Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[O:1][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)nc1
Yield: 72.7 %

Procedure:
Using a method similar to Example 365, step 1, using 4-hydroxy-3-fluoro-benzaldehyde (3.00 g, 21.4 mmol), 6-chloro-nicotinonitrile (2.98 g, 21.5 mmol), and potassium carbonate (7.40 g, 53.5 mmol) in dimethylacetamide (100 mL) after 6 h at 100° C. provides 3.77 g (73%) of the title compound as a yellow solid (silica gel chromatography conditions: 19:1→1:4 hexanes:ethyl acetate): mass spectrum (electrospray): m/z=243.0 (M+1); 1H NMR (CDCl3): 10.00 (d, 1H, J=2.0 Hz), 8.42 (d, 1H, J=1.5 Hz), 8.01 (dd, 1H, J=2.0, 8.3 Hz), 7.80-7.72 (m, 2H), 7.43 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.8 Hz).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32]1[C:41]2[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[S:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: O=Cc1cc2c(cn1)OCCS2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCCS3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (511 mg, 1.369 mmol) (for a preparation see Example 5(j)) in chloroform (20 ml) and methanol (1 ml) at rt under argon was treated with triethylamine (0.572 ml, 4.11 mmol) and stirred at rt for 0.25 h. The solution was then treated with 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) (248 mg, 1.369 mmol) and stirred for a further 0.5 h. The solution was then treated with NaBH(OAc)3 (870 mg, 4.11 mmol) and stirred at rt for 0.5 h. The reaction was then treated with saturated aqueous NaHCO3 (100 ml) and extracted with 20% methanol/DCM (3×200 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (499 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[N:4][O:5][C:6]=1[CH3:7].[C:17]([O:25][CH3:26])(=[O:24])[CH:18]([CH2:20][CH:21]([CH3:23])[CH3:22])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.CN(C=O)C>[Br:1][C:2]1[C:3]([N:8]([C:9]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:16])[C@H:18]([C:17]([O:25][CH3:26])=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COC(=O)C(O)CC(C)C
Reactant: Cc1onc(NC(=O)OCC(Cl)(Cl)Cl)c1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1noc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry degassed DMF solution (50 mL) of 2,2,2-trichloroethyl 4-bromo-5-methylisoxazol-3-ylcarbamate (2.67 g, 7.58 mmol), DL methyl leucate (2.31 g, 15.8 mmol), and triphenyl phosphine (4.11 g, 15.7 mmol) was added diisopropyl azodicarboxylate (3.1 ml, 15.7 mmol) at 0° C. over 2 hours. The reaction was allowed to warm to room temperature while stirring overnight. Water was added and the product was extracted with ether (2×) then ethyl acetate (2×), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford methyl N-(4-bromo-5-methylisoxazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].NC1C=CC=CN=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1O
Agent: Nc1ccccn1
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
2-Methoxyphenol (5.0 g), 2-aminopyridine (0.3 g), and thionyl chloride (3.24 mL) were stirred at 70° C. in toluene (100 mL) for 19 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure to obtain the title compound as an oil (6.6 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[C:30]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[CH:41][S:40][C:39]=12)(=[O:34])[CH:31]([CH3:33])[CH3:32].C(OCC)(=O)C>C1COCC1>[C:30]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])[S:40][C:39]=12)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)C(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C(C)C)c2s1
Reaction time: 1 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (12 ml) was added to 60 ml of THF. Tri-n-butylstannyl chloride (2.36 ml) and a solution of 1.18 g of 7-isobutyrylimidazo[5,1-b]thiazole in 1.18 ml of THF were added dropwise thereto in an argon atmosphere at −68° C. The mixture was stirred at the same temperature for one hr. Ethyl acetate (450 ml) was added to the reaction solution, and the mixture was washed with 200 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2) to give 1.55 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19](=[O:20])[NH:18][C:13]2=[N:14][CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[OH:21].[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19](=[O:20])[NH:18][C:13]2=[N:14][CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[O:21][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22]
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1c(F)ccc(F)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-chloro-3,6-difluoro-phenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.20 g) (Example 1.2), trimethylacetyl chloride (0.08 ml), and pyridine (0.05 ml) in dichloromethane (5 ml) was stirred at ambient temperature for two hours. The reaction mixture was diluted with ethyl acetate and water. The phases were separated. The organic phase was dried over magnesium sulfate and concentrated to produce a yellow semi-crystalline oil. This was triturated in iso-hexane to produce 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester as a pale brown powder (0.113 g). 1H-NMR (400 MHz, CDCl3): 1.21 (s, 9H), 7.08-7.13 (m, 1H), 7.21-7.27 (m, 1H), 8.55-8.57 (m, 2H), 9.51 (s, 1H) ppm.
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4])[NH2:2].C(O)C.[S:21]=[C:22]=S.[OH-].[K+]>C(OCC)C.O>[S:21]=[C:22]1[O:4][C:3]([C@@H:5]2[CH2:9][CH2:8][CH2:7][C@@H:6]2[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[N:1][NH:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)NN
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1n[nH]c(=S)o1
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl [(1S,2R)-2-(hydrazinocarbonyl)cyclopentyl]carbamate (370 mg) and ethanol (5.6 ml) was ice-cooled, and dithioxomethane (230 μl) and potassium hydroxide (120 mg) were added thereto in this order, followed by stirring at the same temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, warmed, and heated for 6 hours under reflux. The reaction mixture was left to be cooled, and water (50 ml) and diethyl ether (50 ml) were added thereto, followed by liquid separation. The aqueous layer was ice-cooled, and 1 M hydrochloric acid was added thereto to adjust the pH to about 4, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with diisopropyl ether (5 ml) to obtain tert-butyl [(1S,2R)-2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclopentyl]carbamate (308 mg) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Cl:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:3])=[O:5])[N:7]2[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2ccc(Cl)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 334.0 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:22]1[CH:34]=[CH:33][C:32]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)[CH:18]=[CH:17]3.CN(C=O)C.[Br:43]N1C(=O)CCC1=O>O>[Br:43][C:15]1[C:4]2[CH:5]=[C:6]3[C:14]([C:2]([CH3:37])([CH3:1])[C:3]=2[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]([C:22]1[CH:34]=[CH:33][C:32]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([CH3:36])([CH3:35])[C:24]=4[CH:23]=1)[CH:20]=2)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7]3
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccc5c(c4)C(C)(C)c4ccccc4-5)C=C32)C=C2N=c3ccccc3=C21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc4c(c3)C(C)(C)c3ccccc3-4)C=C12
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
The resulting 12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (7.0 g) and DMF (140 ml) were added to a reaction vessel. The mixture was heated up to 100° C., dissolved, and cooled. N-bromo-succinimide (2.6 g) was added under ice-cooled conditions, and the mixture was stirred for 1 hour at a room temperature. Water (500 ml) was added, and the mixture was subjected to filtration to obtain a pale red powder of 7-bromo-12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (5.7 g; yield 70.3%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:10][CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CSc1nccc(CO)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1nccc(COc2ccc(Cl)cc2)n1
Yield: 93.6 %

