Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: Cc1ccc(B(O)O)cc1
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: [K+]
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(O)ccc2O3)cc1

Procedure:
A vial was charged (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (282 mg, 0.809 mmol), p-tolylboronic acid (220 mg, 1.618 mmol), potassium carbonate (559 mg, 4.04 mmol), tetrakis(triphenylphosphine)palladium (46.7 mg, 0.040 mmol). The vial was flushed with Ar (g), then Dioxane (4044 μL) and water (2 mL) were added in sequence. The vial was sealed and placed in an 80° C. oil bath for 1 hour. The mixture was partitioned between brine and 10% iPrOH/EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chomatographed on an 80-g Redi-Sep column, eluting with 0-80% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]2)[C:5]([F:15])=[C:4](Cl)[N:3]=1.O.[NH2:18][NH2:19]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]2)[C:5]([F:15])=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: CC1(O)CCN(c2nc(Cl)nc(Cl)c2F)C1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: CC1(O)CCN(c2nc(Cl)nc(NN)c2F)C1
Yield: 21.7 %

Procedure:
1-(2,6-Dichloro-5-fluoro-4-pyrimidinyl)-3-methyl-3-pyrrolidinol (0.486 g, 1.83 mmol) and hydrazine monohydrate (0.53 mL, 10.96 mmol) in DMSO (5 mL) were heated at 50° C. until the reaction was deemed complete. Purification by RP-HPLC provided 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-3-methyl-3-pyrrolidinol as a brown solid (0.104 g, 21%). LCMS: (M+H)+=262.1.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].ClC([O:25][C:26]1C=CC(Cl)=CC=1)=O.[CH3:33][S:34]([NH:37][NH2:38])(=[O:36])=[O:35].CCN(C(C)C)C(C)C>O1CCOCC1>[O:25]=[C:26]1[N:38]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])[C:3](=[O:21])[C:4]2[C:5](=[CH:6][C:7]([C:16]([F:17])([F:18])[F:19])=[C:8]([C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]=3)[CH:9]=2)[NH:20]1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2cnccn2)c(C(F)(F)F)cc1N
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3cnccn3)cc2c1=O
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A solution of 2-amino-5-pyrazin-2-yl-4-trifluoromethyl-benzoic acid methyl ester (235 mg, 0.79 mmol) and 4-chlorophenyl chloroformate (133 μL, 0.95 mmol) in dioxane (8 mL) was stirred at 80° C. for 105 min. After cooling to r.t., CH3SO2NHNH2 (130.6 mg, 1.19 mmol) and i-Pr2NEt (276 μL, 1.58 mmol) were added. The mixture was heated to 80° C. for 45 min, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (50 g silica gel, DCM→MeOH in DCM (2% to 5%)) to provide the title compound (241.5 mg, 76%) as a white powder. API-ES: m/z 402 [M+H]+, rt 2.69 min.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH:19]([CH2:20][OH:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl[C:28]([O:30][CH3:31])=[O:29]>C(OCC)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH:19]([CH2:20][OH:21])[CH2:18][N:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2CNCC2CO)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(CO)C(c2ccc(OC)c(OC3CCCC3)c2)C1
Yield: 69.1 %

