Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:48][CH2:49][CH3:50])[N:18]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[C:19](=[O:32])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:48][CH2:49][CH3:50])[N:18]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[NH:3][C:4](=[O:7])[O:5][N:47]=3)=[CH:36][CH:35]=2)[C:19](=[O:32])[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(-c2ccc(OC(F)(F)F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(F)(F)F)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-6-oxo-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 62%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6].[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].[OH-].[Na+]>>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:5](=[C:4]([O:3][CH3:2])[CH:10]=[CH:9][C:8]=2[CH3:11])[N:6]=1
Reactant: COc1ccc(C)cc1N
Reactant: C/C=C/C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C)c2ccc(C)nc12
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 0.34 l concentrated HCl at 40° C. was added 275 parts 2-methoxy-5-methylaniline and further heated to 80° C. Then 154 parts crotonaldehyde was added dropwise, heated to 100° C. for 1 hour. The reaction was cooled to 30° C. and poured into 2.5 l ice water and neutralized with 50% NaOH. The product was filtered, washed with water, water pressed, washed with hexane and air dried to give 65% yield of 2,5-dimethyl-8-methoxyquinoline.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[CH3:44][C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:47][C:46]=1[CH2:56][C:57]1[O:58][C:59]2[CH:65]=[CH:64][C:63]([CH:66]=[O:67])=[CH:62][C:60]=2[CH:61]=1>ClCCl>[OH:67][C@H:66]([C:63]1[CH:64]=[CH:65][C:59]2[O:58][C:57]([CH2:56][C:46]3[N:47]=[C:48]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:49][C:45]=3[CH3:44])=[CH:61][C:60]=2[CH:62]=1)[C@H:15]([O:16][CH2:17][CH3:18])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:19]
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=O)ccc2o1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of (S)-4-benzyl-3-(ethoxyacetyl)oxazolidin-2-one (1.0 g, 3.8 mmol) in dichloromethane (10 ml), cooled to 0° C., was added freshly distilled dibutylboron triflate (1.1 ml, 4.6 mmol) dropwise, followed by triethylamine (0.69 m), 4.9 mmol). After 5 minutes the solution was cooled to -78° C. and a precooled solution of 2-(5-methyl-2-phenyl-4-oxazolyl) methyl-5-benzofurancarboxaldehyde (1.33 g, 4.2 mmol) in dichloromethane (5 ml) was added. After 20 minutes the mixture was warmed to 0° C. and stirred at that temperature for 1 hour then quenched with a solution of pH 7 buffer (10 ml) in methanol (30 ml), followed by a solution of 30% hydrogen peroxide (10 ml) in methanol (30 ml), and stirred at 0° C. for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate, 1:1) and obtained as a yellow solid (1.16 g, m.p. 66° C.).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[C@H:11]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C:9]([CH3:22])([CH3:21])[O:8]1)(=O)=O.[I-:23].[Na+]>C(#N)C>[CH2:14]([O:13][CH2:12][C@H:11]1[C@@H:7]([CH2:6][I:23])[O:8][C:9]([CH3:22])([CH3:21])[O:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [I-]
Reactant: CC1(C)O[C@@H](COCc2ccccc2)[C@H](COS(C)(=O)=O)O1
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)O[C@@H](COCc2ccccc2)[C@@H](CI)O1
Temperature: 80 °C
Reaction time: 22 h
Yield: 97.2 %

Procedure:
A solution of 46.19 g of the crude {(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl methanesulfonate obtained in Reference Example (1b) (140 mmol) and 62.87 g of sodium iodide (419 mmol) in acetonitrile (420 ml) was stirred at 80° C. for 22 hours. The reaction mixture was cooled and then concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1.5 M sodium sulfite aqueous solution, water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 49.20 g of the crude title compound.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:13])/[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.CN1CCOCC1.[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24](Cl)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C(OCC)(=O)C>[CH2:23]([C:24]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[N:13]=1)[C:22]([CH3:28])([CH3:27])[CH3:21]
Reactant: N/C(=N\O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Cc1nc(-c2ccc([N+](=O)[O-])cc2)no1
