Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[S:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=2[I:16])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=2[I:16])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(I)c(C(O)c2ccc(Cl)cc2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(I)c(Cc2ccc(Cl)cc2)s1
Temperature: 25 °C
Yield: 85 %

Procedure:
A round-bottomed flask was charged with 5-((4-chlorophenyl)(hydroxy)methyl)-4-iodothiophene-2-carbonitrile (1.67 g, 4.45 mmol). After degassed, dichloromethane (8 mL), TFA (4 mL) and triethylsilane (1.1 mL, 6.9 mmol) was added sequentially through syringe. The reaction was further stirred at rt until complete, and then concentrated. The residue was purified by flash chromatography (hexane:CH2CL2=2:1). 1.36 g (85%) of product was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C@@H:12]1[CH2:22][C:23]#[N:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][C@H:12]1[CH2:22][C:23]#[N:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC[C@H]1C=C(c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CC[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 70.1 %

Procedure:
2.32 g of 20% palladium hydroxide on carbon were added to a solution of 11.60 g (36.4 mmol) of (S)-1-benzyloxycarbonyl-2-cyanomethyl-4-phenyl-3-pyrroline [obtained as described in Preparative Example 6(ii)′ above] in 150 ml of ethyl acetate, and the resulting mixture was stirred for 7 hours at room temperature under a hydrogen atmosphere. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 4:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 8.18 g (yield: 70%) of the title compound as a pale brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH2:14]2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].B.[ClH:28]>O1CCCC1>[ClH:28].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc2c(cc1OC)CN(C(=O)Cc1ccc([N+](=O)[O-])cc1)CC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2

Procedure:
N-(4-Nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (28.45 g, 0.08 m) was added portionwise to a stirred solution of 1 M borane in tetrahydrofuran (320 ml, 0.32 m) which was diluted with 180 ml of dry tetrahydrofuran and maintained under nitrogen. The mixture was heated to reflux for 3 hours, then cooled in an ice bath and carefully treated with 100 ml of 20% HCl. The mixture was heated to reflux for 1 hour, then allowed to cool. The solvent was removed at an aspirator (40°) and the residue slurried with cold water (400 ml) and the solid collected by filtration, washed with water and air dried. The hydrochloride salt was prepared in 300 ml of a methanol, isopropanol, ether mixture and dried to give 18.0 g N-(4-nitrophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride, m.p. 154°-155°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC[F:32]>CN(C=O)C.O.C(O)(=O)C.[Pd]>[F:32][CH2:2][CH2:1][O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Oc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Reactant: FCCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)[nH]c1cc(OCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.2 %

Procedure:
To a round bottom flask containing Compound 8 (50 mg, 0.17 mmol) in DMF (1 ml), was added cesium carbonate (62 mg, 0.19 mmol) and 1-bromo-2-fluoroethane (33 mg, 0.26 mmol). The reaction was stirred at rt for 15 h and then diluted with water (15 mL). White precipitate (50 mg) was collected via filtration and dried in vacu. The solid was dissolved in MeOH (10 mL). To the reaction, was added Pd/C (30 mg) and acetic acid (5 drops). The mixture was stirred under hydrogen (1 atm) atmosphere for 20 h and then filtered through a celite plug, concentrated in vacuo. The residue was purified on HPLC to afford CB-25 (18 mg, 0.053 mmol, 31% yield). 1H NMR (400 MHz, CD3CN) δ: 8.99 (br, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.67 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.58 (dd, J=8.0 Hz, 2.0 Hz, 1H), 4.75-4.74 (m, 1H), 4.63-4.61 (m, 1H), 4.23-4.13 (m, 2H); LRMS for C16H12F4NO3+H+, calc'd: 343.1. found: 246.0 (M+H+-TFA).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH3:25])[C:21]([NH2:26])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[C:21]2[NH2:26])=[CH:16][C:15]=1[O:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: Cc1cc2c(N)nccc2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(N)nccc2cc1OC1CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (231 mg, 1.15 mmol), triphenylphosphine (301 mg, 1.15 mmol), 1-amino-7-methylisoquinolin-6-ol (200 mg, 1.15 mmol) in DMF (5 ml) at 0° C., under argon, was added dropwise diethylazodicarboxylate (181 [μL, 1.15 mmol). The mixture was then warmed to ambient temperature and stirred for 24 h. Methanol was added and the mixture loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester. A mixture of the (3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml) and trifluoroacetic acid (3 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 7-methyl-6-(piperidin-3-yloxy)isoquinolin-1-ylamine, El-MS: m/z=258.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1(F)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][C:3]1=O>C1COCC1>[F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1(F)F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2[nH]cc(F)c2c1
Yield: 92.5 %

