Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)#N.CC(O)=[O:26].N1C=CC=CC=1.CN(C=O)C>O.CCOC(C)=O.[Ni]>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[O:26]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C#N)ccc23)cc1
Agent: [Ni]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C=O)ccc23)cc1
Temperature: 55 °C
Yield: 39 %

Procedure:
To a mixture of (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (606 mg, 2 mmol) in HOAc/pyridine/DMF (4 mL/8 mL/6 mL) was added a solution of NaH2PO2 (704 mg, 8 mmol) in H2O (4 mL), followed by Raney-Nickel 2400 (slurry in H2O, 0.4 mL). The resulting mixture was heated for 1 h at 55° C. (oil temp.). After cooling to rt, it was diluted with EtOAc (80 mL) and washed with H2O (30 mL). Aqueous layer was extracted with EtOAc (50 mL). Combined organic layers were washed with 2 N HCl (20 mL), H2O (20 mL) and dried (Na2SO4). Evaporation of solvent gave crude title compound as an orange solid which was triturated with EtOAc (10 mL), followed by suction filtration to give the title compound (240 mg, 39%) as light beige solid. The filtrate was concentrated, triturated with H2O, sonicated and the resulting precipitates were collected by suction filtration and rinsed with H2O, dried to give additional title compound (151 mg, 25%) as orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 10.14 (s, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.88 (d, J=7.6 Hz, 2H), 7.77 (d, J=16.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 3.86 (s, 3H); MS ESI 307.0 [M+H]+, calcd for [C18H14N2O3+H]+ 307.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOCCn1cc(C2=CCN(C(=O)OCC)CC2)c2cccnc21
Solvent: CO
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2cccnc21
Reaction time: 6 h
Yield: 55.2 %

Procedure:
0.19 g of palladium, 10% (dry basis) on activated carbon (50% in water) were added to a solution of 1.46 g (4.25 mmol) of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester in 40 ml methanol and this mixture was hydrogenated at 2 bar for 6 hours. After filtering through celite and removing the solvent under reduced pressure, 0.81 g (55% of yield) of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained. NMR (300 MHz, CDCl3) δ=1.05-1.38 (m, 6H), 1.55-2.12 (m, 5H), 2.90-3.05 (m, 2H), 3.20-3.50 (m, 4H), 3.60-3.65 (m, 2H), 4.03-4.26 (m, 2H), 4.30-4.45 (m, 2H), 6.97-7.26 (m, 2H), 7.90-8.03 (m, 1H), 8.22-8.27 (m, 1H).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:14]#[N:15])=[C:11]([OH:13])[CH:12]=1.[Br:16]Br>CO>[Br:16][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([OH:13])=[C:10]([C:14]#[N:15])[CH:9]=1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(Br)c(Cl)cc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Methanol (100 ml) was added to sodium acetate (1.97 g) and 5-chloro-2-cyanophenol (1.84 g, mp. 155°-157° C.) which was synthesized according to a known method. The mixture was allowed to cool to -78° C., and to the solution was added dropwise a solution of bromine (1.53 g) in methanol (25 ml). After stirring at -78° C. for 30 minutes, the solvent was distilled off under reduced pressure, and ethyl acetate and aqueous potassium bisulfate solution were added to the residue. The ethyl acetate layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane to obtain 4-bromo-5-chloro-2-cyanophenol (0.53 g, mp. 229°-231° C. (dec.)).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:36]=[CH:37][CH:38]=2)[CH2:33]1>CN(C)C=O>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:34]=2[CH2:33][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:41][CH2:40]3)[CH2:43][CH2:44]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 4-morpholinobenzoic acid (0.89 g, 4.3 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) in anhydrous N,N-dimethylformamide (30 mL) was added 1,1'-carbonyldiimidazole (0.73 g, 4.3 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (1.0 g, 4.1 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent gave 1.5 g (85% yield) of the title compound as white crystals: mp 230-231° C.; [α]21D -49° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (10, M+).
Reaction SMILES: [N:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2([F:28])[C:12]([F:14])([F:13])[C:11]([F:16])([F:15])[C:10]2([F:27])[O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]=C=O)=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)=C=O.Cl>C1(C)C=CC=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:10]2([F:27])[C:11]([F:16])([F:15])[C:12]([F:13])([F:14])[C:9]2([F:28])[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[CH:19][CH:20]=1
Reactant: O=C=Nc1ccc(OC2(F)C(F)(F)C(F)(F)C2(F)Oc2ccc(N=C=O)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Nc1ccc(OC2(F)C(F)(F)C(F)(F)C2(F)Oc2ccc(N)cc2)cc1
Temperature: 80 °C
Yield: 92 %

Procedure:
The 1,2-bis(4-isocyanatophenoxy)hexafluorocyclobutane (1.0 g, 2.3 mmol) is dissolved in 5 ml of toluene. Concentrated hydrochloric acid (10 ml) is added, and the mixture is heated to 80° C. for 2.5 hours. The mixture is neutralized and extracted with ether. The ether extracts are concentrated to yield 0.8 g (92% yield) of 1,2-bis(4-aminophenoxy)hexafluorocyclobutane. The product is identified by 19F NMR, 1 H NMR, and IR spectra. IR (cm-1): 3400 (NH2).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:20]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)C1CCCCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C2CCCCCC2)cc1

