Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([O:55][C:56]2[CH:63]=[CH:62][C:59]([C:60]#[N:61])=[CH:58][C:57]=2[CH:64]2[CH2:66][CH2:65]2)=[N:53][CH:54]=1>CN(C)C=O>[C:60]([C:59]1[CH:62]=[CH:63][C:56]([O:55][C:52]2[N:53]=[CH:54][C:49]([NH:48][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:50][CH:51]=2)=[C:57]([CH:64]2[CH2:65][CH2:66]2)[CH:58]=1)#[N:61]
Reactant: N#Cc1ccc(Oc2ccc(N)cn2)c(C2CC2)c1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)cc2C2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (121.4 mg, 0.60 mmol) was dissolved in N,N-Dimethylformamide (1 mL). N,N-Diisopropylethylamine (0.126 mL, 0.72 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (227.2 mg, 0.60 mmol) were added. The reaction mixture was stirred at r.t. for 30 min. 4-[(5-amino-2-pyridinyl)oxy]-3-cyclopropylbenzonitrile (Reference Intermediate R24, 100 mg) was dissolved in 1.0 mL of DMF and the obtained solution was added to the reaction mixture. The reaction mixture was stirred and heated at 60° C. for 2 h. After cooling down to r.t., the reaction mixture was evaporated under vacuum and the crude obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 50:50 Cyclohexane/EtOAc, then plateau at 50:50) affording 133 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.Cl.[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][N:22]1[C:29]([NH2:31])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][N:27]4[CH2:26][CH:25]5[CH2:21][N:22]([C:29]([NH2:31])=[O:30])[CH2:23][CH:24]5[CH2:28]4)=[CH:4][CH:5]=3)[S:9][C:10]=2[CH:16]=1
Reactant: Fc1ccc2nc(Oc3ccc(CCl)cc3)sc2c1
Reactant: NC(=O)N1CC2CNCC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)N1CC2CN(Cc3ccc(Oc4nc5ccc(F)cc5s4)cc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a suspension of 2-(4-chloromethyl-phenoxy)-6-fluoro-benzothiazole (152 mg, 0.52 mmol), hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide, hydrochloride (110 mg, 0.57 mmol) and Cs2CO3 (676 mg, 2.08 mmol) in DMF (1 mL) was stirred at rt overnight. The resultant mixture was filtered and the residue purified via preparative reverse phase HPLC to afford the title compound (15 mg, 7%). MS (ESI): Mass calcd for C21H21N4O2SF, 412.1; m/z found, 413.1 [M+H]+; 1H NMR (400 MHz, CD3OD): 7.64 (dd, J=8.9, 4.7 Hz, 1H), 7.58 (dd, J=8.4, 2.6 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.19 (dt, J=9.0, 8.9, 2.6 Hz, 1H), 3.66 (s, 2H), 3.59-3.40 (m, 2H), 3.29-3.27 (m, 2H), 2.97-2.83 (m, 2H), 2.77 (d, J=9.3, 6.8 Hz, 2H), 2.46 (d, J=9.3, 3.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: O=Cc1nc(Br)cs1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1csc(CN2CCOCC2)n1
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added morpholine (130 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (76%).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].C(Cl)Cl>C1COCC1>[CH3:9][C:5]1[C:3]2[NH:4][C:10](=[O:11])[O:1][C:2]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(O)c1N
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2oc(=O)[nH]c12
Temperature: 70 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
To a solution of 2-hydroxy-6-methylaniline (583 mg) in THF (8 mL) was added 1,1′-carbonyldiimidazole (1.14 g). The reaction mixture was stirred at 70° C. for 20 h. After cooling down, DCM was added and the mixture was washed three times with 2N NaOH. The aq. phases were combined, cooled down to 0° C. and the pH was brought to 6 by addition of 2N HCl. The suspension was filtered, the resulting powder was washed with cold water and dried in high vacuo to afford 587 mg of beige solid. LC-MS (B): tR=0.64 min. 1H-NMR (DMSO-d6): 11.7 (s, NH); 7.09 (m, 1H); 6.97 (m, 2H); 2.29 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[N:19]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(Cc3ccc4ccccc4c3)CC2)nc1