Procedure:
Add borane-tetrahydrofuran complex (1M, 15 mL) dropwise to the solution of 3,3-difluoro-5-nitroindolin-2-one (650 mg, 3 mmol) in THF (10 mL) at 0° C. After addition, stir the reaction at 70° C. for 5 hrs. Concentrate under reduced pressure, add ethyl acetate to the residue, wash the organic layer with saturated sodium bicarbonate solution twice and then with brine twice, dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=1:3) to yield the title compound (500 mg, 91.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@:11]3([CH2:16][C@@H:15]([C:17]([OH:19])=O)[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1.[NH2:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@:11]3([CH2:16][C@@H:15]([C:17]([NH:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]4[CH2:45][CH2:46]4)=[O:42])=[O:19])[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Product: CCC[C@H](NC(=O)[C@@H]1C[C@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 63.6 %

Procedure:
Following the procedure from Example 1 step I using (5R,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D4) (12 mg, 22 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (7.3 mg, 33 μmol) gave 10 mg (14 μmol) of (5R,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (E4). LC MS+/−: 702.54/700.74 at 3.68 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23](=[O:34])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([OH:33])=O)[CH:26]=2)[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:42][CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=1)=[O:45].CN1CCOCC1>ClCCl.CN(C)C=O>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23](=[O:34])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH:42][CH2:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=3)=[O:45])=[O:33])[CH:26]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)Nc2cccc(C(=O)O)c2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)S[C@H]1C[C@@H](C(=O)Nc2cccc(C(=O)NCC(=O)OCc3ccc([N+](=O)[O-])cc3)c2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 55.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxyphenylcarbamoyl)pyrrolidine (0.49 g, 1 mM) in dichloromethane (10 ml) was added oxalyl chloride (0.20 ml. 1.1 mM) and dimethylformamide (2-3 drops). After 1 hour a further amount of oxalyl chloride (0.20 ml, 1.1 mM) and DMF (2-3 drops) were added and the mixture stirred for a further hour. The solution was evaporated to leave a yellow gum. The gum was dissolved in dichloromethane (10 ml) and added to a suspension of 4-nitrobenzyl 2-aminoethanoate hydrochloride salt (0.30 g, 1.2 mM) and N-methylmorpholine (0.27 ml, 2.4 mM) in dichloromethane (10 ml). After 17 hours the mixture was diluted with dichloromethane (80 ml), washed with water (20 ml), brine (20 ml) and dried (MgSO4). Purification by flash chromatography through silica using a gradient of dichloromethane to ethyl acetate as eluent gave (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(4-nitrobenzyloxycarbonylmethylaminocarbonyl)phenylcarbamoyl)-pyrrolidine (380 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:26])([CH3:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[I-].[Li+].[C-]#N.[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:26])([CH3:25])[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [C-]#N
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C(=O)O)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 170 °C
Yield: 97.8 %

