Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-n2ccc(C(=O)O)n2)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cnn(C)c2)n1
Yield: 66 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1′-methyl-1′H-[1,4′-bipyrazole]-3-carboxylic acid (0.921 mmol, 177 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.767 mmol, 200 mg) using DMF (2 ml) as the solvent. DCM was added and evaporated. The residue was purified by flash chromatography. The product was further purified by dissolving it in DCM and washing three times with 1 M NaHCO3 and evaporating the separated DCM phase. 220 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.14 (d, 3H), 3.89 (s, 3H), 4.27-4.42 (m, 2H), 4.42-4.53 (m, 1H), 6.76 (d, 1H), 6.95 (d, 1H), 7.83-7.87 (m, 3H), 7.94 (dd, 1H), 8.06 (d, 1H), 8.16 (d, 1H), 8.18 (s, 1H), 8.21 (d, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=O)=[CH:12][CH:11]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a three-neck round-bottomed flask equipped with a magnetic stir bar, reflux condenser, rubber septum, and two nitrogen inlets, was added zinc powder (13.0 g, 199 mmol) followed by anhydrous THF (200 mL). To the stirred suspension was slowly added TiCl4 (11.0 mL, 19.0 g, 100.0 mmol) via syringe (caution: vigorous fuming). The reaction mixture was heated at reflux for 2 h. To the refluxing reaction mixture was added a solution of cycloheptanone (9.0 mL, 8.56 g, 76.3 mmol) and (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (6.91 g, 24.9 mmol) in THF (200 mL) slowly via syringe. The reaction mixture was heated at reflux under a nitrogen atmosphere with stirring for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to room temperature. The three neck round-bottomeded flask was equipped with an addition funnel and water (150 mL) was slowly added to the reaction mixture followed by 10% aqueous K2CO3 (150 mL). The reaction mixture was filtered through a pad of Celite. The pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an orange oil. The crude product was partially purified by flush chromatography on silica gel with hexanes:EtOAc (100:0 to 95:5) to give a solid. The solid was triturated with hexanes and filtered to give 6.3 g (71%) of compound (9) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 8H), 2.20 (m, 4H), 6.66 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 9.30 (s, 1H).
Reaction SMILES: [CH:1]1([B-](F)(F)F)[CH2:3][CH2:2]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:16]1[CH:17]=[CH:18][C:19]([C:29]([OH:31])=[O:30])=[N:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>[CH:1]1([C:16]2[CH:17]=[CH:18][C:19]([C:29]([OH:31])=[O:30])=[N:20][C:21]=2[O:22][CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][O:25]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Br)c(OCC2CCCO2)n1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
Palladium(II)acetate (1.19 mg, 5.3 μmol), butylbis(tricyclo[3.3.1.13,7]dec-1-yl)-phosphine (2.85 mg, 7.94 μmol, CAN 321921-71-5), potassium cyclopropyltrifluoroborate (39.6 mg, 267 μmol) and cesium carbonate (259 mg, 794 μmol) were combined to give a white solid. To this solid a degassed solution of 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (80 mg, 265 μmol) in toluene (2.02 mL)/water (224 μL) was added through a septum cap. The reaction mixture was heated to 120° C. and stirred for 20 h. After cooling to ambient temperature the reaction mixture was diluted with water (2 mL), poured onto 20 mL ice water/brine/1 N HCl, extracted with isopropyl acetate (2×40 mL), and washed with 20 mL ice water/brine. The organic layers were dried with Na2SO4 and concentrated in vacuo to give a light brown oily residue which was purified by preparative TLC (silica gel, 2.0 mm, DCM/MeOH, 49:1). The title compound (25 mg, 36%) was isolated as light yellow liquid; MS (ESI): 262.0 [M−H]−.
