Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO[CH2:29][CH2:30][O:31][CH3:32]>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:32][O:31][C:30]1[CH:7]=[CH:6][C:5]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:10][CH:29]=1
Reactant: COCCOC
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 77 %

Procedure:
A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyplhenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20–30% EtOAc in hexanes affording the title compound (251 mg, 77% yield): ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:27])[C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1>>[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)/[C:19](=[C:20](/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)\[C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)/[C:18]2=[O:27])[CH:11]=1
Reactant: Ic1ccsc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccsc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 3-iodo-thiophene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.65 (d, 1H), 6.76-6.82 (m, 2H), 7.06-7.11 (m, 2H), 7.33-7.43 (m, 8H), 7.50 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([C:40](=[O:42])[CH3:41])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol) and triethylamine (33 μL, 0.234 mmol) were dissolved in THF (1 mL). Acetyl chloride (9 mg, 0.117 mmol) was then added dropwise and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 9:1+NH3)=100:0→0:100) to afford the title compound as a foam (tR 3.50 min (conditions 3), MH+=470.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.51 (s, 1H); 8.34 (m, 1H); 8.09 (m, 2H); 8.04 (d, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.48 (m, 2H); 3.92 (m, 1H); 3.21 (m, 1H); 2.72 (m, 1H); 2.04 (m, 5H); 1.89 (m, 1H); 1.75 (m, 1H)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([OH:7])=O.O[NH:18][C:19](=[NH:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:28]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: O=C(O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Temperature: 132.5 °C
Reaction time: 2 h

Procedure:
N,N-Dicyclohexylcarbodiimide (0.615 g, 0.003 mol) is added to a solution of 3-chloro-4-cyclohexyl benzoic acid (0.475 g, 0.002 mol), N-hydroxy-4-hydroxymethylbenzamidine (0.45 g, 0.003 mol) and N-hydroxybenzotriazole monohydrate (0.457 g, 0.003 mol) in N,N-dimethylformamide (10 mL). The reaction mixture is stirred at 130-135° C. for 2 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×20 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (3×15 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 15:85) to give {4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]phenyl}methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.CO[CH2:44][CH2:45]OC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([CH:44]=[CH2:45])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol) and tetrakis(triphenylphosphine)-palladium(0) (2.2 mg, 0.2 mmol, 1.0 mol %) in DME (1.5 mL) under an atmosphere of argon was stirred at room temperature for 10 min. To the resulting mixture was added K2CO3 (26.7 mg, 0.19 mmol, 1.0 equiv) and water (0.5 mL), followed by 2,4,6-trivinyl-cyclotriboroxane pyridine complex (46.4 mg, 0.19 mmol, 1 equiv). The resulting mixture was heated at the reflux temperature for 16 h with monitoring by UPLC-MS. The resulting mixture was concentrated under reduced pressure and treated with water (10 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (10 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 99% CH2Cl2/1% MeOH for 1 min., gradient to 90% CH2Cl2/10% MeOH over 10 min.; 90% CH2Cl2/10% MeOH over 5.2 min.) to give {1-[4-(3-phenyl-7-vinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (77 mg, 85%),:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCCC1>>[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][N:20]([C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)CCNc1ccccc1
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-methylamino-3-nitro-benzoic acid chloride (23.3 mmol) and 3-phenylamino-propionic acid methyl ester (23.3 mmol) in 80 mL dry tetrahydrofuran (THF) triethylamine (50.2 mmol) was added dropwise under stirring at room temperature. After three hours the reaction mixture was evaporated to dryness, the remaining solid triturated with water and the solid product isolated through filtration.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2O.O=P(Cl)(Cl)[Cl:24]>>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2[Cl:24]
Reactant: CCOC(=O)c1cnc2ccc(OC(F)(F)F)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OC(F)(F)F)cc2c1Cl
Reaction time: 0.25 h

Procedure:
6-Trifluoromethoxy-4-hydroxy-3-ethoxycarbonylquinoline (3 g, 10 mmol) and POCl3 (8 mL) were mixed together and the mixture was heated at reflux for 6 h. The excess POCl3 was removed under vacuum. The solid residue was suspended in ice-cold 1N NaOH and the mixture was stirred for 15 min. The solid was filtered off, washed several times with water and dried over P2O5 to give 6-trifluoromethoxy-4-chloro-3-ethoxycarbonylquinoline as an off-white solid.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13]=[O:14])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.CC1C2C=[C:22]3[O:25][CH2:26]C(=O)CO[C:21]3=CC=2CC1>>[CH3:10][C:8]1([CH3:9])[C:3]2[CH:2]=[C:1]3[O:11][CH2:12][C:13](=[O:14])[CH2:26][O:25][C:22]3=[CH:21][C:5]=2[CH2:6][CH2:7]1
Reactant: CC(C)=CCCC(C)CCOCC=O
Reactant: CC1CCc2cc3c(cc21)OCC(=O)CO3
Product: CC1(C)CCc2cc3c(cc21)OCC(=O)CO3

