Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([NH2:24])[CH:18]=2)=[N:6][C:5]1=[O:25])([CH3:3])[CH3:2].[CH:26](OCC)(OCC)OCC>CCOC(C)=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH:26]=[N:24][C:19]=3[CH:18]=2)[NH:6][C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)nc(-c2ccc(O)c(N)c2)c2cc3c(cc21)OCO3
Reactant: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)NC(c2ccc3ocnc3c2)c2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-isopropyl-6,7-methylenedioxy-4-(3-amino-4-hydroxyphenyl)quinazolin-2(1H)-one (93 mg) in triethyl orthoformate (3 mL) was refluxed for 1 h, cooled to rt, diluted with EtOAc (30 mL), washed with water, saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as a tan solid (70 mg, 71%), mp: 84-86° C. 1H NMR (CDCl3): 8.12 (s, 1H), 7.72 (s, 1H), 7.59(d, J=8.3, 2H), 7.39 (d, J=8.3, 1H), 6.71 (s, 1H), 6.28 (s, 1H), 5.92 (s, 1H), 5.90 (s, 1H), 5.49 (s, 1H), 5.14 (s, 1H), 4.45 (m, 1H), 1.58 (d, J=6.6, 3H), 1.55 (d, J=6.6, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:37])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([Cl:37])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of step A (0.33 mmol) in dichloromethane (3 mL) was added a drop of N,N-dimethylformamide followed by oxalyl chloride (0.532 mmol). After stirring for 0.5 hour at room temperature, the solution was heated to reflux for three hours. The solvent and excess oxalyl chloride were evaporated to yield the crude product, which was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:12]([C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)#[C:13][CH3:14].O>C(NCC)C.[Cu](I)I>[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]#[C:2][CH3:3])=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: CC#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CCC)cc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CC#Cc1ccc(C#Cc2ccc(CCC)cc2)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
4-Propylphenylacetylene (7.21 g, 0.05 mol) and 4-(1-propynyl)iodobenzene (12.1 g, 0.05 mol) were dissolved in diethylamine (30 cc), and then copper iodide (0.29 g, 1.5 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.53 g, 0.75 mmol) were added. The resulted mixture was reacted with stirring in nitrogen gas current at about 20° C. for 8 hours. After completion of the reaction, water (100 ml) was added to the resulting reaction mixture. The resulting deposited mass was extracted with toluene (50 ml). The resulting toluene solution was washed with dilute hydrochloric acid, followed by water until the washing water became neutral. The resulting material was dried over anhydrous sodium sulfate. Toluene was distilled off from the toluene solution. The residue was then dissolved in a mixed solvent of n-hexane/methylene chloride (1 vol./1 vol.). The solution was subjected to column chromatography using silica gel as a fixed phase, and using the above mixed solvent as an eluent. Fractions showing a single spot were collected by TLC and the mixed solvent was distilled. The residue after distillation was recrystallized from ethyl alcohol (20 ml) to obtain the objective 4-propyl-4'-(1-propynyl)tolan (compound No. 1) (6.7 g). This compound exhibited liquid crystal phases (CI point: 87.7° C., NI point: 85.1° C.).