Reaction SMILES: [Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][O:16]C(=O)C2C=CC=CC=2)=[C:5](Cl)[N:4]=1.O.[CH2:27]([OH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:5]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=1
Reactant: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(COCCO)c2n1
Temperature: 120 °C

Procedure:
A solution of sodium benzylate in benzyl alcohol was prepared from sodium (2.58 g) and benzyl alcohol (28 ml). The solution was heated to 120° C. and 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (3.47 g) was added over a 10 minute period. The reaction mixture was heated overnight with stirring at 120°-130° C. and then poured into a mixture of ice and water. The resulting mixture was extracted thoroughly with chloroform. The aqueous phase was neutralized with acetic acid, giving a white precipitate which was recrystallized from methanol and then from water to give analytically pure 2-amino-6-benzyloxy-9-(2-hydroxyethoxymethyl)purine, m.p. 291°-292° C. (dec.) in 50% yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH2:15][C:16]([CH:19]=O)([CH3:18])[CH3:17])[C:13](=[O:21])[C@@H:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:11][C@H:10]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH:38]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH2:15][C:16]([CH3:17])([CH3:18])[CH2:19][N:2]([CH3:3])[CH3:1])[C:13](=[O:21])[C@@H:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:11][C@H:10]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH:38]=1
Reactant: CNC
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)C=O)C1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CN(C)C)C1=O
Yield: 58.8 %

Procedure:
Dimethylamine (0.18 g, 4.0 mmol) was added to ethyl trans-7-chloro-5-(1-naphthyl)-1-(2-formyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1 -benzoxazepine-3-acetate (2.0 g, 4.05 mmol) in titanium tetraisopropoxide (3.45 g, 12.15 mmol) at room temperature. Stirring for 1h was followed by addition of sodium cyanoborohydride (0.38 g, 6.0 mmol) and ethanol (20 ml). The mixture was stirred for another 18 hours before 2 N sodium hydroxide was added. The mixture was extracted several times with dichloromethane, and the combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (dichloromethane/ methanol/aqueous ammonia 99:1:0.1 to 98:2:0.2) to give the title compound (1.23 g, 58%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][C:18]#[CH:19])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:43])[CH2:23][CH:24]1[CH2:33][C:32]2[C:27](=[CH:28][C:29](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42].CCOC(C)=O.CCCCCC>CN1CCCC1.[Cu]I>[CH3:20][O:21][C:22](=[O:43])[CH2:23][CH:24]1[CH2:33][C:32]2[C:27](=[CH:28][C:29]([C:19]#[C:18][CH2:17][CH2:16][N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42]
Reactant: COC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2NC1=O
Reactant: C#CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CN1CCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CC1Cc2ccc(C#CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2NC1=O
Temperature: 60 °C
Reaction time: 22 h
Yield: 61.8 %

Procedure:
A suspension of N-but-3-ynyl-imidodicarbonic acid di-tert-butyl ester (4.65 g, 17.3 mmol), [2-oxo-7-(trifluoro-methanesulfonyloxy)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester (6.36 g, 17.3 mmol), tetrakis (triphenylphosphine)palladium (2.0 g, 1.7 mmol) and copper (I) iodide (0.49 g, 2.6 mmol) in N-methylpyrrolidine (50 mL; purged with N2) was heated to 60° C. The resulting solution was treated with the original amounts of both catalysts, two additional times, at 1.5 h intervals. After 22 h, the reaction mixture was filtered and concentrated. The resulting dark oil was treated with saturated aqueous NH4Cl (250 mL), extracted with chloroform (3×250 mL), dried (MgSO4) and concentrated to give a dark mixture of oil and foam (16.2 g). Flash chromatography (260 g silica; 5%, then 10%, then 20%, then 40% EtOAc-hexane) gave the title compound (5.2 g, 62% yield) as an impure yellow foam.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH3:21][O:22][C:23]([O:31][Si](C)(C)C)=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([CH:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]([O:22][CH3:21])=[O:31])=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: COC(=Cc1ccccc1)O[Si](C)(C)C
Reactant: CC(=O)OC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methyl acetate (245 mg, 0.8 mmol) and (1-methoxy-2-phenylvinyloxy)trimethylsilane (1.78 g, 8.0 mmol, prepared using General Silyl Ketene Acetal Method A) in 20 mL of dry DCM was added TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) and then stirred 3 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. MPLC purification using a 0-40% EtOAc/hexane gradient gave 170 mg (60% yield) of methyl 3-(1H-indazol-5-yl)-2,3-diphenylpropanoate. MS found: (M+H)+=357.