Procedure:
Odor: Marine-aldehyde-like, floral-rosy odor with nuances of citronelloxyacetaldehyde [(3,7-dimethyl-6-octenyl)oxyacetaldehyde]. -IR (film): ν=1322/1253/1281/1350 cm−1 (ν ring), 1040/1067 cm−1 (ν C—O—C), 1484/1438 cm−1 (ν C═C, Ar), 1736 cm−1 (ν C═O). 1H-NMR (CDCl3): δ=1.22 (s, 6H, 1-Me2), 1.92 (t, J=7.2 Hz, 2H, 2-H2), 2.79 (t, J=7.2 Hz, 2H, 3-H2), 4.67 (d, J=2.8 Hz, 4H, 6-, 8-H2), 6.75 (s, 1H, 4-H), 6.81 (s, 1H, 10-H). -13C-NMR (CDCl3): δ=28.43 (2q, 1-Me2), 29.29 (t, C-3), 41.68 (t, C-2), 43.61 (s, C-1), 75.47/75.51 (2t, C-6,-8), 113.99 (d, C-10), 116.31 (d, C-4), 138.98 (s, C-3a), 146.83/147.22 (2s, C-4a, -9a), 148.30 (s, C-10a), 205.06 (s, C-7). -MS (EI): m/z (%)=133 (33) [C9H9O+], 145 (6) [C11H13+], 161 (7) [M+-CH3-2CO], 189 (2) [M+-CH3—CO], 217 (100) [M+-CH3], 232 (30) [M+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][CH:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[C:17](=[O:26])[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[CH2:20][CH2:21][CH:15]([NH:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:16]1
Reactant: O=C1CC(NCc2ccccc2)CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CC(NCc2ccccc2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran was cooled to 0° C. and a solution of 8 g of 7-benzylamino-6,7,8,9-tetrahydro [5H] benzocyclohepten-5-one in 150 ml of tetrahydrofuran was added thereto over 30 minutes at 0° to 5° C. The mixture was stirred for 2 hours at 0° C. and was then poured into an aqueous solution saturated with ammonium chloride. The mixture was filtered and the filtrate was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution, was dried and filtered. The filtrate was evaporated to dryness under reduced pressure at 40° C. to 8.4 g of raw product which was a mixture of the A and B isomers of 5ξ-hydroxy-7-benzylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [C:1]1(=[O:11])[NH:7][CH2:6][CH2:5][CH2:4][N:3]2[CH2:8][CH2:9][CH2:10][C@@H:2]12.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32]([N:7]3[CH2:6][CH2:5][CH2:4][N:3]4[CH2:8][CH2:9][CH2:10][C@H:2]4[C:1]3=[O:11])=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:15]=[C:14]([C:13]([F:47])([F:12])[F:46])[CH:19]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1NCCCN2CCC[C@@H]12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1-c1cc(N2CCCN3CCC[C@H]3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h
Yield: 21.6 %

Procedure:
A solution of (9aS)-octahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one (Polish Journal of Chemistry, 59(10-12), 1243-6; 1985) (31 mg, 0.201 mmol), 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (53 mg, 0.0996 mmol), N,N′-dimethyethylendiamine (224, 0.207 mmol), copper(I) iodide (38 mg, 0.200 mmol) and caesium carbonate (65 mg, 0.199 mmol) in 3 mL of dioxane was heated to 100° C. in a sealed vial overnight. Heating was continued for additional 2 days. It was diluted with 10 mL of EtOAc and extracted with water. The organics were dried (Na2SO4) and the solvent removed. The product was isolated by flash chromatography (silica, cyclohexane:EtOAc 90:10 to 30:70). Thus were obtained 14 mg of the target compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].C(=O)(O)[O-].[Na+]>COCCOC.O.C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ncccn2)cc1
Yield: 84.4 %

