Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].Br[CH:4]([CH3:22])[C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6].Cl.O.[CH2:25]([OH:27])[CH3:26]>CN1CCCC1=O>[C:18]([C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH:4]([O:27][CH2:25][CH3:26])[CH3:22])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[OH:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 45 %

Procedure:
6.6 g (117 mmol) of potassium hydroxide are dissolved in 130 ml of ethanol and stirred for one hour. Then 10.0 g (29.3 mmol) of 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-propan-1-one dissolved in 20 ml of n-methylpyrrolidone is added at room temperature while stirring. After stirring for 20 hours the reaction mixture is cooled with an ice bath and 5 ml of concentrated hydrochloric acid and 150 ml of water is added. Then ethanol is evaporated, 200 ml of ethylacetate added and the water phase split off. The organic phase is washed with 100 ml of brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography and crystallisation of the pure fractions from hexane to give 4.1 g (45%) of compound 115; m.p. 64° C.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][OH:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:1]1([S:7]([C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][O:13][S:24]([CH3:23])(=[O:26])=[O:25])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCO)S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)S(=O)(=O)c1ccccc1
Yield: 103.1 %

Procedure:
A solution of 3-benzenesulfonyl-3-methyl-butan-1-ol (2.17 g, 9.5 mmol), triethylamine (2.0 ml, 14.25 mmol), methanesulphonyl chloride (0.9 ml, 11.78 mmol) and 4-N,N-dimethylaminopyridine (12 mg, 0.01 mmol) was stirred at 0° C. for 45 min. After quenching with satd. NaHCO3, the mixture was extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to give the title product (3.0 g).
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14].OC[C@@H](C)CN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.ClC[C@H](C)CO>>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: O[C@@H](CCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)CO)CC2)c1
Agent: C[C@H](CO)CCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (1R)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M+H)+. N-(3-{1-[(2S)-3-HYDROXY-2-METHYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using (2R)-3-chloro-2-methyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([N:1]1[CH2:9][CH:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
A solution of 100 g (0.76 mol) of L-hydroxyproline and 540 ml of water is cooled to 10° and 297 ml (3.7 mol) of pyridine is added. The temperature is lowered to 5° and 151.2 ml (1.6 mol) of acetic anhydride is slowly added. The reaction is stirred at 0°-5° for 45 min and 81 ml (0.97 mol) of pyridine is added followed by 42.7 ml (0.45 mol) of acetic anhydride. The reaction is stirred overnight in an ice bath allowing the bath to come to room temperature. The reaction is evaporated and the residue is dissolved in ethanol and evaporated to an oily residue. This step is repeated a number of times, and the residue is dissolved in acetone, seeded, and cooled. The white crystals are filtered and recrystallized from ethanol-ether and dried under vacuum at 40° to give 84.8 g of N-acetyl-4-hydroxy-L-proline; [α]D23 -117° (cl, water).
Reaction SMILES: C(N(CC)CC)C.CC[S:10]([C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[C:14]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)=[O:15])=O.C1(C)C=CC=CC=1.C1N2C(SC3C=CC=CC=3C2=O)=CC=1>C(Cl)(Cl)Cl>[CH:20]1[CH:19]=[CH:18][N:17]2[C:16]=1[C:14](=[O:15])[C:13]1[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=1[S:10]2
Reactant: CCS(=O)c1ccccc1C(=O)c1ccc[nH]1
Agent: O=c1c2ccccc2sc2cccn12
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c2ccccc2sn2cccc12
Reaction time: 24 h

Procedure:
Triethylamine (0.017 mL, 0.12 mmol, 0.1 eq), 2-(2-ethylsulfinyl) benzoyl pyrrole (0.3 g, 1.2 mmol), and toluene (15 mL) are combined and refluxed with stirring for 24 hours. After removal of volatiles in vacuo, a light brown oil is obtained which solidifies to a dark gold solid. Chromatography of the crude solid with a 1:1 ratio of CHCl3 to hexanes yields a product mix comprising 24 mg (0.12 mmol, 15 percent) of pyrrolo(2,1-b)-(1,3)benzothiazin-9-one, 114 mg (0.57 mmol, 69 percent) of pyrrolo(2,1-b)-(1,2)benzothiazin-10-one and 115 mg of light brown solid which proves by NMR to be a mixture of recovered starting material and 1H, 9H-(1)benzothiopyrano(3,2-b)pyrrol-9-one. By integration, the following approximate amounts for the above mixture are calculated: 93 mg (0.38 mmol) and 22 mg (0.11 mmol, 13 percent), respectively.
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(O)C>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:20][CH2:19]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCCCCCN(C(C)=O)c1ccccc1OC1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCN(C(C)=O)c1ccccc1OC1CCN(Cc2ccccc2)CC1
Yield: 68.8 %

