Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1>>[OH:14][C:15]([CH3:47])([CH3:48])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:12][CH2:11][CH2:10][C:9]4=[O:13])=[N:6][CH:7]=3)=[CH:30][CH:31]=2)[CH3:25])[CH2:19][CH2:18]1
Reactant: O=C1CCCN1c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(N3CCCC3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 1-(5-bromopyrimidin-2-yl)pyrrolidin-2-one and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one following a procedure analogous to that described in Example 28. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=515 [M+H]+; 1H NMR (CD3OD) δ 0.81 (s, 3H), 1.17 (s, 3H), 1.47 (d, 3H), 2.09 (m, 3H), 2.13 (m, 2H), 2.41 (m, 2H), 2.57 (m, 2H), 2.96 (m, 1H), 4.08 (m, 2H), 5.52 (m, 1H), 7.02 (d, 2H), 7.23 (m, 5H), 7.38 (m, 2H), 8.78 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.[C:24]([C:32](O)=[O:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)CCl>C(Cl)Cl>[O:31]=[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]([N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=1)[C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:33]
Reactant: FC(F)(F)c1ccc(CCNc2ccc(C(F)(F)F)nc2)cc1
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of [2-(4-trifluoromethyl-phenyl)-ethyl]-(6-trifluoromethyl-pyridin-3-yl)-amine (50 mg) in CH2Cl2 (3 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (46 mg, 66%) as a light yellow solid. MS m/e: 467.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CC(CC=C)C#N)[CH:6]=[CH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[CH2:28][CH3:29])(=O)C>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:3][CH:4]([CH2:5][CH:28]=[CH2:29])[CH2:8][NH2:7])=[CH:5]2
Reactant: C=CCC(C#N)Cn1ccc2cc(C)ccc21
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CN)Cc1cc2cc(C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a stirred solution of 51 (8.82 g, 39.3 mmol) in THF (400 mL) at 0° C. was added LiAlH4 (4.77 g, 118 mmol). The mixture was stirred at room temperature overnight, then cooled to −78° C. and ethyl acetate (60 mL) was added followed by 10% NaOHaq (15 mL). The reaction was quenched by the addition of moister Na2SO4, filtered through celite, washed with EtOAc (3×100 mL) and MeOH (3×150 mL). Evaporation provided a residue, which was purified by silica gel flash chromatography to provide 52 as colorless oil. (3.52 g, 39% yield). H NMR (d6-DMSO) δ 7.34-7.27 (m, 3H), 6.93 (d, 1H, J=1.5 Hz & 8.3 Hz), 6.31 (d, 1H, J=3.0 Hz), 5.78 (m, 1H), 5.06-4.99 (m, 2H), 4.16 (dd, 1H, J=7.0 Hz & 14.2 Hz), 4.00 (dd, 1H, J=6.5 Hz & 14.2 Hz), 2.42 (t, 2H, J=4.5 Hz), 2.36 (s, 3H), 2.05 (m, 1 H), 1.98-1.90 (m, 2H). FABMS (+Ve) m/z 229 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][CH:12]([NH:15][CH:19]([CH3:21])[CH3:18])[CH2:13][CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (335 mg), acetone (92 ul), acetic acid (0.1 mL) and methanol (3 mL) was stirred at room temperature for 5 minutes. To the reaction solution was added triacetoxy sodium boron hydride (332 mg). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (160 mg). Yield: 41%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15]C=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH:22]1C2C(=CC=CC=2)C(C(Cl)=O)=N1>>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][N:22]=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)c1n[nH]c2ccccc12
Reactant: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: O=C(NCC12CCN(CC1)CC2)c1n[nH]c2ccccc12