Reaction SMILES: [OH-].[Na+].C1COCC1.[F:8][C:9]1[CH:44]=[CH:43][CH:42]=[CH:41][C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[C:30]([CH2:32][O:33][CH2:34][C:35]2[CH:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH:31]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][N:20]=1)=[O:17]>>[F:8][C:9]1[CH:44]=[CH:43][CH:42]=[CH:41][C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[C:30]([CH2:32][O:33][CH2:34][C:35]2[CH:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH:31]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][N:20]=1)=[O:17]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(COCc3cc(C)on3)cc(OCc3ccccc3F)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(COCc2cc(OCc3ccccc3F)cc(C(=O)Nc3ccc(C(=O)O)cn3)c2)no1

Procedure:
Standard ester hydrolysis (2M NaOH/THF), as described in Example A, of methyl 2-[3-(2-fluorobenzyloxy)-5-(5-methyl isoxazol-3-yl methoxy) methyl benzoyl]aminopyridine-5-carboxylate gave the title compound as a colourless solid, 1H NMR δ (300 MHz, d6-DMSO): 2.40 (s, 3H); 4.58 (s, 4H), 5.22 (s, 2H); 6.26 (s, 1H); 7.21–7.30 (m, 3H); 7.38–7.45 (m, 1H); 7.55–7.60 (ap d, 1H); 7.60 (s, 1H); 7.64 (s, 1H); 8.32 (s, 2H); 8.86 (s, 1H); 11.16 (br s, 1H); m/z 492 (M+H)+, 490 (M−H)−
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=O)[CH3:27])[CH:21]=1>CO.C(O)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15]/[N:16]=[C:26](/[C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)\[CH3:27])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CC(=O)c1cccnc1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cccnc1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
3-(Morpholinosulfonyl)benzohydrazide (40 mg, 0.140 mmol) and 1-(pyridin-3-yl)ethanone (16.98 mg, 0.140 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (15 mg). 1H NMR (400 MHz, CDCl3): δ 9.53 (bs, 1H), 8.87 (s, 1H), 8.59 (m, 1H), 8.39 (m, 1H), 8.17 (m, 1H), 7.98 (m, 1H), 7.89 (d, 1H, J=8.0 Hz), 7.67 (t, 1H, J=8.0 Hz), 7.32 (m, 1H), 3.70 (m, 4H), 3.00 (m, 4H), 2.39 (s, 3H). ESI-MS: 389.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc(Cl)cc2)cc1
Yield: 35 %

Procedure:
Following a procedure similar to that described in Example 12, but using 2 g of 2-amino-1-(4-chlorophenyl)ethanol (prepared as described in Preparation 12), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.7 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained as crystals, melting at 78°-79° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]4[CH2:25][CH2:24][CH2:23][N:22]4[C@@H](C4C=CC(OC)=CC=4)C)[CH:20]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]4[CH2:25][CH2:24][CH2:23][NH:22]4)[CH:20]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2c1ccn2-c1cncc([C@@H]2CCCN2[C@H](C)c2ccc(OC)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc2c1ccn2-c1cncc([C@@H]2CCCN2)c1
Yield: 86.7 %

Procedure:
A solution of 1-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-1H-indole-4-carboxylic acid ethyl ester (I-1A-1a: 5.0 g, 11 mmol) in TFA (15 mL) was heated in a microwave tube at 100° C. for 30 minutes. The resulting mixture was concentrated under reduced pressure to give a di-TFA salt of the titled compound as a red oil (3.2 g) which was used directly in the next step without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:41][CH2:40]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CN2CCCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. N-methylhomopiperazine (660 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylhomopiperazin-1-ylmethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:24]=1[N:38]1[CH2:50][CH2:49][N:41]2[C:42]3[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=3[CH:48]=[C:40]2[C:39]1=[O:51])(=[O:20])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CCc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)n[nH]1
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 23.1 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 125a (116 mg, 0.39 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (200 mg, 0.43 mmol), Pd(PPh3)4 (30 mg, 0.0.26 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 23% (50 mg) of 125b as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149)(50 mg, 0.21 mmol) was coupled to aniline (60)(41 mg, 0.21 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[O:6])[CH3:3].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[C:21]([O:13][CH:8]([NH:7][C:5]([O:4][C:2]([CH3:14])([CH3:1])[CH3:3])=[O:6])[C:9]([O:11][CH3:12])=[O:10])(=[O:23])[CH3:22]
