Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([OH:23])=O)[CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([Cl:26])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Product: O=C(Cl)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (10.0 g, 26.2 mmol) prepared in Step 1 was added to thionyl chloride (100.0 mL). The reaction was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: Cl[O-].[Na+].[Br-].[K+].[OH-].[Na+].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH:12]=[O:13].S([O-])([O-])=[O:23].[Na+].[Na+].Cl>O.C1CCCCC1>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=1)[C:12]([OH:23])=[O:13]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To an aqueous solution of sodium hypochlorite (100.3 g, 134.7 mmol, 1.22 equiv.) and potassium bromide (13.5 g, 112.3 mmol, 1.02 equiv.) in sodium hydroxide solution (32%, 34.5 g, 276.0 mmol, 2.50 equiv.) was added slowly (during 35 min) at 50° C. 3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (25.0 g, 110.4 mmol). The reaction mixture was stirred at 50° C. for 60 min, cooled to ambient temperature and quenched upon addition of sodium sulfite (60.4 g, 474.5 mmol, 4.3 equiv.) in water (450 ml) to give a clear yellow solution. The solution was treated with HCl (25%, 100 ml, 788.7 mmol, 7.14 equiv.) adjusting the pH to <2. The formed precipitate was extracted with toluene (300 ml), the organic phase was washed with a solution of sodium chloride (5%, 100 ml), dried over sodium sulfate and the solvents were removed under vacuum to give the crude product as light yellow solid. The crude product was dissolved in hot cyclohexane (125 ml), and the solution was cooled to ambient temperature, whereupon white crystals precipitated. The crystals were filtered off, washed with cyclohexane (25 ml) and dried under vacuum until weight constancy to give the title compound as white crystals (23.0 g, 85.8% yield). MS (EI): m/z 241.1 ([M−H]−, 100%). 1H-NMR (DMSO, 400 MHz): δ 14.08 (br s, 1H), 8.37-8.35 (dd, 1H), 8.11-8.09 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:13]([C@:16]1([CH2:44][OH:45])[O:22][C@@:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=2)([OH:21])[C@:19]([C:33](=[O:35])[CH3:34])([OH:32])[C@@:18]([C:37](=[O:39])[CH3:38])([OH:36])[C@@:17]1([C:41](=[O:43])[CH3:42])[OH:40])(=[O:15])[CH3:14].[NH4+].[Cl-]>C1COCC1>[C:13]([C@:16]1([CH2:44][OH:45])[O:22][C@@:20]([O:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:31])=[CH:28][CH:29]=2)([OH:21])[C@:19]([C:33](=[O:35])[CH3:34])([OH:32])[C@@:18]([C:37](=[O:39])[CH3:38])([OH:36])[C@@:17]1([C:41](=[O:43])[CH3:42])[OH:40])(=[O:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(=O)[C@]1(O)[C@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@](O)(Oc2ccc(C=O)cc2)[C@@]1(O)C(C)=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@]1(O)[C@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@](O)(Oc2ccc(C(O)c3ccccn3)cc2)[C@@]1(O)C(C)=O
Reaction time: 2 h
Yield: 25 %

