Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)#[N:2].[SH2:30]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)(=[S:30])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 18 h

Procedure:
t-Butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (430 mg, 1.10 mmol) was dissolved in a mixed solution of pyridine (30 ml) and triethylamine (7 ml), and hydrogen sulfide gas was blown in for 10 minutes at room temperature, which was followed by stirring for 18 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with a 2N aqueous potassium hydrogensulfate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give t-butyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. The solid was dissolved in acetone (50 ml) and methyl iodide (2 ml) was added. The mixture was refluxed under heating for 40 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give t-butyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Thereto were added methanol (30 ml) and ammonium acetate (280 mg, 3.64 mmol), and the mixture was refluxed under heating for 3 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-3/1) to give 596 mg of hydriodide of compound (8) as a yellow solid (quantitatively in 3 steps).
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][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]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][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:34])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: O=C(Cl)N1CCCCC1
Product: O=C(c1cn(C(=O)N2CCCCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available piperidine-1-carbonyl chloride as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:72][C:73]([F:76])([F:75])[F:74])[C:67](=[O:71])[C:68]([NH2:70])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:72][C:73]([F:74])([F:76])[F:75])[C:67](=[O:71])[C:68]([NH2:70])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:54])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(F)(F)F)C(=O)C(N)=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(F)(F)F)C(=O)C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
80 mg (0.074 mmol) of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-αaspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxovaleramide were dissolved in 3 ml of trifluoroacetic acid and the solution was stirred at room temperature for 30 minutes. The solution was then diluted with 10 ml of toluene and the solvent was removed by evaporation. The residue was purified by reverse-phase high-pressure liquid chromatography on a Dynamax C18 column (5 micron, 300A, 21.4×50 mm). The elution gradient comprised 90% SSA 10% SSB to 95% SSB 5% SSA over 8.5 minutes (SSA is 0.1% trifluoroacetic acid in water; SSB is 0.1% trifluoroacetic acid in 70% acetonitrile and 30% water). After lyophilization overnight there were obtained 12 mg of 3(R or S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxo-valeramide (diastereoisomer A); MS: m/e 916.3 [M+H]+, which was eluted first, and 8 mg of 3(R or S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxo-valeramide (diastereoisomer B); MS: m/e 916.2 [M+H]+, which was eluted subsequently.
Reaction SMILES: O.S(=O)(=O)(O)O.C1([O:12][C:13]2[CH:14]=[C:15]([C@@H:21]([C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)[NH2:32])[CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])CCCC1>O1CCOCC1>[OH:12][C:13]1[CH:14]=[C:15]([C@@H:21]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc([C@H](Cc2ccncc2)c2cccc(N)c2)cc1OC1CCCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@H](Cc2ccncc2)c2cccc(N)c2)cc1O
Temperature: 90 °C
Yield: 90.5 %