Procedure:
In analogy to the procedure of Example I, the title compound is prepared from 31.7 g (0.293 mol) of anisole, 47 g (0.352 mol) of aluminium chloride and 49.5 g (0.308 mol) of cycloheptanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=O)[C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23].C([O-])(O)=O.[Na+]>O>[Cl:23][C:10]1[N:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ccc(-c2cnnc(Cl)c2-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (5.1 g, 18.0 mmol) and POCl3 (20 mL) was stirred at 80° C. for 2 h. The reaction mixture was cooled to RT and the POCl3 was removed by rotary evaporator to obtain a gum. This gum was cooled in an ice bath and water (50 mL) was added. The pH of this mixture was adjusted to 6 with aqueous NaHCO3. The resulting mixture was extracted with EtOAc (2×75 mL). The combined organic layers were washed with water (2×50 mL) followed by saturated aqueous NaCl (2×25 mL). The organic layer was dried over MgSO4 and filtered through a silica gel pad (˜20 g). Upon evaporation of the solvents under reduced pressure, the title compound, 3-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazine, (5.1 g, 94%) was obtained as a white solid. HPLC: 2.01 min; MS, M+H=302. 1H NMR (CDCl3, 500 MHz): δ 9.08 (1H, s), 8.56 (2H, d, J=5.0 Hz), 7.21 (2H, d, J=10.0 Hz), 7.09 (2H, d, J=5.0 Hz), 7.01 (2H, J=10.0 Hz).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].C[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:35])([F:34])[F:36])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:43][CH:42]([O:41][CH3:40])[CH2:39]1)=[O:10])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC1CN(C(=O)CCNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), 3-methoxyazetidine, HCl (6.15 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (3 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(3-(3-methoxyazetidin-1-yl)-3-oxopropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (14.1 mg, 0.025 mmol, 49.6% yield): LCMS=572.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, dd, J=8.41, 1.88 Hz), 7.54-7.77 (7 H, m), 5.11 (1 H, d, J=2.01 Hz), 4.06-4.31 (3 H, m), 3.84-3.98 (1 H, m), 3.69-3.83 (1 H, m), 3.43-3.56 (2 H, m), 3.26 (3 H, d, J=2.76 Hz), 2.29-2.44 (2 H, m); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.ClCCl.[Pd+2].[Cl-].[Cl-].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[CH3:25])=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2nncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc23)c(C)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 58.2 %

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.110 g, 326 μmol), 2,4,6-trimethylbenzeneboronic acid (53 mg, 326 μmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(ii) dichloromethane adduct (12mg, 16 μmol) in 5 mL toluene/ethanol (4:1) was treated with 2 M potassium carbonate (488 μl, 977 μmol). The mixture was stirred at 100° C. under nitrogen and followed by MS for about 15 h. (product MS=422 (M+1)). The mixture was concentrated under vacuum and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (80 mg). Found MS (ES+): 422(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[I:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([I:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([I:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(I)cc1
Reactant: C#Cc1ccc(F)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(I)cc2)c2ccc(I)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-iodobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form Z-4-fluorostyryl 4-iodobenzylsulfide. The title compound is obtained following oxidation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.Cl.[C:13](Cl)(Cl)=[O:14]>ClC1C=CC=CC=1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([N:1]=[C:13]=[O:14])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: COc1ccc(N=C=O)cc1OC

