Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][N:7]=1.C[Si](C)(C)[O:18][C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1>C(Cl)Cl>[C:1]([N:7]1[N:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]1[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C:19]1=[O:18])(=[O:4])[CH:2]=[CH2:3]
Reactant: c1ccc2cnncc2c1
Reactant: C=CC(=O)Cl
Reactant: C[Si](C)(C)OC1=CCCCC1
Solvent: ClCCl
Product: C=CC(=O)N1N=Cc2ccccc2C1C1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.53 ml of acryloyl chloride in 3 ml of methylene chloride is slowly added dropwise at 0° C. to a solution of 0.78 g of phthalazine and 1.2 ml of 1-trimethylsiloxy-cyclohexene. After the addition the mixture is stirred at 0° C. for a further 30 min., then concentrated, treated with ice-water and made basic by the addition of sodium carbonate. The mixture is extracted 3 times with 100 ml of ethyl acetate each time. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is concentrated. 1.63 g of (RS)-2-(2-acryloyl-1,2-dihydro-phthalazin-1-yl)-cyclohexanone (mixture of diastereomers) are isolated as a brownish oil. MS: 282 (M+).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:16]=1>COCCOC>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22]/[C:23](/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:3]/[C:1]#[N:2])=[CH:19][CH:20]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22]/[C:23](/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:3]\[C:1]#[N:2])=[CH:19][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(CCc1ccc(Cl)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#C/C=C(/CCc1ccc(Cl)cc1)c1ccccc1
Product: N#C/C=C(\CCc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl cyanomethylphosphonate (0.8 ml) was added dropwise at rt to a slurry of sodium hydride (60% in mineral oil, 0.2 g) in anhydrous 1,2-dimethoxyethane (15 ml) under nitrogen atmosphere. The reaction mixture was stirred at rt for 1 hour and 3-(4-chlorophenyl)-1-phenylpropan-1-one (0.4 g) was added. After stirring at 80° C. for 4 h the resultant solution was poured into ice water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4), and evaporated in vacuo. The crude mixture was separated by flash chromatography on silica gel (hexane/ethyl acetate 10:1) to afford (Z)-5-(4-chlorophenyl)-3-phenylpent-2-enenitrile (80 mg) and (E)-5-(4-chlorophenyl)-3-phenylpent-2-enenitrile (284 mg) as colourless oils.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[N:18][CH:19]=[N:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
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: COC(=O)c1c(O)c2ccc(-c3cncnc3)cc2sc1=O
Yield: 35.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added pyrimidine-5-yl boronic acid (104 mg, 0.84 mmol), Pd(PPh3)4 solid (65 mg, 0.08 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling, the reaction mixture was diluted with water (80 mL), acidified using 1 N HCl to pH 3-4 and extracted with EtOAc. The two phases were filtered through a pad of Celite® to form two clear layers. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (10 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-2-oxo-7-pyrimidin-5-yl-2H-thiochromene-3-carboxylic acid methyl ester (79 mg). MS ESI(−) m/e: 313.09 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[OH2:19].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.0138 mole) and 1,1'-carbonyldiimidazole (2.24 g, 0.0138 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. A solution of dimethylamine in tetrahydrofuran (42 ml of 0.5M solution) was added, and the reaction mixture was allowed to stir at room temperature for 1/2 hr.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][CH2:4][C:3]=1[C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11]C(C)=O.N1CCCC1.[CH2:20](O)[CH3:21]>CO>[C:7]([C:3]1[C:2](=[CH2:1])[C:6]([CH3:11])=[C:5]([CH3:4])[C:20]=1[CH3:21])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCO
Reactant: CC1=C(C(C)(C)C)CC=C1
Reactant: CC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: C=C1C(C)=C(C)C(C)=C1C(C)(C)C
Temperature: -78 °C

