Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[CH:3]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cn1cncc1C=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: Cn1cncc1/C=N/[S@](=O)C(C)(C)C
Yield: 51.1 %

Procedure:
A solution of 1-methyl-1H-imidazole-5-carbaldehyde (1.46 g, 13.26 mmol), (R)-2-methylpropane-2-sulfinamide (2.893 g, 23.87 mmol), and tetraethoxytitanium (10.89 g, 47.73 mmol) in THF (100 mL) was heated to 65° C. for 12 h. The reaction was cooled and poured onto water. The solids were filtered off, and the filtrate was extracted with EtOAc. The layers were separated, and the organic layer was concentrated. The resulting residue was purified by SiO2 eluting with a DCM/MeOH gradient (1.5 to 2% MeOH) to afford 1.444 g (51.1%) of (R,E)-2-methyl-N-((1-methyl-1H-imidazol-5-yl)methylene)propane-2-sulfinamide (128).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([NH2:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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]>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:29]5[CH:30]=[N:25][CH:26]=[N:27][CH:28]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([NH2:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1cc(-c3cncnc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A mixture of 5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine (0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 558 (65.8 mg, 16.9%). 1H-NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 9.00 (s, 2H), 8.77 (s, 1H), 7.582 (s, 1H), 7.53-7.52 (d, J=2.4 Hz, 1H), 7.50-7.50 (d, J=2.4 Hz, 1H), 5.74-5.68 (m, 1H), 4.57-4.55 (m, 2H), 4.49-4.48 (m, 2H), 4.05 (s, 2H). MS (ESI) m/z 389.18 [M+H+]
Reaction SMILES: [N+]([CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:8][CH:7]=1)([O-])=O.C(O)(=[O:20])C>[Fe]>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:20])[CH3:17])=[CH:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: CC(=O)O
Reactant: CC(Cc1ccc(-n2cccn2)cc1)[N+](=O)[O-]
Agent: [Fe]
Product: CC(=O)Cc1ccc(-n2cccn2)cc1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
A stirred suspension comprising iron (10.7 g, 191.9 mmol) in glacial acetic acid (150 ml) under an inert atmosphere of argon is heated to 40° C. and then treated with a solution of 1-[4-(2-nitro-propyl)-phenyl]-1H-pyrazole (8.8 g, 38.39 mmol) in glacial acetic acid (100 ml). The reaction mixture is heated to 100° C. for 2 hours and then allowed to cool to room temperature. The mixture is poured onto ice-water (200 ml), stirred for 5 minutes and then filtered through celite washing through with DCM (50 ml). The organic portion of the filtrate is separated and the aqueous is extracted with DCM (150 ml). The organic portions are combined, washed with water (3×50 ml), brine (1×25 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a red oil. [MH+ 201.25].
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH2:21][C:22]#[N:23])[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[N:10]=[CH:9][CH:8]=1.Cl>CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH2:21][C:22]([NH2:2])=[NH:23])[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[N:10]=[CH:9][CH:8]=1
Reactant: N#CCc1ccc2c(c1)Nc1nccnc1S2
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: N=C(N)Cc1ccc2c(c1)Nc1nccnc1S2
Yield: 38.6 %

Procedure:
2.68 g of ammonium chloride was added to 20 ml of dry toluene in a nitrogen atmosphere. Then 36.5 ml of a 15% solution of trimethylaluminum in n-hexane was added thereto under stirring and ice-cooling. The reaction mixture was brought back to room temperature and 70 ml of dry toluene was further added. The resulting mixture was subjected to ultrasonication until the ammonium chloride disappeared completely. A 60 ml portion of the solution thus obtained was taken and 1.5 g of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile was added thereto. The obtained mixture was heated under reflux for 18 hours. After bringing back to room temperature, the reaction mixture was distributed into ethyl acetate and dilute hydrochloric acid and repeatedly extracted with water. The aqueous layer was washed with methylene chloride and the solvent contained in the solution was eliminated under reduced pressure. The obtained residue was purified by High-porous gel column chromatography (CHP20, mfd. by Mitsubishi Chemical Industries, Ltd., 75-15μ) (eluted with water/methanol) to thereby give 620 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH:7]=[C:6]1[C:11]([O:13][CH3:14])=[O:12])=[O:4].[BH4-].[Na+]>CO>[CH3:14][O:13][C:11]([CH:6]1[CH2:7][CH:8]([OH:10])[CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)C1=CC(=O)CC1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC(O)CC1C(=O)OC
Yield: 93.1 %

