Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:2]([S:7]([NH:10][C:11](=[N:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)SC)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:29][O:30][NH2:31]>O1CCOCC1>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:2]([S:7]([NH:10][C:11]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)=[N:31][O:30][CH3:29])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CON
Reactant: CSC(=Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Solvent: C1COCCO1
Product: CON=C(Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 63.3 %

Procedure:
4.12 g of 1-(2-biphenylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)2-methylisothiourea was dissolved in 50 ml of dioxane, 2.35 g of O-methylhydroxylamine was added to the solution, and the mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2.6 g of the desired N-(2-biphenylsulfonyl)N'-(4,6-dimethylpyrimidin-2-yl)N"-(methoxy)guanidine of the following formula, mp. 190°-192° C.: ##STR21##
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]=O>C(O)=O>[CH3:27][N:18]1[CH2:19][CH2:20][C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([NH:15][S:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=2)(=[O:13])=[O:14])[CH2:17]1
Reactant: C=O
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCNC2)cc1
Solvent: O=CO
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Temperature: 110 °C
Yield: 71 %

Procedure:
To a solution of ethyl 2-(3-(4-pentylphenylsulfonamido)pyrrolidin-3-yl)acetate (55 mg, 0.14 mmol) in formic acid (2 mL) was added formalin (15 μL, 0.16 mL). The solution was heated to 110° C. for 2 h. The mixture was concentrated and dissolved into CH2Cl2 (25 mL) and washed with sat. bicarbonate (2×5 mL), H2O (5 mL), dried over MgSO4 and concentrated to dryness to give the title compound as a brown oil (40 mg, 71%). MS ESI 397.2 [M+H]+, calcd for [C20H32N2O4S+H]+ 397.21.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].F[C:24]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:25]=1[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC#N>[NH2:1][C:2]1[N:6]([C:24]2[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:25]=2[CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C:3]=1[C:20]([NH2:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(COC2CCCCO2)c(F)c1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2COC2CCCCO2)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (27.6 mg, 0.1 mmol) in DMF (3 mL) and CH3CN (5 mL) was added 2-(2-fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran (25.5 mg, 0.1 mmol) and K2CO3 (27.6 mg, 0.2 mmol). After stirring at 80° C. under N2 for 16 hr, the mixture was concentrated and recrystallized with PE/EA to afford 40 mg (80%) of 5-amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 512.2.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(#N)C>[O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:20](=[O:21])[O:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=[N:2]1
Reactant: Nc1cccc(-c2ncno2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1,2,4-oxadiazol-5-yl)phenyl amine (0.97 g, 0.006 mol, prepared in sequence by the procedures described in Lin et al. J. Org. Chem., 1979, 44, 4160 and Lin et al., J. Org. Chem., 1979, 44, 4160) in acetonitrile (25 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° C. was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 10% citric acid, resulting in separation of a solid, insoluble in either phase. The solid was collected and triturated with anhydrous ether and dried in vacuo to yield 1.54 g of [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester, m.p. 195°-197° C. TLC, silica gel, EtOAc/MeOH (20:1), Rf =0.75; M.S. (M+H)+ at 327, M.W. 326. This compound contained minor impurities and was used without further purification.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=3[CH3:31])=[C:8]([C:20]([F:23])([F:22])[F:21])[S:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2csc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: COc1ccc(-c2csc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-methoxyphenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-methoxphenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.35 (d, J=7.5 Hz, 2H), 6.95 (d, J=8.0 Hz, 1H), 6.90 (d, J=7.8 Hz, 2H), 6.63 (d, J=8.0 Hz, 1H), 4.88 (s, 2H), 3.82 (s, 3H), 2.95 (t, J=7.0 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.48 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[NH:25][CH2:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:20][C:19]=1[NH:25][CH2:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1cc(CNc2cc(O)ccc2Cl)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CNc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 61.3 %

Procedure:
In the same manner as in Example 257 and using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (210 mg, 0.65 mmol), 4-chloro-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}phenol (240 mg, 0.97 mmol), potassium carbonate (220 mg, 1.6 mmol) and N,N-dimethylformamide (1.5 mL) as starting materials, the title compound (180 mg, 61%) was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2([C:2]1[CH:3]=[C:4]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[OH:26]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(C2OCCO2)cc1Br
Product: COc1ccc(C2OCCO2)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 43.8 %

