Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.CN(C=O)C.[Pd]>[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31]
Reactant: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A solution of give 7-benzyloxy-4-(indol-5-ylamino)-6-methoxyquinazoline hydrochloride (10 g, 23.1 mmol) in methanol (300 ml) and DMF (100 ml) containing ammonium formate (22 gr, 347 mmol) and 10% palladium on charcoal (1 g) was stirred overnight at ambient temperature. The solution was filtered over celite and washed with DMF followed by methanol. The filtrate was evaporated. The residue was dissolved in aqueous ammonia 2 mM (300 ml) and stirred for 15 minutes. The solid was filtered, washed with water followed by ethyl acetate and ether and dried under vacuum at 50° C. for 2 days. The solid was purified by column chromatography eluting with methanol/methylene chloride (1/9). The volatiles were removed under vacuum and the solid was left under vacuum at 70° C. for 2 days to give 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (6.8 g, 97%)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[NH2:18][NH2:19]>C(O)C>[N:18](=[C:1]=[C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH2:4]1)[NH2:19]
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reactant: NN
Solvent: CCO
Product: NN=C=C1CC=C(c2ccc(-c3cccs3)s2)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 200 ml of ethanol. 2 ml of hydrazine was dropped in slowly. After 2 ml of H2 SO4 (2N) was dropped in and stirred for 3 hours at room temperature, the reaction solution was monitored by thin layer chromatography to determine whether the reaction was completed. Ethanol was removed under reduced pressure. Then, it was extracted with ethyl acetate and treated in situ on column chromatographic separation. From the eluate of ethyl acetate/n-hexane (1/9) the mixture of syn-5-hydrazonomethylidene-2,2':5',2"-terthiophene and anti-5-hydrazonomethylidene-2,2':5',2"-terthiophene were thus obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][C:21]([O:24][C:25](=[O:43])[NH:26][CH:27]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:28](=[O:35])[NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:32]4[CH2:33][CH2:34][CH:30]([NH:29][C:28](=[O:35])[CH:27]([NH:26][C:25]([O:24][C:21]([CH3:22])([CH3:20])[CH3:23])=[O:43])[CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH2:31]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A suspension of 14.1 g (50 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 18.3 g (55 mmol) of [R-(R*,S*)]-[1-phenylmethyl-2-oxo-2-[(3-pyrrolidinyl)amino]ethyl]carbamic acid 1,1-dimethylethyl ester, 15.2 g (0.15 mol) of triethylamine and 200 ml of acetonitrile was heated at reflux for four hours. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with 100 ml of cold 1.0M hydrochloric acid and then water. After drying (MgSO4) and filtering, the solvent was removed in vacuo to give 26.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccc(Cl)cc1)Oc1ccc(Br)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A mixture of 6-bromo-2-(4-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 1.48 mmol) and Lawesson's Reagent (596 mg, 1.48 mmol) in 1,4-dioxane (25 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(4-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (450 mg, 69%). 1H-NMR (MeOD): 2.24 (m, 1H), 2.45 (m, 1H), 6.82 (m, 1H), 6.91 (m, 1H), 7.20 (m, 1H), 7.44 (m, 5H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([NH:13][CH:14]([C:17]2[C:18](=[O:28])[NH:19][C:20]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:21][N:22]=2)[CH2:15][CH3:16])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:22]3[C:17]([C:18](=[O:28])[NH:19][C:20]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[N:21]3)=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCC(C(C)(C)C)CC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 350 mg (0.90 mmol) crude 4-tert-butyl-N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclohexanecarboxamide, 140 mg (0.90 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used. The isomers are separated by chromatography.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.B1(C=C)O[C:16](C)(C)[C:15](C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[F:12][C:4]1[CH:3]=[C:2]([CH:15]=[CH2:16])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7]
Reactant: CNC(=O)c1ccc(Br)cc1F
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc(C(=O)NC)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 119.8 %