Reaction time: 1 h

Procedure:
To a suspension of (Z)—N′-hydroxy-4-nitrobenzimidamide (0.500 g, 2.76 mmol) in dichloromethane (6 ml) was added 4-methylmorpholine (0.455 ml, 4.14 mmol) followed by 3,3-dimethylbutanoyl chloride (0.422 ml, 3.04 mmol). After 1 hour, the crude reaction mixture was purified by normal phase chromatography and the collected intermediate was dissolved in dichloromethane (8 ml) and treated with tetrabutylammonium fluoride (1.0M in THF) (8.28 ml, 8.28 mmol). After 3 hours at room temperature, the mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [S].[BH4-].[Na+].[CH2:4]([O:7][C:8]1[CH:9]=[C:10]([N:18]([CH3:20])[CH3:19])[CH:11]=[C:12]([F:17])[C:13]=1[N+:14]([O-])=O)[CH:5]=[CH2:6].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>O1CCCC1.CCOCC>[CH2:4]([O:7][C:8]1[CH:9]=[C:10]([N:18]([CH3:20])[CH3:19])[CH:11]=[C:12]([F:17])[C:13]=1[NH:14][C:33]1[C:34]([Cl:38])=[CH:35][N:36]=[C:31]([Cl:30])[N:32]=1)[CH:5]=[CH2:6]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C=CCOc1cc(N(C)C)cc(F)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Agent: [S]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOc1cc(N(C)C)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Sulfur (1.2 g, 38 mmol) was added to Sodium tetrahydroborate (0.48 g, 13 mmol) in Tetrahydrofuran (20 mL). After 20 min, a solution of (3-Allyloxy-5-fluoro-4-nitro-phenyl)-dimethyl-amine (0.61 g, 2.5 mmol) in Tetrahydrofuran (20 mL) was added, and after 20 min the mixture was heated at 60° C. for an additional 2.5 h. The mixture was cooled, quenched with 100 mL satd. sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic extract was washed with brine, dried over sodium sulfate and conc. in vacuo. The residue was dissolved in N-Methylpyrrolidinone (10 mL) and N,N-Diisopropylethylamine (0.65 mL, 3.7 mmol) and 2,4,5-Trichloro-pyrimidine (0.60 mL, 5.2 mmol) were added. The mixture was heated under an atmosphere of Nitrogen at 80° C. After 2 h, the solution was cooled, diluted with 100 mL Ether and washed with water (3×20 mL) and brine (50 mL). The aq. extract was back extracted with DCM (2×50 mL), which was then diluted with 100 mL ether and washed with water (50 mL) and brine (50 mL). The organic extracts were combined, dried over sodium sulfate and diluted with an equal volume of hexane before filtering through a 2″h×3″w circular pad of silica gel to remove baseline colored impurities. The filtrate was conc. and chromatographed (ISCO 80 g silica gel, 0-20% EtOAc:Hex), with the product eluting at 20%. Following conc., 2-Allyloxy-N(1)-(2,5-dichloro-pyrimidin-4-yl)-6-fluoro-N(4),N(4)-dimethyl-benzene-1,4-diamine was isolated as a green film (140 mg, 15% over two steps). 1H-NMR (CDCl3): 8.11 (s, 1H), 6.62 (s, 1H), 6.12 (d, 1H, J=13.1 Hz), 5.97 (s, 1H), 5.95 (m, 1H), 5.32 (d, 1H, J=17.2 Hz), 5.23 (d, 1H, J=9.4 Hz), 4.55 (m, 2H), 2.96 (s, 6H); 19F-NMR (CDCl3): −118.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[C:38]6[CH:37]=[CH:36][C:35](Br)=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:40](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:41].[CH3:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>C1(C)C=CC=CC=1>[CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[C:38]6[CH:37]=[CH:36][C:35]([C:55]7[CH:54]=[CH:53][C:58]([CH:40]=[CH2:41])=[CH:57][CH:56]=7)=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)cc2)cc1
Temperature: 85 °C

Procedure:
9-(4′-(9H-carbazol-9-yl)biphenyl-4-yl)-3-bromo-9H-carbazole (0.5 g, 0.88 mmol) and 4-vinyl boronic acid (0.14 g, 0.98 mmol) and Pd(dba)3 (0.097 g, 0.01 mmol), CsCO3 (0.289 g, 0.88 mmol) were dissolved in toluene (25 mL). Tri-t-butyl phosphine 10 wt % in hexane (0.053 g, 0.026 mmol) was added and the reaction mixture was stirred vigorously while refluxed at 85° C. for 24 h. The reaction mixture was cooled down to room temperature, diluted with toluene and filtered through a celite filter bed. The organic extract was evaporated to dryness and purified by silica column chromatography using dichloromethane and pet-ether (40-60° C.) to give slightly brownish colour powder as the product (0.3 g)
