Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:32][CH2:31]3)[CH2:22][CH2:21]2)=[O:19])=[CH:6][C:5]=1[Cl:33].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:33][C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:31][CH2:32]3)[CH2:22][CH2:21]2)=[O:19])[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:34])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a suspension of 3.68 g (7.38 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid methyl ester (Example 27) in 40 mL dioxane and 40 mL water were added 0.387 g (9.22 mmol) lithium hydroxide mono hydrate. The reaction mixture was stirred 1.5 hours at room temperature upon which a yellow solution formed. Dioxane was removed by evaporation and the resulting suspension was diluted with 50 mL water and the pH was adjusted to 1 using 10 mL 25% aqueous hydrochloric acid. The resulting suspension was stirred for approx. 2 hours at room temperature, filtered, washed with water and dried under high vacuum to give 3.49 g (97%) of the desired compound as a light brown solid. MS (ESI): m/z=484.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 84.2 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (2.62 g, 5.68 mmol), pyrrolidine (808 mg, 11.36 mmol, 2.0 eq), triethylamine (575 mg, 5.68 mmol, 1.0 eq); and sodium iodide (85 mg, 0.56 mmol, 0.1 eq) in anhydrous DMF (28 mL) was stirred at 55° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude was triturated from MeOH, filtered, and washed with cold MeOH and ether to provide 2.16 g (84.2%) of the desired product as a white solid. 1H-NMR (DMSO-d6) 8.54 (s, 1H), 7.89 (s, 1H), 7.80 (d, 1H), 7.58 (s, 1H), 7.36 to 7.30 (m, 5H), 7.14 (d, 1H), 6.59 (s, 1H), 5.65 (s, 2H), 2.90 (t, 2H), 2.48 to 2.39 (m, 6H), 1.87 to 1.83 (m, 2H), 1.67 to 1.64 (m, 4H); LC-MS [M+H]+=452, RT=2.14 min.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH2:13]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC(Oc2ncccc2Br)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3Br)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (243 mg, 1 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and p-toluenesulfonyl chloride (380 mg, 2 mmol) was added dropwise. After 1 hour, the reaction mixture was warmed to room temperature, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide (318 mg, 0.8 mmol, yield 80%). ESI-MS (M+1): 397 calc. for C16H17BrN2O3S 396.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[N:11][C:4]=2[NH:3]1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]2[C:27]3=[C:28]([Cl:36])[CH:29]=[N:30][C:31]4[CH:32]=[CH:33][C:34](=[O:35])[N:25]([C:26]=43)[CH2:24]2)[CH2:18][CH2:17]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[ClH:36].[Cl:36][C:28]1[CH:29]=[N:30][C:31]2[CH:32]=[CH:33][C:34](=[O:35])[N:25]3[CH2:24][CH:23]([CH2:22][N:19]4[CH2:18][CH2:17][CH:16]([NH:15][C:12]([C:10]5[CH:9]=[CH:8][C:5]6[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=6[N:11]=5)=[O:14])[CH2:21][CH2:20]4)[C:27]=1[C:26]=23
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: O=C1CSc2ccc(C(=O)NC3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)CC3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (for a synthesis see WO2003087098, Example 301(b)) (50 mg, 0.236 mmol), 4-[(4-amino-1-piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (75 mg, 0.236 mmol) and triethylamine (0.066 ml 0.472 mmol) in DMF (2 ml) was added HATU (95 mg, 0.25 mmol) and the reaction was stirred at room temperature for 18 h. The reaction mixture was then evaporated to dryness, kept under high vacuum for 30 minutes, treated with dichloromethane and aqueous sodium bicarbonate solution and stirred vigorously for 30 minutes. The solid was filtered off, washed with water and dichloromethane and dried in vacuo to provide the free base of the title compound (100 mg, 83%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:12]=[C:11]([CH:13]=[CH2:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Br[CH:18]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[C:25]([Cl:31])[CH:24]=1)[C:19]([F:22])([F:21])[F:20].N1C=CC=CC=1C1C=CC=CN=1>CN1CCCC1.O.[Cu]Cl>[Cl:29][C:27]1[CH:28]=[C:23]([CH:18]([C:19]([F:22])([F:21])[F:20])/[CH:14]=[CH:13]/[C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][C:2]([F:15])([F:16])[F:1])[CH:12]=2)[CH:24]=[C:25]([Cl:31])[C:26]=1[F:30]
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Reactant: C=Cc1ccc(C(=O)O)c(OC(F)(F)F)c1
Agent: Cl[Cu]
Agent: CN1CCCC1
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Product: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1OC(F)(F)F
Temperature: 150 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N methylpyrrolidine (5.0 mL) was added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150° C. for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J=16.0 Hz, 1H), 6.50 (dd, J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M−H]−).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:41][C:5]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester and 5N NaOH (0.7 mL) in ethanol (6 mL) is refluxed for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is diluted with CH2Cl2, washed, dried, and concentrated to provide the title compound (0.186 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 2H, J=8.3 Hz), 7.35 (d, 2H, J=8.3 Hz), 7.24-7.17 (m, 4H), 7.00 (t, 1H, J=7.4 Hz), 6.89 (d, 2H, J=7.4 Hz), 6.73 (d, 2H, J=8.3 Hz), 4.45, 4.37 (ABq, 2H, J=15.7 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.68-3.62 (m, 1H), 3.38 (t, 1H, J=8.3 Hz), 3.32, 3.10 (ABq, 2H, J=12.9 Hz), 3.00 (t, 1H, J=8.3 Hz), 2.84 (s, 3H), 2.27-2.19 (m, 1H), 1.92-1.85 (m, 1H), 1.39 (s, 3H). MS [EI+] 557 (M+H)+, [EI−] 555 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7]C)=O.N1CCCN2CCCN=C12.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH2:26][CH2:25]1>C1(C)C=CC=CC=1.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]1)=[O:7]
Reactant: CN1CCN(c2ccccc2CN)CC1
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N

