Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O1)=[O:5])[CH3:2].[N-:15]=[N+]=[N-].[Na+].[Cl-].[NH4+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N#N>CCO>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:15]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1OC1c1ccccc1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1N[C@H]1c1ccccc1
Reaction time: 5 h

Procedure:
The title compound was synthesized using a literature method (Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989, 30, 4881). To a mixture of 3-phenyloxirane-2-carboxylic acid ethyl ester (9.6 ml, 55 mmol) and 183 ml of EtOH in a flame-dried two-necked flask equipped with a water condenser and magnetic stirring rod was added NaN3 (10.73 g, 165 mmol) and ammonium chloride (8.83 g, 165 mmol). The reaction mixture was brought to 65° C. and stirred for 5 hours at which point GC analysis showed that the reaction was complete. The mixture was filtered and concentrated under reduced pressure. The crude 1H NMR showed that the product of nucleophilic opening of the epoxide by azide was pure enough to carry over to the next step. In a flame-dried two-neck flask fitted with a water condenser and equipped with a magnetic stirring bar was added the product from above (12.93 g, 55 mmol) dissolved in 183 ml of acetonitrile. The reaction mixture was brought to 40° C., at which point PPh3 (16 g, 61 mmol) was added slow enough to avoid rapid evolution of N2. The reaction was then brought to 83° C. and stirred for 5 hours. The reaction mixture was then cooled and concentrated under reduced pressure. The crude mixture was then dissolved in 5% EtOAc in pentane and filtered. The filtrate was concentrated and subsequently dissolved in pentane and placed in the freezer overnight (−15° C.). Any resulting precipitate that formed was filtered off and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (eluent 20% EtOAc in hexanes) to yield a pale yellow oil in 61% over two steps. 1H NMR (200 MHz. CDCl3) (δ: 7.36-7.25 (m, 5H), 4.25 (qd, J=7 Hz, 1.2 Hz, 2H), 3.25 (s, 1H), 2.58 (s, 1H), 1.89 (bs, 1H), 1.31 (t, J=7 Hz, 3H) ppm. 13C NMR (75 MHz. CDCl3) δ: 171.6, 137.8, 128.3, 127.6, 126.1, 61.6, 40.2, 39.3, 14.0 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.[CH:16](O)([CH3:18])[CH3:17]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CCOCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:17]2[CH:7]=[N:6][C:5]([CH3:4])=[CH:18][CH:16]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc(C)nc2)cn1
Temperature: 115 °C
Reaction time: 0.03 h
Yield: 51.2 %

