Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[CH:4][CH:3]=1.[C:17](O)(=[O:19])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:17]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:19]
Reactant: CC(=O)O
Reactant: Cc1ccc(O)c2c1C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
Formylation. 1-Hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (78 g, 0.358 mol) was stirred with glacial acetic acid (632 mL) and hexamethylenetetramine (93.6 g, 0.669 mol). The mixture was heated at 105°-110° C. for 10 h. Hot water (632 mL) was added and the heating was continued for an additional 2.5 h at 100° C. The mixture was cooled to 20° C., toluene (250 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×50 mL), then neutralized with 5% NaHCO3 solution, and finally washed with brine (50 mL). The solvent was removed by distillation and the residue distilled to yield 2-formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (45 g), bp 138°-146° C./1 mm, GLC purity 95%. 1H-NMR (CDCl3) δ11.63 (1H, s), 9.73 (1H, s), 7.09 (1H, s), 2.52 (3H, s), 1.66 (3H, s), 1.47 (6H, s), 1.42 (6H, s). 13C-NMR (CDCl3) δ196 (1C, d), 159 (1C, s), 155 (1C, s), 134.7 (1C, d), 134.1 (1C, s), 128 (1C, s), 118.1 (1C, s), 39.3 (1C, t), 37.8 (1C, t), 36.5 (1C, s), 35.2 (1C, s), 28.7 (2C, q), 27.9 (2C, q), 23.5 (1C, q). IR (KBr) 1637 cm- 1, MS (m/e) 246.2 (M+, 36.1), 231.2 (100.0), 161.2 (41.6), 189.1 (27.9).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:23]([OH:25])=[O:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].C([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:23]([OH:25])=[O:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:1])[CH3:3].[NH:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:34]([OH:40])=[O:33]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN1

Procedure:
A solution of Boc-D-3,3-diphenylalanine-L-proline benzyl ester (8.0 g, 15.0 mmol) in ethanol (200 ml) was hydrogenated in the presence of 10% Pd/C (2.0 g) a t atmospheric pressure for 24 h. The reaction mixture was then filtered through Celite and the filtrate concentrated in vacuo to give the title compound as a white solid: 1H NMR (CDCl3) d 1.20-1.40 (m, 1 H), 1.35 (s, 9 H), 1.40-1.60 (m, 1 H), 1.70-1.90 (m, 1 H), 2.21-2.30 (m, 1 H), 2.70 (q, J=9 Hz, 1 H), 3.75 (br t, J=9 Hz, 1 H), 4.16 (d, J=9 Hz, 1 H), 4.35 (d, J=11.5 Hz, 1 H), 4.97-5.18 (m, 2 H), 7.22-7.39 (m, 10 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCOC1CCCCO1)COc1ccc(F)cc1