Procedure:
To a mixture containing 5.0 g. of β-chloromethylnaphthalene, 3.0 g. of sodium carbonate and 30 ml. of dimethylformamide is added 4.6 g. of pyrimidinylpiperazine. The mixture is stirred and heated on a steam bath for approximately two hours. The mixture is then cooled, filtered and the filtrate is concentrated to a small volume in vacuo. The residue is washed with water and crystallized from ethanol to yield 1-(β-napthylmethyl)-4-(2-pyrimidinyl)-piperazine having a melting point of 109°-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 53.2 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (86.35 mg, 0.2553 mmol), 3-Chlorobenzaldehyde (39.5 mg, 0.281 mmol) and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 62.33 mg (53%) of the title compound. (300 MHz, DMSO-d6) 3.42 (s, 1H), 8.18 s, 1H), 8.09 (d, J=8 Hz, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.62-7.53 (m, 2H), 7.27-7.22 (m, 2H), 6.38 (m, 2H), 5.19 (t, J=17 Hz, 9 Hz, 1H), 2.90 (s, 1H), 2.79 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.40 (d, J=8 Hz, 1H). MS=460 (M+H), HPLC: 2.75 min. (G Method)
Reaction SMILES: [CH:1]([NH:5][C:6]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[CH:1]([NH:5][C:6]([CH2:8][CH:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: NCCCCCCO
Reactant: CCC(C)NC(=O)C=CC(=O)OC
Product: CCC(C)NC(=O)CC(NCCCCCCO)C(=O)OC
Reaction time: 8 h

Procedure:
To methyl 3-(sec-butylcarbamoyl)acrylate from the above reaction at room temperature was added the 6-amino-1-hexanol (13.7 g, 117 mmol) and the resulting mixture was stirred overnight to give the desired product.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:24])=[C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[CH3:23][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=3[CH3:24])[O:14][N:13]=2)[CH:20]=[C:19]([CH3:21])[C:18]=1[O:22][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: ClCC1CO1
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a solution of 4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (515 mg, 1.50 mmol) in isopropanol (20 mL), 3 N aq. NaOH (5 mL) followed by epichlorohydrine (473 mg, 5.12 mmol) is added and the mixture is stirred at rt for 15 h. Another portion of epichlorohydrine (473 mg, 5.12 mmol) is added and stirring is continued for 24 h. The mixture is diluted with sat. aq. Na2CO3 and is then extracted with DCM (4×75 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated. The residue is purified by CC on silica gel eluting with heptane:EA 4:1 to give rac-3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (382 mg) as a white powder; LC-MS: tR=1.22 min, [M+1]=399.28.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[OH:24]O.[OH-].[NH4+]>C(O)=O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][CH:13]5[C:14]([CH:15]=[CH:16][C@:17]2([OH:24])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 3 h
Yield: 149.6 %