Procedure:
To a solution of 4-(N-acetyl-N-hexylaminophenyloxy)piperidine (1.4 g) in ethanol (10 ml) were added potassium carbonate (1.2 g) and benzyl chloride (0.54 g) and the mixture was heated under reflux overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate (50 ml×3). The combined extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol =10/1 (v/v)) to obtain 4-(N-acetyl-N-hexylaminophenyloxy)-1-phenylmethylpiperidine (1.2 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=O)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(C)S(C(F)(F)F)(=O)=O.[NH2:23][NH2:24].C(OCC)C>C(Cl)Cl.CO>[C:1]1([CH:7]2[NH:12]/[C:11](=[N:23]\[NH2:24])/[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1CCCC(c2ccccc2)N1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: N/N=C1/CCCC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirring solution of 6-phenyl-piperidin-2-one (0.35 g, 2 mmol) in methylene chloride (1 mL) at 0° C. under nitrogen atmosphere was added methyl triflate (0.23 mL, 2 mmol). The reaction mixture was stirred at room temperature for three hours, then added to a stirring 0°C solution of anhydrous hydrazine (0.5 mL) in methanol (1 mL). The mixture was stirred for 3.5 hours at room temperature, then poured into a 1:1 mixture of methylene chloride and diethyl ether. The mixture was washed with 1.5M aqueous sodium carbonate, dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to give 0.34 g (90%) of [6-phenyl-piperidin-(2Z)-ylidene]-hydrazine as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:12]2[C:22](=[O:37])[N:23]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:24][C:11]2=[CH:10]1.C(OCC)C.O>C(Cl)Cl>[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[C:12]2[C:22](=[O:37])[N:23]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:24][C:11]2=[CH:10]1
Reactant: COCCn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1c2c(cn(CCO)c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.4 %

Procedure:
Boron tribromide (0.5 ml, 0.445 mmol) and 5-(2-methoxy-ethyl)-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (50 mg, 0.111 mmol, see Example 18) were dissolved in DCM (30 ml) in a round-bottomed flask. The reaction was stirred at about 0° C. for about 3 h, diethyl ether and afterwards water were added. The obtained crude material was purified by preparative HPLC to give the title compound (20 mg, 0.046 mmol, 41.3% yield).
Reaction SMILES: CO[C:3]1[C:10]([C:11]2C=CC=[CH:13][C:12]=2C)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:18][C:19]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([OH:33])=[CH:22][C:23]([C:30]([OH:32])=[O:31])=[CH:24]2.Cl.Cl.N[C:37]1[CH:38]=[C:39](S(O)(=O)=O)[C:40]2[C:45]([C:46]=1N)=[C:44](O)[CH:43]=[CH:42][CH:41]=2>>[CH:37]1[C:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:13]=[CH:12][C:11]=1[C:10]1[CH:3]=[C:4]([C:5]2[NH:29][C:28]3[CH:27]=[CH:26][C:25]4[C:20](=[C:21]([OH:33])[CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=4)[C:19]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: COc1c(C=O)cccc1-c1ccccc1C
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(O)c2c1N
Agent: Cl
Product: O=C(O)c1cc(O)c2c(ccc3[nH]c(-c4cccc(-c5ccc6c(c5)Cc5ccccc5-6)c4)nc32)c1