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1.ClC(OCC)=O.O[N:55]1[C:59](=[O:60])[CH2:58][CH2:57][C:56]1=[O:61]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([O:47][N:55]3[C:59](=[O:60])[CH2:58][CH2:57][C:56]3=[O:61])=[O:46])=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:33]3[C:28]([N:27]=[C:26]4[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:19])=[CH:13][CH:12]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)O)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Agent: Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
1.41 ml of triethylamine are added to 3.1 g of (4) in 50 ml of tetrahydrofuran, the mixture is cooled to -20° C., and 0.474 ml of ethyl chloroformate is added. After stirring for 20 min, 575 mg of N-hydroxysuccinimide are added, and the mixture is stirred at -20° C. for 3 hours and left to reach room temperature overnight while stirring. The precipitate is filtered off with suction, the filtrate is concentrated, the residue is taken up in dichloromethane or ethyl acetate, and the resulting solution is washed with water, NaHCO3 solution and water and dried over MgSO4. The organic phase is concentrated, and the residue is recrystallized from toluene.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24]3[C:23]4[CH:22]=[C:21]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:20]=[CH:19][C:18]=4[N:17]=[CH:16][C:15]=3[N:14]([CH3:35])[C:13]2=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24]3[C:23]4[CH:22]=[C:21]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:20]=[CH:19][C:18]=4[N:17]=[CH:16][C:15]=3[N:14]([CH3:35])[C:13]2=[S:46])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3ncc21
Solvent: C1COCCO1
Product: Cn1c(=S)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3ncc21

Procedure:
100 mg (0.213 mmol) of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile (Example 7) and 95 mg (0.234 mmol) Lawesson reagent (Fluka, Buchs, Switzerland) in 1 ml of dioxane are heated at 100° C. for 96 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue is purified by preparative HPLC to provide the title compound as an off-white solid. ES-MS: 486 (M+H)+; analytical HPLC: tret=3.29 minutes (Grad 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH3:21])[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
Treat a mixture of (s)-(+)-2-sec-butylamino-6-methanesulfonylamino-isonicotinic acid methyl ester (13.63 g, 0.04523 mol) and potassium carbonate (12.50 g, 0.09046 mol) in DMF (42 mL) with iodomethane (7.90 g, 0.05563 mol). Stir at room temperature for 18 h, and add water (200 mL). The aqueous layer was extracted with methyl tert-butyl ether (5×150 mL). Wash the combined organic layers with 1 N lithium chloride (5×100 mL), dry (magnesium sulfate) and concentrate to give the title compound as a solid (13.19 g, 92%).
Reaction SMILES: Cl.C[N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][C:15]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14]3)[CH2:5][CH2:4]1.[Cl:28]C(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[ClH:28].[C:22]1([S:19]([C:15]2[CH:16]=[N:17][C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[N:6]2[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A stirred solution of 8-(4-methyl-piperazin-1-yl)-3-phenylsulfonylquinoline hydrochloride (D10) (0.148 g, 0.4 mmol), 1-chloroethyl chloroformate (0.093 ml, 0.85 mmol) and N,N-diisopropylethylamine (0.148 ml, 0.85 mmol) in 1,2-dichloroethane (9 ml) was heated at reflux for 1.25 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane, pooling fractions which contained the major component (Rf 0.9, methanol/dichloromethane 1:19). The purified material was redissolved in methanol (15 ml) and the solution was refluxed for 1 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to a solid which was stirred with diethyl ether (5 ml) and filtered to afford the title compound (D11) (0.08 g, 0.21 mmol, 51%);
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2].[OH-].[K+].C([OH:25])(C)(C)C>O>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:25])[NH2:2]
Reactant: N#CCc1c(-c2ccccc2)[nH]c2ncccc12
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1c(-c2ccccc2)[nH]c2ncccc12
Temperature: 25 °C

Procedure:
