Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1ccccc1

Procedure:
101 mg (68%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(4-chlorophenyl)piperazine (84 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [C:1]([C:3]1([C:6]([N:8]2[CH2:15][CH:14]([NH:16]C(=O)OC(C)(C)C)[C:10]3([CH2:13][CH2:12][CH2:11]3)[CH2:9]2)=[O:7])[CH2:5][CH2:4]1)#[N:2].Cl>>[NH2:16][CH:14]1[C:10]2([CH2:13][CH2:12][CH2:11]2)[CH2:9][N:8]([C:6]([C:3]2([C:1]#[N:2])[CH2:4][CH2:5]2)=[O:7])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C2(C#N)CC2)CC12CCC2
Agent: Cl
Product: N#CC1(C(=O)N2CC(N)C3(CCC3)C2)CC1
Reaction time: 0.83 h

Procedure:
A solution of (+/−)-tert-butyl (6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-yl)carbamate (0.190 g, 0.595 mmol) in HCl (4.0 M in dioxane) (2.0 mL, 8.00 mmol) was stirred @ r. t. for 50 minutes. +/−MS analysis after 50 min indicated that no starting material could be detected (m/e 220.2, M+H for desired product). The HCl/dioxane was removed under vacuum, and co-evaporated with ether. Additional ether was added to the flask and then decanted off. The ether wash was repeated, and the residual ether was removed under vacuum to afford 0.172 g of the hydrochloride salt of the title compound as a tan, hygroscopic solid. +/−MS: m/e 220.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (br. s., 2H), 3.74 (br. s., 1H), 3.58-3.49 (m, 1H), 3.45-3.34 (m, 2H), 2.95 (s, 3H), 2.36-2.22 (m, 1H), 2.09-1.92 (m, 2H), 1.91-1.81 (m, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[O-:30][Mn](=O)(=O)=O.[K+]>CC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:30])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a solution of N-(6′-bromo-1′-(1-ethoxyvinyl)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-yl)-2-methylpropane-2-sulfinamide (5) (200 mg, 0.48 mmol) in acetone (15 mL) at room temperature (23° C.) was added a KMnO4 solution (5.8 mL, prepared by dissolving 9.5 g of KMnO4 in 100 mL of H2O). The mixture was stirred room temperature for 16 h. Another portion of KMnO4 solution (2.2 mL) was added and stirred another 12 h. The reaction was quenched with 5% NaHSO3, stirring until colorless clear solution achieved before combined. The combined organic phases were extracted with EA 2 times, washed with brine, dried over Na2SO4, evaporated after filtration. The residue was purified by flash chromatography on silica gel eluted with EA in hexane (0-60%) to afford the desired amino ester (6) (62.8 mg, 31%). MS ESI+ve m/z 486 (M+H)30.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>CS(C)=O>[CH3:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cccc(N)c1C
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Product: Cc1cccc(Nc2ccccc2[N+](=O)[O-])c1C

Procedure:
In an entirely analogous manner, using 117.00 g (0.830 mol) of 1-fluoro-2-nitrobenzene and 222.00 g (1.826 mol) of 2,3-dimethylaniline in 585 ml of dimethyl sulphoxide as starting materials there is obtained N-(2,3-dimethylphenyl)-2-nitroaniline having a melting point of 118°-120° after recrystallisation from methylene chloride/hexane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][C:15]=1[O:23][CH3:24].[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][C:33](/[CH:35]=[C:20](/[C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:15]([O:23][CH3:24])[CH:16]=3)\[C:21]#[N:22])=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: COc1cc(/C(C#N)=C/c2ccc3c(c2)OCCO3)ccc1OCCCCCCCCCCCO
Yield: 80 %

Procedure:
(2Z)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile and commercial 1,4-Benzodioxan-6-carboxaldehyde according the same procedure following for example 1 in 80% yield.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([N:27]2[CH2:30][CH2:29][CH2:28]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: C1CNC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(N3CCC3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 4, using 5-bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 1e) and azetidine as starting materials, and isolated (29 mg, 41%) as light yellow oil; MS (EI): 413.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]([C:22]([NH2:24])=O)[CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]([CH2:22][NH2:24])[CH2:10]1
Reactant: COc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccccc1N1CCN(Cc2ccccc2)C(CN)C1

