Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([P:23](Cl)(Cl)=[O:24])=[CH:19][CH:18]=1>>[F:28][C:16]([F:15])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=P1(c2ccc(C(F)(F)F)cc2)c2ccccc2CN1c1ccccc1
Yield: 4 %

Procedure:
The procedure of Example 38 was employed utilizing N-benzylaniline and 4-trifluoromethylphenyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was crystallized from diethyl ether and petroleum ether and recrystallized from diethyl ether to yield 1-[4-(trifluoromethyl)phenyl]-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.5 g, 4% yield) having a melting point of 187°-189° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:42])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 54 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 54% of theory, C27H29N7O3 (499.6) ##EQU49##
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([SH:14])[N:3]=1.[CH3:15]I>[OH-].[Na+]>[OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(S)nc1O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1c(C)nc(SC)nc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
Methyl (4-hydroxy-6-methyl-2-mercapto-5-pyrimidinyl)-acetate (40 g, 0.19 mol) is dissolved in an aqueous solution of NaOH (8 g in 400 ml H2O). Methyl iodide (29.5 g, 0.2 mol) is added and the mixture is stirred at room temperature for 4 hours. Filtration and drying at high vacuum gives methyl (4-hydroxy-6-methyl-2-methylmercapto-5-pyrimidinyl)-acetate (25.4 g, 60%) as a crystalline solid, having a m.p. of 200° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([O:31][CH2:32][CH2:33][O:34][CH3:35])([C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:46]1([N:52]2[CH:56]=[C:55](B3OC(C)(C)C(C)(C)O3)[CH:54]=[N:53]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:55]3[CH:54]=[N:53][N:52]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:56]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([O:31][CH2:32][CH2:33][O:34][CH3:35])([C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Temperature: 90 °C
Yield: 73 %

Procedure:
A mixture of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (3.06 g, 3.93 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.38 g, 5.11 mmol), PdCl2(dppf)CH2Cl2 (321 mg, 0.393 mmol), and K3PO4 (2.50 g, 11.8 mmol) in dioxane/H2O (40/4 mL) was degassed and then heated at 90° C. for 16 h. LCMS showed very good conversion to the desired product (795), and about 10% de-iodination byproduct (653). The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.6 in 50% EtOAc/Hexanes) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a brown oil (2.28 g, 73%).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:27]2[CH:26]=[C:25]([CH3:24])[O:29][N:28]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
10-Bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 32.6 mg of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 454 (M)+. 1H NMR (400 MHz, DMSO) δ 11.08 (q, J=4.2 Hz, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.05 (d, J=10.5 Hz, 1H), 6.56 (s, 1H), 6.35 (s, 1H), 5.04-4.95 (m, 2H), 4.59-4.51 (m, 2H), 2.80 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:14]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:14]=1[O:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: Oc1cnc2ccccc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Temperature: 0 °C

Procedure:
3-Hydroxyquinoline (1) (prepared according to the procedure of Naumann et. al., Synthesis 4:279-281 (1990)) (3 g) and 1,2,3-trichloro-5-nitrobenzene (4.7 g) were dissolved in DMF (80 mL) and heated with cesium carbonate (7.4 g) for 2 h at 60° C. The reaction was poured into ice/water (500 mL). The resulting off-white precipitate was collected by filtration and rinsed with hexane to afford compound II as a solid (6.9 g) suitable for use in the next reaction.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S([O-])(=O)(=O)C>C1COCC1.CCOC(C)=O>[C:5]1([C:8]#[C:9][CH2:10][NH:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: N[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: CS(=O)(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc([C@H]2CC[C@H](NCC#Cc3ccccc3)CC2)cc1

Procedure:
A mixture of trans-4-(4-hydroxyphenyl)cyclohexylamine 5 (0.35 g, 1.8 mmol) and mesylate 7 (0.32 g, 1.5 mmol) in THF (15 mL) was refluxed under N2 for 17 hours. The reaction mixture was diluted with EtOAc (40 mL) and washed with H2O, then saturated NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 99:1 CHCl3:MeOH to 97:3 CHCl3:MeOH) and conversion to the maleate salt gave trans-4-[4-(3-phenylprop-2-ynylamino)cyclohexyl]phenol (160 mg, 26%) as a white solid: mp 171-179° C.; IR (KBr): 2938, 1700, 1516cm−1; 1H NMR (300 MHz, CD3OD) δ 7.52-7.35 (m, 5H), 7.04 (d, J=8 Hz, 2H), 6.69 (d, J=8 Hz, 2H), 6.25 (s, 2H), 4.21 (s, 2H), 3.45-3.35 (obs m, 1H) 2.52-2.42 (m, 1H), 2.31-2.20 (m, 2H), 2.05-1.60 (m, 2H), 1.67-1.48 (m, 4H); CI-MS (methane) (m/z): 306 [M+H]+; HPLC: method A, 7.63 minutes (97.9%); method B, 14.01 minutes (97.6%); Anal. Calcd for C21H23NO.C4H4O4: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.21; H, 6.51; N, 3.22.
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[Na]>>[C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC(=O)OC
Reactant: OCCCCCCOc1ccc(Nc2ccccc2)cc1
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na]
Product: CCCCCCCC(=O)OCCCCCCOc1ccc(Nc2ccccc2)cc1