Procedure:
Follow the procedure of example 1c) except substituting 3-(9H-Fluoren-2-yl)-benzaldehyde for 2-methoxy-3-(2′-methylphenyl)benzaldehyde and 5,6-diamino-4-hydroxynaphthalene-2-carboxylic acid for 3,4-diamino-5-hydroxy-1-naphthalene sulfonic acid dihydrochloride, the title compound was prepared as a solid (0.004 g, 8%). MS(ES) m/z 469 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]=[C:5]([C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O)[C:6]([O:8][CH3:9])=[O:7].[CH3:31][O:32][C:33](=[O:38])/[CH:34]=[C:35](\[NH2:37])/[CH3:36]>CC(O)C>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]1[C:34]([C:33]([O:32][CH3:31])=[O:38])=[C:35]([CH3:36])[NH:37][C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])=[C:5]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C(/C)N
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
92.1 g of methyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate was dissolved in 108 ml of 2-propanol at 80° C. 31.3 g of methyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 24 hours. The mixture was evaporated to dryness. The residue was dissolved in 162 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The solid was filtered off and washed with 83 ml of glacial acetic acid. The solid was suspended in 68 ml of methanol and agitated for 30 minutes. The solid was filtered off, washed with 23 ml of methanol and dried. The product was recrystallized from ethyl acetate.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]([O-])=O.[Na+].[Cl:10][C:11]1[CH:17]=[C:16]([O:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([Cl:23])[C:12]=1[NH2:13].[C:24]([CH:26]([CH2:32][C:33]#[N:34])C(OCC)=O)#[N:25]>C(O)(=O)C.ClCCl>[NH2:34][C:33]1[N:13]([C:12]2[C:11]([Cl:10])=[CH:17][C:16]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[N:6]=[C:26]([C:24]#[N:25])[CH:32]=1
Reactant: CCOC(=O)C(C#N)CC#N
Reactant: Nc1c(Cl)cc(OC(F)(F)F)cc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1cc(N)n(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)n1
Temperature: 15 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To sulphuric acid (18M, 54 ml) was added sodium nitrite (13.9 g, 201.2 mmol) and the solution was stirred at 15° C. for 1 h. To the solution was added acetic acid (200 ml), followed by 2,6-dichloro-4-(trifluoromethoxy)aniline (45.0 g, 182.9 mmol) in acetic acid (90 ml), ensuring the temperature of the solution did not rise above 20° C. After addition was complete, the mixture was heated at 50° C. for 1 h, cooled to room temperature and added dropwise to a solution of ethyl 2,3-dicyanopropanoate (Hainzl, D.; Cole, L. M.; Casida, J. E. Chemical Research in Toxicology (1998), 11(12), 1529-1535, 27.8 g, 182.9 mmol) in acetic acid (115 ml) and ice cold water (145 ml). The reaction mixture was then stirred overnight at room temperature. To the reaction mixture was added dichloromethane (500 ml) and the mixture was stirred for 10 min. The two phases were separated and the organic phase was washed with water (200 ml) and ammonia (0.88, 400 ml) was added dropwise, maintaining the temperature of the mixture below 10° C. This mixture was stirred overnight at room temperature and the organic phase was separated and concentrated in vacuo. The residue was re-crystallised from toluene/pentane [2:1] to give the titled compound (22.4 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=1>C(OC(=O)C)(=O)C>[CH3:31][N:30]([CH3:32])[C:26]1[CH:25]=[C:24]([N:23]([CH3:33])[CH3:22])[CH:29]=[CH:28][C:27]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:17])[O:16]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1[nH]c2ccccc2c1C(=O)c1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1[nH]c2ccccc2c1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
A mixture of 8.37 g (0.03 mole) of 2-[(2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 8.37 g (0.05 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 10 ml of acetic anhydride was interacted at 50° C. as described in part B of Example 8 above to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2). After purification by slurrying in a benzene and ligroin mixture, the collected and dried product melted at 183°-186° C. The product had mass spectrum with a m/e peak at 425 (M+). Both the infrared and nuclear magnetic resonance spectra were consistent with this structure. A toluene solution of the product spotted on a phenolic resin coated paper developed an intense grape-colored image.
Reaction SMILES: ClC1[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[O:3]1>O>[OH:3][C:4]1[CH:10]=[C:9]([CH:8]=[CH:7][C:5]=1[OH:6])[C:11]#[N:12]
Reactant: N#Cc1ccc2c(c1)OC(Cl)O2
Solvent: O
Product: N#Cc1ccc(O)c(O)c1

Procedure:
hydrolyzing 2-chloro-benzo[1,3]dioxole-5-carbonitrile by contacting it with water to produce 3,4-dihydroxybenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10](=[O:24])[CH:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH3:12])=[CH:4][CH:3]=1.[I-].[NH2:26][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10](=[O:24])[CH:11]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])[CH3:12])=[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]3[N:26]=2)=[CH:4][CH:3]=1
Reactant: N[n+]1ccccc1
Reactant: CC(C(=O)C#Cc1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C(=O)c1c(-c2ccc(F)cc2)nn2ccccc12)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.1 g (3.4 mmol) of 2-(5-(4-fluorophenyl)-3-oxopent-4-yn-2-yl)isoindoline-1,3-dione and 785 mg (3.4 mmol) of N-aminopyridinium iodide in 10 ml of acetonitrile was added dropwise 1.04 g of DBU in 5 ml of acetonitrile at 0° C. for 20 minutes under a nitrogen atmosphere. The reaction was stirred at RT overnight, and it was worked up with ethyl acetate and ammonium chloride to produce 2-(1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl)isoindoline-1,3-dione as a crude solid. The phthalimide intermediate was reacted with 500 μl of hydrazine hydrate at RT in ethanol overnight. After workup with ethyl acetate and ammonium chloride, 1 g of crude product was obtained. The crude product was purified by C18-reverse-phase preparative HPLC. Addition of dilute HCl to the fractions containing purified product followed by lyophilization furnished 110 mg of 2-amino-1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride. Compound 1052.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:21]([C@@H:24]3[CH2:29][C@@H:28]4[C@@H:26]([CH2:27]4)[N:25]3C(OC(C)(C)C)=O)[NH:22][CH:23]=1)[CH:13]=[CH:12]2>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:21]([C@@H:24]3[CH2:29][C@@H:28]4[C@@H:26]([CH2:27]4)[NH:25]3)[NH:22][CH:23]=1)[CH:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc3cc(Br)ccc3c2)c[nH]1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166.3 %