Procedure:
2-Bromopyridine (726 mg, 440 μl, 4.6 mmol) is dissolved in 5 ml of THF at ambient temperature. Isopropylmagnesium chloride (2.3 ml, 4.6 mmol, 2M in THF) is added dropwise under argon and the mixture is left stirring for 2 hours. This solution is added to a solution of tetraacetyl-(p-formylphenoxy)-β-galactose (2.07 g, 4.6 mmol) in 3 ml of THF at ambient temperature. The mixture is left stirring for 18 h and then a saturated NH4Cl solution is slowly added. The resulting aqueous solution is extracted with ethyl acetate. The organic phase is dried over Na2SO4 and evaporated under vacuum. The crude reaction product is purified by chromatography on silica gel (ether/pentane 2/1 pure ether). A yellow solid is then obtained (600 mg, yield 25%).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: CC[C@@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(=O)OC
Agent: Cl
Product: CC[C@@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: ClC1N=C(N[C@H]2CCCC3(CNC(=O)C3)C2)C(F)=CN=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:30]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:48][CH2:47][CH2:46][C:40]5([CH2:44][NH:43][C:42](=[O:45])[CH2:41]5)[CH2:39]4)[C:34]([F:49])=[CH:33][N:32]=3)=[CH:29][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:25]2=[N:26][CH:27]=1.C[O-].[Na+]>CO>[Cl:21][C:22]1[CH:23]=[C:24]2[C:30]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:48][CH2:47][CH2:46][C:40]5([CH2:44][NH:43][C:42](=[O:45])[CH2:41]5)[CH2:39]4)[C:34]([F:49])=[CH:33][N:32]=3)=[CH:29][NH:28][C:25]2=[N:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC5(CNC(=O)C5)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: O=C1CC2(CCC[C@H](Nc3nc(Cl)ncc3F)C2)CN1
Agent: [Na+]
Solvent: CO
Product: O=C1CC2(CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)CN1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of (7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one, 62d, (0.091 g, 0.159 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25% w/v, 9.255 mmol). The reaction was stirred for 0.5 hours then concentrated in vacuo. The material was purified by reverse phase HPLC (Water/HCl:MeOH) to give a mixture of diastereomers. The fractions containing pure product were combined and concentrated to give 50 mg of the HCl salt of 969.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]1.Cl>O1CCOCC1.C(O)C>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)[CH2:24][CH2:23]1
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: c1ccc(-c2noc(-c3ccccc3OCCN3CCOCC3)n2)cc1
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 100 ml of anhydrous dioxane and stirred with 0.3 g of 80% sodium hydride suspension in oil for 15 minutes at 25-30° C. To this solution is added 75 ml of absolute dioxane, mixed with 3.72 g of 2-(morpholino)ethylchloride hydrochloride and 0.6 g of 80% sodium hydride suspension in oil. This solution is also stirred for 15 minutes at 25-30° C. The combined solutions are heated to 100° C. for 6 hours and then concentrated by evaporation in vacuo. The residue is mixed with water and 20 ml of 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel with ethyl acetate/isopropanol (70:30, mixed with 1.5% of a 25% ammonia solution). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 1.9 g (49% of theory). m.p.: 194-195° C.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH:17]([CH:19]3[CH2:24][N:23]([C:25](=[O:37])[NH:26][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21][N:20]3[C:38](OCC3C=CC=CC=3)=O)[CH3:18])[CH:13]=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C=O.[BH3-]C#N.[Na+]>>[N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH:17]([CH:19]3[CH2:24][N:23]([C:25](=[O:37])[NH:26][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21][N:20]3[CH3:38])[CH3:18])[CH:13]=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(Nc1ccnc(-n2cnc3ccccc32)n1)C1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(Nc1ccnc(-n2cnc3ccccc32)n1)C1CN(C(=O)Nc2cccc3ccccc23)CCN1C

Procedure:
The title compound was prepared from 2-[benzimidazol-1-yl]-4-[1-(1-(benzyloxycarbonyl)-4-(N-naphth-1-yl-carbamoyl)-piperazine-2-yl)ethylamino]pyrimidine (50 mg), 37% aqueous formaldehyde (17 μL), and NaBH3CN (4.4 mg) according to the procedure described in EXAMPLE 14, Step G. Mass spectrum (ESI) 507.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.[K].[CH2:23](I)[CH2:24][CH:25]([CH3:27])[CH3:26]>N>[CH3:1][O:2][C:3]1[C:4]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)CCI
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: N
Agent: [K]
Solvent: CC(C)(C)O
Product: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of methyl 2-methoxynaphthoate (1.0 g, 4.6 mmol) and tert-butyl alcohol (0.44 ml, 4.6 mmol) at −78° C. was added liquid ammonia (20 mL). Potassium metal was added in small pieces until the solution stayed dark blue for 30 min. Isoamyl iodide (1.9 mL, 14.8 mmol) was added dropwise (the blue coloration disappeared about half-way through addition) and stirring was continued for 1 hour at −78° C. The solution was allowed to warm to room temperature and purged with nitrogen to remove excess ammonia. To the resulting slurry a solution of saturated sodium bicarbonate (100 mL) was added, and the solution was extracted with ether (3×50 mL). The combined organic phases were washed with 10% Na2S2O3 (aq), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (5%-15% ethyl acetate/hexane) afforded product as a light yellow oil (1.1 g, 85%). 1H NMR (300 MHz, CDCl3) δ ppm 0.55 (m, 1 H), 0.75 (dd, J=14.71, 6.62 Hz, 6 H), 0.88 (m, 1 H), 1.39 (m, 1 H), 2.06 (m, 1 H), 2.27 (m, 1 H), 3.55 (d, J=3.31 Hz, 2 H), 3.60 (s, 3 H), 3.61 (s, 3 H), 5.05 (t, J=3.68 Hz, 1 H), 7.16 (m, 4 H); MS m/z 289.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([I:10])[CH:4]=1.[C-:11]#[N:12].[Li+]>CN(C=O)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:11]#[N:12])=[CH:4][C:5]=1[I:10]
Reactant: [C-]#N
Reactant: Fc1ccc(CBr)cc1I
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(F)c(I)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromomethyl-1-fluoro-2-iodo-benzene (33.8 g, 107 mMol) was added to 240 mL of a 0.5M solution of lithium cyanide in DMF. The reaction mixture was heated to 80° C. under an atmosphere of dry N2 and stirred overnight at this temperature. The mixture was then cooled to ambient temperature and partitioned between Et2O and 0.1N aqueous NaOH. The Et2O layer was then washed 4 more times with 0.1N aqueous NaOH. The Et2O layer was then dried over MgSO4, fiftered and concentrated under vacuum to give 24.7 9 of the titled compound as a red solid which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>CC(C)=O>[CH2:15]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:17]1[O:19][CH2:18]1
Reactant: Oc1cccc(F)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cccc(OCC2CO2)c1
Yield: 44.3 %