Procedure:
A mixture of 4-bromo-2-fluoro-N-methylbenzamide (0.80 g), vinylboronic acid pinacol cyclic ester (0.80 g) and 2M aqueous sodium carbonate solution (3.45 mL) in DME (17.3 mL) was argon-purged. Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was added thereto, and the mixture was stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to short silica gel column chromatography, and the solvent was evaporated under reduced pressure to give the title compound (0.74 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:20][CH:21]([CH3:26])[CH:22]([OH:25])[C:23]#[CH:24]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH:22]([OH:25])[CH:21]([CH3:26])[CH3:20])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CC(O)C(C)C
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)C(O)C#Cc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Sonogashira reaction of 39 with 4-methyl-pent-1-yn-3-ol yielded tert-butyl 3-hydroxy-3-(3-(3-hydroxy-4-methylpent-1-ynyl)phenyl)propylcarbamate as dark brown oil. Yield (1.73 g, 81%): 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.28-7.34 (m, 3H), 4.86 (bs, 1H), 4.72 (bs, 1H), 4.39 (t, J=6.0 Hz, 1H), 3.46-3.51 (m, 2H), 3.11-3.19 (m, 1H), 1.78-2.04 (m, 4H), 1.45 (s, 9H), 1.02 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9]([CH:12]=O)[CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1[S:11][CH:10]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1csc(-c2ncccn2)c1
Product: O=C/C=C/c1csc(-c2ncccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyrimidinyl)-3-thiophenecarboxaldehyde (prepared as described in Reference Example 93) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C@@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.IC1C=CC=CC=1C(O)=O>C1COCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:16][CH:17]=1
Reactant: OCCCCC[C@H](O)COc1ccc(F)cc1
Agent: O=C(O)c1ccccc1I
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=CCCCC[C@H](O)COc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To a solution of (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (3.6 g, 14.8 mmol) in dry THF (60 ml) was added dropwise a solution of 2-iodobenzoic acid (5 g, 17.8 mmol) in dry DMSO (4 ml) over a period of 25 minutes at room temperature. After 15 minutes the reaction mixture was decomposed with crushed ice, filtered through celite and concentrated. The residue was extracted with ethylether, washed with brine, dried over Na2SO4 and the organic solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using EtOAc-hexane (1:9) to give (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2.2 g, 61.6%); [α]D+12 (c 3.8, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.4-1.8 (m, 6H), 2.49 (dt, 2H), 3.71-4.05 (m, 4H), 6.782-7.02 (m, 4H), 9.8 (s, 1H); HRMS (FAB): calcd. for C13H17O3F (M+) 240.116173 found 240.116465.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[C:9](=[O:20])/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:22])[CH3:23])[C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)/C=C\c1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)CCc1cccc(C#N)c1
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
Palladium on carbon (740 mg of 10% wt/wt Pd/C) was added to a degassed solution of [(R)-(Z)-4-(3-cyano-phenyl)-1-isopropyl-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester (7.4 g, 22.5 mmol, 1 equiv) in methanol (200 mL) at room temperature. The reaction mixture was thoroughly degassed and backfilled with hydrogen gas from a balloon. Hydrogenation proceeded at atmospheric pressure for 2.5 h. The (degassed) reaction mixture was then diluted with diethyl ether (300 mL), filtered through Celite, and washed with additional ether (2×100 mL). Upon concentration in vacuo, the residue was purified by (lash column chromatography (20% ethyl acetate-hexanes) to provide the ketone product as a white solid (5.9 g, 79%). ESMS [M+H]+: 331.2. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.46 (m, 1H), 7.41 (m, 1H), 5.07 (m, 1H), 4.24 (m, 1H), 2.98 (m, 2H), 2.86 (m, 2H), 2.11 (m, 1H), 1.45 (s, 9H), 0.98 (d, 3H, J=6.76 Hz), 0.74 (d, 3H, J=6.78 Hz). [α]D=+24.74 (c=0.95, CH3OH).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:4]([OH:6])=[O:5].COC(OCC)C([O-])=O.[AlH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.[AlH]1CCCCO1>O>[CH3:1][O:2][CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:4]([O-:6])=[O:5].[AlH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: CCOCCOC(OC)C(=O)O