Procedure:
TFA (1.028 mL, 13.34 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 120) (606 mg, 1.334 mmol) in DCE (20 mL) and reaction was stirred at rt for 2 h. Then additional TFA (1 mL) was added and the reaction was stirred at rt for 4 h. The reaction was concentrated to dryness and the crude brown oil was dissolved into diethyl ether and concentrated under vacuum (2×) to yield a TFA salt of (1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (786 mg) as a yellow solid. The material was used without further purification. LC-MS retention time 2.558 min; m/z 352.03, 354.05 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 10.55 (br. s., 1H), 8.02 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.8 Hz. 1H), 7.59 (dd, J=8.8, 2.0 Hz, 1H), 7.52 (dd, J=8.7, 1.6 Hz, 1H), 7.44 (s, 1H), 5.10 (dd, J=11.8, 7.3 Hz, 1H), 3.49-3.54 (m, 1H), 2.94 (td, J=12.7, 4.6 Hz, 1H), 2.68 (dd, J=13.2, 7.2 Hz, 1H), 2.06-2.14 (m, 1H), 1.20-1.26 (m, 1H), 1.00-1.09 (m, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31])[CH:17]=[CH:16]2.[OH-:33].[Ca+2].[OH-:35]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31])(=[O:35])=[O:33])[CH:17]=[CH:16]2
Reactant: [OH-]
Reactant: C[C@H](O)c1ccccc1Sc1ccc2cc(Br)ccc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
3-Chloroperoxybenzoic acid (2.85 g, 12.7 mmol) was added to a stirred solution of (1S)-1-{2-[(6-bromo-2-naphthyl)thio]phenyl}ethanol (2.28 g, 6.3 mmol) in dichloromethane (50 mL) at ambient temperature under nitrogen. Calcium hydroxide (1.50 g, 20.2 mmol) was added after 2 hours, stirred for a further 1 hour then filtered and concentrated in vacuo. Purification by flash column chromatography eluting with a 10-40% ethyl acetate/isohexane gradient followed by trituration using isohexane gave solid (1S)-1-{2-[(6-bromo-2-naphthyl)sulfonyl]phenyl}ethanol (1.47 g, 59%). 1H NMR (500 MHz, CDCl3) δ 8.50 (1H, s), 8.16 (1H, d, J 7.9 Hz), 8.08 (1H, s), 7.90-7.82 (2H, m), 7.77-7.70 (3H, m), 7.67 (1H, t, J 7.5 Hz), 7.50 (1H, t, J 7.7 Hz), 5.60 (1H, q, J 6.3 Hz), 2.46 (1H, s), 1.33 (3H, d, J 6.3 Hz); m/z (ES+) 373, 375 [(M-OH)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1O)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI.O.CN(C)[CH:23]=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:24][CH3:23])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid (3.45 g, 20 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (6.9 g, 50 mmol) and methyl iodide (large excess) and the mixture was stirred at 60° C. for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (4.0 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[Cl:18].[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=O)[CH2:22][C:21]1=[O:27]>>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:22]3[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]=3[NH:1][C:2]3[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]2=3)=[CH:12][C:11]=1[Cl:18]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(Br)c(Cl)c1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)C(C)(C)CC1)C2c1ccc(Br)c(Cl)c1
Yield: 67.2 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.08 g, 0.75 mmol), 3-chloro-4-bromobenzaldehyde (0.13 g, 0.75 mmol) from Example 40C, and 4,4-dimethyl-1,3-cyclohexanedione (0.10 g, 0.75 mmol) were processed as described in Example 22 to provide the title compound (0.22 g, 67%). 1H NMR (DMSO-d6) δ 0.92 (s, 3H), 0.98 (s, 3H), 1.78 (t, 2H), 2.55 (m, 2H), 3.47 (s, 3H), 4.81 (s, 1H), 7.0 (dd, 1H), 7.29 (d, 1H), 7.55 (d, 1H), 9.52 (bs, 1H), 9.67 (s, 1H); MS (ESI−) m/z 436 (M−H)−; Anal. Calcd for C19H19N3BrClO2: C, 52.23; H, 4.35; N, 9.62. Found: C, 52.35; H, 4.24; N, 9.62.