Procedure:
A solution of 3-fluorophenol (1.8 g, 16.1 mmol) in acetone (100 mL) was treated with potassium carbonate (6.65 g, 48.2 mmol) and refluxed under nitrogen for 15 minutes. Epibromohydrin (4.4 g, 32.1 mmol) was then added by syringe, and the mixture was refluxed 3 hours. The mixture was cooled and filtered, and the filtrate evaporated to dryness. The residue was partitioned between ether/water, and the layers separated. The ether layer was washed with saturated NaCl, dried over sodium sulfate and evaporated. The resulting oil was distilled under vacuum to give 1.2 g of 3-fluorophenyl glycidyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[CH:10][C:11]1[C:16](Br)=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Br:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc(Br)c(C=NNc2ccccc2F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(Br)c2cnn(-c3ccccc3F)c2c1
Yield: 41 %

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (2-fluorophenyl)hydrazone (Intermediate 25, 767 mg, 1.99 mmol), tripotassium phosphate (1.06 g, 4.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (73 mg, 0.08 mmol) and racemic BINAP (50 mg, 0.08 mmol) were dissolved in toluene (26 mL) and heated under reflux for 16 hours in a nitrogen atmosphere. The mixture was then cooled and evaporated under reduced pressure. The residue purified by silica gel chromatography using the Flashmaster II (100 g cartridge) eluting with a 100:0 to 0:100 cyclohexane:dichloromethane gradient over 40 minutes to give the title compound (249 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>[OH-].[Na+].CO.CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)C(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Yield: 82 %

Procedure:
Each diastereomer of methyl 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 27 mg (82% yield, 2 steps) and 35 mg of the diastereomers of acid 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid. MS found: (M+H)+=281.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.CN.CC(O)=O.[BH3-][C:19]#[N:20].[Na+]>CO>[CH3:19][NH:20][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2ccccc2o1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
To a stirred solution of 2-benzofurancarboxaldehyde (2.22 g, 15.2 mmole) in MeOH (5 mL) was added 2 M methylamine in MeOH (15 mL), HOAc (0.86 mL, 15 mmole), and NaBH3CN (1.0 g, 15.9 mmole). The reaction was stirred for 18 h at RT then concentrated under vacuum. The remaining residue was taken up in Et2O, and the solution was washed with 1 N NaOH then brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (5% (5% NH4OH in MeOH)/CHCl3) gave the title compound (1.23 g, 50%) as a pale yellow oil: MS (ES) n/e 162.4 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[NH2:18][C:19]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[C:26]2[C:21](=[CH:22][C:23]([C:36](O)=[O:37])=[CH:24][CH:25]=2)[N:20]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:18][C:19]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[C:26]2[C:21](=[CH:22][C:23]([C:36]([NH:1][CH:2]([CH2:8][C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[C:3]([N:5]([CH3:6])[CH3:7])=[O:4])=[O:37])=[CH:24][CH:25]=2)[N:20]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: CN(C)C(=O)C(N)Cc1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4nc5ccccc5s4)C(=O)N(C)C)ccc23)CC1
Yield: 49.9 %