Procedure:
With 30.0 g of the compound obtained in Step 196-1 and 17.52 g of 5-chloroisatin as starting materials, 15.3 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C@H:35]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][CH:46]=1)[CH2:36][C@:37]([CH2:42][OH:43])([CH3:41])[C:38]([OH:40])=[O:39].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:57][C:55]1[CH:54]=[CH:53][C:52]([F:58])=[C:51]([C:48]2[CH:47]=[CH:46][C:45]([CH2:44][C@@H:35]([NH:34][C:7]([C:4]3[O:3][C:2](=[O:1])[NH:6][CH:5]=3)=[O:9])[CH2:36][C@:37]([CH2:42][OH:43])([CH3:41])[C:38]([OH:40])=[O:39])=[CH:50][CH:49]=2)[CH:56]=1
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1c[nH]c(=O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.4 %

Procedure:
2-Oxo-2,3-dihydrooxazole-5-carboxylic acid (7.1 mg, 55 μmol) and HATU (21 mg, 55 μmol) were combined in DMF (0.3 mL) and stirred at room temperature for 5 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF (0.5 mL) and DIPEA (29 μL, 164 μmol) were added, and the resulting mixture was stirred for 10 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (3 mg). MS m/z [M+H]+ calc'd for C23H22ClFN2O6, 477.12. found 477.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[ClH:11].CCOCC.Cl.[Cl:18]N1C(=O)CCC1=O>CCOCC.Cl.C(O)(=O)C>[ClH:18].[Cl:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1cnccc1C
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)CCl
Yield: 83.2 %

Procedure:
In a 500 mL round bottom flask was placed 1-(4-methyl-3-pyridinyl)ethanone (10.0 g, 74.1 mmol) in 90 mL of Et2O. To this solution was added 88.9 mL of 1M HCl/Et2O (1.2 eq, 88.9 mmol) with stirring and the solution allowed to stir for 1 h at room temperature, at which point, the precipitate was filtered and washed with Et2O. The solid was then dried in vacuo at about 60° C. This HCl salt (12. g, 70.0 mmol) was then dissolved in 70.0 mL of 1M HCl/acetic acid where 9.34 g (1 eq, 70.0 mmol) of N-chlorosuccinimide (NCS) was added and the reaction allowed to stir under Argon at room temperature overnight. At this point, 300 mL of Et2O was added resulting in an off-white precipitate. This was allowed to stir for 1 h at which point the solid was filtered and rinsed with Et2O to provide 12.0 g (83%) of the desired 2-chloro-1-(4-methyl-3-pyridinyl)ethanone hydrochloride. 1H-NMR (DMSO-d6) δ 2.51 (s, 3H), 5.15 (s, 2H), 7.68 (d, 1H), 8.68 (d, 1H), 9.06 (s, 1H); MS GC-MS [MH]+ 169.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([O:17][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(OC2CCCCO2)cc(Br)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 2-bromo-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (4.52 g, 15.0 mmol) in THF (50 mL) was added potassium carbonate (2.07 g, 15.0 mmol), followed by iodomethane (4.23 g, 30.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by saturated NaHCO3 aqueous solution (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid. (4.53 g, Yield: 95.8%). 1H NMR (400 MHz, DMSO-d) δ0.19 (s, 1H), 6.98-6.98 (d, J=2.0 Hz, 1H), 6.81-6.82 (d, J=2.0 Hz, 1H), 6.73-6.74 (m, 1H), 3.88 (s, 3H), 3.60-3.75 (m, 2H), 1.75-1.89 (m, 3H), 1.53-1.67 (m, 3H). MS (ESI) m/z=315 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[I:18][C:9]1[CH:8]=[N:7][C:6]([NH2:10])=[C:5]2[O:1][CH:2]=[CH:3][C:4]=12
Reactant: Nc1nccc2ccoc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1ncc(I)c2ccoc12
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of furo[2,3-c]pyridine-7-ylamine (1.5 g, 11.2 mmol) in acetonitrile (40 mL) was added NIS (3.02 g, 13.4 mmol) portionwise over a period of 15 min. The resultant mixture was stirred at RT for 16 h. The reaction mixture was quenched with 20% aqueous sodium thiosulfate solution (20 mL) and stirred for 10 min. The mixture was extracted with ethyl acetate (70 mL). The organic layer was washed with aqueous 20% sodium thiosulfate solution (20 mL), water (2×50 mL), and brine (40 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (25% ethyl acetate:hexanes) afforded 2.5 g (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[C:24]([F:25])=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:26])[CH:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[C:24]([F:25])=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:26])[CH:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)c1cc(F)c(COc2cnc(OCC(C)C)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COc1ncc(OCc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a solution of methyl 4-((5-chloro-6-isobutoxypyridin-3-yloxy)methyl)-2,5-difluorobenzoate (Preparation 4, 623 mg, 1.6 mmol) in THF (10 mL) was added lithium hydroxide (1.8 mL of a 1 M solution in water) and the mixture stirred at room temperature under nitrogen for 18 hours. The solvent was evaporated in vacuo to give the title compound (352 mg, 59%) as a pale yellow solid and was used directly in the next step.
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14])=[O:5].[ClH:19].Cl.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37]C4N=CC=CC=4C(NC4C=CC=CC=4C)=O)=[CH:33][C:32]=3[F:54])=[C:24]2[CH:23]=[CH:22]1>>[ClH:19].[ClH:19].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:2]4[N:18]=[CH:17][CH:16]=[CH:15][C:3]=4[C:4]([NH:6][C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=4[CH3:14])=[O:5])=[CH:33][C:32]=3[F:54])=[C:24]2[CH:23]=[CH:22]1
Reactant: Cc1cc(F)ccc1NC(=O)c1cccnc1F
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Product: Cc1cc(F)ccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 42 %