Procedure:
A solution of methyl 3-amino-4-methylbenzoate (commercially available) (1.609 g, 9.74 mmol), TBD (2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine) (0.678 g, 4.87 mmol) and (2-(4-methylpiperazin-1-yl)phenyl)methanamine (commercially available) (2 g, 9.74 mmol) in toluene (30 ml) was heated at reflux overnight. The reaction mixture was diluted with EtOAc and washed with sat.NaHCO3 and water. The organic portion was separated, dried (MgSO4) and concentrated in vacuo. The product was purified by chromagraphy on silica eluting with a gradient of 0-20% 2M NH3 in MeOH/DCM to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-hydroxyphenyl)amino]piperidine (50 mg) was dissolved in N,N-dimethylformamide (1 ml), added with methyl bromoacetate (17 μl) and potassium carbonate (25 mg) and stirred at room temperature for 17 hours. The reaction mixture was added with water (3 ml) and extracted twice with ethyl acetate (3 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:1) to obtain 51.8 mg of the title compound. Yield: 83%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(O)c(CNc2ccccc2)c1
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A mixture of 15.2 g of 2-hydroxy-5-methoxybenzaldehyde, 15 g of aniline and 200 ml of methanol was stirred for 3 hours. The mixture was then hydrogenated at 40 psi in the presence of 2.0 g of 10% Pd/C until 0.1 mole of hydrogen was consumed. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to a yellow oil which was crystallized from ether-n-hexane to yield 18 g of N-(2-hydroxy-5-methoxybenzyl)aniline. M.p. 82.5°-8° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:33]=[C:34]([B:38]([OH:40])[OH:39])[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:31][C:32]2[CH:33]=[C:34]([B:38]([OH:40])[OH:39])[CH:35]=[CH:36][CH:37]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(CBr)c1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C[C@@H](c1ccc(OCc2cccc(B(O)O)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 48 h
Yield: 17.7 %

Procedure:
The phenol (7.5) (400 mg, 1.02 mmol) and 3-(bromomethyl)phenylboronic acid (219 mg, 1.02 mmol) were dissolved in DMF (10 mL). Cesium carbonate (664 mg, 2.04 mmol) was added to the mixture, and the slurry was stirred for 48 hours. The reaction was then diluted with water and extracted with EtOAc (2×100 mL). The organic layers were combined and washed with a 1 M lithium chloride solution (1×50 mL) and brine (1×50 mL), and dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 30 to 100% EtOAc:hexanes) to give 34.1 (95.0 mg). MS ESI (pos.) m/e: 527.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[CH:9][N:4]2[CH:3]=1.C(O)C.C(OCC)C.[ClH:24]>>[ClH:24].[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)Cc1cn2cc(C)sc2n1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1cn2cc(CC(=O)O)nc2s1
Temperature: 25 °C
Yield: 93 %

