Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:21])[C:3](=[CH:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[C:4]#[N:5].[CH:22]([O:25][C:26]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]([NH2:33])[CH:27]=1)([CH3:24])[CH3:23]>C(O)(C)C>[NH2:32][C:30]1[N:31]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[C:27]2[CH:6]([C:7]3[C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:20])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[C:3]([C:4]#[N:5])=[C:2]([CH3:21])[NH:33][C:28]=2[N:29]=1
Reactant: CC(=O)C(C#N)=Cc1cccc2c1-c1ccccc1C2=O
Reactant: CC(C)Oc1cc(N)nc(N)n1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c2-c2ccccc2C3=O)c2c(nc(N)nc2OC(C)C)N1

Procedure:
81 mg (0.29 mmol) of 3-oxo-2-[(9-oxo-9H-fluoren-4-yl)methylene]butanenitrile are dissolved with 50 mg (0.29 mmol) of 6-isopropoxypyrimidine-2,4-diamine in 5 ml of isopropanol and heated under reflux under argon for 6 h. The suspension is cooled and then filtered with suction, and the remaining solid is washed with isopropanol. 74 mg (59% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[O:25]1[CH2:28][CH:27]([NH2:29])[CH2:26]1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[CH2:13][C@@H:12]([OH:24])[CH2:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([NH:29][CH:27]2[CH2:28][O:25][CH2:26]2)[N:7]=[CH:6][N:5]=1)=[O:9]
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Reactant: NC1COC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(NC2COC2)ncn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propyl)pyrimidine-4-carboxamide (347 mg, 1 mmol) in i-PrOH (5 mL) was added oxetan-3-amine (73.1 mg, 1 mmol) and DIPEA (129 mg, 1 mmol). The resulting mixture was stirred at 110° C. for 16 hours, at which time LCMS showed the completion of the reaction. After evaporation of the solvent, the residue was purified by preparative HPLC to give the target compound (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide (62.5 mg, yield: 16.3%). 1H NMR (400 MHz, MeOD-d4) δ 8.24 (s, 1H), 7.15-7.05 (m, 4H), 7.02-6.98 (m, 1H), 5.09 (s, 1H), 4.95 (t, J=6.8 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 4.10-4.03 (m, 1H), 3.72 (s, 2H), 3.56-3.46 (m, 2H), 2.96-2.91 (m, 2H), 2.87-2.80 (m, 2H), 2.65 (d, J=6.3 Hz, 2H). LCMS (m/z): 384.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]1>>[CH3:15][C:5]1[N:4]=[N:3][C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)=[C:7]2[C:6]=1[N:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]2
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: CN1CCN(CCCN)CC1
Product: Cc1nnc(NCCCN2CCN(C)CC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-methyl-1-(3-aminopropyl)piperazine at 150° C. gave the title compound as the free base (yellow solid, 16% of theory) after purification by HPLC and trituration with i-propylether, mp 60° C. (foams). The free base was converted to the trihydrochloride salt mp. 280° C., 275° C. shrink (hydroscopic).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1([CH2:13]O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.CCOCC.C(#N)C.[I:52]I>>[CH2:1]([N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1([CH2:13][I:52])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN(Cc1ccccc1)CC1(CO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CN(Cc1ccccc1)CC1(CI)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 63.8 %

Procedure:
To a stirred solution of methyl (benzyl{[1-(hydroxymethyl)cyclopropyl]methyl}-amino)acetate (1.1 g, 0.0042 mol), triphenylphosphine (2.74 g, 0.0104 mol) and 1H-imidazole (0.711 g, 0.0104 mol) in ether (30.0 mL, 0.286 mol) and ACN (10.0 mL, 0.192 mol) at 0° C. was added iodine (2.12 g, 0.00835 mol). The resulting yellow suspension was stirred at 0° C. for 50 min. The reaction was quenched by the addition of 10% aqueous Na2S2O3 (30 ml) and saturated aqueous NaHCO3 (30 mL). The product was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Combiflash chromatography eluting with 0-15% EtOAc/hexanes to afford the desired product (1.0 g). LC/MS: 374.1 (M+1H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.C(O)(=[O:29])C>O>[CH3:1][S:2]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:19][CH:20]=2)[C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1)=[O:29]
Reactant: CC(=O)O
Reactant: CSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: O
Product: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (505 mg) was dissolved in acetic acid (12 ml), and a solution of oxoso (registered mark) (1.05 g) in water (3 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (50 ml), and the white precipitate was collected by filtration, and washed with diisopropyl ether. The obtained solid was dried under reduced pressure, and subjected to azeotropic distillation with acetonitrile to give the title compound (528 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][N:10]1[CH:11]=[CH:12][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH2:8][C:9]1=[O:13]
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Reactant: ClCCCBr
Product: COc1ccc2c(c1)CC(=O)N(CCCCl)C=C2