Procedure:
A mixture of 5-bromo-2-methyl-pyridine (1.37 g, 8 mmol), Pd(OAc)2 (90 mg, 0.4 mmol), K2CO3 (1.10 g, 8 mmol), tetra-n-butylammonium bromide (1.29 g, 4 mmol) in DMF (0.9 mL)/H2O (0.35 mL) was stirred at 115° C. under argon for 2 minutes. Isopropanol (480 mg, 8 mmol) was added. After stirring for 48 h, the reaction mixture was allowed to cool down to room temperature. The mixture was added water and ether, and the organic phase was separated, washed with brine, and dried over anhydrous Na2SO4. The solvent was then evaporated under reduced pressure and the residue was purified by silica gel column chromatography to afford the desired product as white crystals (0.377 g, 51%): 1H NMR (500 MHz, C6D6) δ 8.71 (d, J=1.5 Hz, 2H), 7.18 (dd, J=8.0 Hz, 2.5 Hz, 2H), 6.66 (d, J=8.0 Hz, 2H), 2.45 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:29]1([C:32]2[O:36][C:35]([CH3:37])=[N:34][C:33]=2[CH2:38]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:38][C:33]2[N:34]=[C:35]([CH3:37])[O:36][C:32]=2[CH:29]2[CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1nc(COS(C)(=O)=O)c(C2CC2)o1
Product: Cc1nc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)c(C2CC2)o1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 5-cyclopropyl-2-methyl-oxazol-4-ylmethyl ester (prepared by mesylation of (5-cyclopropyl-2-methyl-oxazol-4-yl)-methanol) gave the title compound. ES-MS m/e (%): 534.2 (M+H+).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>[OH-].[Na+].C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12]([NH:8][C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: C=CC[C@H](N)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a mixed solvent of 2N aqueous sodium hydroxide solution (27.4 ml) and THF (55 ml), L-allylglycine (5.22 g) was dissolved, and 2,6-dichlorobenzoyl chloride (7.79 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. After concentrating the reaction solution to remove methanol, water (100 ml) was added thereto and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.65 g). NMR (H1, CDCl3): δ 2.66-2.73 (1H, m), 2.80-2.86 (1H, m), 4.99 (1H, td, J=7.6, 5.6 Hz), 5.18-5.25 (2H, m), 5.76-5.86 (1H, m), 6.39 (1H, brd, J=7.6 Hz), 7.25-7.34 (3H, m) (2) Under an argon atmosphere, a solution of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.46 g) in methanol (120 ml) was cooled to 0° C. Thionyl chloride (5.22 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (11.68 g). NMR (H1, CDCl3): δ 2.62-2.69 (1H, m), 2.76-2.83 (1H, m), 3.79 (3H, s), 4.96 (1H, td, J=7.8, 5.4 Hz), 5.14-5.21 (2H, m), 5.72-5.82 (1H, m), 6.42 (1H, brd, J=6.8 Hz), 7.25-7.34 (3H, m)
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:3][CH:2]=1.[ClH:31].O1CCOCC1>>[ClH:31].[C:13]([O:12][C:10](=[O:11])[CH2:9][CH:8]([NH2:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:6][CH:5]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CC(N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg, 0.267 mmol), a solution of 4 M HCl in 1,4-dioxane (0.668 ml, 2.67 mmol) is added. After stirring for 1 h, the reaction mixture is concentrated to give crude 3-amino-4-biphenyl-4-yl-butyric acid tert-butyl ester hydrochloride.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH:14]1([C:19]([OH:21])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.Cl.[NH2:24][C:25]1[CH:57]=[CH:56][C:28]([O:29][C:30]2[CH:31]=[CH:32][C:33]3[N:37]=[C:36]([CH2:38][O:39][C:40]4[CH:53]=[CH:52][C:43]([CH2:44][CH:45]5[S:49][C:48](=[O:50])[NH:47][C:46]5=[O:51])=[CH:42][CH:41]=4)[N:35]([CH3:54])[C:34]=3[CH:55]=2)=[CH:27][CH:26]=1>CN(C)C=O>[O:50]=[C:48]1[NH:47][C:46](=[O:51])[CH:45]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([O:39][CH2:38][C:36]3[N:35]([CH3:54])[C:34]4[CH:55]=[C:30]([O:29][C:28]5[CH:56]=[CH:57][C:25]([NH:24][C:19]([CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18]6)=[O:21])=[CH:26][CH:27]=5)[CH:31]=[CH:32][C:33]=4[N:37]=3)=[CH:53][CH:52]=2)[S:49]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(O)C1CCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCC4)cc3)cc21

Procedure:
A reaction was conducted by a similar procedure to that described in Example 58 using triethylamine (0.32 ml), ethyl chloroformate (0.08 ml), cyclopentanecarboxylic acid (0.09 ml), anhydrous N,N-dimethylformamide (8 ml) and 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg). The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. To the residue was added water and ethyl acetate and the insoluble material was isolated by filtration to afford the title compound (236 mg, white powder, mp 227-228° C.).
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:16]/[C:17](=[CH:21]\[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1)/[C:18]([OH:20])=O.[NH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH:39]([C:43]2[C:48]([F:49])=[CH:47][C:46]([F:50])=[CH:45][C:44]=2[F:51])[C:38]1=[O:52].C(N(C(C)C)CC)(C)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:16]/[C:17](=[CH:21]\[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1)/[C:18]([NH:36][N:37]1[CH2:42][CH2:41][CH2:40][CH:39]([C:43]2[C:44]([F:51])=[CH:45][C:46]([F:50])=[CH:47][C:48]=2[F:49])[C:38]1=[O:52])=[O:20]
Reactant: NN1CCCC(c2c(F)cc(F)cc2F)C1=O
Reactant: COc1cc(/C=C(\F)C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C(\F)C(=O)NN2CCCC(c3c(F)cc(F)cc3F)C2=O)ccc1-n1cnc(C)c1