Reactant: COC(=O)C(O)NC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of the product of Example 1 (10.0 g, 48.8 mmol), pyridine (7.71 g, 97.6 mmol) and DMAP (300 mg, 2.5 mmol) in THF (50 ML) was added acetic anhydride (5.47 g, 53.6 mmol) slowly at room temperature. After stirring at ambient temperature for 3 hours, the reaction was diluted with EtOAc and washed successively with 1N NaHSO4 and sat'd NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure affording 11.8 g (98%) of product as a colorless oil.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[C:13]([F:31])[CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[C:13]([F:31])[CH:12]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)cc2F)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1cc(Cl)ccc1C1=CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>O>[N+:12]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:11])=[CH:6][CH:7]=1)([O-:14])=[O:13]
Reactant: O=C1CCCc2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
Under ice-cooling, 1-tetralone (15.0 g, 0.103 mol) was gradually added dropwise to fuming nitric acid (100 ml). The reaction mixture was stirred for 30 minutes, which was poured into water. Resulting crystalline precipitate was collected by filtration and washed with water, which was dissolved in ethyl acetate. The solution was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/isopropyl ether to give 7-nitro-1-tetralone. This compound was dissolved in ethanol (100 ml), to which 5% Pd.-C (50% hydrous, 1 g) was added. The mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration, and the filtrate was concentrated. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 3:2), followed by recrystallization from ethyl acetate/isopropyl ether to give 1.70 g (yield from 1-tetralone, 10%) of the above-titled compound, m.p.141-143° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17]3[C:20]([NH:22][C:23](=O)[C:16]=3[CH2:15]2)=O)=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][C:17]3[CH:15]2[CH2:16][CH2:23][NH:22][CH:20]=3)=[CH:12][CH:13]=1
Reactant: O=C1NC(=O)C2=C1CCC(c1ccc(F)cc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C2CCC3=CNCCC32)cc1
Reaction time: 0.75 h
Yield: 21.6 %

Procedure:
4.5 g (118 mM) of lithium aluminum hydride were added in portions to 9.4 g (38 mM) of 4-p-fluorophenyl-1-cyclohexene-1,2-dicarboximide in 300 ml of tetrahydrofuran at room temperature while stirring vigorously over the course of 45 min. The mixture was stirred for 0.5 h and refluxed for 6 h. After cooling, ten percent sodium hydroxide solution was cautiously added dropwise while cooling in ice and stirring vigorously, and the precipitated hydroxides were filtered off with suction and washed with tetrahydrofuran. The filtrate was evaporated to dryness, and the residue was partitioned between water and methyl t-butyl ether at pH=10. The organic phase was subsequently extracted twice with ten percent hydrochloric acid, after which the acidic aqueous phase was made alkaline again with concentrated sodium hydroxide solution. It was then extracted twice with methyl t-butyl ether. After drying and concentration, 1.8 g (22%) of product were isolated as a pale oil.
Reaction SMILES: [CH3:1][N:2]([C:11](=[O:24])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH3:23])[CH:15]=1)=O)[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].CO.O.[OH-].[Li+].Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11](=[O:24])[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:23])[CH:15]=2)=[C:5]([S:6]([CH3:9])(=[O:8])=[O:7])[C:4]([CH3:10])=[N:3]1
Reactant: CC(CS(C)(=O)=O)=NN(C)C(=O)C(=O)c1cn(C)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1nn(C)c(=O)c(-c2cn(C)c3ccccc23)c1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a 50 ml volume three-necked flask, 1-methyl-1-[2-(1-methyl-1H-indol-3-yl)-2-oxoacetyl]-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-203)-(13)-28) (2.0 g), methanol (7.59 ml), and toluene (2.31 ml) were added under a nitrogen atmosphere, then added lithium hydroxide monohydrate (0.24 g) under cooling on ice-bath of −5° C., and stirred for 2 hours. To the mixture, cold dilute hydrochloric acid was added under ice-cooling, and stirred for 5 minutes. Then, the mixture was added to ice water. The precipitated solids were collected by filtration, and dried under reduced pressure to give 1.7 g of 2,6-dimethyl-4-(1-methyl-1H-indol-3-yl)-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-203)-(13)-28).