Procedure:
To a cold solution (−30° C.) of compound 26 (3.18 g, 16.1 mmol) dissolved in MeOH (23 mL), NaBH4 (0.66 g, 17.5 mmol) was added. After nine minutes the excess of NaBH4 was destroyed by adding brine (80 mL). The mixture was concentrated and extracted with ethyl acetate (4×80 mL). The organic phases were dried, filtrated and concentrated and gave the title compound (3.0 g, 92%) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.N1CCCCC1>C(O)(=O)C>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[C:11]2[CH2:1][CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccncc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccncc2)CCc2ccccc21

Procedure:
A mixture of 73.0 grams (0.50 moles) of α-tetralone, 64.2 grams (0.60 moles) of 4-pyridinecarboxaldehyde, 10 grams of piperidine and 10 grams of acetic acid are heated at 80° for 19 hours. The resultant solid is crystallized from about 400 ml. of ethanol to give 2-(4-pyridylmethylene)- 1-tetralone; (m.p. 112°-114°C).
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@H:4]([CH2:6][CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[Si:30]([N:5]1[C:2](=[O:1])[CH2:3][C@H:4]1[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H](CC=CC(=O)OCc2ccccc2)N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CC=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a mixture of benzyl 4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate (16 mg) and triethylamine (18 μl) in dimethylformamide (0.5 ml) was added tert-butyl-dimethylchlorosilane (15 mg) at 5° C. The mixture was stirred at the same temperature for one hour and at room temperature for 30 minutes. The resultant mixture was diluted with ethyl acetate (20 ml), washed with chilled dilute hydrochloric acid, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and removal of the solvent left an oil (23 mg), which was chromatographed on a silica gel plate (developing solvent: 5% methanol in dichloromethane) to give benzyl 4-[(2R)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl)but-2-enoate (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[C:15](/[CH3:25])=[CH:16]\[C:17](=[N:22]/[O:23][CH3:24])\[C:18]([O:20]C)=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:25])=[CH:16][C:17](=[N:22][O:23][CH3:24])[C:18]([NH:27][CH3:26])=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: CO/N=C(\C=C(\C)COc1ccn(-c2ccc(Cl)cc2)n1)C(=O)OC
Solvent: C1CCOC1
Product: CNC(=O)C(C=C(C)COc1ccn(-c2ccc(Cl)cc2)n1)=NOC

Procedure:
0.68 g (1.87 mmol) methyl(Z,2E)-5-[1-(4-chlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-4-methyl-pent-3-enoate and E-isomer from the previous reaction have been dissolved in 3.0 ml THF. 2.0 ml 40% aqueous methylamine have been added at ambient temperature with stirring which was continued over night. After removal of the solvent in vacuo the mixture was purified by chromatography on silica with a heptane/ethyl acetate gradient. 90 mg of the desired Z-isomer have been collected. 1H-NMR (CDCl3): δ=2.03 (s); 2.85 (d); 3.97 (s); 4.64 (s); 5.87 (s); 6.02 (d); 6.65 (br); 7.35 (d); 7.50 (d); 7.67 (d).
Reaction SMILES: Cl[C:2]1[NH:16][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:9]=[C:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][C:20]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[O:23]2)[CH2:19][CH2:18]1>CC(N(C)C)=O>[C:10]1([C:8]2[N:9]=[C:4]3[N:3]=[C:2]([N:17]4[CH2:22][CH2:21][C:20]5([C:30]6[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:24](=[O:31])[O:23]5)[CH2:19][CH2:18]4)[NH:16][C:5]3=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Clc1nc2nc(-c3ccccc3)cnc2[nH]1
Solvent: CC(=O)N(C)C
Product: O=C1OC2(CCN(c3nc4nc(-c5ccccc5)cnc4[nH]3)CC2)c2ccccc21