Procedure:
BOPCl (221 mg) was added to a suspension of (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (CAS No. 870838-71-4, 240 mg), 1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one (106 g) and IPEA (0.45 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for 16 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 110 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[BH4-].[Na+]>CO.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Br:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:2]([CH3:3])[CH3:1])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=Cc1ccc(Br)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CN(C)Cc1ccc(Br)nc1
Reaction time: 5 h
Yield: 47 %

Procedure:
To a solution of titanium tetraisopropoxide (6.4 g, 22 mmol) and 2.0 M of dimethylamine in methanol (22 mL, 44 mmol), 6-bromo-pyridine-3-carbaldehyde (2.10 g, 11 mmol) in 20 mL of methanol was added. After being stirred at r. t. for 5 hrs, sodium borohydride (0.43 g, 11 mmol) was added and the mixture was stirred overnight. The reaction was quenched by addition of 10 mL of water and extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 20-40% methanol in EtOAc and 0.5% NH4OH, 1.15 g oil was obtained (47% yield), MS: (M+H)+ 214.0, 216.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]I)[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(#N)C>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]([CH2:24][CH2:25][N:47]1[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]1)[CH:12]=[C:11]2[C:9]1[N:8]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[CH:10]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 86.9 %

Procedure:
But using 1 g of 5-fluoro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.223 g of potassium carbonate and 0.323 g of 1-methylpiperazine in 100 ml of acetonitrile. 0.83 g of 2-[5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:44][CH2:45][N:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:46])[F:47])[CH:35]=5)[CH2:41][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.98 (M+H+); retention time=1.07 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:18](OCC)(OCC)([O:20][CH2:21][CH3:22])[CH3:19]>CCCCCC>[CH2:18]([O:20][C:21](=[N:17][S:14]([C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1)(=[O:16])=[O:15])[CH3:22])[CH3:19]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(-c2nsc(S(N)(=O)=O)n2)cc1
Solvent: CCCCCC
Product: CCOC(C)=NS(=O)(=O)c1nc(-c2ccc(OC)cc2)ns1

Procedure:
A mixture of 1.5 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide and 5 ml of triethyl orthoacetate was refluxed for 4 hours. The mixture was cooled and diluted with hexane (15 ml), and the solids were collected and washed with hexane to give 1.7 g of solid. Recrystallization from 3:1 cyclohexane/benzne (100 ml) gave 1.16 g of needles, m.p. 156°-158°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])[CH3:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)CCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN1C(=O)c2ccccc2C1=O
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedure used to prepare 1,3-dihydro-1,3-dioxo-2H-isoindole octanoic acid ethyl ester. Thus, a mixture of 100 g (0.48 mole) of ethyl 5-bromovalerate (99%, Aldrich) and 94.5 g (0.50 mole) of potassium phthalimide (98%, Aldrich) in 300 mL of dimethylformamide gave 107.6 g (81%) of viscous oil. A 2.0 g sample of this oil was purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:10). Fractions containing title compound were combined and the solvents evaporated under reduced pressure to give 1.9 g (95% recovery) of colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Reaction time: 24 h
Yield: 78 %