Procedure:
Water (25 ml) and sulphuric acid (40 ml, concentrated) was added to a solution of 3-[1-(R)-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline (3.8 g, 9.8 mmol prepared as described in International Patent specification No. WO95/17386) in 1,4-dioxane (50 ml) at RT. The mixture was heated at 90° C. for 1 h, cooled and concentrated in vacuo. The pH of the residue was adjusted to pH 8.0-8.5 by the addition of solid NaOH. The mixture was diluted with ethyl acetate (100 ml) and water (50 ml) and extracted with ethyl acetate (2×50 ml). The extract was washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to give a crude product which was washed with ethyl acetate to afford 3-[1-(R)-(3-hydroxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline (Intermediate 1) as a pale yellow powder (2.84 g, 91%). (Found: C, 73.83; H, 6.44; N, 8.09. C20H20N2O2 +0.25 mol. eqv. of ethyl acetate requires C, 73.66; H, 6.48; N, 8.18%), δH (d4 -methanol) 3.3 (2H, d, J 8.0 Hz), 3.77 (3H, s), 4.06 (1H, t, J 8.0 Hz), 6.5 (1H, d, J 2.2 Hz), 6.53-6.78 (5H, m), 6.97 (1H, t, J 7.7 Hz), 7.13 (2H, d, J 5.8 Hz), and 8.25 (2H, d, J 5.6 Hz). m/z (ESI--MH+ 321 (25), 228 (100).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:8][C:5]([O:4][CH2:1][CH:2]1[CH2:3][O:18]1)([CH3:9])[CH2:6][OH:7]
Reactant: C=CCOC(C)(C)CO
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)OCC1CO1
Temperature: 0 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2-allyloxy-2-methyl-propionic acid ethyl ester (1.72 g, 10 mmol) in anhydrous tetrahydrofuran (40 mL) was stirred at room temperature under nitrogen. Lithium borohydride (44 mg, 20 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C. and saturated ammonium chloride solution was cautiously added followed by hydrochloric acid (2 M) to acidify the reaction mixture to pH 2. The mixture was extracted with diethyl ether and the organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-allyloxy-2-methyl-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 153.2 [M+Na], Tr=1.16 min. A suspension of 2-allyloxy-2-methyl-propan-1-ol (10 mmol) in dichloromethane (40 mL) was stirred at 0° C. Meta-chloroperbenzoic acid (70% pure containing 20% water and 10% meta-chlorobenzoic acid, 2.9 g, 12 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 24 h. The reaction mixture was cooled to 0° C. and saturated sodium hydrogen carbonate solution and sodium thiosulfate solution were added and the mixture was stirred at 0° C. for 15 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 169.2 [M+Na], Tr=0.72 min. A solution of 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) in dichloromethane (50 mL) and racemic camphor-10-sulfonic acid (765 mg, 3.3 mmol) was stirred at room temperature for 18 h. Saturated sodium hydrogen carbonate solution was added and the organic layer separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 2:3 to 1:4 to afford the title compound (826 mg, 57% over 3 steps) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 1.02 (s, 3H), 1.20 (s, 3H), 3.23 (d, J=11.1 Hz, 1H), 3.30-3.50 (m, 6H), 4.68 (t, J=5.4 Hz, 1H). LCMS (m/z) 169.2 [M+Na], Tr=0.72 min.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12]C(=O)OC(C)(C)C)[CH2:10][C:9]2[C:4](=[C:5]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1.Cl.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[NH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[C:5]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (5.0 g) was suspended in ethyl acetate (30 mL), and 4N hydrochloric acid in ethyl acetate (28.3 mL) was added thereto, followed by stirring at 35-40° C. for one hour. The reaction mixture was added to a solution of potassium bicarbonate (11.3 g) in water (20 mL), and the mixture was partitioned at 45° C. The aqueous layer was extracted with ethyl acetate twice, and the organic layers were combined. The combined organic layer was concentrated under reduced pressure until precipitates were formed. The concentrated residue was stirred at room temperature for 30 minutes, and the formed precipitates were recovered through filtration. The thus-obtained solid was washed with ethyl acetate, and then dried under reduced pressure, whereby the title compound (2.93 g) was yielded as crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH:26](Br)[CH2:27][CH2:28]Cl)=[O:25])=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[N:1]1([C:26]2([C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:19][CH:20]=3)=[O:25])[CH2:28][CH2:27]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)C(Br)CCCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc(-c2ccccc2)cc1)C1(n2cncn2)CC1
Temperature: 0 °C

Procedure:
44.7 g (0.648 mol) of 1,2,4-triazole and 89.5 g (0.648 mol) of anhydrous potassium carbonate were suspended in 525 ml of acetonitrile, and, under reflux, 202 g (0.6 mol) of of acetonitrile, and, under reflux, 202 g (0.6 mol) of 1-bromo-3-chloropropyl 4-phenylphenyl ketone were added in portions over 20 minutes. After a reaction time of 3 hours under reflux, the mixture was poured into ice water and the crystals obtained were filtered off under suction. 162.0 g (93% of theory) of colorless crystals of melting point 154°-5° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:40]=[CH:39][C:28]([O:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:41][C:24]([F:23])([F:42])[C:25]1[CH:40]=[CH:39][C:28]([O:29][CH:30]2[CH2:31][CH2:32][N:33]([C:36]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:37])[CH2:34][CH2:35]2)=[CH:27][CH:26]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@](O)(COC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 15.5 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.16 g, 4.68 mmol) and triethylamine (1.63 ml, 11.70 mmol) were added to a suspension of 4-(4-trifluoromethylphenoxy)piperidine-1-carbonylchloride (0.72 g, 2.34 mmol) in toluene (40 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenoxy)-piperidine-1-carboxylate (184 mg, yield 16%) as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10](OC)=[O:11])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:15][Si:2]([CH3:1])([CH3:14])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1
Reactant: COC(=O)CCc1coc([Si](C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(CCCO)co1
Reaction time: 3 h