Procedure:
In a manner similar to Preparation 2, react 4-(2-methoxyphenyl)-1-(phenylmethyl)-2-piperazinecarboxamide (4.0 g, 16.6 mmol) with lithium aluminum hydride (1.0 g, 26 mmol) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]3([OH:44])[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OCC4C=CC=CC=4)=O)=[C:13]([O:28][CH3:29])[CH:12]=3)[C:3]=12>[Pd].C(O)C.O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]3([OH:44])[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:35][CH2:36]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:28][CH3:29])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 1000 %

Procedure:
A mixture of tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.000017 mol) and palladium on carbon (0.01 g) in ethanol (2.5 mL) and tetrahydrofuran (2.5 mL) was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered and additional palladium on carbon (0.01 g) was added. The mixture was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered through celite and the solvents were removed under reduced pressure to give tert-butyl 4-{[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00017 mol).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]([C:18]3[CH:19]=[N:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[NH:3][C:4](=[O:12])[C:5]=2[CH:10]=[CH:9]1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)nc3)nc21
Temperature: 150 °C
Yield: 6.8 %

Procedure:
A high pressure microwave reaction vial was charged with 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (55 mg, 0.3 mmol), 6-(trifluoromethyl)pyridin-3-ylboronic acid (68.6 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (21.9 mg, 0.03 mmol), a 2M aqueous sodium carbonate solution (0.45 mL, 0.9 mmol), and ethanol (2 mL). The vessel was sealed, degassed and flushed with nitrogen three times. The reaction was then heated at 150° C. for 10 min in a Biotage microwave reactor. At this time, the resulting black mixture was concentrated in vacuo. The residue was treated with ethyl acetate (20 mL), stirred and filtered. The filtrate was concentrated in vacuo. Reverse phase chromatography (10-100% acetonitrile/water) and lyophilization afforded 7-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (6 mg, 6.81%) as a white solid. LC-MS calcd. for C13H10F3N4O [(M+H)+] 295, obsd. 294.8.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCOC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(C3CCOC3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A mixture of tert-butyl 9-(tetrahydrofuran-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (430 mg, 1.35 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (320 mg, 92.8%) as a solid.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>C(OC(O)C)C>[F:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:12])[NH:6][CH:5]=[N:7]2)=[CH:14][CH:15]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: CCOC(C)O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Yield: 88.5 %

Procedure:
Formamidine acetate (31.2 g, 300 mmol) and 2-amino-4-fluorobenzoic acid (23.3 g, 150 mmol) are heated at reflux in ethoxyethanol for 16 h. The crude product is poured into saturate sodium bicarbonate solution. The solid is collected, washed, and dried, affording the titled 7-Fluoro-3H-quinazolin-4-one (21.8 g, 89%).
Reaction SMILES: [CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49](B(O)O)[CH:48]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>C1(C)C=CC=CC=1.O>[CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:49]2[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=2)=[CH:42][CH:41]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([C@H](Cc1ccccc1)N(Cc1ccc(Br)cc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C([C@H](Cc1ccccc1)N(Cc1ccc(-c2cccnc2)cc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
In an inert atmosphere, N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-bromo-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (60 mg, 0.087 mmol) was dissolved in toluene (0.5 mL) followed by the addition of 3-pyridineboronic acid (11 mg, 0.087 mmol), 2M potassium carbonate solution (0.5 mL) and iso-propanol (0.5 mL). The mixture was degassed with argon for 5 min and heated to 100° C. followed by the addition of tetrakis-(triphenylphosphine)palladium (3 mg, 0.003 mmol). The mixture was stirred for 3 h at 110° C., cooled to rt again and water (1 mL) was added. The product was extracted with EtOAc (3×3 mL). The combined organic layers were evaporated to dryness and the residue was purified by prep. HPLC to give 21 mg (35%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-3-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=0.85 min; [M+H]+=689.68.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[CH2:9]([CH:16]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Br)CC.C(O)(=O)C>C1COCC1>[CH2:9]([CH:16]1[NH:20][C:19](=[O:21])[CH:18]([CH2:2][CH2:1][CH3:3])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1CCC(Cc2ccccc2)N1
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCBr
Product: CCCC1CC(Cc2ccccc2)NC1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 5-benzylpyrrolidin-2-one and the mixture is stirred for 1.5 hours at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 hours at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted 3 times with dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 5-benzyl-3-propylpyrrolidin-2-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[OH-].[Na+].OO.Cl>CO.O>[OH:9][C:10]1[C:11](=[O:12])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8][C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12
Temperature: 12.5 °C
Reaction time: 24 h

