Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8]C1C=CC(C(F)(F)F)=CC=1C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[C:1]([NH:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:29]=[CH:30][CH:31]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-Boc 2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, et al., Synlett 1992, 360) was transformed into its methyl ester as described in procedure (80a). A solution of this ester (125 mg, 0.39 mmol) in DMF (6 mL) was charged with K2CO3 (216 mg, 1.6 mmol) and para-chlorobenzyl bromide (160 mg, 0.78 mmol). After 1.5 h, the solution was diluted with EtOAc and was washed with brine solution followed by 1N HCl solution. The organic layer was then washed with Na2CO3 solution, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue provided the desired N-Boc benzylamine (69 mg), which was dissolved in THF (0.9 mL). The solution was charged with 1N LiOH (0.3 mL) and MeOH (0.3 mL). After stirring for 18 h, the THF was removed and the solution was made acidic (pH=5) with 1N HCl. This solution was extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to give N-Boc 2-(para-chlorobenzyl)amino-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:12]1(C)[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)C.Cl>[CH:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[C:2]1[C:16]3[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=3[N:18]=[C:1]12
Reactant: O=C1CCc2ccccc21
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: C1=C2C(=Nc3ccccc32)c2ccccc21

Procedure:
A mixture of 1-indanone (30.6 g, 232 mmol) and p-tolylhydrazine hydrochloride (37.0 g, 233 mmol) in ethanol (350 mL) and aqueous HCl (12 N, 18 mL) are heated to reflux for 90 minutes. The mixture is cooled and filtered, and the solid is washed with ethanol (600 mL) followed by 20% aqueous ethanol (400 mL) and finally hexanes (200 mL). The off-white solid is dried under vacuum (36.5 g, 72%).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>C(Cl)Cl.O>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][OH:4])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(CCO)CC2)cc1
Temperature: 45 °C
Yield: 89 %

Procedure:
7.5 g (60 mmol) of 2-bromoethanol is added, under argon atmosphere, to a mixture of 10.35 g (50 mmol) of 1-(4-nitrophenyl)piperazine, 7.6 g (55 mmol) of K2CO3 and 9 ml (65 mmol) of Et3N in 200 ml of CH2Cl2. The whole is then heated at 45° C. for 18 hours. The reaction mixture is finally diluted with 50 ml water, agitated and decanted. The organic phase is washed with 50 ml of salt water, dried over MgSO4, filtered and concentrated under vacuum. The residue is crystallized from diisopropyl ether. A yellow solid is obtained with a yield of 89%. Melting point: 98–99° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:24])[C:16]([C:18]12[CH2:23][CH:22]1[CH2:21][CH2:20][CH2:19]2)=O.S(=O)(=O)(O)O.[Cl-].[Na+]>CCCCCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:13][O:14][C:15](=[O:24])[C:16]([C:18]12[CH2:23][CH:22]1[CH2:21][CH2:20][CH2:19]2)=[CH2:1]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(=O)C12CCCC1C2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C(=O)OC)C12CCCC1C2
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
1.4 ml (10 mmol) diisopropylamine and 65 ml (100 mmol) 1.55 M n-BuLi solution in hexane were added under argon at −78° C. to a well-stirred suspension of 37.5 g (105 mmol) methyltriphenylphosphonium bromide in 400 ml anhydrous tetrahydrofuran (THF). The reaction mixture was allowed to heat to room temperature, cooled again and then at −78° C. a solution of 16.8 g (100 mmol) 2-(bicyclo-[3.1.0]hex-1-yl)-2-oxoacetic acid methyl ester in 20 ml THF was added dropwise so that the temperature did not exceed −50° C. The solution was then stirred for 10 hours at room temperature and acidified with 5% sulphuric acid. After the addition of 50 ml saturated sodium chloride solution the organic phase was separated off, the aqueous phase extracted with diethyl ether and the combined organic phase washed with saturated sodium chloride solution. 10 mg 2,6-di-t-butyl-p-cresol (BHT) were added for stabilizing, then the solvent was distilled off and the residue purified by column chromatography (pentane/diethyl ether 20:1). 15.7 g (85% yield) of BCHAM was obtained as colourless liquid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:35][NH:36][CH3:37].O>C(#N)C.C(O)C>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: CN(C)CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (177 mg) in acetonitrile was added potassium carbonate (118 mg) and 33% dimethylamine in ethanol (480 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-Dimethylamino-N-[6-(2-phenyl-chroman-6-yloxy)-pyridin-3-yl]acetamide was isolated as its hydrochloride salt. 1H-NMR (300 MHz; d6-DMSO) δ: 11.3 (s, 1H), 8.41 (d, 1H, J 2.3 Hz), 8.07 (dd, 1H, J 2.3, 8.8 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J 8.5 Hz), 4.20 (s, 2H), 3.01-2.69 (m, 8H), 2.20-1.91 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([O:16]CC4C=CC=CC=4)=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C1CCCCC=1>[OH-].[Pd+2].[OH-]>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2ccc3sc(-c4ccccc4)nc3c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Oc1ccc2sc(-c3ccccc3)nc2c1