Procedure:
A solution of methyl 3-(2-trimethylsilyl-4-furyl)-propionate (from above) in tetrahydrofuran (3 ml) was added dropwise to a suspension of lithium aluminum hydride (27 mg) in tetrahydrofuran (4 ml) at room temperature. After 3 hours, the mixture was quenched with ethyl acetate and extracted with ether. Evaporation of the dried (magnesium sulphate) extracts gave the title alcohol, which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[CH:24][C:23]([NH:22][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])=[CH:44][CH:43]=4)=[CH:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (197 mg, 973 μmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (80 μL, 973 μmol) and N,N-dimethylformamide (2 drops) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A solution of N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 649 μmol) in N,N-dimethylacetamide (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from ethanol/water to give the title compound (187 mg, 39%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH:21]([CH3:24])[C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH:22]([CH3:23])[C:21]#[CH:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: C#CC(C)Cl
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)N1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 50.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2.5 g) is alkylated using (rac)-3-chloro-but-1-yne (0.86 g; 9.5 mmol) and K2CO3 (3.28 g; 23.7 mmol) at 50° C. for 14 days. After aqueous work-up the crude material (1.51 g) is de-acetylated in MeOH (40 ml) using DBU (0.3 ml) at reflux. After aqueous work-up (rac)-5-amino-3,3-dimethyl-1-(1-methyl-prop-2-ynyl)-6-nitro-1,3-dihydro-indol-2-one (1,3 g) is obtained and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]CC4C=CC=CC=4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1CC=CCC=1>CCO.[Pd]>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.9 %

Procedure:
To a refluxing mixture of cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (46 g, 113 mmol), 10% Pd/C (2 g) in EtOH (400 mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirring was continued for 2-5 h until the reaction was complete. The mixture was cooled to rt, filtered through celite, and washed with EtOH. The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHCl3 (200 mL). The resulting suspension was stirred for 15 nm at rt. The solid was filtered, and dried in the air to give cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (34.4 g, 95%, yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18])[CH2:6]2.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH:23]=O>C(O)C.O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CCCN)C2
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCCNCC(OC)OC)C2
Reaction time: 12 h
Yield: 90 %

Procedure:
1 g (3.7 mmoles) of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropane-1,3-diamine is dissolved in 20 mL of ethanol. 520 mg (0.45 mL) of a 60% solution of glyoxal 1,1-dimethyl acetal in water and then 100 mg of Pd/C 10% are added. The reaction mixture is hydrogenated at atmospheric pressure and ambient temperature for 12 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. 1.2 g of expected product are obtained in the form of an oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1)(O)=[O:2].[CH3:33]C1(C)OC(=O)CC(=O)O1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1.C(O)(=O)C.O>[O:2]=[C:1]([CH3:33])[CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1
Reactant: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 3-[2-(2-carboxymethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2 g) in dichloromethane (20 ml) was added in turn 2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg), 1,3-dicyclohexylcarbodiimide (1.1 g) and 4-dimethylaminopyridine (720 mg) at 0° C. A reaction mixture was allowed to warm to ambient temperature and stirred for overnight. Precipitate was removed by filtration, and mother liquor was washed with 1N-aqueous hydrochloric acid and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was dissolved in a mixture of acetic acid (15 ml) and water (15 ml), and which was. refluxed for 10 hours. A reaction mixture was extracted with ethyl acetate (200 ml) and organic layer was separated, which was neutralized with saturated sodium hydrogen carbonate in water. Organic phase was separated, washed in turn with saturated sodium hydrogen carbonate in water (50 ml) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (100 g) eluting in turn with 33%, 50%, 80% ethyl acetate in n-hexane and ethyl acetate to give 3-[2-{2-(2-oxopropyl)-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.5 g).