Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][CH:23]([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:27]5[S:28][C:24]([CH:23]([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(C(F)F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)F)s4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (350 mg), (5-(difluoromethyl)-2-thienyl)methanol (409 mg) and tributylphosphine (755 mg) in THF (12 ml) was added 1,1′-(azodicarbonyl)dipiperidine (942 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (hexane/EtOAc then MeOH/EtOAc). The resulting solid was recrystallized from EtOH-hexane to give the title compound (80 mg) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:16][OH:17].C(N(CC)CC)C>CO>[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NO)CC1
Yield: 63.8 %

Procedure:
15.5 g (77.6 mmol) of N-Boc-4-piperidone was refluxed for one hour in methanol in the presence of 7.0 g (100.8 mmol) of hydroxylamine hydrochloride and 14.1 ml (100.8 mmol) of triethylamine. Then, methanol was distilled off, and the residue was thoroughly washed with water in chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 10.6 g of N-Boc-4-hydroxyiminopiperidine as white powder.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.O=S(Cl)[Cl:14].CN(C=O)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]([C:7]([Cl:14])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(I)ccc1O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1O

Procedure:
5-Iodosalicylic acid (2.0 g, 7.58 mmol) in toluene was treated with SOCl2 (1.66 mL, 22.7 mmol) and catalytic DMF at reflux for 1 h. The reaction mixture was evaporated to dryness and the acid chloride used in the next step without purification.
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1>[CH:1]1([C@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: [H][H]
Solvent: C1CCOC1
Product: COC(=O)C[C@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 35 °C
Reaction time: 22 h

Procedure:
A solution of (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 815 mg) in tetrahydrofuran (THF, 8.0 mL) in a pressure glass tube was treated with the catalyst [Rh(COD)(−)-DuanPhos](BF4) (4.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 35° C. under this hydrogen pressure for 22 h. When HPLC analysis showed that the substrate was almost completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 94.7% ee (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with tetrahydrofuran (THF, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (778 mg) was analyzed by chiral HPLC analysis and result showed a 94.7% of enantiomeric excess favoring the second peak (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]\[C:32]#[N:33])=[CH:26][CH:25]=1>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]2[CH:10]=[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[CH:31]=[C:32]([NH2:33])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccc(F)cc2F)n1)c1ccccc1
Reactant: N#C/C=C\c1ccncc1
Product: Nc1cc(-c2ccncc2)cc2nc(-c3ccc(F)cc3F)nn12

Procedure:
The title compound, MS m/e (%): 323 (M+, 100), 303 (60), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole and (E)/(Z)-3-pyridin-4-yl-acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1C
Yield: 92 %

Procedure:
To 5-chloro-2-methyl-4-nitrobenzoic acid (900 mg, 4.15 mmol) in methanol (10 mL) was added thionyl chloride (0.3 mL, 4.15 mmol) dropwise. The mixture was heated to reflux for 5 h and then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give methyl 5-chloro-2-methyl-4-nitrobenzoate (880 mg, 92%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=230 at 4.25 min. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.73 (s, 1H), 3.95 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: I(Cl)(=O)=O.[I:5](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH2:20]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH:22]2[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[CH:21]12.C(Cl)Cl.O>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[I:5][C:37]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][CH:22]3[CH:21]([C:39]=2[CH:38]=1)[CH2:20][CH:24]=[N:23]3
Reactant: O=I(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccccc3OCC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Ic1ccc2c(c1)C1CC=NC1CO2
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Zinc chloride (2.49 g, 18.3 mmol) and benzyltrimethylammonium dichloroiodate (4.25 g, 12.2 mmol) were added to a suspension of tert-butyl 1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole-3(2H)-carboxylate (2.8 g, 10.2 mmol) in acetic acid (30 mL). The reaction mixture was stirred at 50° C. for 16 h, cooled to r.t. and DCM (60 mL) was added followed by H2O (60 mL). The layers were separated. The organic layer was washed with H2O (2×) and saturated NaHSO3 (15 mL), and the solvent was evaporated to afford 8-iodo-1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole, which was taken directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1ncc(Br)cn1
Product: CN1CCN(c2ncc(Br)cn2)CC1