Procedure:
To a solution of (2-(methylthio)pyrimidin-4-yl)methanol (US 2005/0148610) (0.515 g, 3.30 mmol), 4-chlorophenol (0.466 g, 3.63 mmol), and triphenylphosphine (1.297 g, 4.95 mmol) in THF (10 mL) was added a solution of 1,1′-(azodicarbonyl)dipiperidine (1.248 g, 4.95 mmol) in THF (10 mL) dropwise. After stirring the reaction at RT overnight, the solids were filtered. The filtrate was diluted with EtOAc (30 mL), washed with water (20 mL) and by brine. The organic phase was dried (Na2SO4) and concentrated to afford the crude product. The crude product was purified using flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford the desired product 4-((4-chlorophenoxy)methyl)-2-(methylthio)pyrimidine 6A (0.825 g, 3.09 mmol, 94% yield) as a light yellow solid. 1H NMR (400 MHz, Chloroform-D) δ 8.45 (1H, d, J=5.02 Hz), 7.18 (2H, d, J=8.78 Hz), 7.07-7.13 (1H, m), 6.80 (2H, d, J=8.78 Hz), 4.99 (2H, s), 2.51 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([NH:12]C(=O)C)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>Cl>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2](=[O:1])[CH2:3][CH2:4][CH2:5]2
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cccc2c1C(=O)CCC2
Temperature: 25 °C
Yield: 55.6 %

