Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14]1([CH3:13])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: COC(OC)C(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COC(OC)C1(C)CC(=O)c2cc(C#N)ccc2O1
Yield: 85.7 %

Procedure:
In 100 ml of toluene were dissolved 8.06 g (50 mmole) of 3-acetyl-4-hydroxybenzonitrile and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, 1.67 ml (20 mmole) of pyrrolidine was added at room temperature thereto. 30 Minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added to the residue so obtained. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml×2), washed with 50 ml of water and then with 50 ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate (4:1) to obtain 11.19 g (yield 86%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Fc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)cc2c1=O
Yield: 77.3 %

Procedure:
170 mg of 1-(4-fluorophenyl]-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 210 mg of 5-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 177 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][C:19]([S@@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)/[CH:5]=[N:24]/[S@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1c(F)ccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred suspension of 3-chloro-2,6-difluorobenzaldehyde (0.615 g, 3.48 mmol) and Cs2CO3 (1.702 g, 5.23 mmol) in DCM (20 mL) was added a solution of (S)-2-methylpropane-2-sulfinamide (0.422 g, 3.48 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred at rt overnight. After overnight stirring, the reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product (0.98 g, 100%) as yellow oil. MS (ESI) m/z: 282.0 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.Cl>C1COCC1>[CH:1]1([NH:4][CH2:5][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Agent: Cl
Solvent: C1CCOC1
Product: C1CN[C@H](CNC2CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid cyclopropylamide (3.4 mmol) in THF (5 mL) at 0° C. was added BH3 (6.3 mL, 1 M in THF) dropwise. It was then warmed to room temperature and heated to reflux for 20 hours. The cooled reaction was acidified with 3M HCl (2.5 mL) and stirred at 75° C. for 10 minutes. The reaction was concentrated and the residue was basified with 2M NaOH. It was then extracted with 10% of methanol in dichloromethane. The organic layer was dried and concentrated to give a yellow oil of cyclopropyl-(S)-1-pyrrolidine-2-ylmethyl-amine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25](Cl)[CH:24]=4)[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH:24]=4)[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)nn1Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 140 °C
Yield: 22 %

Procedure:
3-(4-(tert-Butyl)phenyl)-5-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole (90 mg, 0.221 mmol) and 1-methylpiperazine (265 mg, 2.65 mmol) were dissolved in DMSO (3 mL) in a sealed tube reaction vessel. The reaction was heated at 140° C. overnight and then cooled to RT and partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with H2O (2×25 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by prep-HPLC (MeCN/H2O 20%-60% MeCN, containing 0.1% TFA). The product was taken up in EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated to afford 3-(4-(tert-butyl)phenyl)-5-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole as a yellow foam (23 mg, 22%). MS (ES+) C26H32N8O requires: 472. found 473 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.19-8.15 (m, 3H), 7.51 (d, J=8.4 Hz, 2H), 6.42 (d, J=4.9 Hz, 1H), 6.39 (s, 1H), 5.36 (s, 2H), 3.70-3.50 (m, 4H), 2.69-2.46 (bs, 3H), 2.54 (s, 3H), 2.46-2.30 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:26]COCC>C1COCC1>[C:1]([N:8]([C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:11])[CH3:26])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCOCC
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(2R,3R)-3-(N-Boc-N-methylamino)-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was synthesized according to Method Y above by the treatment of (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and MeI (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after silica gel column chromatography with a 0-10% Et2O in hexanes gradient. (Yield 370 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([O:29][Si](C)(C)C)=[C:26]([CH3:28])[CH3:27]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:22])([CH2:18][CH:19]([CH3:20])[CH3:21])[C:26]([CH3:28])([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-one (220 mg, 0.742 mmol) was dissolved in 10 mL of dry DCM and 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.162 mL, 0.8 mmol) was added. The reaction mixture was cooled to 0° C. and TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) was added portionwise and then stirred 12 h. The reaction was quenched with aqueous sodium bicarbonate and extracted 2×DCM. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified SiO2 chromatography eluting with 1:1 EtOAc/hexane to give 280 mg (95% yield) of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2,5-trimethylhexanoate. MS found: (M+H)+=399.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.[Cl-].[Na+].O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[NH:4][CH2:5][C:6]1=[O:12]
Reactant: O=C1CNc2c(F)cccc2N1
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (150 mg, 0.90 mmol) in DMF (3.0 ml) was added sodium hydride (60%, 36 mg, 0.90 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled again in an ice/water bath and methyl bromoacetate (85 μl, 0.90 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 40:60) to give a white solid; yield 140 mg, 65%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1)=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2cc(C=O)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzaldehyde 63 (0.793 g, 5 mmol) in DMSO (5 mL) was added methyl piperidine-4-carboxylate (0.7 mL, 5 mmol) and cesium carbonate (1.76 g, 5 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 70° C. for 2 h, and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 30% to 60% EtOAc in hexanes) gave methyl 1-(5-formyl-2-nitrophenyl)piperidine-4-carboxylate 64 (0.931 g, 68% yield) as a yellow oil. Mass spectrum: calculated for C14H16N2O5 292.1. found 293.1 (M++1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:35]N)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(O)(=O)C>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc2ccccc12
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ccccc34)n2)c1