Procedure:
A mixture of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanoate (330 mg, 0.93 mmol), lithium iodide (500 mg, 3.7 mmol), sodium cyanide (180 mg, 3.7 mmol), and pyridine (3 mL) was heated in CEM Explorer microwave reactor under nitrogen at 170° C. for 30 min. The reaction mixture was concentrated in vacuo, mixed with water (10 mL) and ethyl acetate (10 mL), and acidified with 10% aqueous citric acid solution to pH=4. The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic solutions were dried (Na2SO4) and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanoic acid (310 mg, 0.91 mmol, 98% yield) that was used as such for the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][NH:6]1)=[O:4].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[O:20])[NH:6]1)=[O:4]
Reactant: CSc1nccc(C(=O)Cl)n1
Reactant: COC(=O)C1CCCNN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN(C(=O)c2ccnc(SC)n2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
To a solution of hexahydro-pyridazine-3-carboxylic acid methyl ester (1.5 g, 8.3 mmol) in CH2Cl2 (80 mL) is added 2-methylsulfanyl-pyrimidine-4-carbonyl chloride, 16, (1.41 g, 7.5 mmol) and triethylamine (1.2 mL, 8.3 mmol). The mixture is stirred at room temperature for 3 hours. The reaction solution is then diluted with1 N HCl (100 mL) and the organic phase is decanted. The aqueous phase is extracted with additional solvent and the organic layers are combined, dried, and concentrated in vacuo. The crude product is purified over silica(ethyl acetate/hexane 1:1) to afford 0.9 g (36% yield) of the desired product as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:5]([C:6]#[N:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CN(C)[CH:18]=[O:19].C[O-].[Na+]>CO>[CH3:18][O:19][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:5]([C:6]#[N:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: N#Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(C#N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To 1.92 g (9.11 mmol) of 4-fluoro-2,6-dinitrobenzonitrile dissolved in 20 mL methanol and 3 mL dimethylformamide at 0° C. was added 1.87 mL (1 eq., 4.87 M in methanol) sodium methoxide over 1 hour. The mixture was stirred an additional hour at 0° C., partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography, eluting with ethyl acetate/hexanes, provided 1.32 g of 4-methoxy-2,6-dinitrobenzonitrile.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].O[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(OC1C=CC(C2C=CC(C(OCCCCCCCC)=O)=CC=2)=CC=1)=O>>[CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][O:4][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1
Reactant: CC[C@H](C)CO
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(OC[C@@H](C)CC)cc1

Procedure:
Quantities: (S)-(-)-2-methylbutan-1-ol (5.00 g, 0.057 mol), ethyl 4-hydroxybenzoate (7) (9.47 g, 0.057 mol), DEAD (9.93 g, 0.057 mol), triphenylphosphine (14.95 g, 0.057 mol). The experimental preocedure was as described for the preparation of compound 5. The crude product was purified by column chromatography (10% petrol/dichloromethane) to give a colourless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC2(C=Cc3ccccc32)CC1
Yield: 102 %

Procedure:
In the same manner as in Example 22, step 4 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.091 g, 0.242 mmol) obtained in Example 22, step 3 and spiro[inden-1,4′-piperidine]hydrochloride (WO2004/028459, 0.059 g, 0.267 mmol), the title compound (0.127 g, 95%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:34]=[CH:33][C:22]([C:23]([O:25]CC4C=CC=CC=4)=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2>[Pd].O1CCOCC1>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][CH2:15][C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:33][CH:34]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(CCC(=O)Oc3ccc(C(=O)O)cc3)ccc21
Reaction time: 3 h

Procedure:
1.7 g (3.7 mmol) of benzyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]-benzoate, 40 ml of dioxane and 340 mg of palladium on charcoal (10%) are introduced into a reactor. The mixture is hydrogenated at 40° C. and at a pressure of 7 bar for three hours. The catalyst is filtered off and the mixture is evaporated to dryness. The solid obtained is triturated from hexane, filtered off and dried. 1.2 g (85%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propanoyloxy]benzoic acid, with a melting point of 183-4° C., are collected.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.Cl.[C:24](Cl)(=O)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:24]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: Cl
Agent: NC(=O)c1ccccc1
Product: COc1ccc2c(O)nc(-c3ccncc3)nc2c1C
Yield: 60 %