Procedure:
The amide (Intermediate J2, 4.12 g, 20.3 mmol) was heated at 90 EC in 6N HCl (140 mL) for 3 h. The mixture was cooled to rt and Na2CO3 was added in small portions followed by addition of 2N NaOH until the mixture was at pH 8. The aqueous layer was extracted with EtOAc and the organic fractions were combined, washed with brine, dried, filtered and concentrated to give 8-amino-3,4-dihydro-2H-naphthalen-1-one (Intermediate J3) as a dark red solid 1.82 g (56%).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1.O>C(O)CCC>[N:23]1[CH:3]=[C:2]([CH2:5][C:6]2[CH:16]=[CH:15][C:9]3[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=3[CH:7]=2)[N:18]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:17]2
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: Nc1cccnn1
Solvent: CCCCO
Solvent: O
Product: CSc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (500 mg, 1.8 mmol) from Step 4 of Example 117 and pyridazin-3-amine (350 mg, 3.6 mmol) in 1-butanol (20 mL) was heated at reflux for 15 h. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL×3) and the combined organic layers were washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 5% MeOH in DCM to afford 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (460 mg, 80%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 8.32 (dd, J=4.5, 1.5 Hz, 1H), 7.94 (dd, J=9.3, 1.5 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (m, 1H), 4.45 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=[O:4].[N-:14]=[N+:15]=[N-:16].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[N:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=[O:4])=[N+:15]=[N-:16]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: [N-]=[N+]=NCC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
2-Bromo-2′-nitroacetophenone (2.69 g, 11.0 mmol) in acetonitrile (20 mL) was cooled to 0° C. under nitrogen and treated with tetrabutylammonium azide (3.29 g, 11.6 mmol, TCI America, Portland, Oreg.) in acetonitrile (20 mL) dropwise. After stirring at room temperature for 30 minutes, the solution was poured into ice water (100 mL) and extracted with diethyl ether (3×30 mL). The extracts were combined, dried over magnesium sulfate, and the volatiles were removed by evaporation under reduced pressure to yield 2.19 g of 2-azido-2′-nitroacetophenone.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]([C:24]3[O:25][C:26](=[O:40])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[C:6]=12.O=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1>>[CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]([C:24]3[O:25][C:26](=[O:40])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][N:37]([CH:42]5[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45]5)[CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[C:6]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: O=CO
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 19.2 %

Procedure:
Compound was prepared following the procedure described for the synthesis of Intermediate D24, from 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (300 mg, 0.551 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (236 mg, 1.379 mmol), to afford tert-butyl 3-(4-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridin-1(2 H)-yl)azetidine-1-carboxylate formate (74.4 mg, 0.106 mmol, 19.30% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:17])[CH2:12][O:13]C(=O)C)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1C=CC=CC=1.C=O.C(C1C=CC([C@@H](C)CO)=CC=1)(C)C>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:17])[CH2:12][OH:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@@H](C)c1ccc(CC(C)C)cc1
Agent: C=O
Agent: CC(C)c1ccc([C@@H](C)CO)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)Cc1ccc(C(C)CO)cc1