Procedure:
3-(3-Chloro-propyl)-8-methoxy-1,3-dihydro-benzo[d]azepin-2-one was prepared from 8-methoxy-1,3-dihydro-benzo[d]azepin-2-one and 1-bromo-3-chloropropane in an analogous manner to Example 251a. Product isolated as a brown solid (5.87 g, 84%). LC/MS (ESI+) 266 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:11])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[CH:12]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[NH2:11])=[O:5])[CH3:2]
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 25 °C

Procedure:
Ethyl-3-Aminopyrazole-4-carboxylate 9 (Acros, 15.5 g, 100.0 mmol), cyclohexylbromide (Acros, 21.9 g, 130 mmol), anhydrous potassium carbonate (Fisher, 27.6 g, 200 mmol), Adogen 464 (Acros, 2.5 g) and aqueous sodium hydroxide (0.1 mL of a 12.5M solution) were combined in 250 mL of toluene and refluxed under argon overnight. Additional cyclohexylbromide (21.9 g, 130 mmol) and potassium carbonate (27.6 g, 200 mmol) were then added and the reaction mixture was resubjected to the reaction conditions for an additional 24 hours. The reaction was permitted to cool to room temperature and the organics were washed with 100 mL water. The organic layer was separated and dried (magnesium sulfate). Concentration of the organics afforded a solid which was subjected to flash chromatography on silica gel (gradient elution 9:1 to 6:1 to 3:1 hexane: ethyl acetate) to afford two principle products. Compound 11 (923 mg, 4%) elutes first and Compound 10 (1.755 g, 7%) elutes second. A considerable amount of material was present in mixed fractions. Compound 10: MS (ES+ calculated: 237.30; found: 238.10 M+H). HPLC (98% purity, retention time 13.623 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 6.19 (br s, 2H), 4.43 (q, J=7 Hz, 2H), 4.05 (m, 1H), 1.83-1.22 (m, 10H), 1.23 (t, J=7Hz, 3H). Compound 11: MS (ES+ calculated: 237.30; found: 238.14 M+H). HPLC (100% purity, retention time 13.408 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 5.29 (br s, 2H), 4.15 (q, J=7 Hz, 2H), 3.89 (m, 1H), 1.97-1.25 (m, 10H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.ClCCl.O>CN1C(=O)CCC1>[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH2:16][CH2:15]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CN1CCCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: CN1CCCN(c2ccn3ncc(C=O)c3n2)CC1
Temperature: 140 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in NMP was added 1-methylhomopiperazine (103 μL, 0.829 mmol). The mixture was heated in microwave for 10 minutes at 140° C. Dichloromethane and water were added, and the product extracted in dichloromethane. The organic layer was then washed with water and dried over Na2SO4 and concentrated under reduced pressure to yield 5-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=260)
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[C:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])([C:22]#[N:23])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2([C:22]#[N:23])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[C:25]([F:31])[CH:26]=1
Reactant: COc1ccc(Cl)cc1C1C(C(=O)OC(C)(C)C)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1C(C(=O)O)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 97 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 85b (0.3 g, 0.56 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.32 g, 97%).
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[CH:29]([C:31]1[CH:45]=[CH:44][C:34]([O:35][CH2:36][CH2:37][CH2:38]OS(C)(=O)=O)=[CH:33][CH:32]=1)=[O:30].O>C(#N)C>[F:1][CH2:38][CH2:37][CH2:36][O:35][C:34]1[CH:44]=[CH:45][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)OCCCOc1ccc(C=O)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCCCF)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Potassium fluoride (Fluka, 7.2 mg, 0.124 mmol) and kryptofix 222 (Fluka, 46.7 mg, 0.124 mmol) were dissolved in dry acetonitrile (2.5 ml). After 10 min the mixture was added to a stirred solution of methanesulfonic acid 3-(4-formylphenoxy)propyl ester 13 (16.0 mg, 0.062 mmol) in dry acetonitrile (1.5 ml). The reaction mixture was heated at 60° C. for 30 minutes. The product was confirmed by analytical HPLC (column Phenomenex Luna C18(2) 3 μm 4.6×50 mm, solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 10-80% B over 10 min; flow 2.0 ml/min, UV detection at 214 and 254 nm) co-eluting with commercial standard (Fluorochem) at 5.0 minutes.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].I[CH2:13][CH2:14][CH3:15].Cl>O.CN1CCCC1=O>[OH:9][C:8]1[CH:7]=[C:5]([OH:6])[N:4]=[C:2]([S:3][CH2:13][CH2:14][CH3:15])[N:1]=1
Reactant: CCCI
Reactant: O=C1CC(=O)NC(=S)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCSc1nc(O)cc(O)n1