Procedure:
Palladium hydroxide (100 mg) was added to a solution of 27 (260 mg, 0.8 mmol) of ethanol/cyclohexene (5 mL/2 mL) followed by warming for reflux for 16 h. The reaction mixture was cooled and the catalyst was removed by filtration (through Celite). The solvent was evaporated to provide compound 29 as a white solid. Synthesis of 5-(oxiran-2-ylmethoxy)-2-phenylbenzothiazole (59):
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].OS(O)(=O)=O>O>[CH3:7][C:4]1([CH3:5])[CH2:3][C:2]([CH3:1])([CH3:8])[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:15]1
Reactant: CC(C)(O)CC(C)(C)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CC(C)(C)c2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2.98 g (14.3 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl) phenol (Compound 39) and 40 ml of 20% aqueous H2SO4 was heated at reflux, under nitrogen, for 4 h. The mixture was stirred at room temperature for a further 72 h and then diluted with 50 ml of water. The mixture was extracted with 3×20 ml of hexanes. The organic extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo to give the title compound as a colorless oil. PMR (CDCl3):
Reaction SMILES: O.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.N#N.[C:20]([C@@:25]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H:29]([CH2:30][OH:31])[C@@H:27](O)[CH2:26]1)(=O)[CH:21](C)C.C(Cl)(=O)C1C=CC=CC=1>>[C:30]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:2]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]2)[C:11](=[O:12])[N:13]=1)(=[O:31])[C:29]1[CH:21]=[CH:20][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)C(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: N#N
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Product: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1

Procedure:
This compound was prepared from 2'-deoxycytidine monohydrate by the same procedure used for the preparation of N2 -isobutyryl-2'-deoxyguanosine except that 9.0 mL (77.5 mmol, 5.17 equiv.) of benzoyl chloride was used instead of isobutyric anhydride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[C:5]([F:29])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:15])([F:16])[F:17])[O:11][C:10]([NH2:18])=[N:9]2)[C:5]([F:29])=[CH:4][CH:3]=1
Reactant: O=C(NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a 20 mL resealable vial was added N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.500 g, 1.046 mmol), MeOH (10 mL) and finally 1,8-diazabicyclo-[5.4.0]undec-7-ene (Aldrich; 0.312 mL, 2.091 mmol). The vial was sealed and stirred at 75° C. for 2 h. The reaction mixture was poured into sat NaHCO3 and extracted with EtOAc. The combined extracts were washed with water and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 9.0% MeOH/CH2Cl2) afforded (4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine. The material still contained some impurities. MS m/z=375.8 [M+H]+. Calculated for C11H9BrF5N3O: 375.0.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[K+].C(O)C>O>[C:1]([NH:4][CH:5]([C:6]([OH:8])=[O:7])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(C)c(C)c1)(NC(C)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NC(Cc1ccc(C)c(C)c1)C(=O)O
Temperature: 25 °C
Yield: 56 %