Procedure:
Thebaine (100.0 g dry weight) was dissolved in 85% formic acid (252.3 g). 30% Hydrogen peroxide (43.6 g) was added over a period of about two hours. The mixture was stirred for three hours. Ammonium hydroxide solution was added to the mixture to increase the pH to 8–9. The solid precipitate was filtered and washed with water and ethanol. The solid was dried on the filter and in an oven. The product was 14-hydroxycodeinone (150.52 g damp, 75.32 g dry weight, 75% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](Cl)=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Reactant: COCCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCNC(=O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
3-Methoxypropylamine (0.026 g, 0.29 mmol) was added to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (intermediate 4) (26 mg 0.29 mmol) in tetrahydrofuran (2 ml) and the mixture stirred at room temperature for 15 min. Triethylamine (0.2 ml, 1.4 mmol) was then added and the resulting mixture stirred overnight. 1M Hydrochloric acid (3–4 ml) was added dropwise to precipitate a yellow solid which was filtered and dried under suction to give the amide (79 mg, 0.20 mmol) as a yellow solid, LCMS m/z 395.25 [M+H]+ @ RT 1.04 min; δH(400 MHz, (CD3)2SO) 8.59 (1H, m), 8.57 (1H, s), 8.39 (1H, app d J 9.3 Hz), 8.08 (1H, app d J 7.3 Hz), 7.66–7.53 (5H, m), 3.37–3.33 (4H, m), 3.27 (3H, s), 1.83–1.77 (2H, m).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=NC=[CH:17][CH:18]=2)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4].N[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(CC(=O)CCC=C)#N.C(Cl)Cl>CO>[CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=[C:20]3[C:21](=[CH:17][CH:18]=2)[N:22]=[CH:23][CH:24]=[CH:25]3)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Nc1cccnc1
Reactant: C=CCCC1=NN=C(N)C1=NNc1cccnc1
Agent: C=CCCC(=O)CC#N
Solvent: ClCCl
Solvent: CO
Product: C=CCCC1=NN=C(N)C1=NNc1ccc2ncccc2c1
Yield: 54 %

Procedure:
In a similar manner, 5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine was prepared from 3-aminopyridine (113 mg, 1.2 mmole) and 1-cyano-5-hexen-2-one (123 mg, 1 mmole). The crude material was pruified by preparative TLC (CH2Cl2:MeOH=21:1) to yield 131 mg (54%) of the title compound as an orange powder. MS (m/z, ES+): 243 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.89 (s, 1H), 8.46 (m, 1H), 7.96 (d, 1H), 7.46 (dd, 1H), 7.19 (brs, 2H), 5.87 (m, 1H), 5.07 (dd, 1H), 4.96 (d, 1H), 2.84 (br m, 2H), 2.46 (t, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:12])([CH3:11])[C:6](=O)[CH2:7][C:8]#[N:9]>CCO>[C:5]([C:6]1[CH:7]=[C:8]([NH2:9])[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:2]=1)([CH3:12])([CH3:11])[CH3:4]
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: O
Solvent: CCO
Product: CCCCCn1nc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 20 h
Yield: 117.3 %

Procedure:
To a solution of Example 99A (10.0 g, 41.3 mmol) in EtOH (85 mL) was added hydrazine hydrate (3.02 mL, 61.9 mmol). The mixture was warmed to reflux (85° C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (7.78 g, 61.9 mmol) was added and the mixture was again warmed to reflux (85° C.) and was allowed to stir for 4 hours then the mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (50 mL) was added slowly. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc) provided the title compound (7.6 g, 36.3 mmol, 88% yield). MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14](O)=[O:15]>>[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: COc1ccc(N)cc1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Yield: 92.9 %

Procedure:
Using p-anisidine (738 mg, 6.0 mmol) and 3-methyl-4-nitrobenzoic acid (906 mg, 5.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.33 g (93.0%) of the title compound in the form of yellow powder.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>ClC1C=CC=CC=1Cl>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[NH:19][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Reactant: NCCc1ccc(O)cc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2cccc(NCCc3ccc(O)cc3)c2C(=O)c2c(NCCc3ccc(O)cc3)cccc21
Temperature: 160 °C
Yield: 60.6 %