Procedure:
Stir 2-chloro-5-phenyl-1H-imidazo[4,5-b]pyrazine (231 mg, 1 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (406 mg, 2 mmol) in dimethylacetamide (5 mL) at 120° C. for 14 hours. Cool the mixture and partition between EtOAc and half-saturated NaHCO3, wash several times with water, dry and concentrate in vacuo. Purify by chromatography (1:1 hexanes/EtOAc) to obtain 1′-(5-Phenyl-1H-imidazo[4,5-b]pyrazin-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a tan solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1.C(N(CC)CC)C.[CH3:26][C:27]1[O:31][C:30]([C:32](O)=[O:33])=[C:29]([O:35][CH:36]([CH3:38])[CH3:37])[CH:28]=1.C(C1NN=NN=1)(=O)N>C(#N)C>[CH3:26][C:27]1[O:31][C:30]([C:32]([NH:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:33])=[C:29]([O:35][CH:36]([CH3:38])[CH3:37])[CH:28]=1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(OC(C)C)c(C(=O)O)o1
Agent: NC(=O)c1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OC(C)C)c(C(=O)Nc2nnn[nH]2)o1

Procedure:
Following the procedure described in Example 120, 0.60 g (3.7 mmol, 1.1 equiv) of 1,1'-carbonyl diimidazole, 0.33 g (3.9 mmol, 1.2 equiv) of 5-aminotetrazole and 0.80 g (7.9 mmol, 2.4 equiv) of triethylamine in refluxing (16 hours) acetonitrile (15 mL) are used to convert 0.61 g (3.3 mmol) of the carboxylic acid described above to 0.45 g of the carbamoyltetrazole as a tan solid. Recrystallization gave 0.35 g (1.26 g theo., 28% overall) of analytically pure 5-methyl-3-isopropoxy-N-1H-tetrazol-5-yl-2-furancarboxamide as a tan, crystalline solid; mp 240°-242° C. (dec).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13]Cl>>[C:1]([N:3]=[C:4]1[N:8]([CH2:13][C:12]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:10]([Cl:9])[CH:11]=2)[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: N#CN=C1NCCS1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: N#CN=C1SCCN1Cc1ccc(Cl)c(Cl)c1
Yield: 79.2 %

Procedure:
3.82 g (30 mmoles) of 2-cyanimino-thiazolidine are reacted with 6 g (31 mmoles) of 3,4-dichlorobenzyl chloride as described in the previous Example, and the evaporation residue is recrystallized from 50 ml of ethanol to yield 6.8 g of 2-cyanimino-3-(3,4-dichlorobenzyl)-thiazolidine, melting at 130° to 132° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]2[CH:5](C3CC2C=C3)[C:4](=[O:12])/[C:3]/1=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(=O)OC(=O)C=C1.C[Al](Cl)Cl.CCCCCC>ClCCl>[CH3:1][CH:2]1[CH:10]=[CH:5][C:4](=[O:12])/[C:3]/1=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1/C(=C\c2ccccc2)C(=O)C2C3C=CC(C3)C12
Agent: C[Al](Cl)Cl
Agent: O=C1C=CC(=O)O1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1C=CC(=O)/C1=C/c1ccccc1
Yield: 74.9 %