Procedure:
To a three necked round bottomed flask, equipped with reflux condenser, calcium chloride guard tube and nitrogen inlet and magnetic stirrer, was charged methanol (200 mililiters (ml)), benzaldehyde (10.6 grams (g)) and 2-hydroxy acetophenone (13.6 g). The mixture was cooled to 10-15° C. and sodium hydroxide (15 g in 40 milliliters (ml) water) was slowly added. The reaction mixture was stirred at room temperature (˜25° C.) for 24 hours. Then methanol was added to the reaction mixture and the mixture was cooled to below 15° C. To this cooled mixuture sodium hydroxide (15 g in 40 ml water) and hydrogen peroxide (56 ml) were added and the reaction mixture was stirred for 6 to 8 hrs at room temperature. After this the reaction mixture was cooled to 10° C., neutralized using hydrochloric acid and the solid product that precipitated out was filtered. The solid was washed with water till the filtrate was free of acid. The solid product was dried in an oven at 70° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]([OH:33])[C:28]([F:35])([F:34])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, yellow solid (39 mg, 35%), MS (ISP) m/z=455.4 [(M+H)+], mp 179° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxy-propionic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([OH:19])=O)[N:11]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:66]1[CH2:71][CH2:70][N:69]([CH2:72][CH2:73][NH2:74])[CH2:68][CH2:67]1>CCOC(C)=O.CN(C=O)C>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([NH:74][CH2:73][CH2:72][N:69]4[CH2:70][CH2:71][O:66][CH2:67][CH2:68]4)=[O:19])[N:11]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:24])=[O:25])[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cccc(C(=O)O)c3)cc3c4c(cnc32)cnn4C)cc1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cccc(C(=O)NCCN4CCOCC4)c3)cc3c4c(cnc32)cnn4C)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
A flask was charged with 3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)benzoic acid (0.10 g, 0.22 mmol, prepared using D from Preparation #1 with 3-boronobenzoic acid), DIEA (0.039 mL, 0.224 mmol), HATU (0.085 g, 0.224 mmol) and DMF (3 mL). The mixture was stirred at about 40° C. for about 30 min. To the mixture was added 2-morpholinoethanamine (0.038 mL, 0.291 mmol). The mixture was allowed to stir at about 40° C. for about 2 h. The mixture was stirred overnight at rt and then diluted with EtOAc (10 mL) and washed with water (10 mL). The aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient of 0 to 7.5% MeOH/DCM to give 3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-N-(2-morpholinoethyl)benzamide (0.123 g, 98%): LC/MS (Table 2, Method c) Rt=1.20 min; MS m/z 559 (M+H)+.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:24])([CH3:25])[C:19]([OH:21])=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)OCC)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)O)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl (±)-5-dodecyl-α,α-dimethyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 68°-71° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][C:24]=1F.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:24]3[CH:23]=[CH:22][C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=3[Cl:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccc3c(ccn3Cc3ccccc3)c2)c(Cl)c1
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A slurry of 0.413 g (1.85 mmol) 1-benzyl-5-hydroxy-1H-indole, 0.3 ml (2.2 mmol) 3-chloro-4-fluorobenzotrifluoride, and 1.0 g (3.0 mmol) Cs2CO3 in 12 ml DMF was heated to 130° C. with stirring for 16 hr. The solution was allowed to cool and then filtered to remove Cs2CO3. The solution was concentrated under vacuum and chromatographed on silica using 5–7% EtOAc-hexane to afford 0.51 g 1-benzyl-5-(2-chloro-4-trifluoromethyl-phenoxy)-1H-indole as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1.CI.[CH3:39]N(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:39][O:1][CH2:2][C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(CO)sc32)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COCc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a mixture of 4′-{[6-(hydroxymethyl)-2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.45 g), methyl iodide (0.11 mL) and N,N-dimethylformamide (5 mL) was added 60% sodium hydride (0.05 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.35 g, 77%).