Procedure:
A solution of 0.163 m of 4-aminoveratrole in 250 ml of chlorobenzene was treated with excess HCl gas resulting in a heavy precipitate. The mixture was refluxed and treated with a stream of phosgene for 1/2 hr (50 g, 0.49 m). After refluxing an additional 1/2 hr chlorobenzene was evaporated in vacuo. Distillation of the residue afforded 23 g (79%) b.p. 145°-150° C, 17-18 mm.
Reaction SMILES: O1CCOCC1.O.[CH:8]1(B(O)O)[CH2:10][CH2:9]1.Br[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N+:24]([O-:26])=[O:25])[N:17]([CH2:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][CH3:34])[N:29]=2)[N:16]=1>C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>[CH:8]1([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N+:24]([O-:26])=[O:25])[N:17]([CH2:27][C:28]3[CH:32]=[CH:31][N:30]([CH2:33][CH3:34])[N:29]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: OB(O)C1CC1
Reactant: CCn1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCn1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
A 100 mL flask was charged with 1,4-dioxane/H2O (50 mL/10 mL). The flask was cooled to 0° C. under vacuum for 20 minutes. A 250 mL round bottom flask was charged with cyclopropylboronic acid (5.22 g, 60.8 mmol), 3-bromo-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (8.51 g, 24.3 mmol), palladium diacetate (0.218 g, 0.972 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.997 g, 1.94 mmol). The flask was evacuated and back filled with N2 (repeated 3 times). The cold degassed dioxane/H2O mixture was added to the 250 mL flask, which was evacuated and back filled with argon (repeated 5 times). The reaction mixture was heated to 100° C. for 6 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite, and the filter pad was washed with H2O and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give a dark colored residue, which was dissolved in DCM (20 mL) and silica gel (20 g) was added. DCM was removed under reduced pressure. The crude product absorbed by silica gel was loaded onto a short pad of silica gel and eluted with EtOAc/hexanes (1:1). The desired fractions were concentrated under reduced pressure to give the product (7.55 g).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@@H:15]1[C@H:21]([OH:23])[CH3:22].N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:20][C:17]1([CH3:19])[O:16][C@H:15]([C@H:21]([OH:23])[CH3:22])[C@H:14]([CH2:13][O:12][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[O:18]1
Reactant: C[C@@H](O)[C@H]1OC(C)(C)O[C@H]1CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@@H]1[C@@H](C)O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
4.46 mL of triisopropylsilyl chloride was added dropwise to a solution of 3.5 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethan-1-ol and 1.63 g of imidazole in 50 mL of N,N-dimethylformamide in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 23 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 7.1 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethan-1-ol in the form of a colorless oily product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Cl.[Cl:24][C:25]1[N:29]([CH3:30])[C:28]([CH2:31]Cl)=[N:27][CH:26]=1.BrCC1CCCCO1>>[Cl:24][C:25]1[N:29]([CH3:30])[C:28]([CH2:31][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:27][CH:26]=1
Reactant: Cn1c(Cl)cnc1CCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Product: Cn1c(Cl)cnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (94%) as a colorless solid: mp 91-95° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.39 (d, J=7.8 Hz, 1H), 7.27 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.14 (dd, J=7.2, 0.9 Hz, 1H), 7.05 (ddd, J=7.4, 7.4, 0.8 Hz, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.12 (d, J=15.6 Hz, 1H), 4.93 (d, J=15.6 Hz, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.4, 144.8, 141.9, 141.7, 138.5, 131.6, 129.3, 124.8, 124.0, 123.8, 120.7, 119.5, 111.5, 110.7, 99.6, 80.3, 64.6, 64.0, 58.1, 38.2, 31.0; MS (ES+) m/z 426.2 (M+1), 424.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH:15]=[CH2:14])=[CH:7][N:6]=1)=[O:4]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)nc1
Reaction time: 0.5 h

Procedure:
4.7 g of 5-hydroxy-2-pyridinecarboxylic acid methyl ester is added to a stirred suspension of 1.30 g of sodium hydride (57% mineral oil dispersion) in 10 ml of dimethylformamide at room temperature while maintaining a nitrogen atmosphere. The mixture is stirred for 30 minutes and then is added a solution of 3.90 g of allyl bromide in 20 ml of dimethylformamide. The mixture is heated to 100° and maintained at 100° for 5 hours. Then the mixture is cooled, filtered and the filtrate evaporated to a residue. The residue is partitioned between water and methylene chloride, the layers are separated and the water layer is extracted with methylene chloride. The methylene layer is combined with the methylene extract, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated and the residue is distilled to yield 5-allyloxy-2-pyridinecarboxylic acid methyl ester boiling at 124°-130°/0.15 mm/Hg.
Reaction SMILES: Cl.C(Cl)(=O)C.C(OC([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[N:20]([CH3:35])[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C.Cl[C:44]1[N:49]=[CH:48][N:47]=[C:46]2[NH:50][N:51]=[CH:52][C:45]=12>CO.O.CS(C)=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[N:23]=[C:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:44]4[N:49]=[CH:48][N:47]=[C:46]5[NH:50][N:51]=[CH:52][C:45]=45)[CH2:18][CH2:17]3)[N:20]([CH3:35])[CH:21]=2)=[CH:25][C:26]=1[C:31]([F:33])([F:32])[F:34]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Prepare an anhydrous HCl solution by slow addition of acetyl chloride (193.14 mL; 2.71 moles; 4.00 eq) to methanol (1160 mL) over 45 minutes at <5° C. Add the resulting solution to a separate flask containing a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (290 g; 678.46 mmoles) in methanol (2320 mL) over 90 minutes at 20° C. Stir the reaction mixture at 20° C. overnight. Concentrate the reaction mixture under vacuum at 30° C. Add DMSO (1080 mL; 15.20 moles; 1.08 L; 1.19 kg) and the distillation continues until the internal temperature reaches 50° C. at a pressure of 20 mm Hg. Add DMSO until the total volume is 2030 mL. Then add triethylamine (473 mL; 3.39 moles; 5 eq) via addition funnel over 30 minutes. Charge solid 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (110.29 g; 713.58 mmoles; 1.05 eq) in equal portions equally spaced over 30 minutes. Stir the resulting slurry at 20° C. overnight. Heat the slurry to 80° C. Add water (229 mL) to afford a clear solution. Seed the reaction and add more water (1273 mL) slowly over 4 hours to fully crystallize the product. Cool the slurry to 50° C. and filter the solid. Wash the cake with 30% water in DMSO (2×290 mL), then water (290 mL). Dry the solids under vacuum at 60° C. to afford 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (301 g, 99%) as an off white solid.