Procedure:
In a 500 ml flask is placed 12.60 g of the product obtained in step B and dissolved in 40 ml of methanol. The mixture is cooled down to −78° C. 2.15 g acetone in 10 ml of ethanol is added slowly. In the next step 4 g of pyrrolidine in 10 ml of methanol is added. After six hours the reaction is terminated by addition of 10 ml of acetic acid. After separation of organic phase, drying, evaporation of solvents and distillation an orange oil is obtained (8.95 g).
Reaction SMILES: O=[C:2]([CH3:20])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:27][CH:28]=1)[N:26]=[C:2]([CH3:20])[C:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[C:4]2[OH:6]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A round-bottomed flask equipped with a Dean-Stark apparatus was charged with ethyl 3-oxo-2-(4-(trifluoromethyl)benzyl)butanoate (7.00 g, 24.3 mmol, Intermediate 57: step a), 4-bromoaniline (4.20 g, 24.2 mmol), para-toluenesulfonic acid (0.418 g, 2.4 mmol), and toluene (121 mL). The mixture was heated to 125° C. After 16 h, the flask was cooled to room temperature. The toluene was removed by rotary evaporation to provide an orange colored solid. A mixture of the solid and diphenyl ether (48.4 mL) was heated to 220° C. After 60 min, the mixture was cooled to room temperature at which point a yellow solid crashed out of solution. Hexanes (150 mL) were added. The whole was filtered through paper, rinsing with hexanes. The yellow solids were collected, dried, and then used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][CH2:12]2)=[CH:8][CH:7]=1.C1COCC1>CO>[CH3:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH2:12]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(C)C1=CCc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CC=C2C(C)C(=O)O
Temperature: 38 °C
Reaction time: 17 h
Yield: 90.3 %

Procedure:
In a 1 L three-neck flask charged with NaOH (18.57 g, 0.464 mol) and water (216 mL), was slowly added (over 15-20 min) a solution of methyl 2-(6-methoxy-1H-inden-3-yl)propanoate (Example 10) (53.92 g, 0.232 mol) in MeOH (215 mL). During the addition, the reaction temperature increased to 38° C. To this mixture was added THF (108 mL) and then the mixture was heated to 40-45° C. for a period of 8 h and subsequently stirred at rt for 17 h. The solvent was removed under vacuum and the resulting aqueous mixture was extracted with CH2Cl2 (3×100 mL). The aqueous layer was acidified with HCl (38 mL, 37% aqueous solution) to pH˜2.5 and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (4×150 mL) and brine (50 mL), dried over Na2SO4, and filtered. The solvent was evaporated under vacuum, and the resulting oil was dried under vacuum at 40-45° C. for 16-18 h to give 45.71 g (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (1H, d), 7.05 (1H, s), 6.83 (1H, dd), 6.19 (1H, s), 3.73 (3H, s), 3.68 (1H, q), 3.30 (2H, s), 1.39 (3H, d); LC-MS: RT=2.43 min, (M+H)+: 219.1.
Reaction SMILES: CN1CCOCC1.[NH:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[NH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].CP(OP(CC)(C)=O)(CC)=O.C([O-])(O)=O.[Na+]>>[NH:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:20]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: COC(=O)CN
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCP(C)(=O)OP(C)(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 10 h

Procedure:
At 0° C. there were added while stirring 6.5 ml of N-methyl morpholine to a mixture of 3.35 g (0.05 mol) of Z-Trp-OH and 1.25 g of H-Gly-OMe. Into the solution obtained there were added dropwise at the temperature specified, while stirring, 4 g of methylethylphosphinic acid anhydride. The mixture was allowed to stand at room temperature for 10 hours and the solvent was separated by distillation in vacuo at room temperature. The residue was taken up by a mixture of 25 ml of water and 70 ml of ethyl acetate, the ethyl acetate extract was separated and the aqueous solution was extracted twice using each time 10 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice using each time 7 ml of water, a 5% potassium sulfate solution (until an acid reaction took place) and a saturated NaHCO3 solution until a slightly alkaline reaction took place. Upon drying over magnesium sulfate and clearing with active carbon, the solvent was largely separated by distillation in vacuo and the residue was digested with diisopropyl ether.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[CH3:13][C:14]([CH3:16])=O.[CH3:17][CH2:18][CH2:19]CC>O>[CH3:13][C:14]1([CH3:16])[O:6][C@@H:5]2[C@@H:3]([CH2:2][O:1][C@@:9]3([CH2:11][OH:12])[O:10][C:18]([CH3:19])([CH3:17])[O:8][C@H:7]32)[O:4]1
Reactant: CC(C)=O
Reactant: CCCCC
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(CO)OC(C)(C)O[C@@H]23)O1
Temperature: 0 °C