Procedure:
The following are obtained: 590 mg of (S)-2-(4- isobutyl-phenyl)-1-acetoxy-propane, as a colorless oil with [α]D20 -7.0° (C=1, benzene), ee 98%, H-NMR (90 MHz in COCl3) (ppm): 0.9 (6H, d, CHHD 3CHCHHD 3; 1.3 (3H, d, CHHD 3CH); 1.5-2.0 (1H, m, CH3CHH3); 2.1 (3H, s, COCH3 ; 2.4 (2H, d, C6H4CHHD 2); 3.1-2.7 (1H, m, C6H4CHHD 2); 4.1 (2H, d, CH2O); 7.0 (4H, s, aromatics); and 490 mg of (R)-2-(4-isopropyl-phenyl)-propan-1-ol as a colorless oil with [α]D20 +12.8° (C=1, CHCl3), ee 97%, H-NMR (90 MHz in COCl3)δ(ppm): 0.9 (6H, d, CHHD 3CHCHHD 3); 1.3 (3H, d, CHHD 3CH), 1.7-2.2 (1H, m. CH3CHH3); 2.5 (2H, d, C6H4CH2); 2.7-3.2 (1H, m, C6H4CH); 3.7 (2H, d, CH2O); 7.0 (4H, s, C6H4).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([OH:14])[CH:6]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[CH:6]=1)[CH3:2]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(OCC)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.5 g (2.38 mmol) of 4-Ethoxy-3-hydroxy-benzoic acid ethyl ester was dissolved in 10 ml of anhydrous tetrahydrofuran. To this solution was added 0.5 g (2.62 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 2.38 g (equivalent to 7.13 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.24 g (7.13 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([CH2:12][O:13][CH3:14])[NH:11][C:7]=2[C:6]([C:15]([O:17]C)=[O:16])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([CH2:12][O:13][CH3:14])[NH:11][C:7]=2[C:6]([C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1
Reactant: COCc1nc2c(OC)ccc(C(=O)OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1nc2c(OC)ccc(C(=O)O)c2[nH]1
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
A solution of methyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [12.12 g, Reference Example 3(a)] in methanol (100 ml) was treated with 2M sodium hydroxide (48 ml). The resulting mixture was heated to 50° C. then stirred at this temperature for 6 hours. The reaction mixture was concentrated to half its original volume then treated with 1M hydrochloric acid (98 ml). The solution was cooled in an icebath and the resulting solid filtered then dried under high vacuum overnight to give the title compound (11.0 g) as a solid. M+236. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15].[NH2:19][C:20]([CH:24]([F:26])[F:25])=[CH:21][C:22]#[N:23]>>[F:25][CH:24]([F:26])[C:20]1[NH:19][C:16]([CH3:17])=[C:13]([C:14]#[N:15])[CH:12]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[C:6]3[CH3:11])[C:21]=1[C:22]#[N:23]
Reactant: N#CC=C(N)C(F)F
Reactant: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F
Product: CC1=C(C#N)C(c2cc3c(C)n[nH]c3cc2F)C(C#N)=C(C(F)F)N1

Procedure:
Following the procedure described for Example 1, 100 mg (0.411 mmol) (2E)-2-[(6-fluoro-3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 4A) were treated with 3-amino-4,4-difluorobut-2-enenitrile. The crude product was purified by preparative RP-HPLC (aceto-nitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 50 mg (35% of th.) of the racemic title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.CI.[C:20]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reaction time: 65 h
Yield: 82.5 %

Procedure:
A mixture of 2-chloro-6-((R)-3-methylmorpholin-4-yl)-9H-purine (635 mg, 2.50 mmol), methyl iodide (187 μL, 3.00 mmol) and K2CO3 (484 mg, 3.50 mmol) in THF (15 mL) were stirred at r.t. for 18 h before further methyl iodide (187 μL, 3.00 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (552 mg, 83%). LCMS (method H): RT 2.76 min [M+H]+ 268.3