Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.O>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[C:20](=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Solvent: O
Solvent: ClCCl
Product: CN(CCCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirred solution of N,N-dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (1 g, 3.80 mmol) in dichloromethane (20 ml) was added phenyl carbonochloridate (0.715 ml, 5.70 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 50-100% ethyl acetate in hexanes, giving the desired phenyl methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (1.02 g, 2.76 mmol, 72.7% yield). 1H NMR (DMSO-d6) δ 7.88 (t, J=7 Hz, 1H), 7.78 (s, 1H), 7.37 (t, J=7 Hz, 2H), 7.20 (t, J=7 Hz, 1H), 7.12-7.06 (m, 2H), 6.70 (d, J=9 Hz, 1H), 3.50-3.33 (m, 6H), 3.06, 2.93 (2s, 3H), 2.76-2.71 (m, 2H), 1.92-1.81 (m, 4H). ESI-MS (m/z, %) 370 (MH+, 100).
Reaction SMILES: [C@@H:1]1([C:10]2[C:11](=[O:17])[NH:12][CH:13]=[C:14](I)[CH:15]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(N(CC)CC)C.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C.[Cu]I.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>[C@@H:1]1([C:10]2[C:11](=[O:17])[NH:12][CH:13]=[C:14]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=c1[nH]cc(I)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=c1[nH]cc(C#Cc2ccccc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
3-(β-D-Ribofuranosyl)-5-iodopyridin-2(1H)-one prepared in Example 1(1) (71 mg, 0.20 mmol) was dissolved in DMF (1.0 ml), followed by addition of CuI (6 mg, 0.032 mmol), triethylamine (42 μl, 0.30 mmol), phenylacetylene (33 μl, 0.30 mmol) and Pd(Ph3P)4 (11 mg, 0.010 mol). The reaction mixture was stirred under an argon atmosphere at room temperature for 6 hours. After addition of ethyl acetate (10 ml), the reaction mixture was extracted three times with water (10 ml each). The combined aqueous layers were concentrated under reduced pressure and then purified by reversed-phase HPLC to give 3-(β-D-ribofuranosyl)-5-(2-phenylethynyl)-pyridin-2(1H)-one (60 mg, 92%) as a white product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].CN1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: Oc1ccccc1Cl
Agent: Cn1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N3CCc4ccc(Oc5ccccc5Cl)cc4C3)nc(N)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20.0 mg, 0.0496 mmol), 2-chlorophenol (0.00765 g, 0.0595 mmol, Aldrich, Cat. No. 185779), 1-methylimidazole (2.04 mg, 0.0248 mmol, Aldrich, Cat. No. M50834), Cuprous monochloride (0.245 mg, 0.00248 mmol, Aldrich, Cat. No. 229628), and potassium carbonate (13.7 mg, 0.0992 mmol) in 1,4-dioxane (0.8 mL) was heated at 140° C. overnight. The reaction mixture was cooled to r.t. and concentrated. Then the reaction mixture was dissolved in MeOH and filtered, the filtration was purified by RP-HPLC (pH=10) to afford the desired compound. LCMS(M+H)+: m/z=451.3.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>[Cu]=O>[C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:16])=[O:15]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1n[nH]c2ccccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nn(-c2ccccc2C(=O)O)c2ccccc12
Yield: 72.7 %

Procedure:
3-Methylindazole (3.30 g), 3.92 g of 2-chlorobenzoic acid, 3.82 g of potassium carbonate and 0.18 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 4.58 g (72.7%) of 1-(2-carboxyphenyl)-3-methylindazole.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C@@H:4]([CH2:6][CH:7]2[O:11][CH2:10]O[O:8]2)[N:3]1C(=O)C(OC)=O.[N+](=C)=[N-]>CO.C(OCC)C>[O:1]=[C:2]1[NH:3][C@@H:4]([CH2:6][C:7]([O:11][CH3:10])=[O:8])[CH2:5]1
Reactant: COC(=O)C(=O)N1C(=O)C[C@H]1CC1OCOO1
Agent: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C[C@H]1CC(=O)N1
Temperature: 0 °C
Yield: 17.1 %