Procedure:
N-((quinuclidin-4-yl)methyl)-1H-indazole-3-carboxamide was prepared in a similar manner to N-((quinuclidin-4-yl)methyl)-1H-indole-3-carboxamide, substituting 1H-indazole-3-carbonyl chloride as the electrophile. 1HNMR: 13.6 (bs, 1H); 9.65 (bs, 1H); 8.45 (t, 1H); 8.15 (d, 1H); 7.62 (d, 1H); 7.41 (t, 1H); 7.2 (t, 1H); 3.28 (m, 2H); 3.21 (m, 6H); 1.70 (m, 6H). MS (m/e): 285.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:2]#[CH:3].[OH-].[Na+].[I:13]I.O>CO>[I:13][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: II
Reactant: C#CCOc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: IC#CCOc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
In 300 ml methanol was dissolved 39.0 g (0.27 mole) 3-(2-propynyloxy)pyridine. This solution was cooled to 0° C. and 54.0 g (1.35 moles) sodium hydroxide was added slowly while maintaining the temperature at 0°-5° C. Iodine (82.0 g, 0.32 mole) was added portionwise followed by the addition of 400 ml methanol. After stirring for 2 hours at room temperature, the reaction mixture was poured into cold water. The resulting precipitate was filtered and dried. This crude product was recrystallized from 350 ml methanol and 75 ml toluene to give 60.0 g (86% yield) 3-(3-iodo-2-propynyloxy)pyridine, mp 130° C. with decomposition.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([S:27][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Sc1cccc(Cl)c1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cnc(Sc2cccc(Cl)c2)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (167 mg), 3-chlorobenzenethiol (98 mg), cesium carbonate (221 mg), and N,N-dimethyl formamide (2 mL) was stirred at room temperature for 15 hours, and then at 70° C. for 10 hours. To the reaction liquid was added ethyl acetate (30 mL), followed by washing with saturated brine (20 mL) and a saturated aqueous ammonium chloride solution (20 mL) in this order, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate) to obtain 4-({2-[(3-chlorophenyl)sulfanyl]-4-(trifluoromethyl)pyrimidin-5-yl}carbonyl)morpholine (183 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[C:9](Cl)[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.[Br:13]C1C=CC=C2C=1C(=O)CC2>>[Br:13][C:9]1[CH:10]=[CH:2][CH:3]=[C:4]2[C:8]=1[CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cccc(Br)c21
Reactant: NC1CCc2cc(Cl)cc(Cl)c21
Product: NC1CCc2cccc(Br)c21

Procedure:
This compound was prepared using a method analogous to that of 5,7-dichloro-2,3-dihydro-1H-inden-1-amine (A.2.13), 7-bromo-1-indanone replacing 5,7-dichloro-1-indanone.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)/C=C/c1ccccc1Cl
Yield: 128.9 %

Procedure:
(E)-2-(2-Chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (4.55 g, 12.3 mmol) was stirred for 15 minutes in a 1:1 mixture of trifluoroacetic acid and dichloromethane (18 mL). The solution was concentrated in vacuo to afford a solid. The solid was washed with dichloromethane (5 mL) and heptane (150 mL) and was collected by suction filtration. The solid was dried under vacuum at room temperature to afford crude (E)-2-(2-chloro-phenyl)-ethenesulfonic acid amide (3.45 g) which was taken on to the next step without further purification.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[NH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and aminodiphenylmethane (0.54 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide (0.48 g, 1.5 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a solution of 5% hydrogen chloride in methanol (2 ml) to form a solution. The solution was further crystallized from methanol-diethyl ether to give N-cyano N'-diphenylmethyl 3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [CH:1]([C:4]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:5]#[N:6])([CH3:3])[CH3:2].C=O.[CH:38](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([C:4]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[CH3:38])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: COc1cc(C(C#N)(CCCNCCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C#N)(CCCN(C)CCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 2.58 g of alpha-isopropyl-alpha-[3-[N-[3-(2-nitrophenoxy)propyl]amino]propyl]-3,4,5-trimethoxyphenylacetonitrile, 4.35 ml of 37% of formalin, and 4.35 ml of 90% formic acid was stirred for 1 hour at 90° C. After cooling, to the mixture were added water and potassium carbonate to make it alkaline. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using 1% methanol-chloroform as an eluent to give 1.43 g of the desired compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4].[CH2:30]([NH2:33])[CH2:31][NH2:32]>>[NH2:32][CH2:31][CH2:30][NH:33][C:26]([C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([NH:16][C:14]([C:12]1[O:13][C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH2:1])=[CH:29][C:10]=3[CH:11]=1)=[O:15])=[CH:25][CH:24]=2)=[O:28]
Reactant: NCCN
Reactant: NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1
Product: NCCNC(=O)c1cc2cc(NC(=O)c3cc4cc(NC(=O)CN)ccc4o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 340 mg (0.05 mmol) 131 resin 8 mL 1,2-ethylenediamine was added. The resin was agitated for 1 hr at ambient temperature then it was filtered off, washed twice with DMF. The filtrates were pooled and were evaporated to dryness. The remaining oily residue was dissolved in DMF and evaporated again in order to get rid of the amine traces. The crude material was dissolved in 5 mL aqueous 0.1% TFA solution and was purified on a preparative reverse phase HPLC column using acetonitrile gradient. The fractions containing the pure product were pooled, evaporated to dryness dissolved in 3 mL methanol and treated with 1 mL 4.0M HCl in dioxane. 133 was precipitated with ether as bis-HCl salt, filtered off and dried to yield 44.8 mg (88%). MS: 435.19 (M+H+).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)/[C:6](O)=[O:7])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][O:66][C:67](=[O:88])[C:68]1[C:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[CH:72][CH:71]=[CH:70][C:69]=1[O:82][CH2:83][CH2:84][CH2:85][CH2:86][NH2:87]>CN(C=O)C>[CH3:65][O:66][C:67](=[O:88])[C:68]1[C:73]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[CH:72][CH:71]=[CH:70][C:69]=1[O:82][CH2:83][CH2:84][CH2:85][CH2:86][NH:87][C:6](=[O:7])/[C:5](/[NH:4][C:1](=[O:3])[CH3:2])=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: CC(=O)N/C(=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Reactant: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
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: CN(C)C=O
Product: COC(=O)c1c(OCCCCNC(=O)/C(=C\c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)NC(C)=O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (260 mg, 0.58 mmol) in DMF (10 mL) is added diisopropylethylamine (0.11 mL, 0.64 mmol) and HATU (243 mg, 0.64 mmol). The mixture is stirred at RT for 10 min then a solution of 2-(4-aminobutoxy)-6-benzyloxybenzoic acid methyl ester (Example 110, step C) (286 mg, 0.87 mmol) in DMF (1 mL) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:29]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:28]([OH:47])[C:27]3=[O:48])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO.O>[NH:19]1[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:29]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:28]([O:47][CH3:3])[C:27]3=[O:48])=[CH:22][C:21]=2[N:17]=[CH:18]1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2cnc3ccccc3c2)N1c1ccc2nc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1=C(c2ccccc2)C(c2cnc3ccccc3c2)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq) ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(quinolin-3-yl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.230 g, 0.5 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.003 g (1.4%); MS m/z: 433.4 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 4.17 (s, 3H), 6.85, 6.87 (2s, 1H), 7.19-7.22 (m, 1H), 7.30-7.34 (m, 2H), 7.37-7.41 (m, 1H), 7.45-7.53 (m, 2H), 7.60-7.63 (m, 1H), 7.69-7.71 (m, 2H), 7.78-7.80 (m, 1H), 7.84-7.86 (m, 2H), 8.11 (s, 1H), 8.35 (s, 1H), 8.84 (s, 1H); HPLC (METHOD [A]): rt 12.26 min (100%)
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1OCCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccccc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
3-(2-Isopropylphenoxy)propionic acid tert-butyl ester (10) (4.3 g) was dissolved in dichloromethane (40 mL), and to the mixture was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 3 h, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain the compound (11) 3.14 g.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (532 mg) in DMF (45 ml) was dripped into a suspension of 60% sodium hydride-oil (144 mg) in DMF (12 ml) on an ice-water bath. The mixture was stirred at room temperature for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.02 g) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-yellow powder (711 mg, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:25]1[N:26]=[C:27]2[C:33]([C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.CN(C=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[C:37]([NH:36][C:34]([C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:26]=2)[NH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 25 °C
Yield: 82 %