Procedure:
Ethyl (2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetate (151.3 g, 0.67 mol) was dissolved in 10% aqueous HCl (435 mL) and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give a yellow oil. Ethanol (100 mL) and diethylether (200 mL) were added and the resulting white precipitate was collected by filtration and dried in a vacuum oven overnight to give 144.3 g (93%) the title compound. MS (ES+) 197.1 (M+H)+. 1H NMR (CD3OD) δ 2.48 (s, 3H), 3.88 (s, 2H), 7.81 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[O:23]=[C:18]1[CH2:19][O:20][CH2:21][CH2:22][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:25](=[O:26])[O:27][CH3:28])=[CH:16][CH:15]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3 min to a stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2, 25 g, 130.07 mmol) in CH2Cl2 (750 mL). The reaction mixture was stirred at room temperature for 15 min and methyl chloroformate (11.6 mL, 149.58 mmol) was added drop-wise over 10 min. The resulting thick suspension was stirred for another 1 h and filtered through a Buchner funnel. The solid was washed with CH2Cl2 (2×75 mL) and dried under vacuum to obtain methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g, 95%) as a crystalline solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2occc2c1
Reactant: Nc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1cc(NCc2ccc3occc3c2)ccn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
Benzofuran-5-carbaldehyde (330 mg, 2.19 mmol, 1.0 equiv.) and 4-aminopyridine (227 mg, 2.41 mmol, 1.1 equiv.) were combined in 1,2-dichloroethane (22 mL) and treated with acetic acid (138 μL, 2.41 mmol, 1.1 equiv.) and sodium triacetoxyborohydride (969 mg, 4.34 mmol, 1.98 equiv.). The mixture was stirred at 60° C. overnight, and then quenched by addition of saturated NaHCO3 solution. The two phases were separated and the water layer was extracted twice with ethyl acetate. The combined organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica gel, eluting with ethyl acetate/dichloromethane/methanol to afford N-(benzofuran-5-ylmethyl)pyridin-4-amine as a white solid (62 mg, 13% yield). Mass: 225 (MH)+. Purity >99% (HPLC).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH:8]=[C:9]3[C:14](=[CH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:17]=[C:16]2[C:7]([CH:8]=[C:9]3[C:14](=[CH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2cc3c(cc2c1)CCCC3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cc3c(cc2c1)CCCC3
Reaction time: 5 h
Yield: 97.8 %

Procedure:
A mixture of 4 mg (17.62 mmol) of 1,2,3,4-tetrahydro-7-nitroanthracene (John D. Scribner and James A. Miller; J. Chem. Soc., 5377 (1965)) and 0.5 g of palladium-on-carbon catalyst in 200 ml of methanol was shaken with hydrogen at 50 p.s.i. for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 3.4 g (97%) of 7-amino-1,2,3,4-tetrahydroanthracene. To a solution of 3.2 g (16.24 mmol) of the latter in 50 ml of dry tetrahydrofuran was added 2.7 g (26.7 mmol) of triethylamine followed by 3 g (24.9 mmol) of trimethylacetylchloride. After stirring at room temperature overnight, the solvent was removed and the residue was triturated with warm water to give 4.52 g (99%) of 7-trimethylacetylamino-1,2,3,4-tetrahydroanthracene, crystallized from methanol into colorless crystals of melting point 202°-204° C. and providing the following analysis:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH2:30](O)[C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC(C)(C)CO
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC(C)(C)COC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
Using the procedure of Step A of Example 15, 3.89 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 1 g of neopentyl alcohol were reacted and the mixture was stirred at room temperature for 4 hours and was filtered. The filtrate was washed with N hydrochloric acid, with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-neopentyloxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:29]1[C:25](=[O:35])[C:26]3[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28]1=[O:30])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 45 °C
Yield: 82.1 %

Procedure:
To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (539 mg, 1.5 mmol) in dry N,N-dimethylformamide (5 ml) at room temperature was added potassium phthalimide (278 mg, 1.5 mmol). The mixture was heated at 45° C. for 48 hours, then diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate, water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure, leaving a white solid, which was washed with a cold solution of 10% diethylether/hexanes, dried under reduced pressure, to provide ethyl 6-chloro-2-((1,3-dioxoisoindolin-2-yl)methyl)-4-phenylquinoline-3-carboxylate (580 mg, 82%) as a white powder. TLC Rf=0.41 using 1:1 ethyl acetate:hexanes eluent on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 7.98 (m, 2H); 7.78 (m, 3H); 7.58 (m, 5H); 7.38 (m, 2H); 5.30 (s, 2H); 4.04 (q, 2H, J=7.0 Hz); 0.89 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 471.
Reaction SMILES: [Cu][C:2]#[N:3].N1C=CC=CC=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:23]3=[O:29])[S:20][CH:21]=2)=[C:13]([F:30])[CH:12]=1>CC(N(C)C)=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>[CH3:27][C:26]1([CH3:28])[CH2:25][O:24][C:23](=[O:29])[N:22]1[C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:2]#[N:3])=[CH:12][C:13]=2[F:30])[N:18]=1
Reactant: N#C[Cu]
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2F)cs1
Yield: 116.6 %

Procedure:
Copper (I) cyanide (0.09 g, 1.0 mmol) and pyridine (0.17 mL, 1.6 mmol) were added under a nitrogen atmosphere to a solution of 3-[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]-4,4-dimethyl-1,3-oxazolidin-2-one (0.4 g, 1.0 mmol), prepared in step 7 of Example 78, and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) in dimethylacetamide. The reaction solution was sealed and placed in a microwave reactor (200° C./1 h). LC/MS indicated the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified on silica gel using a stepwise gradient of 1-3% methanol:methylene chloride to give the title compound (370 mg, 55%) as a yellow solid, mp 237° C. (dec.).