Procedure:
A mixture of 27.7 grams (0.1 mole) of 1,8-dichloroanthraquinone, 30 grams (0.22 mole) of p-(2-aminoethyl)phenol in 200 milliliters of o-dichlorobenzene was heated to 160° C. for 18 hours. The mixture was cooled to room temperature, and the product was collected by filtration. Thereafter, the aforementioned product was recrystallized from isopropanol to yield 29 grams (62 percent) of 1,8-bis[2-(p-hydroxyphenyl)ethylamino]anthraquinone as a red powder, m.p. 181° to 182° C.; vis (DMF), λmax 520 nm (ε 12,000); ms 478 (M+); Analysis Calculated for C30H26N2O4 : C, 75.29; H, 5.48; N, 5.86; O, 13.38. Found: C, 74.94; H, 5.30; N, 5.63; O, 13.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]>C1COCC1>[Cl:33][C:31]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[N:32]=1
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)ccc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine (64.7 g, 353 mmol) in anhydrous THF (170 mL) was added a solution of LHMDS (555 mL, 1 M in hexanes, 555 mmol) dropwise over 45 minutes under a nitrogen atmosphere. After 2.5 hours at −78° C., a solution of 2,6-dichloro-nicotinic acid (33.8 g, 177 mmol) in anhydrous THF (100 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to room temperature. After 18 hours stirring at room temperature the reaction was quenched with crushed ice and the pH adjusted to pH 1 by the addition of concentrated HCl (ca. 90 mL). The resultant solution was extracted with ethyl acetate and the organic layer washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated three times successively with methanol and filtered to afford the title compound as a yellow solid (46.7 g, 78%). LCMS (method B): RT=4.83 min, M+H+=339.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]([CH2:47][NH2:48])[OH:46]>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:48][CH2:47][CH2:45][OH:46])[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: NCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCCO)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) and ethanolamine (0.020 mL) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification. MS (ES+) 546.7 (M+H)+
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)[CH:25]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:28]1[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]3[O:31][C:32]([CH3:38])([CH3:37])[C:33]([CH3:36])([CH3:35])[O:34]3)[CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 4.05 g, 15.05 mmol), 4,4,5,5-tetramethyl-2-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane (Intermediate G2, 5 g, 15.05 mmol), X-Phos-Pd-G2 (1.184 g, 1.505 mmol) and K3PO4.H2O (9.81 g, 30.1 mmol) were dispersed in THF (42 ml) and deoxygenated under argon, then water (42 mL) was added and the mixture stirred at rt overnight. The reaction was diluted with AcOEt (250 ml) and washed with 0.2 M of HClaqueous (250 ml), once with saturated NaClaqueous, anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50 G SNAP with a gradient of hexane and AcOEt to give the title compound (5.4 g, 91%) as dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1([SiH3])C=CC=CC=1>C1COCC1.C(Cl)Cl.C([Sn](Cl)(Cl)CCCC)CCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 204.8 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-amino-thiophene-2-carboxylic acid methyl ester (1.512 g, 5.97 mmol) and N-tert-butoxycarbonyl-piperidin-4-one (1.189 g, 5.97 mmol) in 2 mL of dry THF is added dibutyltin dichloride (181 mg, 0.60 mmol), and the mixture is stirred for 10 min at room temperature under nitrogen. Then phenylsilane (810 μL, 6.57 mmol) is added, and the mixture is stirred for 24 h at room temperature. Additional 595 mg of N-tert-butoxycarbonyl-piperidin-4-one, 90 mg of dibutyltin dichloride and 405 μL of phenylsilane are added, and the mixture is stirred for another 24 h. Then the mixture is diluted with CH2Cl2, washed with brine, organic fraction is separated, dried over Na2SO4, and concentrated to give 5.142 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-(N-tert-butoxycarbonyl-piperidin-4-yl)amino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([OH:32])=[C:27](B(O)O)[CH:28]=1>>[OH:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][C:26]=3[OH:32])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c(O)c1
Yield: 44 %

Procedure:
6-(2-Hydroxy-4-methylphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 5-methyl-2-hydroxyphenylboronic acid in 44% yield using method F; δH [2H6]-DMSO 13.60,(1H, b), 13.10,(1H, b), 8.32,(2H, t), 8.23,(2H, m), 8.13,(2H, d), 8.03,(1H, d), 7.95,(1H, s), 7.18,(1H, d), 6.92,(1H, d), 6.83,(2H, m), 2.33,(3H, s), 2.34,(3H, s); MS 369 (MH)+; HPLC retention time (system 1) 4.46 minutes.