Procedure:
Diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate (13.8 g) and potassium hydroxide (2.76 g) were dissolved into a mixed solution of ethanol (138 ml) and water (138 ml) and the solution was stirred under reflux for 8.5 hours. After being cooled to room temperature, the solution was concentrated under reduced pressure and the resulting aqueous solution was adjusted to pH 10 with aqeuous saturated sodium hydrogen carbonate solution. The solution was washed with ethyl acetate and made acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give crystals of N-acetyl-3,4-dimethyl-DL-phenylalanine (5.42 g).
Reaction SMILES: [K].[CH2:2]([O:4][C:5]([C:7]1[O:11][C:10](=[S:12])[NH:9][N:8]=1)=[O:6])C.IC.[CH3:15][CH2:16]O>>[CH2:15]([SH:12]=[C:10]1[NH:9][N:8]=[C:7]([C:5]([O:4][CH3:2])=[O:6])[O:11]1)[CH3:16]
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Reactant: CCO
Agent: [K]
Solvent: CI
Product: CC[SH]=c1[nH]nc(C(=O)OC)o1
Yield: 50 %

Procedure:
Following the procedure of Partyka and Crenshaw in U.S. Pat. No. 4,001,238, a solution of ethyl-1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (4.1 g, 24 mmol) and iodomethane (6.7 g, 47 mmol) are heated for 1 hour at reflux in EtOH (20 mL). A solid is removed by vacuum filtration, and the filtrate is concentrated. Water (40 mL) is added to the resultant material, a solid is isolated by vacuum filtration, dried at 50° C./0.5 mmHg overnight to afford the desired product (2.3 g, 50%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9](C(OCC)=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[C:15]([O-])(O)=O.[Na+]>>[CH:3]1[N:2]=[CH:15][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cccnc1CN
Agent: Cl
Agent: [Na+]
Product: c1ccn2cncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 67.2 mL of acetic anhydride and 28.8 mL of formic acid was heated at 50-60° C. oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added into the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat NaHCO3 solution. Solution was extracted with DCM, dried and evaporated to provide imidazo[1,5-a]pyridine as a yellow solid. MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H]+.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])(=O)=O.O>C(O)C>[CH2:23]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:22][CH2:21][CH2:20][C:19]#[CH:18]
Reactant: C#CCCCCOS(C)(=O)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C#CCCCCC(C(=O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium (1.2 g) was dissolved in dry ethanol (200 ml). Diethyl malonate (7.8 ml) was added and the mixture was stirred for 30 minutes and hex-5-ynyl methanesulphonate (9.0 g) was added. The mixture was stirred and refluxed for 1 hour. The mixture was cooled and the volume was reduced in vacuo. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The crude ester was added to a solution of aqueous sodium hydroxide solution (100 ml of 15% solution) and methanol (50 ml) and the mixture was stirred at 20° for 24 hours. The mixture was extracted with diethyl ether. The aqueous alkaline phase was acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 2-(Hex-5-ynyl)malonic acid was obtained as a colourless solid (4.5 g) and was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ClCC1[C:24]([CH:39]2[CH2:41][CH2:40]2)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[N:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:24]([CH:39]3[CH2:40][CH2:41]3)=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:27][CH:28]=2)=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 142D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give the title compound as colorless oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cn1
Yield: 81 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 5-bromo-2methoxypyridine, the title compound was formed in 81% yield as a white solid, mp 218°-222° C. free base: 1H NMR (CDCl3, 250 MHz) 8.28 (d, J=2.5 Hz, 1H), 7.69 (dd, J=2.6, 8.7 Hz, 1H), 7.22 (m, 4H), 6.95 (m, 4H), 6.71 (d, J=8.7 Hz, 1H), 4.28 (s, 1H), 3.93 (s, 3H), 3.48 (s, 2H), 2.91 (m, 2H), 2.78 (dt, J=2.4, 11.7 Hz, 2H), 2.62 (d, J=1.4 Hz, 2H), 2.07 (dt, J=4.4, 12.8 Hz, 2H), 1.75 (m, 2H), 1.59 (s, 1H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (19) hydrochloride salt:
Reaction SMILES: [NH2:1][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]#[N:14])[CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([F:26])[C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Br:15][C:16]1[CH:17]=[C:18]([F:26])[C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21]([NH: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]#[N:14])[CH:3]=1)=[O:22]
Reactant: O=C(O)c1cc(Br)cc(F)c1Cl
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Product: N#Cc1cc(NC(=O)c2cc(Br)cc(F)c2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Preparation 16 using 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53) and 5-bromo-2-chloro-3-fluorobenzoic acid.
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[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[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][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: NCCN1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN4CCOCC4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 2-morpholin-4-ylethanamine using diethyl cyanophosphonate as a coupling reagent. Mass: 621.20 (M+H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]([CH2:8][CH:9]([O:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[CH2:10]2)[CH2:6]1)=O.CC(C)([O-])C.[K+].CCOC(C)=O.CO.Cl>C1COCC1.O>[CH3:18][O:17][C:15]([CH:14]1[C:3](=[O:2])[CH:5]2[CH2:12][CH:11]3[CH2:10][CH:9]([O:19][C:20]([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[NH:24][CH:23]=4)=[O:21])[CH2:8][CH:7]([CH2:6]2)[N:13]13)=[O:16]
Reactant: COC(=O)CN1C2CC(OC(=O)c3c[nH]c4ccccc34)CC1CC(C(=O)OC)C2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)C1C(=O)C2CC3CC(OC(=O)c4c[nH]c5ccccc45)CC(C2)N31
Reaction time: 3 h
Yield: 80.8 %