Procedure:
Under nitrogen, a solution of 3-methyl-2-[1-phenyl-meth-(E)-ylidene]-2,3,3a,4,7,7a-hexahydro-4,7-methano-inden-1-one (5) (250 mg, 1 mmol., 1 eq.) and maleic anhydride (490 mg, 5 mol., 5 eq.) in dichloromethane (10 cm3) was treated with a 1.0 M solution of MeAlCl2 in hexane (1.1 cm3, 1.1 mmol., 1.1 eq.). This mixture was heated to reflux for 5 hours. Silica (ca. 2.5 g) was added and the solvent was removed under reduced pressure. Flash column chromatography (Hex-EtOAc; 3:1) gave 4-methyl-5-[1-phenyl-meth-(E)-ylidene]-cyclopent-2-enone (6) (compound CTC-150) (138 mg, 75%) as a colourless solid. Rf=0.5 (Hex-EtOAc; 3:1); δH (400 MHz, CDCl3) 1.22 (3H, d, J 7.0 Hz, CH3), 3.84-4.00 (1H, m, CH), 6.40 (1H, dd, J 1.75, 5.75 Hz, CH), 7.39-7.44 (4H, ArH), 7.54 (2H, d, J 7.0 Hz, AH, 7.60 (1H, ddd, J 1.0, 2.5, 5.75 Hz, CH); δC (100 MHz, CDCl3) 16.3, 38.8, 128.7, 129.3, 130.6, 131.7, 133.6, 134.8, 138.3, 163.9, 197.4; Found C, 84.66; H, 6.60%, C13H12O requires C, 84.78; H, 6.57%.
Reaction SMILES: [C:1](=[O:18])([O:15][CH2:16]Cl)[O:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4].[I-:19].[Na+]>C(#N)C>[C:1](=[O:18])([O:15][CH2:16][I:19])[O:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4]
Reactant: [I-]
Reactant: C[C@H](OC(=O)OCCl)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](OC(=O)OCI)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
[(1S)-1-(benzyloxycarbonyl)ethyl] chloromethyl carbonate (2.7 g) was dissolved in acetonitrile (4 ml) and sodium iodide (6.0 g) was added. The mixture was stirred at 60° C. for 2 hours under an argon atmosphere. After the reaction mixture was concentrated under reduced pressure, diethyl ether (100 ml) and water (100 ml) were added to the residue. The diethyl ether layer was separated and washed with an aqueous 5% sodium thiosulfate solution (80 ml), water (80 ml), and a saturated sodium chloride aqueous solution (80 ml) successively. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [(1S)-1-(benzyloxycarbonyl)ethyl] iodomethyl carbonate (3.3 g) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(C(=O)O)c1N
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 2-amino-3-methoxy benzoic acid (2.0 g, 11.90 mmol) in THF (30 mL) was added EDCl (2.7 g, 14.3 mmol), HOBt (1.9 g, 14.3 mmol) and NMM (1.6 mL, 14.3 mmol). The reaction was stirred at room temperature for 2 hours and then NH4OH (1 mL) in H2O (1 mL) was added. After stirring overnight, the reaction was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The solids were suspended in Et2O and filtered off to afford 2-amino-3-methoxybenzamide (1.1 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 7.71 (br s, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.08 (br s, 1H), 6.87 (d, J=7.1 Hz, 1H), 6.45-6.53 (m, 1H), 6.26 (br s, 2H), 3.78 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][C:10](=[O:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7]2)[CH2:3][CH2:2]1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)#[N:19]>C1COCC1>[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:1]2[CH2:6][CH2:5][C:4]3([CH2:12][CH2:11][C:10](=[O:13])[C:9]4[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=4[NH:7]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: O=C1CCC2(CCNCC2)Nc2ccccc21
Reactant: N#Cc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CN2CCC3(CCC(=O)c4ccccc4N3)CC2)cc1
Reaction time: 12 h
Yield: 63.6 %