Procedure:
Following the method of Example 1, a mixture of 28.5 g. of 6-(p-anilinophenoxy)hexanol, 47.5 g. of methyl octanoate, 0.3 g. of aluminum isopropylate and a small chip of sodium metal (about 0.1 g.) was heated at 160°-170° C. for a total of 9 hours. The reaction mixture was then cooled and recrystallized from 2-propanol to afford the ester, 6-(p-anilinophenoxy)hexyl octanoate as a crystalline solid, m.p. 42°-43° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:19])=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Reaction time: 15 h
Yield: 88.2 %

Procedure:
Benzyl bromide (5.7 g, 33.09 mmol) was added to a suspension of 3-(4-hydroxyphenyl)propanoic acid (5.0 g, 30.08 mmol) and anhydrous potassium carbonate (8.31 g, 60.17 mmol) in anhydrous DMF (60 ml), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate, and the organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (6.8 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[NH:24](C(OC(C)(C)C)=O)[CH2:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][N:15]([C:26](=[O:27])[CH2:25][NH2:24])[CH2:16][CH2:17]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: NCC(=O)N1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
(5-Chloro-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine prepared in Example 93 and N-BOC-Gly-OH were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)C(C)=O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>CC(O)=O.CCO>[NH2:1][C:5]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1cccc2c(Cl)cccc12
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])c2c(Cl)cccc12
Yield: 32 %

Procedure:
1-Acetamino-5-chloronaphthalene (150 mg, 0.68 mmol, prepared as described in Example 213A) was dissolved in 1 mL AcOH and treated with 82 μL of red fuming HNO3 and subsequently deacylated with 1 mL 40% aqueous NaOH solution in 3 mL EtOH according to the procedure described in Example 209A to yield 49 mg (32%) of compound 214A as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[N:12]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)c2nc(CNC(=O)c3cccnc3)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.34 mmol) and nicotinoyl chloride hydrochloride (91 mg, 0.51 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (167 mg, 1.2 mmol). The reaction was stirred for 2 h at 0° C. The mixture was washed successively with H2O, 0.1 M HCl, H2O and 5% NaHCO3. The reaction was extracted with EtOAc (3×10 mL), washed with brine, dried (MgSO4) and concentrated providing 64 mg of the title compound. 1H NMR (CDCl3) δ 8.76 (s, 1H), 8.29 (d, 1H), 8.11 (s, 1H), 7.78 (d, 1H), 7.58 (t, 1H), 7.45 (t, 1H), 7.14 (d, 2H), 7.05-7.01 (m, 2), 6.93 (d, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 3.61 (s, 3H); LC-MS (ESI+; 400 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[CH:21]=[C:20](S(C)=O)[N:19]=[C:18]([CH3:25])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[OH-].[NH4+:27]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:17]=[C:18]([CH3:25])[N:19]=[C:20]([NH2:27])[CH:21]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(Nc2nccnc2-c2cc(S(C)=O)nc(C)n2)cn1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2cc(N)nc(C)n2)cn1
Temperature: 100 °C
Yield: 83 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylsulfinyl)pyrimidin-4-yl)pyrazin-2-amine (11.40 mg, 0.032 mmol) (crude product from the last step) and ammonium hydroxide, 28.0-30.0% (0.5 mL, 12.84 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 80% EtOAc/hexanes to give 6-(3-(6-methoxypyridin-3-ylamino)pyrazin-2-yl)-2-methylpyrimidin-4-amine (8.2 mg, 0.027 mmol, 83% yield). 1H NMR (300 MHz, CDCl3) δ 12.46 (s, 1H); 8.42 (s, 1H); 8.15 (s, 1H); 8.10 (dd, J=8.77, 2.48 Hz, 1H); 7.98 (d, J=1.32 Hz, 1H); 7.47 (s, 1H); 6.78 (d, J=8.62 Hz, 1H); 4.95 (s, 2H); 3.95 (s, 3H); 2.64 (s, 3H). m/z (ESI, +ve ion) 310.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Mg+].[Br-]>C1COCC1.CCOCC>[CH3:14][C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a solution of commercially available 1-(phenylmethyl)-3-pyrrolidinone (1.0 g, 5.71 mmol) in THF (30 mL) and ether (30 mL) at 0° C. was added MeMgBr (1.4 M solution in toluene:THF (3:1)) (6.1 mL, 8.65 mmol). The reaction was stirred at 0° C. for 1.5 hours, then quenched with water and extracted. Removed organic solvent in vacuo and extracted again with ether, dried organics (Na2SO4) and removed solvent in vacuo. Purified by RP-HPLC to provide racemic 3-methyl-1-(phenylmethyl)-3-pyrrolidinol as a yellow oil (0.501 g, 46%). LCMS: (M+H)+=192.3.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>C1COCC1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a suspension of 60% NaH (3.13 g) in THF (20 mL) was added dropwise a solution of pyrrole (5.00 g) in THF (20 mL). The mixture was stirred for 30 minutes, and thereto was added a solution of p-toluene sulfonylchloride (14.2 g) in THF (20 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the organic layer was separated, dried, filtered, and concentrated. The residue was recrystallized from a mixed solvent of methanol and water (each 35 mL), and the resulting crystals were collected by filtration, and dried to give 1-p-toluenesulfonyl-1H-pyrrole (16.3 g, 99%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu].CN(C=O)C>[C:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][CH:9]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(N(c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)c2cccc3ccccc23)cc1
Temperature: 200 °C
Yield: 55.8 %