Procedure:
To a stirred solution of trans-4-benzyloxycarbonylaminocyclohexanol (21.5 g, 86.3 mmol) in acetic acid (160 mL) at room temperature under nitrogen was added chromium trioxide (8.63 g, 86.3 mmol). After 1 d, the reaction mixture was evaporated under vacuum to yield a residue. The residue was suspended in acetone and filtered through a plug of Celite®. The filtrate was evaporated to obtain a green solid. The green solid was purified by silica gel chromatography (eluted with 5% methanol in methylene chloride) to obtain the title compound (16.65 g, 78%) as an off-white solid. 13C NMR (400 MHz, CDCl3) δ 209.6, 155.8, 136.2, 128.5, 128.2, 128.1, 66.8, 47.9, 38.8, 32.1. 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 5H), 5.09 (s, 2H), 4.84 (br s, 1H), 3.97 (s, 1H), 2.38 (m, 4H), 2.20 (m, 2H), 1.68 (m, 2H). HPLC/MS [M+H]+, 248.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](SC)[N:3]=1.[CH:18]1([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CC(C)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:24])[CH2:26][CH2:27]2)[N:3]=1
Reactant: COc1cc2nc(SC)nc(N)c2cc1OC
Reactant: O=C(C1CCCC1)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 4-amino-2-methylmercapto-6,7-dimethoxyquinazoline (0.1 mole) and from 0.1 to 0.15 mole of N-(cyclopentylcarbonyl)piperazine in 150 ml. of isoamyl alcohol is refluxed for a period of 8 to 24 hours. The solvent is evaporated and residual material, treated according to procedure of Example 127(a), provides 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:36][O:37][CH2:38][CH3:39])[N:19]([CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1>CC#N>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:36][O:37][CH2:38][CH3:39])[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]3[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=3)[C:3](=[O:4])[CH2:2][Cl:1])[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCNCc1cccc(CC(=O)OC)c1
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (0.059 mL) was added to the product of step (v) (25 mg) in MeCN (2 mL) at rt under nitrogen. The resulting solution was stirred at rt for 2 h, then concentrated in vacuo and azeotroped with toluene, yield 30 mg.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:37])[NH:11][C:12]2[C:13]([CH3:36])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:46](OCC)=[O:47]>C(Cl)Cl>[C:1]1([C@H:7]([O:9][C:10](=[O:37])[NH:11][C:12]2[C:13]([CH3:36])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]5[NH:33][O:34][C:46](=[O:47])[N:35]=5)[CH2:30][CH2:31]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=N)NO)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(-c3ccc(C4(c5nc(=O)o[nH]5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-{4′-[1-(N-hydroxycarbamimidoyl)-cyclopropyl]-biphenyl-4-yl}-3-methyl-isoxazol-4-yl)-carbamic acid (R)-1-phenyl-ethyl ester (0.66 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.19 mL, 1.32 mmol) and ethyl chloroformate (0.127 mL, 1.32 mmol), and the reaction was stirred overnight at room temperature. Additional triethylamine (0.19 mL, 1.32 mmol) was added, and the reaction was stirred for 6 hours. Additional triethylamine (0.19 mL, 1.32 mmol) was added, and the reaction was stirred until complete. The mixture was diluted with CH2Cl2 (20 mL) and washed with 10% aqueous citric acid, and then dried over MgSO4, filtered, and concentrated. The residue was dissolved in toluene (10 mL), and the solution was refluxed for 3 days. After concentrating, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1>CO.[Pd]>[N:10]1[C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=2)[C:14]#[N:15])=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: COCCOc1cc(C#N)cc(-c2cn3nc(Cl)ccc3n2)c1
Agent: [Pd]
Solvent: CO
Product: COCCOc1cc(C#N)cc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile (10 mmol) in 100 ml MeOH was added Pd/C(1 mmol) and stirred at room temperature for 4 h. Pd-C was removed and the filtrate was concentrated to provide 3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile (98.9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1CBr
Yield: 26.1 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-phenethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (1 g, 2.86 mmol), N-bromosuccinimide (0.56 g, 3.14 mmol), and benzoyl peroxide (70 mg, 0.286 mmol) in CCl4 (25 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 320 mg of the title compound as a tan solid. MS: (+) m/z 452.06 (M+Na).