Procedure:
A solution of diamine 11 (5 mg, 0.022 mmol) in anhydrous THF and 4-cyanobenzyl bromide (5 mg, 0.026 mmol) was agitated at room temperature for 16 h, and piperidinomethyl polystyrene N-2-(mercaptoethyl) aminoethyl polystyrene (26 mg, 0.033 mmol) was then added. The reaction was agitated for another 12 h and then filtered. The filtrate was concentrated to yield 24 (5 mg, 0.014 mmol, 66%) as an oil. LRMS: M+345.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[C:27]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)[CH:22]=[CH:23][C:24]=1[Cl:29]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (6.16 g, 22.13 mmol) and 4-Bromo-1,2-dichloro-benzene (2.84 ml, 22.13 mmol) were dissolved in DMF (20 ml) under nitrogen atmosphere. Bis(triphenylphosphine)-palladium(II) chloride (0.777 g, 1.107 mmol) was added along with sodium carbonate (22.13 ml, 44.3 mmol) and the resulting mixture was stirred at 50° C. for 3 h. DMF was evaporated, water was added (15 ml) and extracted with ethyl acetate. Combined organic phases were dried with Na2SO4, filtered and dried with vacuum at 40° C. The product was purified by recrystallization from diethyl ether and diethyl ether/heptane, respectively. 1H-NMR (400 MHz; DMSO-d6): δ 1.50-1.69 (m, 3H), 1.77-1.84 (m, 1H), 1.91-2.00 (m, 1H), 2.31-2.44 (m, 1H), 3.54-3.62 (m, 1H), 3.96-4.02 (m, 1H), 5.23 (dd, 1H), 6.89 (d, 1H), 7.53 (dd, 1H), 7.60 (d, 1H), 7.77-7.82 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O-:3])=[O:2].FC(F)(F)S(O[C:33]1[CH2:37][CH2:36][CH2:35][CH:34]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:6]=2)[CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl (2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (16 g, 43.9 mmol, 1.0 equiv.) in 1,4-dioxane (320 mL) were added cyclopent-1-en-1-yl trifluoromethanesulfonate (11.4 g, 52.7 mmol, 1.2 equiv.), Pd (PPh3)4 (2.54 g, 2.2 mmol, 0.05 equiv.) and a solution of Na2CO3 (5.6 g, 52.7 mmol, 1.2 equiv.) in water (160 mL) at room temperature. The reaction was then heated to 110° C. and stirred for 4 h. The reaction mixture was filtered through celite then concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to give tert-butyl (5-(cyclopent-1-en-1-yl)-2-nitrophenyl)carbamate (4.3 g, 32% yield).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:29])[C:19]([C:27]#[N:28])=[C:20]4[C:26]=3[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.O=[C:31]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:26]4[O:25][CH2:24][CH2:23][N:22]([CH:31]5[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]5)[CH2:21][C:20]=4[C:19]([C:27]#[N:28])=[C:18]([Cl:29])[CH:17]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CN(C(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C
Yield: 35.7 %

Procedure:
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (0.030 g, 0.078 mmol) was dissolved in methanol (3.0 mL), and the tert-butyl 3-oxoazetidine-1-carboxylate (0.027 g, 0.16 mmol) and then sodium cyanoborohydride (0.0098 g, 0.16 mmol) were added. The reaction was heated to 60° C. for 3 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and washed with brine. The organic layer dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The oil was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient at pH 10 to give tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate (0.015 g, 35%). LCMS calculated for C26H32ClN8O3 (M+H)+: m/z=539.2; found: 539.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](OB(O)O)=[CH:26][CH:25]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CC=CC=1.ClCCl>O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:27]2[CH:28]=[CH:29][C:24]([O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])=[CH:25][CH:26]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OB(O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.8 %

Procedure:
A mixture of 4-benzyloxy-1H-pyridin-2-one (200 mg, 0.994 mmol), 4-[tert-butyl(dimethyl)silyloxy]phenyboric acid (752 mg, 2.98 mmols), cupric acetate (270 mg, 1.49 mmols), pyridine (0.08 mL, 1.99 mmols) molecular sieve 4A (220 mg) and dichloromethane (4 mL) was stirred for 3 days at room temperature. Chloroform and water were added to the reaction liquid and the insoluble matter was filtered off. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300, methanol:chloroform=1:100) to provide the title compound (234 mg, 58%).