Procedure:
7-(1H-Indole-3-carbonyloxy)-9-methoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl ester (4.87 gr, 11.75 mmol) dissolved in THF (150 mL) is added to a mixture of potassium tert-butoxide (5.26 gr, 46.9 mmol) in THF (150 mL), under nitrogen. The resulting suspension is stirred for 3 h, until the starting product has been used up as shown by thin-layer chromatography (AcOEt/MeOH 9:1). When the reaction is considered completed, water is added and the pH adjusted to 7.5 with 1 M hydrochloric acid. The product is extracted with dichloromethane, and the organic phase is dried and evaporated, to provide 5-(1H-Indole-3-carbonyloxy)-10-oxo-8-aza-tricyclo[5.3.1.03,8]undecane-9-carboxylic acid methyl ester as a solid (3.63 gr, 81%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(C)C)C(C)C.C1C(=O)N([Br:23])C(=O)C1.S(=O)(=O)(O)O>C(Cl)Cl.O>[Br:23][C:5]1[CH:4]=[CH:3][CH:2]=[C:1]([CH3:8])[C:6]=1[OH:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(Br)c1O
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of o-cresol (20.0 g, 0.19 mol) and iPr2NH (2.63 mL, 18.5 mmol) in CH2Cl2 (500 mL), a solution of NBS (32.9 g, 0.19 mol) in CH2Cl2 (500 mL) was added dropwise over 7 h and the mixture was stirred over night at room temperature. The reaction mixture was acidified to pH=1 with conc. sulfuric acid and water (400 mL). The organic layer was separated, dried with Na2SO4, and concentrated under reduced pressure. 34.6 g of the crude product was obtained (yield: 97%). 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 5.54 (s, 2H), 6.71 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>>[Br:12][CH:13]([CH3:17])[C:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][CH2:7][CH:8]([CH3:9])[CH3:10])=[O:15]
Reactant: CC(C)COC(=O)NCCO
Reactant: CC(Br)C(=O)Br
Product: CC(C)COC(=O)NCCOC(=O)C(C)Br

Procedure:
by using isobutyl 2-hydroxyethylcarbamate and 2-bromopropionyl bromide there is obtained isobutyl 2-(2-bromopropionyloxy)-ethylcarbamate, nD20 1.4731;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][OH:11])=[CH:2]1.[CH3:12]O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][O:11][CH3:12])=[CH:2]1
Reactant: OCc1c[nH]c2ccccc12
Reactant: CO
Solvent: O
Product: COCc1c[nH]c2ccccc12

Procedure:
Relatively pure 1H-indole-3-methanol (I3C™ from Designed Nutritional Products, Orem, UT, US) in a water solution was prepared for HPLC analysis. One sample was diluted with water and the other was diluted with methanol. By the time the partial methanol solution could be injected into the HPLC, the reaction with methanol had taken place to form 1H-indol-3-yl methoxy methane, the methyl ether of 1H-indole-3-methanol, and two peaks of about the same magnitude were observed. The same solution when diluted with water showed only one peak.