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-2-pentyne (13.4 g., 0.04 mole) is dissolved in ethyl acetate (100 ml.). 5% Palladium on carbon is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 41 lbs./in2 and 25°. When 0.08 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil, yield 12.90 g.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]3[N:20]=[CH:21][C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=[O:28])=[CH:23][C:18]3=[N:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7].C1COCC1.Cl>CO.O>[CH3:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]3[N:20]=[CH:21][C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([OH:29])=[O:28])=[CH:23][C:18]3=[N:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)OC)c4)cnn23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)O)c4)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium hydroxide, monohydrate (89 mg, 2.1 mmol) was added to a mixture of methyl 3-[3-(3-{[(methylamino)carbonyl]amino}phenyl)imidazo[1,2-b]pyridazin-7-yl]benzoate (0.17 g, 0.43 mmol) in methanol (4.0 mL)/THF (2.0 mL)/water (1 mL) and then the reaction was stirred at r.t. for 4 h. The mixture was adjusted with conc. HCl to PH˜3. The volatiles were removed under reduced pressure to provide the crude product which was directly used in the next step without further purification. LCMS (M+H)+: m/z=388.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:13]([NH:21][C:22](=[S:23])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To an ice cold solution of tert-butyl 3-aminopropylcarbamate (3.56 g, 20.43 mmol) in CH2Cl2 (80 mL) is added dropwise benzoyl isothiocyanate (3.50 g, 21.45 mmol). The reaction mixture is stirred at room temp for 2 h after which the solvent is removed in vacuo. The resulting residue is partitioned with CH2Cl2 and water, the water layer is extracted with CH2Cl2, the organic layers are combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 6.89 g (quantitative yield) of the title compound. LC/MS (Condition A): ret. T=3.56 min, (M+H)+ 338.26.
Reaction SMILES: S(C1C(F)=C(F)C(F)=C(F)C=1C(O)=O)(O)(=O)=O.FS(C1C(F)=C(F)C(F)=C(F)C=1C(F)=O)(=O)=O.[S:35]1[CH2:41][C:39](=[O:40])[NH:38][C:36]1=[S:37].[F:42][C:43]1[C:48]([CH:49]=O)=[C:47]([F:51])[C:46]([F:52])=[C:45]([F:53])[C:44]=1[F:54]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:42][C:43]1[C:44]([F:54])=[C:45]([F:53])[C:46]([F:52])=[C:47]([F:51])[C:48]=1[CH:49]=[C:41]1[S:35][C:36](=[S:37])[NH:38][C:39]1=[O:40]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: O=C(F)c1c(F)c(F)c(F)c(F)c1S(=O)(=O)F
Agent: O=C(O)c1c(F)c(F)c(F)c(F)c1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1NC(=S)SC1=Cc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Production of 2-sulpho tetrafluorobenzoic acid ##STR61## and 2-fluorosulphonyl tetrafluorobenzoyl fluoride ##STR62## 38 g of triethylamine were added dropwise to a well stirred suspension of 50 g of rhodanine and 70 g of pentafluorobenzaldehyde in 100 ml of chloroform, the temperature being held below 40° C. by external cooling. After one hour, the solution was washed with dilute HCl, then water. The solvent was removed and the resultant yellow residue recrystallised from IMS/water to give 82 g of 2,3,4,5,6-pentafluorobenzylidene rhodanine having a melting point of 132-135° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[N:8]=[C:5]2[S:6][CH:7]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Na+].[I-]>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]=[C:5]2[N:4]([CH:10]=1)[C:3]([CH2:2][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)=[CH:7][S:6]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CCl)csc2n1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1cn2c(Cn3cncn3)csc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
3-Chloromethyl-6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole (64.0 g, 0.22 mol) was dissolved in DMF (600 mL), followed by the addition of 1H-[1,2,4]triazole (30.4 g, 0.44 mol), K2CO3 (91.0 g, 0.66 mol) and NaI (20 mg). The reaction mixture was stirred at room temperature overnight, and then at 35° C. (8 h). The mixture was passed through a silica gel pad, and the filtrate was concentrated in vacuo to give a yellow solid. The solid was washed with ethyl acetate to give 6-(2-nitro-phenyl)-3-[1,2,4]triazol-1-ylmethyl-imidazo[2,1-b]thiazole as a yellow solid (54 g, 75% yield). 1H-NMR (DMSO-d6, 400 MHz): δ 5.75 (s, 2H), 7.40 (s, 1H), 7.52 (m, 1H), 7.68 (m, 1H), 7.79 (m, 2H), 8.05 (s, 1H), 8.19 (s, 1H), 8.83 (s, 1H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1.[Cl:36]C1C=CC(C2NC3C=C(CN4CCN(C)CC4)C=CC=3N=2)=CC=1I>>[Cl:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc2cccnn12
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5cnc6cccnn56)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine (as prepared in Example 3) and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzoimidazole in a manner similar to that described for in Example 1. The intermediate compound 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole was made as for Example 1 (Step 4 to 7) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 8.52 (1H, s), 7.95-7.98 (1H, d, J=9.0 Hz), 7.45-7.48 (1H, d, J=9.0 Hz), 7.43-7.46 (1H, d, J=9.0 Hz), 7.23 (1H, s), 7.21-7.24 (1H, d, J=9.0 Hz), 3.59 (2H, s), 2.51 (8H, brs), 2.29 (3H, s).
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:33][C:30]1[O:29][C:28]([C:25]2[NH:24][C:23]([C:21]3[CH:22]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][N:11]=4)[CH:20]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:27][CH:26]=2)=[N:32][N:31]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)o1
Reaction time: 1.5 h
Yield: 58.8 %

Procedure:
2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-(methylsulfonyl)pyrazine (382 mg, 0.79 mmol) synthesized in Example (970 was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 1.58 mL, 1.58 mmol) was added at −78° C. under nitrogen atmosphere. Subsequently the temperature was brought back to room temperature, followed by stirring for 1.5 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (219 mg, yield 59%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1.ClCCl>CO.[O-2].[O-2].[Mn+4]>[OH:9][C:8]1[C:3]([C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C(O)c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(O)c(C(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2-(Hydroxy-phenyl-methyl)-6-methyl-pyridin-3-ol (553 mg) was dissolved in methanol (3 ml) and dichloromethane (9 ml) to prepare a solution. Manganese dioxide (2.05 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite and was then washed with chloroform and methanol. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give (3-hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (439 mg, yield 80%).
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.C(N)(C)C.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH:25]([NH:24][C:22]([C:18]1[CH:17]=[C:16]([O:35][C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][CH:31]=2)[CH:21]=[CH:20][N:19]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)NC(=O)c1cc(Cl)ccn1
Agent: O=C(Cl)c1cc(Cl)ccn1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 106: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. 3-Amino-2-methoxyquinoline was reacted with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method C2c to afford the urea.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.O>[C:24]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reaction time: 24 h