Reaction SMILES: CO[C:3](=[O:24])[CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:16]=[N:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]=2[CH:11]=[N:12][CH:13]=1)=[O:7].O.[NH2:26][NH2:27].O>CCO>[NH:26]([C:3]([CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:16]=[N:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:10]=2[CH:11]=[N:12][CH:13]=1)=[O:7])=[O:24])[NH2:27]
Reactant: COC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of {[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-acetic acid methyl ester (0.50 g, 1.5 mmol) in EtOH (6 mL) was added hydrazine hydrate (2 mL) and the mixture was warmed at 60° C. After 18 hours, the mixture was cooled to room temperature and poured into water (100 mL). The solid was collected by filtration to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid hydrazinocarbonylmethyl-amide (purity 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:18][CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)[C:3]=1[F:19].O.[NH2:21][NH2:22]>O1CCOCC1>[F:19][C:3]1[C:4]([N:9]2[CH2:18][CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[N:5][C:6]([CH3:8])=[N:7][C:2]=1[NH:21][NH2:22]
Reactant: Cc1nc(Cl)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NN)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (9aS)-8-(6-chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (assumed 31.03 g, 108.2 mmol) in dioxane (430 mL) was added hydrazine monohydrate (31 mL). The mixture was heated and stirred at 80° C. overnight, and then at 85° C. for 7 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (500 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and dried under high vacuum overnight to provide (9aS)-8-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (27.98 g, 92% yield for 2 steps) as a light yellow solid. LCMS: (M+H)+: 283.3.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:11][F:12])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.C([O-])(=O)C.[Na+].BrBr.[F:21][C:22]1[N:27]=[C:26]([OH:28])[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)(=O)C.C(#N)C>[CH3:1][C:2]([CH3:13])([CH2:11][F:12])[C:3](=[O:10])[CH:4]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[N:27]=1)[N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Reactant: Oc1cccc(F)n1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(CF)C(=O)C(Oc1cccc(F)n1)n1cncn1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
18.5 g (0.1 mole) of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one were dissolved in 150 ml of glacial acetic acid, and, after adding 8.2 g (0.1 mole) of sodium acetate, 16 g (0.1 mole) of bromine were added dropwise at 45° C., until the mixture was completely decolorized. The mixture was then poured into ice-water and extracted with chloroform. The combined chloroform extracts were washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The oily 1-bromo-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one which remained was dissolved in 50 ml of acetonitrile, and 11.3 g (0.1 mole) of 6-fluoro-2-hydroxy-pyridine and 10.5 g (0.1 mole) of triethylamine, both dissolved in 120 ml of acetonitrile, were added, while stirring. The mixture was stirred under reflux for 1 hour. It was then concentrated by distilling off the solvent in vacuo, and the residue was stirred with water. The crystalline precipitate formed was filtered off and recrystallized from cyclohexane. 20 g (68% of theory) of 3,3-dimethyl-4-fluoro-1-(6-fluoro-pyridin-2-yl-oxy)-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 116° C. were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:23])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:24]=[O:25])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:32].[Na+].P([O-])(O)(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:21][OH:22])[CH2:18][CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[C:9]([F:23])[CH:8]=[C:7]2[C:3]=1[C:4]([C:24]([OH:32])=[O:25])=[CH:5][NH:6]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(CO)CCC4)cc3)c(F)c12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4(CO)CCC4)cc3)c(F)c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