Procedure:
To 32.4 g (148 mmol) of N-phenyl-1-naphthylamine were added 25.1 g (61.5 mmol) of 4,4′-diiodobiphenyl, 2.14 g of polyethylene glycol (PEG-6000 (a trade name) manufactured by Wako Junyaku K.K.), 17.1 g (0.124 mol) of potassium carbonate and 15.7 g (247 mmol) of copper (powder) were added, and heated to 200° C. The reaction was traced by high-performance liquid chromatography. Heating was continued under stirring until the peaks of raw materials and intermediates were disappeared (for 12 hours). After the completion of the reaction, water and DMF are added, and the resulting mixture is dispersed, filtrated, and washed with water. The resulting crystal is purified by silica gel chromatography to afford 20.2 g (yield: 55.9%) of N,N′-di(l-naphthyl)-N,N′-diphenyl-4,4′-diaminobiphenyl represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1.CO>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)nc1)NC(=O)OCc1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)nc1)NC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A flask was charged with 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-acrylic acid methyl ester (0.50 g, 1.2 mmol), Wilkinson's catalyst (200 mg, 0.2 equiv), methanol (5 mL), and toluene (3 mL). The flask was flushed with nitrogen, then hydrogen, heated to 35° C., and allowed to stir under an atmosphere of hydrogen for 4 days. The reaction was flushed with nitrogen, diluted with methanol, filtered, and concentrated to afford the crude product which was purified by column chromatography to give 145 mg (29%).
Reaction SMILES: C[C:2]([CH3:29])=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:28])[C:14]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[OH:15])[CH2:8][CH2:7]1.Cl.Cl.N[CH:33]1[CH2:38]CN(CC2CCCCCC2)C[CH2:34]1>>[CH:4]1([CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:28])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[OH:15])[CH2:10][CH2:11]2)[CH2:38][CH2:33][CH2:34][CH2:29][CH2:2][CH2:3]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccccc2F)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccccc1F)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-(2-fluorophenyl)-2-cyclopentyl-2-hydroxyacetic acid obtained in Example 54 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C=O)C>[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][CH3:36])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: COc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1OCCOc1nccnc1N1CCNCC1
Reaction time: 15 h
Yield: 10.9 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 60 mg, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and added to a stirred solution of the product from Step 2 (100 mg, 0.31 mmol), 2-methoxyphenol (124 mg, 1.00 mmol) and triphenylphosphine (92 mg, 0.35 mmol) in THF (1 mL). The reaction mixture was stirred for 15 h and then concentrated under reduced pressure. The residue was passed through a bed of silica gel using toluene/EtOAc/MeOH (45:45:10) as eluent, and the pure fractions were combined, concentrated and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min. The mixture was concentrated and the residue was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The combined product-containing fractions were concentrated and partitioned between 5% aqueous NaOH and CH2Cl2. The organic phase was concentrated, and the residue was purified by chromatography on silica gel using CH2Cl2/MeOH (8:2) as eluent to give 11.2 mg (11%) of the title product. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1707.