Agent: C1CC[AlH]OC1
Agent: CCOC(OC)C(=O)[O-]
Solvent: O
Product: CCOCCOC(OC)C(=O)[O-]
Reaction time: 2 h

Procedure:
Methoxy(ethoxyethoxy)acetic acid (60 mL) was dissolved in 300 mL of water and Vista Captal B boehmite (12 g) was slowly added and allowed to reflux for 96 hours. The clear/yellow solution was filtered and the filtrate was evaporated under reduced pressure to a yellow gel. The gel was dissolved in ethanol and the white/yellow powder product was obtained upon addition of diethyl ether. Yield: 13.6 g. The TGA of the methoxy(ethoxy)acetate-alumoxane showed 22.3% ceramic yield (weight loss of 77.7% ). The alumoxane was heated from 25° C. to 200° C. at the rate of 1.5° C.min−1, soaked for 2 h. at 200° C., followed by a temperature ramp up to 1000° C. at the rate of 5° C.min−1, soaked for 2 h.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@H:11]1[CH2:15][NH:14][CH2:13][C@@:12]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:9]=[CH2:10].[CH2:31]([N:38]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:40](O)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH2:8]([C@H:11]1[CH2:15][N:14]([C:40](=[O:41])[CH2:39][N:38]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH2:13][C@@:12]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:9]=[CH2:10]
Reactant: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1CN(C(=O)CN(Cc2ccccc2)C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A stirred mixture of the crude racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate trifluoroacetate (Step 1, ˜1 mmol) and N-benzyl-N-(tert-butoxycarbonyl)glycine (337 mg, 1.27 mmol) in methylene chloride (9 mL) was treated with Et3N (0.495 mL, 3.55 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 502 mg, 1.32 mmol), and the resulting mixture was stirred at room temperature and monitored by HPLC. At 1 h, the reaction was diluted with methylene chloride (20 mL), washed with water (20 mL), 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (20 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g column, 15-30% ethyl acetate in hexanes) gave 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azido-1-[N-benzyl-N-(tert-butoxycarbonyl)glycyl]pyrrolidine-3-carboxylate (365 mg, 64%) as an amber gum which was used as is in the next step. LC-MS ESI+ MS found for C30H35N5O6 m/z 562.3 (M+H), 584.3 (M+Na). 1H NMR (CDCl3, 400 MHz) δ 7.92 (m, 2 H), 7.66 (m, 1 H), 7.53 (m, 2 H), 7.30 (m, 5 H), 5.75 (m, 1 H), 5.52 (m, 2 H), 5.12 (m, 2 H), 4.58 (m, 2 H), 4.22-3.42 (m, 6 H), 2.60 (m, 1 H), 2.50 (m, 1 H), 2.12 (m, 1 H), 1.48 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.CC(O)=O>[Pt]>[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1
Reactant: Cc1cncc(NC(=O)OC(C)(C)C)c1
Agent: [Pt]
Solvent: CC(=O)O
Product: C[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 24 h

Procedure:
A Parr bottle was charged with tert-butyl 5-methylpyridin-3-ylcarbamate (365 mg, 1.75 mmol) and AcOH (10 mL, 0.17 mol). Nitrogen was bubbled through the mixture for several minutes with stirring before 5% Pt/C (365 mg, 0.027 mol) was added, and the bottle was placed under an atmosphere of hydrogen (60 psi) for 24 h. The mixture was filtered and the solvent concentrated in vacuo to afford the title intermediate as an oil, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1[CH3:23])[CH3:3].Cl>CO>[NH:12]1[CH2:11][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:6]([CH3:23])[CH:7]=2)[CH2:13]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Agent: Cl
Solvent: CO
Product: Cc1cc(OC2CNC2)ccc1CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Intermediate 20B (3.1 g, 9.7 mmol) was dissolved in MeOH (10 mL) and HCl in MeOH (1.25 M, 50 mL) was added. The reaction mixture was stirred at RT overnight. The mixture was concentrated, the residue was dissolved in water (15 mL) and DCM (100 mL) was added. While stirring an aqueous solution of K2CO3 (sat., 30 mL) was added and the two phases were separated through a phase separator. The solvent was removed by evaporation. There was obtained 1.96 g (92%) of 20C as a colorless oil. 1H NMR (600 MHz, CDCl3): δ 2.21 (s, 6H), 2.32 (s, 3H), 3.29 (s, 2H), 3.71-3.83 (m, 2H), 3.84-3.95 (m, 2H), 4.92-5.02 (m, 1H), 6.51 (d, 1H), 6.57 (s, 1H), 7.10 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([CH3:16])[CH:8]=2)=[C:4]([Cl:20])[CH:3]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]1([N:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH3:16])[N:10]=[CH:11][C:12]=2[C:13]([N:60]2[C:61]3[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:57]([CH:54]3[CH2:56][CH2:55]3)[CH2:58][CH2:59]2)=[O:15])=[C:4]([Cl:20])[CH:3]=1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: Cc1cc(Oc2cc(Cl)c(Br)cc2Cl)c(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)c(Br)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
