=[CH:14][CH2:15][CH3:16]
Reactant: CCC=CCBr
Reactant: Oc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=CCOc1ccccc1I
Temperature: 25 °C
Yield: 10.8 %

Procedure:
An ice-cold solution of 2-iodophenol (6.00 g, 272 mmol) in DMF (100 mL) was added dropwise to a solution of NaH (1.30 g, 54.4 mmol) in DMF. 1-Bromo-pent-2-ene (4.87 g, 327 mmol) was then added. The mixture slowly warmed to room temperature overnight. The reaction was quenched with water (50 mL) and the mixture was extracted with CH2Cl2 (3×). The combined organics were washed with brine and dried over Na2SO4 to give the title compound (8.50 g, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.75 (dd, J=7.5, 1.2, Hz, 1H), 7.36-7.30 (m, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.76-6.71 (m, 1H), 6.01-5.89 (m, 1H), 5.67 (t, J=5.7 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 2.08 (t, J=7.5 Hz, 2H), 0.98 (t, J=7.5 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:31][CH2:32][OH:33])[CH2:20][C:21]([N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:31][CH:32]=[O:33])[CH2:20][C:21]([N:23]([CH3:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C(=O)CC(CC=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reaction time: 0.5 h
Yield: 117.3 %

Procedure:
Oxalyl chloride (7.74 g) in CH2Cl2 (80 mL) was added to a -78° C. solution of DMSO (9.5 g) in CH2Cl2 (30 mL) over 15 mins. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (50 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (17.15 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (14.76 g) in CH2Cl2 (20 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was washed with water (100 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (20 g). Silica gel chromatography eluting with 5-15% EtOAc/Hex gave the title compound (15.2 g).
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](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[NH2:28][CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:41]5[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12](=[O:15])[CH2:13][CH3:14])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 8.5 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino)pyridin-2-yl)pyrrolidin-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 (81 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (8 mg, 9% over two steps) as an orange-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.27-8.19 (m, 2H), 8.07-7.99 (m, 2H), 7.85-7.70 (m, 1H), 7.29 (s, 2H), 6.96 (d, J=9.2 Hz, 1H), 4.15-4.05 (m, 1H), 4.07-3.99 (m, 1H), 3.89-3.80 (m, 1H), 3.79-165 (m, 2H), 3.27-3.18 (m, 2H), 2.63-2.52 (m, 1H), 2.34-2.23 (m, 1H), 1.31-1.22 (m, 3H); ESI MS m/z 522 [C27H25Cl2N5O2+H]+; HPLC 95.7% (AUC), tR=10.98 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:23])[NH:10][C:11]3[C:16]([C:17]=2[OH:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:13]([Cl:22])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38]O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38][O:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([Cl:22])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=2)[NH:10][C:9](=[O:23])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(O)c1-c1cccc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
To a solution of 3-(3-bromophenyl)-7-chloro-4-hydroxy-6-nitro-1H-quinolin-2-one (100 mg in 4.0 mL of tetrahydrofuran) at 0° C. was added 64 mg of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and 93 mg of triphenylphosphine followed by 0.050 mL of diethyl azodicarboxylate and the mixture warmed to room temperature. After 20 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethylacetate, 2:1) to give the title compound (92 mg).
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[C:11](=[C:27]1[CH2:28][CH2:29][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)[CH3:16]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.67 h

Procedure:
To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mol) in dry THF (300 mL), under N2 atmosphere, was added a solution of methyl 2-(diethoxyphosphoryl)-propionate (33.6 g, 0.15 mol) in dry THF (150 mL) at such a rate to keep the temperature below 30° C. After being stirred at r.t for 40 min, a solution of N-benzyl-4-piperidone (28.35 g, 0.15 mol) in dry THF (100 mL) was added dropwise keeping the temperature below 30° C. After the addition was completed, the mixture was stirred at r.t for 30 min. The reaction was quenched with NH4Cl (sat. aq., 400 mL). The mixture was extracted with Et2O (300 mL×2) and the combined extracts were washed with brine, dried and concentrated to give the crude product as a red oil, which was used directly in the next step.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[C:3]([O:5]C)=[O:4].C(=O)([O-])[O-:18].[Na+].[Na+].Cl.[Cl-].[Na+]>O>[OH:18][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCCC(O)C(=O)O

Procedure:
A stirred mixture of 295 g. of dimethyl 2-bromononanedioate, [Acta. Chim. Acad. Sci. Hung., 46, 85(1965)], 371 g. of anhydrous sodium carbonate, and 3 liters of water is heated at reflux for 22 hours. The solution which forms is cooled and acidified with 600 ml. of 12 N hydrochloric acid. The mixture is saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give 184 g. of white solid, m.p. 86°-92° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>COCCOC>[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[S:31])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CCCCC2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CCN(CC)c1ccc(S(=O)(=O)N2CCCCC2=S)cc1

Procedure:
A suspension comprising 5.5 g of 1-[4-(diethylamino)benzenesulphonyl]-2-piperidinone and 3.74 g of Lawesson reagent in 80 cm3 of ethylene glycol dimethyl ether is heated to reflux for 1 hour. The mixture is allowed to return to room temperature and is then evaporated to dryness. The residue is chromatographed on silica (eluant: ethyl acetate/n-hexane, 1:1) and 4 g of product (m.p. 135°-140° C.) are obtained, which product is purified by 3 successive crystallizations in ethanol. 2 g of expected pure product are obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[C:14]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[N:24]S(C(C)(C)C)=O)#[N:15].Cl>C(OCC)C>[Br:13][C:9]1[CH:8]=[C:7]([C:23]2([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:17]3[C:16](=[C:21]([F:22])[CH:20]=[CH:19][CH:18]=3)[C:14]([NH2:15])=[N:24]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: COc1cc(C(=NS(=O)C(C)(C)C)c2cccc(F)c2C#N)ccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
n-Butyllithium (1.7 mL, 4.17 mmol) (2.5 M in hexanes) was dropwise added to 1,3-dibromobenzene (0.504 mL, 4.17 mmol) in diethyl ether (25.00 mL) at −78° C. under argon. The resulting mixture was stirred at −78° C. for 1 h. Additional n-butyllithium (2.5 M in hexanes) (0.8 mL, 2.00 mmol) was added and the resulting reaction mixture was stirred at −78° C. for 30 min. N-((2-Cyano-3-fluorophenyl)(2-methoxypyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.500 g, 4.17 mmol) in diethyl ether (10.00 mL) was added dropwise and stirring was continued for 1 h at −78° C. Hydrochloric acid (25.04 mL, 12.52 mmol) (0.5 M in methanol) was added and the resulting reaction mixture was stirred at room temperature over night and concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica chromatography using 0% to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound 0.812 g, (47% yield).