Procedure:
A solution of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide in 1 mL of anhydrous pyridine is treated with 0.032 mL of acetic anhydride. After 24 h, an additional 0.005 mL of acetic anhydride is added and the mixture is stirred for an additonal 48 h. The mixture is diluted with 2 mL of distilled water and the precipitate is collected by filtration. It is washed with two 1 mL portions of distilled water and dried in a stream of air. It is dried at 20 torr/75°C./16 h. The product is obtained as 78 mg of a tan solid.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+].[O-2].[Al+3].[O-2].[O-2].[Al+3].[C:19](=[O:21])=[O:20]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:19]([OH:21])=[O:20])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C=O
Agent: [Al+3]
Agent: [Na+]
Agent: [O-2]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 170 °C
Yield: 75 %

Procedure:
p-Acetaminophenol 15 g, sodium hydroxide 22.5 g, and aluminum oxide 15 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 3.0 MPa and heated to 170° C., maintained for 3 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve sodium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% nitric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 97% and the yield is 75%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1(C)C
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
2,2-Dimethyl-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.63 g, 43.5 mmol) was dissolved in THF (400 mL) to which Raney Nickel (6.8 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a purple solid (11.26 g, 84.5%). 1H NMR δ(400 MHz, CDCl3) 7.63 (d, J=2.4 Hz, 1H), 7.06 (dd, J=2.9, 8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 3.68 (m, 2H), 3.16 (m, 2H), 2.98 (s, 2H), 1.48 (s, 9H), 1.43 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[C:5]([C:4]1[CH:3]=[C:2]([C:31]#[C:30][CH2:29][OH:32])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(I)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(C#CCO)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 3-iodobenzonitrile (10.0 g), copper(I) iodide (166 mg), triphenylphosphine (572 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (904 mg), propargyl alcohol (2.83 ml), diisopropylethylamine (30.5 ml) and tetrahydrofuran (170 ml) was stirred at room temperature for 23 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-67:33) to give the object product (5.59 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[H][H]>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1

Procedure:
1-(4-Chlorobenzoyl)-2-(4-nitrophenyl)hydrazine (2.92g, 0.01 mole) and 5% palladium on barium sulfate (catalytic amount) were suspended in a mixture of ethanol (350 ml) and concentrated hydrochloric acid (5 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a tan solid. Yield 2.9 g (99%), m.p. 209° C (dec.).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[CH2:13][NH:14][C:15](=[O:17])[CH3:16]>ClC(Cl)C>[Cl:1][CH2:2][C:3]([C:20]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[C:11]([CH3:10])[CH:21]=1)=[O:4]
Reactant: CC(=O)NCc1ccccc1C
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCc1ccc(C(=O)CCl)cc1C
Temperature: 0 °C
Yield: 29.7 %

Procedure:
Chloroacetyl chloride (17 g) was added dropwise to a mixture of aluminum chloride (13.3 g) in dichloroethane (60 ml) at ambient temperature under stirring and the mixture was stirred for one hour. To the resulting mixture was added N-(2-methylbenzyl)acetamide (13.3 g) at ambient temperature and the mixture was stirred at 25° to 50° C. for 1.5 hours. The reaction mixture was poured into ice water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was washed with ethyl acetate and diisopropyl ether to give N-(4-chloroacetyl-2-methylbenzyl)acetamide (5.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][NH:73]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:81])([CH3:82])[C:76]32[CH2:77][CH2:78][CH2:79]3)[CH2:74]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCOCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 8 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(4-methyl-tetrahydro-pyran-4-yl)-acetic acid (0.306 g; 1.12 mmol) (prepared according to Tetrahedron Let 2007, 48, 6343-6347) and HATU (0.581 g; 1.53 mmol) in DCM (20 mL) was stirred for 10 min at ambient temperature. DIPEA (1.05 mL; 6.11 mmol) and (5R,8S)-10,10-Dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.57 g; 1.02 mmol) were added, the reaction mixture was stirred overnight and purified without workup by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.55 min; M/z=706 [M+]; HPLC (method A3): Rt=6.16 min
Reaction SMILES: [NH2:1][C:2]1[C:9](Br)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>CCN(CC)CC.[Cu]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>[NH2:1][C:2]1[C:9]([C:17]#[C:16][C:15]([CH3:19])([CH3:18])[CH3:14])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])cc(C#N)c1N
Temperature: 80 °C
Reaction time: 10 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in dry Et3N (60 mL) was added CuI (380 mg, 5% mol) and Pd(PPh3)2Cl2 (470 mg, 5% mol) at room temperature. 3,3-dimethyl-but-1-yne (2.1 g, 25 mmol) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at 80° C. for 10 h. The reaction mixture was filtered and the filtrate was poured into ice (60 g), extracted with ethyl acetate. The phases were separated and the organic phase was dried over Na2SO4. The solvent was removed under vacuum to obtain the crude product, which was purified by column chromatography (2-10% EtOAc in petroleum ether) to obtain 2-amino-3-(3,3-dimethylbut-1-ynyl)-5-nitrobenzonitrile (1.7 g, 71%). 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.7 Hz, 1H), 8.27 (d, J=2.7 Hz, 1H), 5.56 (br s, 2H), 1.37 (s, 9H).