Procedure:
The mixture of 6-fluoro-3-(tributylstannyl)-1H-indazole (500 mg, 1.17 mmol), 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (258 mg, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), copper iodide (10 mg 0.052 mmol) in 15 ml, of dry DMF was heated to 90° C. for 2.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with 50 mL of water and filtered. The solid was washed with dichloromethane and hot methanol, then filtered to give N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a yellow solid (260 mg, 82%). 1H NMR (300 MHz, DMSO): δ 13.82 (s, 1H), 12.96 (s, 1H), 9.10 (s, 1H), 8.48-8.43 (m, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.44-7.41 (m, 1H), 7.12-7.06 (m, 1H), 3.14 (d, 1H, J=5.1 Hz), 1.51 (s, 9H). LCMS: 353.0, [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CC(C)N(C)C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CC2CNCC2N1C

Procedure:
7.25 g (34.2 mmol) of ethyl 2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time, the extracts are dried over potassium carbonate and concnetrated, and the residue is distilled.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C(=O)N([Br:31])C(=O)C1.C1C(=O)N(Br)C(=O)C1.C1COCC1>C1COCC1>[Br:31][CH:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4]1
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)OCC(Br)C2=O
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
4-Oxochroman-7-carbonitrile (11.0 g, 63.5 mmol) was dissolved in THF (250 mL) and cooled to −30° C. prior to the addition of LiHMDS (66.7 mL, 66.7 mmol) dropwise. The resulting solution was stirred for 20 min. Next, the temperature was lowered to −78° C. and the solution was stirred for 0.5 h. In another flask, NBS (11.3 g, 63.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Then the anion solution was transferred into NBS/THF solution at −78° C. via cannula. The resulting solution was stirred at −78° C. for 40 min. The reaction was quenched with aqueous saturated NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with 1N HCl, brine, dried (MgSO4), and filtered. The filtrate was concentrated and the resulting residue was purified by flash chromatography with 10% to 20% EtOAc/hexane on 120 g ISCO column to afford 3-bromo-4-oxochroman-7-carbonitrile (10.0 g, 39.7 mmol, 62.5% yield) as a pale yellow solid: LCMS=251.9 [M+H]+.