To a solution of 4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde (34 mg, 0.10 mmol) in acetonitrile (5 mL) and tert butanol (5 mL) was added 2-methyl-2-butene (700 g, 10.0 mmol). The mixture was cooled to 0° C. with ice bath. The sodium chlorite (273 mg, 3.00 mmol) and sodium dihydrogenphosphate (360 mg, 3.00 mmol) were dissolved in water (5 mL). The aqueous was added to the organic solution and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 48 hours. TLC (petroleum ether/ethyl acetate=1:1) showed the reaction was complete. A solution of sodium sulfite was added slowly to the stirring mixture. The reaction mixture was allowed to stir 1 hour. Then the organics were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. The residue was purified by preparative reverse phase HPLC to give the title compound (15 mg, 42%) as a white solid. MS (ES+) 380.0 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.41 (d, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 3.76 (s, 2H), 2.36 (m, 4H), 2.13 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.Cl.[O:16]=[C:17]1[N:21]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:20][C:19]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:18]1.CCN(C(C)C)C(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[CH3:10][C:8]1[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]([CH2:4][N:34]2[CH2:35][CH2:36][C:19]3([O:18][C:17](=[O:16])[N:21]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=4)[CH2:20]3)[CH2:32][CH2:33]2)=[C:2]([Br:1])[CH:9]=1
Reactant: Cc1cc(Br)c(C=O)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(C(F)(F)F)c(C)cc4Br)CC3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 2-bromo-4-methyl-5-trifluoromethylbenzaldehyde (100 mg, 0.374 mmol) in DMF (3 mL) was added methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate (122 mg, 0.374 mmol) (from Example 1-1, Step 2) and DIPEA (0.326 mL, 1.87 mmol). The mixture was stirred at room temperature for 15 minutes and then acetic acid (0.107 mL, 1.87 mmol) and sodium triacetoxyborohydride (120 mg, 0.562 mmol) were added. The reaction was stirred at room temperature and was followed by LC/MS until complete. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were combined and dried over sodium sulfate and evaporated. The residue was purified on silica gel (CombiFlash 4 gm pre-packed column) eluting with a 10-30% ethyl acetate/hexanes gradient to afford the title intermediate (130 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[O:8][C:4]=2[CH:3]=1.Cl.Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:9]([C:7]1[O:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:13]=[CH:12][C:5]=3[CH:6]=1)=[O:11])[CH2:18]2
Reactant: O=C(O)c1cc2ccc(Br)cc2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reaction time: 0.33 h

Procedure:
3.8 g (15.77 mmol) of 6-bromobenzofuran-2-carboxylic acid (Example 1A), 3.14 g (15.77 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 7.19 g (18.92 mmol) of HATU, 7.34 g (56.76 mmol) of N,N-diisopropylethylamine and 50 ml of DMF are reacted by general method C. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed successively with methanol, dichloromethane and again with methanol. The product is eluted with methanol/triethylamine 90:10. The solvent is removed in a rotary evaporator under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 5.14 g (85% of theory) of the title compound are isolated. For analysis, a small amount is converted into the hydrochloride with 4 N hydrogen chloride in dioxane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:31])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][C:20]([F:30])=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([OH:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:31])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][C:20]([F:30])=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:35]3[CH:36]=[C:37]([OH:39])[CH:38]=[C:33]([F:32])[CH:34]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccc(F)cc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(c1oc(=O)c2ccc(F)cc2c1-c1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 120 °C
Yield: 35.2 %

Procedure:
In a sealed vial, a mixture of 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-4-phenyl-1H-isochromen-1-one (intermediate D32, 0.240 g, 0.455 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (0.156 g, 1 mmol) and K2CO3 (0.138 g, 1 mmol) in dioxane/H2O 4:1 (10 ml) was degassed; Pd(dppf)Cl2 (0.04 g, 0.054 mmol) was added and the reaction was heated at 120° C. for 4 hrs. 1M HCl was added (pH≈1) and the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed and the crude was purified by flash chromatography on Biotage silica gel cartridge (cyclohexane:EtOAc=95:5 to =20:80) and then triturated with ACN to yield title compound as a white solid (0.08 g, 0.16 mmol).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([F:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCl)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Chloroacetyl chloride (0.60 ml, 7.54 mmol) was dissolved in toluene (6 ml), and the solution was added with 4-fluoroaniline (0.72 ml, 7.52 mmol) at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure to obtain the title compound as pale yellow solid (1.07 g, yield: 76%).