Procedure:
3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and naphthalen-1-yl-hydrazine (2 eq) were dissolved in a sealed tube in DMF with 2 drops acetic acid and irradiated in MW at 120° C. for 15 min. The solvent of the reaction mixture was removed and the crude product was purified by preparative HPLC yielding the desired product.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([NH:21][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of 2-chloro-5-nitrobenzoic acid (5.0 g) and benzylamine (15.0 g) in ethanol (40 ml) is refluxed for 10 hours and then concentrated under reduced pressure. To the residue is added water (100 ml), and the resulting solution is adjusted to the pH of about 4 with acetic acid and stirred for 1 hour. The precipitate is collected and recrystallized from ethanol to give the title compound (4.8 g), mp 238°-248° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[NH:9]1)=[O:7])(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:42])([CH3:43])[CH2:33][OH:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.1 g, 1.68 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[C:16]([Br:24])=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:26])=[C:17]3[C:16]([Br:24])=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Temperature: 120 °C

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate C) (9 g, 61% purity) was mixed with dioxane (100 ml) and ammonium hydroxide (100 ml) in a pressure vessel. The mixture was heated to 120° C. overnight. Solvent was removed and the residue was purified via flash column chromatography using ethyl acetate as the mobile phase to give 1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.94 (d, J=11.23 Hz, 2H), 2.21(m, 2H), 2.35 (m, 2H), 3.04 (d, J=11.48 Hz), 3.57 (s, 2H), 4.71 (m, 1H), 5.98 (s, 2H), 7.34(m, 5H), 8.33 (s,1H); LC/MS (MH+=389).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH:17][CH2:18][CH:19]([OH:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26]CC1C=CC=CC=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16].C(O)C>[C].[Pd].O>[ClH:1].[CH3:2][CH:3]([NH:17][CH2:18][CH:19]([OH:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16]
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)c(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(C)NCC(O)c2ccccc2O)c(OC)c1OC
Yield: 72.4 %

Procedure:
A mixture of 1.0 g of α-[(α-methyl-2,3,4-trimethoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol hydrochloride [the diastereoisomer of M.p. 135°-136° C.], 400 mg of 10% palladium-carbon, 45 ml of ethanol and 5 ml of water is treated in the same manner as described in paragraph (6-a). The crude product thus obtained is recrystallized from a mixture of isopropylalcohol and isopropyl ether (1:2). 590 mg of α-[(α-methyl-2,3,4-trimethoxyphenethylamino)methyl]-2-hydroxybenzylalcohol hydrochloride [the diastereoisomer of M.p. 145°-146° C.] are thereby obtained as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[BH3:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][CH:14]1[C:13]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:10]([CH:21]([CH3:23])[CH3:22])=[N:11][C:12]=2[CH2:17][CH2:16][CH2:15]1)(=[O:35])=[O:34].[BH3:24]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCO)CCC2
Reactant: CS(=O)(=O)Cl
Agent: B
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCOS(C)(=O)=O)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred suspension of Intermediate 76 (830 mg) in Dichloromethane (DCM) (40 mL), under nitrogen, was treated with triethylamine (0.501 mL) then cooled to ca. 0° C. (ice bath). Methanesulfonyl chloride (0.222 mL) was added via syringe, then the cooling bath was removed and stirring continued for 2 h. The solution was partitioned between aqueous ammonium chloride (200 ml) and DCM (200 ml). The layers were separated and the aqueous phase was further extracted with DCM (200 ml). The combined organic extracts were washed with water (200 mL), dried (Na2SO4), filtered through a hydrophobic frit and evaporated in vacuo. The crude product was purified by column chromatography (silica, 0-25% Methanol in DCM). The appropriate fractions were combined and concentrated to afford the title compound, 368 mg. LC/MS (M-BH2)-411/413, Rt 2.18 mins (5 min run, TFA modifier).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:12]1[C:11]2[S:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:17][C:16]=2[C:15]([F:18])=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(F)c2nc(-c3c(F)cccc3Cl)sc2c1
Product: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Cl)c2s1
Temperature: 25 °C
Yield: 22 %