To a solution of 0.17 g (0.451 mmol) 4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid in 3 mL dry N,N-dimethylformamide was added 0.38 mL (2.225 mmol) N-ethyldiisopropylamine and 207 mg (0.541 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 94 mg (0.541 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a). The reaction mixture was stirred at room temperature for 18 hours and then poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The layers were separated. The aqueous layer was extracted with 30 mL ethyl acetate and the combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 55 mg (23%) of the title compound as a light yellow solid. MS (ESI): m/z=534.018 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:59][C:60]1[CH:61]=[C:62]([CH:64]=[C:65]([C:67]2[CH:68]=[N:69][N:70]([CH2:72][C:73]([CH3:75])=[CH2:74])[CH:71]=2)[CH:66]=1)[NH2:63]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:63][C:62]2[CH:64]=[C:65]([C:67]3[CH:68]=[N:69][N:70]([CH2:72][C:73]([CH3:75])=[CH2:74])[CH:71]=3)[CH:66]=[C:60]([CH3:59])[CH:61]=2)[N:7]=1)[CH3:9]
Reactant: CC(F)c1ccnc(Cl)n1
Reactant: C=C(C)Cn1cc(-c2cc(C)cc(N)c2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C=C(C)Cn1cc(-c2cc(C)cc(Nc3nccc(C(C)F)n3)c2)cn1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
2-Chloro-4-(1-fluoroethyl)pyrimidine (170 mg, 1.06 mmol), Palladium(II) acetate (59.3 mg, 0.26 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (229 mg, 0.40 mmol), and cesium carbonate (860 mg, 2.64 mmol) were added to a solution of 3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)aniline (300 mg, 1.32 mmol) in dioxane (2.5 mL). The solution was degassed by sparging with Ar for 5 minutes and stirred at 110° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-30% EtOAc/Hexane), then further purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford 4-(1-fluoroethyl)-N-(3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-2-amine MS ESI calc'd. for C20H23FN5 [M+H]+ 352. found 352.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-methylbenzene following the procedure of Example 478: MS (ESI) m/z 498.
Reaction SMILES: C(S)C.[Li]CCCC.Cl.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:45]=[CH:44][C:22]([O:23][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:34]C)=[CH:31][CH:32]=4)[CH:27]=[CH:26][C:25]=3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Li]SCC>CN(C=O)C.CCCCCC.[Li]>[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]3[C:33]4[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=4)[CH:27]=[CH:26][C:25]=3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=3)=[CH:44][CH:45]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCS
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of ethanethiol (2.85 ml) in anhydrous DMF (125 mL) under N2 atmosphere was cooled in an ice bath and treated dropwise with 20.1 mL of 1.6 M n-BuLi in hexane. The resulting solution, which was approximately 0.22 M in lithium thioethylate (LiSEt) was allowed to warm to ambient temperature prior to its use. To 1-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-methoxynaphthalene hydrochloride (0.550 g, 1.05 mmol) under nitrogen atmosphere was added 70 mL (15.4 mmol) of the LiSEt solution and the resulting reaction mixture was heated in a 107° C. oil bath for 5 hr. The resulting yellow solution was concentrated under reduced pressure to remove most of the solvent and the yellow oil concentrate was distributed between 300 mL of ethyl acetate and 1N HCl (100 mL) to which 50 g of ice had been added. The ethyl acetate layer extract was washed with 4×25 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to a foul-smelling yellow oil. The crude material was purified in portions by radial chromatography that employed 5% methanol in chloroform as the elution solvent. The appropriate fractions were combined, concentrated, and dried in vacuo to provide 265 mg (53%) of 1-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(3-methoxyphenyl)-6-hydroxynaphthalene, as a grey foam.