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[C:40](=[O:42])=[O:41]>O1CCCC1.C1CCCCC1>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([C:40]([OH:42])=[O:41])[N:3]([CH3:20])[N:4]=[C:5]12
Reactant: O=C=O
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1.46 g) and a few crystals of 1, 10 phenanthroline were dissolved in 25 mL of dry tetrahydrofuran and chilled to −78° C. under an atmosphere of argon. Then a 2.0 M solution of n-butyllithium in cyclohexane was added dropwise until the dark color of the phenanthroline/organolithium complex persisted. Then an additional 2.05 mL of the n-butyllithium solution was added. After 10 minutes, carbon dioxide, generated from dry ice, was bubbled through the reaction mixture for 5 minutes. After the reaction mixture had been stirred at −78° C. for 5 minutes, the cooling bath was removed and the mixture was allowed to warm for 5 minutes before being quenched by the addition of water. The mixture was combined with ethyl acetate and water, acidified with dilute hydrochloric acid, and the phases separated. The ethyl acetate was dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 1.11 g of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid, mp 247.8–248.3° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([O:1][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:3][CH2:4]2)=[O:19])=[CH:16][CH:15]=1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc(/C=C/C(=O)N2CCC(O)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCN(C(=O)/C=C/c2ccc(OC)cc2)CC1

Procedure:
A solution of 6.65 g of 4-hydroxy-(E)-1-[3-(4-methoxy-phenyl)acryloyl]-piperidine in 50 ml of methylene chloride was treated with 4 ml of triethylamine at 0° C. while gassing with argon. 2.7 ml of methacryloyl chloride were added dropwise within 15 minutes. Subsequently, the reaction mixture was concentrated to dryness in a vacuum. Chromatographic purification of the residue on silica gel with ether/hexane (vol. 4:1) gave 4.21 g of 2-methyl-acrylic acid (E)-I-[3-(4-methoxy-phenyl)-acryloyl]-piperidin-4-yl ester as a colourless oil. λmax (methylene chloride)=292.5 nm (ε=22775 l mol-1 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[C:12]([N+]([O-])=O)[CH3:13].C(O)(=[O:19])C.S(=O)(O)[O-].[Na+]>CC(C)=O.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](=[O:19])[CH3:13]
Reactant: CC(=O)O
Reactant: CC(=Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 104g of 5-chloro-3-(2-nitropropen-1-yl)indole, 115g of powdered iron and 6g of ferric chloride dissolved in 1250 ml of acetone is brought to reflux. Heating ceases as soon as reflux commences and a solution of 265 ml of acetic acid in 800 ml of water is added over 30 minutes. The reaction mixture is again brought to reflux and maintained thereat for 4 hours; 25.6g of sodium bisulphite are then added, the mixture cooled to 20°C and filtered. The residue is washed with acetone. The combined filtrate and washings are concentrated after filtering and redissolved in 105 ml of hydrochloric acid and 520 ml of water, extracted with ethyl acetate, washed and dried.
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][C:9]=2[C:8]([CH3:16])=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>C(O)C.Cl>[CH3:16][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[C:10]2[C:11]3([CH2:13][CH2:12]3)[CH2:14][O:15][C:9]=12
Reactant: COCOc1ccc(C)c2c1C1(CC1)CO2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(O)c2c1OCC21CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.1 %

Procedure:
To a solution of 4-(methoxymethoxy)-7-methyl-spiro[2H-benzofuran-3,1′-cyclopropane] (Intermediate 12, 38 mg, 0.17 mmol) in ethanol (5 ml), HCl 6N in water (0.1 mL, 0.6 mmol) was added and the reaction mixture was stirred for 4 days at room temperature. Combined solvents were removed under reduced pressure and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound (24 mg) as a light orange solid.