Procedure:
A stirred solution of 2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (3.0 g, 10.5 mmol) in phosphoryl chloride (50 mL) was heated at 110° C. for 45 minutes. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between a potassium carbonate saturated solution (100 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with water (100 mL), dried and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 10% diethyl ether in pentane to afford the title compound as a colourless solid (0.71 g, 22% yield). 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 7.56-7.46 (m, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H).
Reaction SMILES: [C:1](=[O:17])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1([CH3:6])[CH2:5][CH2:4]1.[F:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:35][C:32]2=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:6][C:3]1([O:2][C:1]([N:41]2[CH2:42][CH2:43][CH:38]([C:36]3[O:35][C:32]4=[CH:33][N:34]=[C:29]([C:20]5[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:19]=5[F:18])[CH:30]=[C:31]4[CH:37]=3)[CH2:39][CH2:40]2)=[O:17])[CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(OC(=O)N2CCC(c3cc4cc(-c5ccc(S(C)(=O)=O)cc5F)ncc4o3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Methyl-cyclopropyl 4-nitrophenyl carbonate (48 mg) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (75 mg) and N,N-diisopropyl-ethylamine (32 μL) in tetrahydrofuran (1 mL) at room temperature. The mixture is stirred at room temperature overnight. The solution is concentrated and the residue is taken up in ethyl acetate. The resulting mixture is washed with 1 M aqueous NaOH solution (3×), water, and brine. The organic phase is dried (Na2SO4) and concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=O)[N:22]=2)[CH2:14][CH:13]1[O:30][CH3:31])=[O:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl.Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)C(OC)C2)nc1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1CN1CCOCC1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a solution of ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate (0.15 g, 0.31 mmol, Example 252) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.1 g, 0.47 mmol) and morpholine (0.03 mL, 0.34 mmol). Reaction was stirred at room temperature and monitored by LCMS. Upon completion, the reaction mixture was diluted with 1N HCl and then partitioned with EtOAc/sat. sodium bicarbonate. Washing with brine, drying with MgSO4 and concentrating yielded a solid. Purification by silica gel flash column (gradient elution 70-100% EtOAc/CH2Cl2) afforded pure product (0.091 g) MS (ES) M+H+: 560 for C23H31Cl2N5O5S; NMR: 1.24 (t, 3 H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.32 (s, 2 H) 3.36 (s, 3 H) 3.52 (s, 2 H) 3.54 (d, 4 H) 3.65-3.75 (m, 2 H) 3.76-3.86 (m, 2 H) 3.93 (s, 1 H) 4.18 (q, 2 H) 4.27 (s, 1 H) 7.16 (d, 1 H) 12.16 (s, 1 H).
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.S(=O)(=O)(O)O>>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:19]2[CH:20]=[CH:21][C:16](=[O:15])[NH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1

Procedure:
To a mixture of 92.1 g (0.5 mole) of benzhydrol and 142.7 g. (1.5 mole) of 2-hydroxypyridine heated at 180°, add with stirring 1.5 ml. of concentrated sulfuric acid. Heat the mixture at 250°-255° for 2 hours with the removal of water. Pour the cooled reaction mixture into water, stir, and extract with chloroform. Concentrate the chloroform extracts to a residue containing 5-(diphenylmethyl)-2-pyridone. Triturate the residue with ethyl acetate and filter the solids to obtain 5-(diphenylmethyl)-2-pyridone plus other isomers. Recrystallize from acetonitrile to obtain the product of this example, m.p. 174°-176° C.