Procedure:
A solution of methyl [(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (60 mg) in methanol (5 ml) was heated at 65°-70° for two hours. The yellowish solution was cooled to 0° C. and treated with a solution of diazomethane (excess) in diethyl ether. After removal of the solvent, the residue was chromatographed on silica gel (1.5 g) eluting with 20% acetone in dicloromethane to give methyl 2-[(2R)-4-oxoazetidin-2-yl]acetate (6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccccc4)nc3n2)CC1
Yield: 65.5 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (13.0 g) from Example 36 in DMF (160 mL) was reacted with 60% sodium hydride suspension (1.16 g) and phenyl isocyanate (3.47 g) according to the general procedure of Example 37. Recrystallization of the chromatographed product from ethyl acetate gave 10.78 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-phenyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=565;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[N:32]=[C:33]([C:36](O)=[O:37])[S:34][CH:35]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[S:34][CH:35]=[C:31]([CH3:30])[N:32]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1csc(C(=O)O)n1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc(C)cs2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 4-methylthiazole-2-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[O:12][CH2:13][CH2:14][NH:15]C(=O)C2C(=CC=CC=2)C(O)=O)=[CH:7][CH:6]=1>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:37]=[N:36][NH:35][CH:34]=3)=[CH:29][CH:28]=2)[O:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccccc1C(=O)NCCOC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCOC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (1590, 3.28 mmol) was added to a solution of N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamic acid (260 mg, 0.55 mmol) in methanol (6 ml) and the reaction mixture stirred at 80° C. for 16 hours. Upon cooling, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2), eluting with dichloromethane: methanol: acetic acid:water (90:18:3:2). Further purification by Phenomenex_Strata_SCX column chromatography, eluting with methanol followed by 2N ammonia in methanol, afforded the desired product as the free base (120 mg), LC/MS: (FL-A) Rt 2.07 [M-NH2CH2CH2O+H]+267. 1H NMR (Me-d3-OD) δ 2.85 (2H, t), 3.55 (2H, t), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95 (2H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(3,4-Difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.104) (0.25 g, 0.67 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.21 g, 0.82 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.25 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:16]2[CH2:17][N:18]([C:19]([O:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C@@H:11]1[C@H:12]([O:15]2)[O:13]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>FC(F)(F)C(O)=O.O.O>[C:1]([O:9][C@H:10]1[C@H:16]([OH:15])[CH2:17][N:18]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C@@H:11]1[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@@H]2CN(C(=O)OC(=O)c3ccccc3)[C@H]1[C@H]2OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
The compound (15.8 g, 41.3 mmol) synthesized in Example 1 (1g) was dissolved in trifluoroacetic acid:water (4:1, 160 mL) and the mixture was stirred at room temperature for 15 minutes. After water (200 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with methylene chloride (300 mL), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (200 mL) and saturated brine (200 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was dissolved in ethanol (150 mL) and the compound obtained by dissolving sodium borohydride (0.78 g, 20.7 mmol) in water (15 mL) was added thereto, followed by stirring of the mixture at 0° C. for 20 minutes. After saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture at 0° C., ethanol was distilled off under reduced pressure. After water (100 mL) was added thereto and the mixture was extracted with ethyl acetate (100 mL), the organic layer was washed with saturated brine (100 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desired title compound (14.2 g, yield 89%) as a colorless oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:27]C[O-].[Na+].CCO.O>C(O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC[O-]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Methyl (1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute ethanol (10 mL and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.35; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.69; S, 7.97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:39]N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:39][C:33]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-phenylhydrazine hydrochloride: ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=O)[CH3:2].B.CSC.CO>O1CCCC1.ClCCl>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: CCNc1cccc(O)c1
Yield: 74 %