3-(Cyanomethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.37 g, 1.39 mmol), powdered KOH (0.82 g), and t-butanol (5 ml) were heated to reflux under argon for 3 h. The reaction mixture was then cooled to room temperature and diluted with deionized water (6.5 ml) to give a precipitate. The suspension was extracted with methylene chloride and filtered. The filter cake consisted of pure title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-].[K+].[Cl:37]CCl>O1CCCC1>[Cl-:37].[C:30]([CH:27]1[CH2:26][CH2:25][CH:24]([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][NH+:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:29][CH2:28]1)([OH:32])=[O:31]
Reactant: CCOC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Reactant: ClCCl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)F)cc[nH+]2)cc(-c2cnc(C3CCC(C(=O)O)CC3)s2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To ethyl 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (0.60 g, 0.12 mmol) in tetrahydrofuran (0.61 mL) was added potassium hydroxide (1.2 mL, 1 M in methanol) and the reaction was stirred overnight at room temperature. Upon completion, the reaction was diluted with dichloromethane and washed twice with hydrochloric acid (2 M in water). The organic layer was dried under reduced pressure to give 2-({3-[2-(4-carboxycyclohexyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-4-(trifluoromethyl)pyrimidin-1-ium chloride (0.060 g, 85% yield). MS ESI: [M+H]+ m/z 463.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=5.2, 1H), 8.06-7.81 (m, 2H), 7.44 (s, 1H), 7.27 (d, J=5.8, 1H), 7.14 (s, 1H), 2.30 (s, 3H), 2.14-2.04 (m, 110, 2.03-1.83 (m, 4H), 1.82-1.61 (m, 3H), 1.55-1.33 (m, 2H). rhSYK activity=+++
Reaction SMILES: [C:1]([CH:6]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:18])(OCC)=O.[C:19]1(=[O:23])[O:22]C[CH2:20]1.C1C=CC=CC=1.[H-].[Na+]>C(OCC)C.C1(C)C=CC=CC=1>[O:18]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:6]1[CH2:1][CH2:20][C:19]([OH:23])=[O:22]
Reactant: O=C1CCO1
Reactant: CCOC(=O)C1CCCCCCCCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(O)CCC1CCCCCCCCCCC1=O

Procedure:
The inventors have established a more effective method for producing β-(2-oxocyclododecyl)propionic acid by the following steps: reacting cyclododecanone with diethyl carbonate to give carbethoxycyclododecanone, reacting the carboethoxycyclododecanone with β-propiolactone in a solvent having no alkoxy group, such as benzene, toluene and ethyl ether in the presence of sodium hydride, hydrolyzing the resulting product, and then decarboxylating to give β-(2-oxocyclododecyl)propionic acid in high yield (79% based on the starting cyclododecanone theoretically).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.[NH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[C:10]1[C:11]([OH:13])=[N:21][C:22]2[N:23]([CH:24]=[CH:25][N:26]=2)[C:16]=1[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: Nc1ncc[nH]1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Oc1nc2nccn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(2,4,6-trifluorophenyl)malonate (U.S. Pat. No. 6,156,925) (870 mg, 3.0 mmol), 2-aminoimidazole (Hel. Acta. Chim. 76, 2066 (1993))(274 mg, 3.3 mmol), and 1.0 mL of tributylamine is stirred under nitrogen atmosphere at 160° C. for 0.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acide (×3) and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is dissolved in ethyl acetate (5 mL) and to this solution is added hexanes (50 mL). The precipitates are collected by filtration, washed with hexanes to give 6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine-5,7-diol as a tan solid (180 mg). MS: m/z 279.9(M−H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
In a round-bottomed flask, a solution of the crude cinnamoyl chloride (25.2 g) in dichloromethane (50 ml) was added to a stirring mixture of pyridine (14.4 g, 182 mmol) and 4-dimethylaminopyridine (1.44 g, 11.8 mmol) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes before a solution of 4-fluoroaniline (13.2 g, 118.79 mmol) in dichloromethane (50 ml) was added over 20 min. After being stirred for 3 h at room temperature, the mixture was quenched with water (500 ml) and extracted with dichloromethane (3×150 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography using 1-5% ethyl acetate in petroleum to elute. The product-containing fractions were combined to afford N-(4-fluorophenyl)cinnamamide as a light yellow solid (17.8 g, 61%); (ES, m/z): [M+H]+ 242; 1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 7.70-7.75 (m, 5H), 7.39-7.65 (m, 3H), 7.15 (t, J=9.0 Hz, 2H), 6.79 (d, J=15.6 Hz, 1H).