Procedure:
2-Fluoro-N-(4-fluoro-2-methylphenyl)nicotinamide (0.050 g, 0.20 mmol) was converted to the title compound (0.043 g, 42%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 10.87 (s, 1H), 10.28 (s, 1H), 8.10-8.40 (m, 4H), 6.96-7.60 (m, 7H), 6.72 (d, 1H, J=6.5 Hz), 6.45-6.53 (m, 1H), 2.20 (s, 3H); HRMS(ESI+), 472.1580 (M+H)+ calc, 472.1590 (M+H)+ found.
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.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>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: C#CC[C@H](C)O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 81 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 57 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH3:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([NH2:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: N
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(N)=O
Yield: 77 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with ammonia to give the title compound as a solid (150 mg, 77%); NMR Spectrum 1.66 (d, 3H), 5.14 (q, 1H), 5.70 (s, 2H), 7.12-7.01 (m, 4H), 7.36 (m, 2H), 7.54 (s, 1H), 7.75 (m, 3H), 7.89 (s, 1H), 8.16 (s, 1H), 8.52 (s, 2H), 10.80 (s, 1H); Mass spectrum 457.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7].[F:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:25]=[CH:24][C:21]([C@H:22]3[O:9][CH2:8][C@H:5]([CH2:4][CH2:3][CH2:2][F:1])[CH2:6][O:7]3)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OCC(CO)CCCF
Reactant: O=Cc1ccc(-c2ccc(F)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FCCC[C@H]1CO[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)OC1

Procedure:
A mixture of 0.1 m of 2-(3-fluoropropyl)-1,3-propanediol, 0.1 m of p-(3,4-difluorophenyl)benzaldehyde (prepared by cross-coupling as described above), 1 g of p-toluenesulfonic acid and 200 ml of toluene is boiled for 1 hour on a water separator. Extractive work-up and purification by crystallization and chromatography give trans-2-(3,4-difluorobiphenyl-4'-yl)-5-(3-fluoropropyl)-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 0.226 g (0.58 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.40 g (2.80 mmol) of 4-aminophenylacetic acid, methyl ester base was heated in a 160° C. to 165° C. oil bath. The resulting solution was heated for 10 minutes and cooled to room temperature. The solution was treated with 1 mL of glacial acetic acid to dissolve. Water (10 mL) was added to precipitate a gum. The mixture was decanted, and the remaining gum was dissolved in 20 mL of chloroform. The chloroform solution was washed with 25 mL of water, dried (magnesium sulfate), filtered, and concentrated. Purification was effected by silica gel chromatography eluting with chloroform and then with 50% hexane/ethyl acetate to obtain the fraction containing pure product. The eluent was concentrated to dryness to obtain a solid; wt 0.141 g.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH:33][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)C(c3ccccc3)c3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 15.5 %

Procedure:
Diphenyl-acetic acid (42.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (13.3 mg, 0.0310 mmol, 15.5%) ESI-MS m/z calc. 429.2, found 430.2 (M+1)+. Retention time of 3.47 minutes.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>CN(C=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]([CH2:2][NH:1][S:31]([CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[N:7][N:6]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)NCC1=NN=C(N)C1=NNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
A solution of 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg, 0.17 mmol) in anhydrous DMF (3 mL) was added to a 10 mL reaction vessel containing PS-DIEA (2.5 eq, 150 mg) and butane-1-sulfonyl chloride (1.1 eq, 0.19 mmol) suspended in anhydrous DMF (3 mL). The reaction mixture was stirred at ambient temperature under argon for approximately 16 hours before it was filtered, washed with DMF (3×5 mL) and concentrated under reduced pressure. The resulting yellow residue was recrystallized from ether to yield 13 mg (22%) of the title compound as a yellow powder. MS (m/z, ES+): 355 (M+1, 100%).