Procedure:
The general procedure described above was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and isonicotinoyl chloride hydrochloride as acid chloride, which gave the title compound (1.6 g, 60%), [M+H]=268.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([NH:20][NH2:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:25][CH2:26][CH3:27])(=O)C>>[C:18]([C:8]1[CH:7]=[C:11]([CH:12]=[CH:27][C:26]=1[OH:25])[C:10]([NH:21][NH:20][C:18]([C:8]1[O:9][CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19])=[O:9])#[N:20]
Reactant: CCOC(C)=O
Reactant: NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O

Procedure:
A mixture of 3,4-diphenyl-2-furancarboxylic acid hydrazide (compound of Reference Example 32, 5.2 g) and the compound of Reference Example 63 (6.1 g) in ethyl acetate (10 ml) was heated at reflux overnight while stirring. The thus-precipitated crystals were collected by filtration and recrystallized from ethyl acetate/diisopropyl ether, thereby giving 5.1 g of the desired compound. Melting point: 178-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][O:13][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1
Reactant: C1=COCCC1
Reactant: CCCc1c(O)ccc(Br)c1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCCc1c(O)ccc(Br)c1COC1CCCCO1
Reaction time: 5 h
Yield: 69.6 %

Procedure:
To a solution of 4-bromo-3-(hydroxymethyl)-2-propylphenol (1.04 g, 4.24 mmol) in dichloromethane (50 mL), p-toluenesulfonic acid-hydrate (81 mg, 0.424 mmol) and 3,4-dihydro-2H-pyrane (535 mg, 6.36 mmol) were added at room temperature. The mixture was stirred at same temperature for 5 hours. The reaction solution was added with water and extracted with chloroform. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and the title compound (972 mg, 70%) was obtained as colorless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32]C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCOCC1.Cl>CO>[CH2:3]([N:10]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCC(=O)N(Cc1ccccc1)Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCC(=O)N(Cc1ccccc1)Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
5 mol/L sodium hydroxide solution (0.3 mL) was added to the compound (45 mg) prepared in Example 6 in a mixed solution of dioxane (2 mL) and methanol (1 mL) and stirred for 2 hours at 80° C. To acidify, 1 mol/L hydrochloric acid was added to the concentrated reaction mixture to be extracted with ethyl acetate. The organic layer was washed with saturated sodium and dried by anhydrous sodium sulfate, and then concentrated to obtain the titled compound (37 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].C(N(C(C)C)C(C)C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1.CO>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc2c(c1)[nH]c1ncnc(Cl)c12
Reactant: CN(C)CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)CCNc1ncnc2[nH]c3cc(C#N)ccc3c12
Temperature: 140 °C
Yield: 18.2 %

Procedure:
A mixture of 4-chloro-9H-pyrimido[4,5-b]indole-7-carbonitrile (23 mg, 0.10 mmol), 2-dimethylaminoethylamine (27 mg, 0.3 mmol) and N-ethyldiisopropylamine (88 μL, 0.50 mmol) in 1 ml of NMP was heated at 140° C. for 20 minutes using microwave irradiation. The reaction mixture was diluted with 5 mL methanol and applied to a 500 mg MP-TsOH SPE cartridge. After washing the cartridge, the product was eluted using 2 N ammonia in methanol. The eluent was concentrated in vacuo and the residue purified by prep HPLC to give 5.1 mg of the title compound as a white solid. 1H NMR (DMSO, δ, ppm) δ 2.3 (6H, s), 2.65 (2H, t, J=6.8 Hz), 3.7-3.8 (2H, m), 7.45 (1H, t, J=6.1 Hz), 7.7 (1H, d, J=8.1 Hz), 7.9 (1H, s), 8.2 (1H, s), 8.4 (1H, s), 8.5 (1H, d, J=8.1 Hz), 12.4 (1H, br s); LC-MS (2) Rt 2.03 min; m/z (ES+) 281.