Procedure:
Water (670 ml) was added to 2-thiobarbituric acid (200 g). The resulting mixture was stirred and sodium hydroxide (126.3 g) was added in portions. The mixture was stirred for 40 mm. then diluted with water. 1-Methyl-2-pyrrolidinone (400 ml) and 1-iodopropane (140.9 ml) were then added. The resulting slurry was stirred at 20° C. for 22 h. The pH of the mixture was then adjusted to 6.5 by addition of 1M HCl (600 ml) over 30 min, then to pH 2.5 by the addition of 6 M HCl (180 ml) over a further 30 min. The resulting slurry was stirred for 18 h and the product was isolated by filtration and washed successively with water (4×100 ml), ethanol (200 ml) and water (2×200 ml). The product was dried under reduced pressure overnight at 50° C. to yield the title product as a white powder (185 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C@@H:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38]Br)=[C:30]2[C:35]=1[NH:34][C:33](=[O:36])[CH:32]=[CH:31]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C@@H:37]([O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[CH2:38][NH:14][CH2:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=3)=[CH:7][CH:8]=2)=[C:30]2[C:35]=1[NH:34][C:33](=[O:36])[CH:32]=[CH:31]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCc1ccc(Oc2cccc(Cl)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(Oc2cccc(Cl)c2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 55.4 %

Procedure:
A slurry of the product of step (b) (1.39 g), 8-(benzyloxy)-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one (2.49 g), sodium iodide (1.14 g) and potassium carbonate (2.11 g) in DMSO (7 mL) was heated at 90° C. for 5 h. The solution was allowed to cool, diluted with dichloromethane (60 mL) and washed with water (4×30 mL) then brine (40 mL). The organics were dried over sodium sulfate, concentrated in vacuo and the residue purified by reverse phase HPLC to afford the title intermediate (1.85 g) as a clear oil. m/z: [M+H+] calcd for C38H43ClN2O4Si 655.3. found 655.5.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][O:8][CH:9]=1)=O.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[C:10]1([C:6]2[C:5]([CH2:3][OH:2])=[CH:9][O:8][N:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1conc1-c1ccccc1
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: OCc1conc1-c1ccccc1
Yield: 59.4 %

Procedure:
As described for example 84d, 3-phenyl-isoxazole-4-carboxylic acid methyl ester (2.95 g, 15 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (1.56 g, 61%) which was obtained as a light green oil. MS: m/e=176.4 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:5].CC(C)([O-:19])C.[K+].O>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:19])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1ccccn1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-(trans)-2-pyridin-2-yl-cyclopropanecarboxylic acid methoxy-methyl-amide (950 mg, 4.61 mmol, 1 eq) in Et2O (30 mL), potassium tert-butoxide (569 mg, 5.07 mmol, 1.1 eq) and H2O (0.4 mL) were added. The mixture was stirred at r.t. for 18 hours. Potassium tert-butoxide (1.86 g, 16.6 mmol, 3.6 eq.) was added again. The mixture was stirred at r.t. for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (5 mL) and formic acid (3 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][N:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62].C(N(C(C)C)CC)(C)C.[Na+].[Cl-]>O1CCCC1.O>[CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[O:11])=[CH:8][N:7]=1
Reactant: COC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 169 %

Procedure:
To a solution of methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinate (400.0 mg, 0.46 mmol) in tetrahydrofuran (5 mL) was added a solution of LiOH monohydrate (378 mg, 9.02 mmol) in water (5 mL) dropwise at 0° C. After the addition, the mixture was stirred at room temperature for 48 hours. Tetrahydrofuran was removed under reduced pressure and the remaining aqueous residue was acidified to pH=3 by addition of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (637 mg, 1.68 mmol) was added. The mixture was stirred for 15 minutes at ambient temperature. Methyl 3-aminopropanoate hydrochloride (150 mg, 1.10 mmol) and diisopropylethylamine (540 mg, 4.2 mmol) were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated NaCl (20 mL) and was extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated. Purification by preparative TLC gave methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoate (400 mg) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.40 (m, 1H), 7.87-7.90 (m, 1H), 7.56-7.61 (m, 4H), 7.41-7.48 (m, 4H), 6.74 (d, 1H), 6.62-6.65 (m, 1H), 6.15-6.19 (m, 1H), 3.59-3.54 (m, 5H), 2.53-2.56 (m, 2H), 1.94-2.01 (m, 1H), 1.57-1.73 (m, 2H), 0.89-0.94 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([S:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39]#[CH:40].CCO>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][S:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCSc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CSc3ccccc3)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and phenyl propargyl sulfide (0.082 mL). The reaction is stirred at room temperature for 7 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 3% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.12 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 1% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.16 g of the title compound as light tan product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:21][CH2:22][O:23][CH2:24][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>O1CCOCC1.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.O>[O:23]1[CH2:22][CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2=CCOCC2)nn1
Yield: 79.2 %

Procedure:
Methyl 6-chloropyridazine-3-carboxylate (1.00 g, 5.79 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (1.22 g, 5.79 mmol), Pd(PPh3)4 (536 mg, 0.44 mmol) and Cs2CO3 (3.40 g, 10.4 mmol) were suspended in dioxane (8 mL) and water (8 mL) and heated in a microwave reactor at 125° C. for 30 min. 1M aq HCl (10 mL) was added, the precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was passed through a silica pad eluting with 30% MeOH in DCM and concentrated in vacuo to give the title compound as a white solid (946 mg, 79.2%). LCMS (ES+): 207.1 [MH]+. HPLC: Rt 3.30 min, 49.9% purity.