Procedure:
A mixture of 200 grams of D-fructose, 2 liters of acetone, 2 liters of pentane and 8 grams of ferric chloride is stirred and heated to reflux temperature. The reaction water is condensed and removed using a Dean-Stark type water separator. After the theoretical amount of water is removed, the mixture is cooled to 0° C., neutralized with 7 grams of sodium hydroxide in 10 milliliters of water and filtered. The filtrate is treated with 10 grams Norite SG, refiltered, and then concentrated to a syrup which is crystallized from ether-pentane to give 164.4 grams of product, m.p. 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:31](=[O:33])[CH3:32])[N:10]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(C)=O)N=C2Cc1c(Cl)cncc1Cl
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
As an alternative to the previous synthesis, the title compound was prepared starting from a solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (2 g, 6.2 mmoles), prepared as described in example 22, in dry THF (60 ml) under stirring and dry N2 at 0° C. The mixture was added with triethylamine (1.57 g, 15.5 mmoles), then with acetyl chloride (0.44 ml, 6.2 mmoles). After 10 minutes the mixture was brought to room temperature and kept at such temperature for 2.5 hours, then poured into water/ice and extracted more times with CH2Cl2. The organic phases were washed with 5% NaOH and water, anhydrified and brought to dryness to give a solid which, by crystallisation from acetonitrile (70 ml), gave 1.95 g of the title compound having the same physochemical characteristics set forth at point A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][CH3:21])=[O:13].[Br:22][CH2:23][C:24](Cl)=[O:25]>ClCCl.O>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH3:21])[C:24](=[O:25])[CH2:23][Br:22])=[O:13]
Reactant: O=C(Cl)CBr
Reactant: CNc1ccccc1C(=O)c1c(OC)cc(C)cc1OC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)cc(OC)c1C(=O)c1ccccc1N(C)C(=O)CBr
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a mixture of 10 g of (2,6-dimethoxy-4-methylphenyl)(2-methylaminophenyl) ketone in 100 ml of dichloromethane and 20 ml of water, cooled to -10° C., are added dropwise 6.34 g of bromoacetyl chloride in 20 ml of dichloromethane. The reaction mixture is allowed to return to room temperature and is then stirred vigorously for 2 hours. The phases are separated after settling has taken place and the organic phase is successively washed with water, dried over sodium sulphate and evaporated to dryness to give beige crystals melting at 121° C.; Yield=99%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:5][CH:4]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:4][CH:5]=1)[CH3:23]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCNc1ccc(CNS(=O)(=O)CC)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of 2.5 g of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) in 30 mL of pyridine was cooled in an ice bath for 15 min and 0.95 g of ethanesulfonyl chloride in 5 mL of pyridine was added rapidly dropwise and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into 75 mL of water containing 0.75 g of NaOH, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over sodium sulfate. The mixture was concentrated in vacuo and the residue was stirred in ether and dried (40° C./0.1 mm) to afford 1.7 g of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]ethanesulfonamide, amide, m.p. 105° C. (dec.). The sulfonamide was dissolved in methanol and treated with methanesulfonic acid in methanol to afford 1.61 g (42%) of the methanesulfonate salt, m.p. 135° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.[C:22](#[N:26])[CH2:23][C:24]#[N:25].N1CCCCC1>>[NH2:26][C:22]1[O:12][C:7]2[C:8]([CH:20]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([Br:13])[CH:15]=3)[C:23]=1[C:24]#[N:25])=[CH:9][CH:10]=[C:11]1[N:3]([CH2:2][OH:1])[CH:4]=[CH:5][C:6]=21
Reactant: OCn1ccc2c(O)cccc21
Reactant: O=Cc1cncc(Br)c1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Product: N#CC1=C(N)Oc2c(ccc3c2ccn3CO)C1c1cncc(Br)c1

Procedure:
The title compound was prepared from 1-hydroxymethyl-4-hydroxy-indole (66 mg, 0.4 mmol), 5-bromo-pyridine-3-carbaldehyde (75 mg, 0.4 mmol), malononitrile (27 mg, 0.4 mmol) and piperidine (0.02 mL, 0.2 mmol), similar to Example 16, to yield 60 mg (38%) of a white solid. 1H NMR (DMSO-d6): 8.58 (d, J=2.1 Hz, 1H), 8.48 (d, J=1.5 Hz, 1H), 7.78-7.76 (m, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.11 (brs, 2H), 6.77 (d, J=8.7 Hz, 1H), 6.49 (d, J=3.3 Hz, 2H), 5.49 (brs, 2H), 4.98 (s, 1H).
Reaction SMILES: [C:1]1(=[O:13])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:4](=[O:12])[CH:3]=[CH:2]1.[NH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15].C(Cl)CCl>C(Cl)Cl>[O:13]=[C:1]1[CH:2]=[CH:3][C:4](=[O:12])[N:5]1[CH2:6][CH2:7][CH2:8][C:9]([NH:15][NH:14][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:11]
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)CCCN1C(=O)C=CC1=O
Yield: 84.7 %