Procedure:
Following the procedure described for Intermediate 234 using 5-bromo-2-chloropyrimidine and N-methylpiperazine provided the title compound. ESMS [M+H]+: 257.0/259.0.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:8][C:7]2[C:9]([CH3:14])=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:13][C:11]1[CH:10]=[C:9]([CH3:14])[C:7]2[NH:8][C:4]([S:3][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:5][C:6]=2[CH:12]=1
Reactant: Cc1cc(Cl)cc2nc(S)[nH]c12
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc2nc(Sc3ccc(C=O)o3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Aldehyde intermediate preparation: A mixture of sodium hydride (60% dispersion in mineral oil, 0.304 g, 7.61 mmol) and 2-mercapto-5-chloro-7-methyl-1H-benzimidazole (0.945 g, 4.76 mmol) in 15 ml of tetrahydrofuran is stirred at room temperature for 2 hours. 5-nitro-2-furaldehyde (0.671 g, 4.56 mmol) in 7 ml of tetrahydrofuran is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 911 mg of 5-(5-chloro-7-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=65%. Analytical LC/MS (method B): retention time: 3.67 min., m/z=292.98 (1 Cl, positive ion mode).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[F:34][C:35]([F:58])([F:57])[CH2:36][O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[C:49]([CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][N:54]1[CH2:55][CH2:56][CH:51]([C:49]([C:41]2[N:40]([CH2:39][CH2:38][O:37][CH2:36][C:35]([F:58])([F:34])[F:57])[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=2)=[O:50])[CH2:52][CH2:53]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(F)cc1
Reactant: O=C(c1nc2ccccc2n1CCOCC(F)(F)F)C1CCNCC1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3n2CCOCC(F)(F)F)CC1)c1ccc(F)cc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(4-fluorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide and 4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1)=O.O1CC[CH2:24][CH2:23]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(OCC)(=O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:3][CH2:23][CH3:24])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(-c2c(C)cccc2C=O)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: CCOC(C)=O
Product: CCCc1cccc(C)c1-c1cccc(C(=O)OC)c1
Yield: 85 %

Procedure:
To a suspension (21 mL) of ethyltriphenylphosphonium bromide (1.55 g, 4.13 mmol) in tetrahydrofuran was added sodium hydride (0.14 g, 3.58 mmol) at room temperature with stirring, and the mixture was stirred at the same temperature for 20 min. A solution (20 mL) of methyl 2′-formyl-6′-methylbiphenyl-3-carboxylate (0.70 g, 2.75 mmol) in tetrahydrofuran was added and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. Then a mixture of the obtained residue, 10% Pd carbon (0.1 g) and methanol (14 mL) was stirred under a hydrogen atmosphere for 2 hrs. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=4/1) to give the title compound (0.63 g, yield 85%) as a colorless oil.
Reaction SMILES: [O:1]([C:9]1[C:10]([CH3:46])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([C:34]3[S:44][C:43]4[N:45]5[C:36](=[CH:37][N:38]=[C:39]5[CH:40]=[CH:41][CH:42]=4)[CH:35]=3)=[O:33])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2)[Si](C(C)(C)C)(C)C.[ClH:47].CO>C(O)C>[ClH:47].[ClH:47].[OH:1][C:9]1[C:10]([CH3:46])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([C:34]3[S:44][C:43]4[N:45]5[C:36](=[CH:37][N:38]=[C:39]5[CH:40]=[CH:41][CH:42]=4)[CH:35]=3)=[O:33])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(CCN1CCC(CNC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN1CCC(CNC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a solution of 1.00 g (1.51 mM) of N-[1-[2-(6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-yl)ethyl]piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (4 ml) was added 4.0 ml (16 mM) of 4N—HCl/methanol and the mixture was stirred at room temperature for 63 hours. After the solvent was distilled off under reduced pressure, ethanol was added and the mixture was stirred at room temperature for 1 hour. The resulting crystal crop was harvested by filtration and rinsed with ethanol and diethyl ether to provide the title compound as orange-colored crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][O:12][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#CCO)CCOCC1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1(C#CCOCc2ccc3ccccc3c2)CCOCC1