Procedure:
A solution of 2-amino-3-(benzo[d]thiazol-2-yl)-N,N-dimethylpropanamide (12.1 mg, 52.2 μmol), 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 34.8 μmol) from Example 21 Step 4, N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.2 mg, 55.7 μmol), N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (12.1 μl, 69.6 μmol) was stirred at 25° C. for 60 min The reaction was purified by prep RP-HPLC (pH=10) to afford the desired compound (0.009 g, 49%) as an amorphous white solid. Analytical LCMS (M+H)+: m/z=519.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:26]1[CH:27]=[N:28][C:29]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:42])[CH:39]=3)[C:34]([S:49][CH3:50])=[CH:33]2)=[N:30][CH:31]=1.[F:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1B(O)O>C1COCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:26]1[CH:27]=[N:28][C:29]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:42])[CH:39]=3)[C:34]([S:49][CH3:50])=[CH:33]2)=[N:30][CH:31]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (5.73 g, 41.57 mmol, 3.0 eq), Pd2(dba)3 (1.26 g, 1.39 mmol, 0.1 eq) and tri-tert-butyl phosphonium tetrafluoroborate (0.2 g, 0.69 mmol, 0.05 eq) were added at room temperature under an argon atmosphere to a stirred solution of (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)-methanone (6.0 g, 13.85 mmol, 1.0 eq) and (2-fluorophenyl)boronic acid (2.31 g, 16.62 mmol, 1.2 eq) in THF/water (100 mL, 4:1). The mixture was stirred for 2 h at 30° C., diluted with ethyl acetate (50 mL), and filtered through a pad of celite. The filtrate was washed with water, dried over sodium sulphate and evaporated. The residue was purified by column chromatography [100-200 mesh; ethyl acetate/petrolether=2:3]. Yield: 4.0 g (64% of theory).
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]([CH3:21])([CH3:20])[CH:11]=[N:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23]/[C:24](=[CH:29]\[C:30]([O:32][CH3:33])=[O:31])/[C:25](OC)=[O:26].[Cl-].[NH4+]>C1COCC1.[Zn]>[CH2:13]([N:12]1[CH:11]([C:10]([S:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH3:21])[CH3:20])[CH:29]([C:30]([O:32][CH3:33])=[O:31])[C:24](=[CH2:23])[C:25]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)/C=C(\CBr)C(=O)OC
Reactant: CC(C)(C=NCc1ccccc1)SCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1C(=O)N(Cc2ccccc2)C(C(C)(C)SCc2ccccc2)C1C(=O)OC
Reaction time: 1.5 h

Procedure:
To a stirred suspension of zinc dust (0.68 g) activated with hydrochloric acid in THF (15 ml), N-(2-benzylthio-2-methylpropylidene)benzylamine (1.42 g) dissolved in THF (15 ml) and dimethyl 2-bromomethylfumarate (1.28 g) dissolved in THF are added dropwise while refluxing under nitrogen atmosphere. The mixture is stirred for additional 1.5 hours under refluxing. To the mixture saturated aqueous ammonium chloride solution is added. After cooling, the mixture is filtered by celite. A reaction product is extracted with ethyl acetate from the filtrate. The organic layer is washed with 1N hydrochloric acid, water and then saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH:17][C:18](=[O:20])[CH3:19])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1sc(NC(C)=O)c(C(=O)OCC)c1C

Procedure:
A solution of 23.0 g (0.09 mol) of 2,4-diethoxycarbonyl-3-methyl-5-aminothiophene in 250 ml. of acetic anhydride was heated to 100° C. for 1.5 hrs. The resulting mixture was cooled in an ice bath and the precipitated crystals were filtered to yield 2,4-diethoxycarbonyl-3-methyl-5-acetylamino-thiophene, m.p. 130°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27](C(OC(C)(C)C)=O)[C:28](=[O:34])[C@@H:29]4[CH2:33][CH2:32][CH2:31][NH:30]4)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:42]([CH3:44])[CH3:43])[NH:11]1>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:34])[C@@H:29]4[CH2:33][CH2:32][CH2:31][NH:30]4)=[CH:25][CH:26]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:42]([CH3:44])[CH3:43])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N(C(=O)OC(C)(C)C)C(=O)[C@@H]4CCCN4)cc3)nc(=O)c1-2
Agent: Cl
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)[C@@H]4CCCN4)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
Fifty mg (0.076 mmol) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one was dissolved in 2 mL of 4 M HCl, and the solution was stirred 1 h at RT. The solution was concentrated under reduced pressure to afford 45 mg (100%) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(prolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. 1H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 10.67(s, 1H); 7.97(s, 2H); 7.49(d, 2H, J=8.5 Hz); 7.23(d, 2H, J=8.4 Hz); 4.27-4.31(m, 1H); 3.82(s, 2H); 3.18-3.34(m, 5H); 2.28-2.40(m, 1H); 1.84-1.95(m, 3H); 1.28(d, 6H, J=6.9 Hz).