Procedure:
A solution of 2-bromopyrimidine (1.00 g, 6.3 mmol) and tetrakistriphenylphosphine(O) palladium (0.218 g, 0.189 mmol) in ethylene glycol dimethyl ether (30 mL) was stirred at room temperature for 10 minutes. A solution of 4-formylbenzene boronic acid (1.14 g, 7.61 mmol) and sodium bicarbonate 1.58 g, 18.9 mmol) in 15 mL water was added and the reaction was hated at reflux for 16 h. The mixture was diluted with water and CH2Cl2. The layers were separated, and the aqueous solution was washed with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (10% to 30% hexanes in EtOAc) to afford the title compound (0.979 g). 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.83 (s, 2H), 8.82 (s, 1H), 7.98 (s, 2H), 7.23 (s, 2H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].[OH:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[CH:1]1([O:4][C:5]2[N:10]=[C:9]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(OC2CC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(-c2c(Oc3ccncc3)nc(OC3CC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Cyclopropyloxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (MRf product) (Example 55, Step A), (25 mg, 0.05 mmol) was reacted with 1.1 equivalents each of sodium hydride (60% in oil, 2.5 mg, 0.06 mmol) and 4-hydroxypyridine (5.9 mg, 0.062 mmol) by the procedure described in Examples 16 to afford the title compound: HPLC/MS: m/e=498 (M++1); Rt=3.49 min. 1H-NMR 400 MHz (CDCl3): δ 1.60-1.90 (m, 4H), 2.74 (m, 1H), 4.12 (d, J=7 Hz, 2H), 7.10-7.18 (m, 3H), 7.20-7.30 (m, 5H), 7.35 (d, J=2 Hz, 1H), 8.66 (d, J=6 Hz, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.CC(C)=O.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>CCCCCC>[CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.[C:41]([O-:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([O-:46])=[O:45]
Reactant: O=C(O)/C=C/C(=O)O
Agent: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
Ticagrelor (0.5 g) and acetone (13 mL) were charged into a round bottom flask and the mixture was stirred at about 25-30° C. for about 15 minutes for clear solution. Then fumaric acid (0.12 g) was added to the above reaction mixture at 25-35° C. and mixture was stirred for 4-5 hours. To the clear solution, n-hexane (50 mL) was added and stirred for about 90 minutes for solid separation. The solid was filtered, washed with n-hexane (5 mL) and dried to afford the title compound in about 65% yield having chiral HPLC purity of about 99.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]4)=[C:8]4[CH:9]=[C:10]([O:17]C)[CH:11]=[C:12]([N:13]([CH3:16])[C:14]=2[CH:15]=1)[C:7]=34.ClC1C=CC2C3N=C4C(C=CC=C4)=C4C=C(OC)C=C(NC=2C=1)C=34.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]4)=[C:8]4[CH:9]=[C:10]([OH:17])[CH:11]=[C:12]([N:13]([CH3:16])[C:14]=2[CH:15]=1)[C:7]=34
Reactant: COc1cc2c3c(nc4ccccc4c3c1)-c1ccc(Cl)cc1N2C
Agent: COc1cc2c3c(nc4ccccc4c3c1)-c1ccc(Cl)cc1N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1c2cc(Cl)ccc2-c2nc3ccccc3c3cc(O)cc1c23

Procedure:
The general procedure (Method K) applied to 10-chloro-6-methoxy-8-methyl-8H-quino[4,3,2-kl]acridine, 33 (2.6 g, 7.5 mmol), with aluminium chloride (3.2 g, 3 eq), and benzene (500 ml) gave the title compound a yellow solid (2.43 g, 7.3 mmol, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:23][C:24]=1[CH3:25].FC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[F:13]
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1F)C(=O)OC
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1F
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (example 13 f]) was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [Na+].[I-:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@H:16]([CH3:38])[C@:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([O:24][C:25]([O:27][CH2:28]Cl)=[O:26])[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:4]>CC(C)=O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@H:16]([CH3:38])[C@:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([O:24][C:25]([O:27][CH2:28][I:2])=[O:26])[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:4]
Reactant: [I-]
Reactant: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OC(=O)OCCl)c1ccc(F)cc1F
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OC(=O)OCI)c1ccc(F)cc1F
Temperature: 50 °C
Yield: 93.1 %

Procedure:
NaI (19.4 mmol) was added to an acetone solution of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane (6.5 mmol). The reaction was heated to 50° C. for 5 hours. After cooling to room temperature, the crude reaction was filtered, concentrated, and then dissolved in EtOAc. The organic layer was washed sequentially with aqueous solutions of NaHCO3 and Na2S2O3. The organic layer was then washed with H2O, dried over MgSO4, and was concentrated to obtain 3.76 g of the subtitled compound as a yellow solid. 1H NMR (DMSO) δ8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 6.08 (s, 2H), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=622).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH:14]=[CH:15]C(OC)=[N:17][C:18]=2[C:19](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:21]=1)=[O:11])[CH3:8].[CH3:32][N:33]([CH:35]=[O:36])[CH3:34]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH:14]=[CH:15][C:35](=[O:36])[N:33]3[CH2:34][C@H:18]([NH2:17])[C:19](=[CH:20][CH:21]=1)[C:32]=23)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c2nc(OC)ccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc2c3c1ccc(=O)n3C[C@@H]2N
Reaction time: 0.33 h

Procedure:
A solution of vinylboronic anhydride pyridine complex (1:1; 3.81 g) in DMF (240 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (731 mg) and stirred under nitrogen for 20 min. The reaction mixture was sequentially treated with K2CO3 (4.372 g) water (73 mL) and 2-methoxy-8-[[(trifluoromethyl)sulfonyl]oxy]-5-quinoline carboxylic acid ethyl ester (12.0 g; prepared in analogy to the corresponding n-butyl ester described in WO 2006/046552) and further stirred at 85° C. overnight. The reaction mixture was diluted with water and extracted with ether. The org. layer was dried over MgSO4, concentrated to dryness and purified by CC (Hex/EA, 4:1), affording a yellow oil (5.40 g; 66% yield).