Procedure:
4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran (1.2 g, 6.97 mmol) was treated with sodium hydride in THF (18 mL). After gas evolution ceased, a solution of 2-(bromomethyl)napthalene (1.70 g, 7.67 mmol) in dry DMF (9 mL) was added. After 3 hours at ambient temperature the reaction was quenched with saturated aqueous ammonium chloride. The resulting two-phase mixture was extracted with ether (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100 g, 10% ethyl acetate: hexanes) provided the title compound. (2.00 g, 92%) as a colorless oil. 1H NMR (300 MHz, CDCl3); 7.80-7.90 (4H, m), 7.47-7.52 (3H, m), 4.70 (2H, s), 4.32 (2H, s), 3.87 (2H, dd, J=12,4.5 Hz), 3.67 (2H, dd, J=12,3 Hz), 3.40 (3H, s), 1.95 (2H, br d, J=13 Hz), 1.49 (2H, ddd, J=13,9,4.5 Hz); MS (M+NH4)+ =328. Analysis calc'd for C20H22O3 : C, 77.39; H, 7.14; Found: C, 76.10; H, 7.10.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred suspension of 6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 990 mg, 5.15 mmol) in DMF (3.0 mL) is added K2CO3 (855 mg, 1.2 equiv.) followed by MeI (0.64 mL, 2.0 equiv.). The resulting solution is stirred overnight at room temperature. Water (20 mL) is then added and the reaction mixture is extracted with ethyl acetate (20 mL×2) and washed with saline (20 mL). The organic layers are collected and dried over MgSO4. Solvent is removed to yield the title compound as a yellow solid (956 mg, 90%). 1H NMR (300 MHz, DMSO) δ 8.16-7.26 (m, 3H), 3.30 (s, 3H), 3.00 (t, 2H), 2.61 (m, 2H).
Reaction SMILES: NC(=O)[C@@H](NC(C1(NC(=O)OC(C)(C)C)CCOCC1)=O)CC1C=CC(C2C=CC(C(F)(F)F)=CC=2)=CC=1.[NH2:39][C:40](=O)[C@@H:41]([NH:60][C:61]([C:63]1([NH:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)=[O:62])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([S:55]([CH2:58][CH3:59])(=[O:57])=[O:56])=[CH:51][CH:50]=2)=[CH:45][CH:44]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:40]([C@@H:41]([NH:60][C:61]([C:63]1([NH:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)=[O:62])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([S:55]([CH2:58][CH3:59])(=[O:57])=[O:56])=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)#[N:39]
Reactant: CCS(=O)(=O)c1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1
Agent: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The mixture of (S)-tert-butyl 4-(1-amino-1-oxo-3-(4′-(trifluoromethyl)biphenyl-4-yl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate and (S)-tert-butyl 4-(1-amino-3-(4′-(ethylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iv), 1.7 g) in dichloromethane (15 mL) was treated with Burgess' reagent (1.19 g) and the mixture was stirred at room temperature for 72 h. The reaction was evaporated onto silica and purified on a silica column eluting with 20% ethyl acetate in isohexane, then 50% ethyl acetate in isohexane and finally 100% ethyl acetate to afford after evaporation of the relevant fractions (S)-tert-butyl 4-(1-cyano-2-(4′-(trifluoromethyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (650 mg) and (S)-tert-butyl 4-(1-cyano-2-(4′-(ethylsulfonyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (920 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C(F)(F)F)cc4)c3)cnc2c1F
Yield: 7 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-trifluoromethylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-4′-trifluoromethylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (10 mg, 7%): m/z (ES+) 433 [MH+].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 70.7 %

Procedure:
0.9 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylate is refluxed for 4 hours in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0.2 ml of concentrated sulphuric acid. At reflux temperature, the reaction mixture is then treated with 10 ml of water. The solid is filtered off with suction at room temperature, washed with water and dried. 0.58 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid (71% of theory) is obtained.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].CCOCC.[NH2:12][CH2:13][CH2:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CC#[N:24]>>[F:1][B-:2]([F:5])([F:4])[F:3].[NH3+:12][CH2:13][CH2:14][C:15]1[CH:21]=[CH:20][C:18]([N+:19]#[N:24])=[CH:17][CH:16]=1.[F:1][B-:2]([F:5])([F:4])[F:3]
Reactant: CC#N
Reactant: NCCc1ccc(N)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: N#[N+]c1ccc(CC[NH3+])cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A 50% solution of tetrafluoroboric acid in Et2O (0.5mL, 3.7 mmol) was added to a solution of 4-(2-aminoethyl)aniline (0.5mg, 3.7 mmol) in MeCN (Amp at −40° C. under argon. The mixture was stirred 10 min, then nitrosyl tetrafluorobbrate (450 mg, 3.8 mmol) was added dropwise. After 30 min of stirring at −40 ° C. Et2O (100 mL) was added. The white precipitate obtained was filtered and washed twice with Et2O to give a white powder (1.18 g, 99%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27](O)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:27]([C:26]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:25]=3[N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:28])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=O.[NH2:11][NH:12][C:13]([NH2:15])=[S:14].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]([F:10])([F:9])[C:3]([C:4]1[S:14][C:13]([NH2:15])=[N:12][N:11]=1)([CH3:8])[CH3:7]
Reactant: NNC(N)=S
Reactant: CC(C)(C(=O)O)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(c1nnc(N)s1)C(F)(F)F

Procedure:
Commercially available, 3,3,3-trifluoro-2,2-dimethylpropanoic acid (Matrix), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 212 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[BrH:17].[OH-].[Na+]>O>[Br:17][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(Br)nc1

Procedure:
2.35 g 6-chloro-3-(4-fluorobenzoyl)-pyridine (see Ex. 5) and 50 ml 47% aqueous HBr are refluxed for 1 hr. After this time a control by gas chromatography reveals no starting chloro-derivative is present. The reaction liquid is added to water, and a yellow solid is formed. The mixture is basified with concentrated NaOH, and the crystalline solid is filtered and recrystallised from methanol:water. Yield: 0.9 g title product, as white crystals, m.p. 97°-8° C.; UV (water): λmax. 278 nm, ε: 16,600; Br 28.34 (28.53); F 7.11 (6.78).