Procedure:
To a solution of 161 g of 3-acetamidophenol in 800 ml of tetrahydrofuran was added dropwise over 1-2 hr 275 ml of a 1.0M solution of borane-methyl sulfide in dichloromethane. The reaction was heated to reflux 4-5 hr and then poured slowly into 1 l of methanol. The solvent was evaporated to a heavy syrup which deposited crystals on cooling and scratching. The solid was collected by filtration and redisolved in methanol. Evaporation and crystallization as above gave a 74% yield of 3-(ethylamino) phenol.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].C(O)(=O)C.[Br:20]Br>O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Br:20])[CH2:12][CH2:11][CH2:10]2)=[O:5]
Reactant: BrBr
Reactant: COCC(=O)Nc1ccc2c(c1)CCC2
Solvent: O
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc2c(cc1Br)CCC2
Temperature: -10 °C
Reaction time: 1 h
Yield: 84705.4 %

Procedure:
A mixture of 5-methoxyacetamidoindan (5.50 g, 0.027 mol) and glacial acetic acid (25 ml) was cooled in an ice-water bath (−10° C.). Bromine (1.5 ml, 0.029 mmol) was then dropwise added over a 20 min period while the temperature was kept between 10-15° C. The reaction mixture was then stirred for a longer 1 hour and then it was poured into an ice-wafer bath (100 ml) with the aid of water (70 ml). The precipitate was collected by filtration, washed with plenty of water (150 ml) and dried in vacuo over P2O5 to afford the title compound (6.98 g, 91%), m.p. 84-86° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.09 (m, 2H, 2-CH2), 2.88 (m, 4H, 1-CH2 and 3-CH2), 3.55 (s, 3H, OCH3), 4.04 (s, 2H, 2-CH2OMe), 7.34, 8.22 (2×s, 2H, 4-H, 7-H), 8.83 (s, 1H, CONH);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:29][CH2:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)(O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h

Procedure:
To a mixture of the title compound of Example 5 (0.457 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added 2-methyl-3-butyne-2-ol (0.097 mL). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to yield 0.248 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:83])[C@H:41]([CH2:60][C:61]([NH:63][C:64]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[NH:42]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1>CN(C)C=O>[CH2:1]([C@H:8]([NH:39][C:40](=[O:83])[C@H:41]([CH2:60][C:61]([NH:63][C:64]([C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)=[O:62])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:34])([CH3:35])[CH3:36])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)C

Procedure:
A solution of Example 168A (45 mg, 0.04 mmol) in N,N-dimethylformamide (0.4 mL) was treated with piperidine (80 μL) at 25° C. for 16 h. The solvents were evaporated to give the crude title compound which was used directly in the next step.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][CH3:30])[N:4]=1.Br>C(O)(=O)C>[CH3:28][C:11]1[N:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([NH:29][CH3:30])=[N:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:17]=1
Reactant: CNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Product: CNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Yield: 53.4 %

Procedure:
A solution of 4-methoxy-N-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.10 g, 0.25 mmol) in acetic acid (5 mL) was treated with HBr (0.12 mL, 1.0 mmol) and heated at 90° C. for 4 h. The mixture was cooled to RT, quenched with ice water, treated with NaHCO3 and NaCl, and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness, the resulting material treated with MeCN (3 mL) and the solid was collected via filtration to afford 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylamino)pyrimidin-4(3H)-one (52 mg, 53%). 1H NMR (400 MHz, DMSO-d6): δ 11.26 (s, 1H), 8.70 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.28 (m, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.70 (br s, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (s, 3H), 2.85 (d, J=4.7 Hz, 3H), 2.35 (s, 3H); MS (ESI) m/z: 390.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([OH:33])=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].[OH-].[Na+].[Cl-].[Ca+2:38].[Cl-]>CO>[Ca+2:38].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:34])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([O-:33])=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:34])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([O-:33])=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)O)cc3)c2)c(C)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)[O-])cc3)c2)c(C)c1
Yield: 96.7 %

Procedure:
To a solution of 2-(4-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}phenyl)cyclopropanecarboxylic acid (1.27 g, 2.76 mmol) in methanol (8 mL) was added 1 M aqueous sodium hydroxide solution (2.76 mL, 2.76 mmol). An aqueous solution (2 mL) of calcium chloride (0.153 g, 1.38 mmol) was added thereto. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (1.28 g, yield 97%) as colorless crystals.