Procedure:
4-Maleimidobutyric acid (245 mg, 1.33 mmol), tert-butyl hydrazinecarboxylate (201 mg, 1.52 mmol) and EDC (400 mg, 2.08 mmol) in 5 ml of CH2Cl2, were stirred overnight under Ar, washed with 1 M NaH2PO4,/NaCl (conc), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with MeOH/DCM (1:25) to afford 335 mg (85%) of the title compound. 1H NMR (CDCl3), 7.83 (br, 1H), 6.65 (s, 2H), 6.50 (br, 1H), 3.58 (t, 2H, J=6.3 Hz), 2.15 (t, 2H, J=7.0 Hz), 1.90 (dt, 2H, J=6.8, 13.4 Hz), 1.40 (s, 9H); 13C NMR 171.30, 155.61, 134.41, 82.00, 37.13, 31.38, 28.36, 24.95; MS m/z+ 320.2 (M+Na).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:18]2[N:19]=[CH:20][C:21]3[N:26]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:24][C:22]=3[N:23]=2)[CH:15]2[CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:9]=[C:10]([N:14]([CH:15]2[CH2:17][CH2:16]2)[C:18]2[N:19]=[CH:20][C:21]3[N:26]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:24][C:22]=3[N:23]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)OC(C)(C)C)c3)C3CC3)nc2s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2cnc(N(c3cccc(N)c3)C3CC3)nc2s1
Yield: 80 %

Procedure:
A solution of the above-mentioned crude product of tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](cyclopropyl)amino}phenyl)carbamate and anisole (1.5 mL) in trifluoroacetic acid (15 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (60 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (9:1, 60 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (820 mg, 80%) as a purple solid.
Reaction SMILES: CC(OC([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=[O:15])=O)(C)C.Cl.O1CCOCC1>ClCCl>[CH:9]12[NH:8][CH:12]([CH2:11][CH2:10]1)[CH2:13][C:14](=[O:15])[CH2:16]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CC2CCC(C1)N2
Reaction time: 60 h
Yield: 128.2 %

Procedure:
A solution of N-Boc nortropinone (0.73 g, 3.24 mmol) in a minimal amount of dichloromethane (1 mL) was treated with a solution of 4 M hydrochloric acid in dioxane (3.2 mL, 12.8 mmol). After stirring for 2.5 days, the reaction was complete by TLC analysis. Solvent was removed under reduced pressure to give 0.52 g of 8-azabicyclo[3.2.1]octan-3-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:19](O)(=[O:23])[CH:20]([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: CC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C(C)C)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.411 mmol), isobutyric acid (36 mg, 0.411 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.452 mmol) and 4-dimethylaminopyridine (55 mg, 0.452 mmol) in dry dichloromethane (5.0 ml) were stirred at room temperature for 4 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator to afford 16 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)isobutyramide as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.95 (bs, 1H), 7.9 (t, 1H), 7.4 (d 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.5-4.61 (m, 1H), 4.1-4.28 (m, 3H), 3.7-3.9 (m, 2H), 3.1-3.2 (m, 2H), 2.95 (s, 3H), 2.4 (s, 3H), 2.19-2.3 (m, 1H), 1.2-1.38 (m, 2H), 0.9 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:25](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:26].ClCCl>CC(C)=O.O>[C:25](=[C:14]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH2:1])[CH:3]=1)[C:11]([OH:13])=[O:12])=[O:26]
Reactant: COc1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1N
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(C(C(=O)O)C(=C=O)c2ccc([N+](=O)[O-])cc2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 153.5 %

Procedure:
2-(3-amino-4-methoxyphenyl)-3-(4-nitrophenyl) propionic acid (6.20 g, 19.6 mmol) was dissolved in a mixed solvent of acetone (50 mL) and water (50 mL), and was gradually added with an acetone solution (50 mL) of 9-fluorenylmethyl chloroformate (5.08 g, 19.6 mmol) over 30 minutes in a drop-wise manner at 0° C. The mixture was heated to room temperature, and further stirred for 3 hours. The mixture was then added with dichloromethane (200 mL) and water (300 mL). The separated aqueous phase was extracted with dichloromethane (150 mL) three times. The extracts were mixed with the first organic phase, and washed twice with a saturated brine (150 mL). The organic phase was dried over sodium sulfate, evaporated under reduced pressure so as to remove the solvent, to thereby obtain N-fluoronylmethoxy carbonyl-2-(3-amino-4-methoxyphenyl)-3-(4-nitrophenyl) propionic acid (yield: 10.3 g, yield ratio: 97%).