Procedure:
To a vigorously stirring mixture of 3-(3-cyclopentoxy-4-methoxyphenyl)-4-(hydroxymethyl)pyrrolidine (328 mg, 1.13 mmol) in 4 mL of 1:1 ethyl acetate:sat aq NaHCO3 was added methyl chloroformate (138 mg, 1.47 mmol). When TLC analysis indicated a complete reaction the mixture was diluted with ethyl acetate, and the layers were separated. The organic layer was dried over K2CO3, filtered, and concentrated under reduced pressure to provide 3-(3-cyclopentoxy-4-methoxyphenyl)-4-hydroxymethyl-1-(methoxycarbonyl)pyrrolidine as a colorless viscous oil (273 mg, 69%). Anal. Calcd for C19H27NO5 ·0.5 H2O: C, 63.67; H, 7.87; N, 3.91. Found: C, 63.30; H, 7.75; N, 3.92.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:34])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH3:35][NH2:36]>O1CCOCC1.C(OCC)(=O)C>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([CH3:13])([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH3:12])[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40% Methylamine solution (50 ml) under nitrogen. The resulting suspension was heated in a sealed system at 100° C. for 4 h. After cooling to room temperature, the solution was evaporated to dryness. The crude product was purified by flash chromatography (SiO2, eluent 10% methanol in dichloromethane and 1% triethylamine). Evaporation of the relevant fractions to dryness and trituration of the residue in diethyl ether gave a solid which was filtered off. The filtrate was collected and evaporated. This residue was purified by preparative HPLC (Waters X-Terra column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness. Further purification by preparative HPLC (phenomenex column, aqueous 0.2% ammonia in acetonitrile as eluent) and freeze-drying of the relevant fractions gave a solid. This freeze dried material readily dissolved in ethyl acetate (30 mL) at room temperature and after stirring for 1 h some solid precipitated. The mixture was then heated to at 85° C. for 1 h to effect dissolution and then cooled and stirred at room temperature for 1 week. The solid was filtered off and dried in vacuo at 40° C. to afford the title compound (2.20 g).
Reaction SMILES: CS(O)(=O)=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([C:15]([CH3:19])([CH3:18])[C:16]#N)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[C:20]([O:23][CH2:24][CH2:25]Br)(=[O:22])[CH3:21].Cl>[Zn].C1COCC1>[CH2:24]([O:23][C:20](=[O:22])[CH2:21][C:16](=[O:3])[C:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([Br:6])[CH:8]=1)([CH3:19])[CH3:18])[CH3:25]
Reactant: CS(=O)(=O)O
Reactant: CC(=O)OCCBr
Reactant: COc1ccc(C(C)(C)C#N)cc1Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)(C)c1ccc(OC)c(Br)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To the THF suspension of zinc (5.72 g, 2 eq.), methanesulfonic acid (25.6 μl, 0.01 eq.) was added, and then stirred at 80° C. for 10 min. Then, the THF solution of 2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (10 g, 39.35 mmol) was added, followed by addition of bromoethyl acetate (11.07 ml, 1.6 eq.) over 1 hr. The mixture was further stirred for 30 min. To the reaction solution, 4 M hydrochloric acid was added, and stirred at room temperature overnight. After extraction with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (orange oily substance, 9.74 g, 72%).
Reaction SMILES: NO.[CH:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([Zn][CH2:14][CH3:15])C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CCCCCC.CCOCC.C1(C)C=CC=CC=1>[C:16]([O:10][CH:9]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC[Zn]CC
Reactant: O=CC1CCCCC1
Agent: NO
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC(OC(C)=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a flask containing aminoalcohol A (0.036 g, 0.15 mmol) prepared as in Example 13 was added freshly distilled cyclohexanecarboxaldehyde (0.34 g, 3.0 mmol) and toluene (3.0 mL). The flask was cooled to 0° C. and 1 M diethylzinc in hexane (6.0 mL) was added dropwise. After 3 hours at 0° C., acetic anhydride (1.2 mL, 13 mmol) was added. After 18 hours at 25° C. the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqeous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 90% hexane and 10% ethyl acetate as eluant. The product (+)-1-cyclohexylpropyl acetate (0.54 g, 97%) was isolated as a colorless liquid by distillation at reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][OH:9].[OH-].[Na+].N(C(O[C:18]([CH3:21])([CH3:20])[CH3:19])=O)=[N+]=[N-].C([O-])(=O)C[C:24](CC([O-])=O)(C([O-])=O)[OH:25].[Na+].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][OH:9])[C:24]([C:18]([CH3:19])([CH3:20])[CH3:21])=[O:25]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: OCCCNCCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)N(CCCO)CCCO
Temperature: 25 °C

Procedure:
Dissolve bis(3-hydroxypropyl)amine (1.33 g, 10 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of t-butyl azidoformate (1.58 g, 11 mmol) at 10° C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3X), dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give bis(3-hydroxypropyl)-t-butylcarboxamide. Dissolve 3,5-di-t-butyl-4-hydroxy-N-[(4-methylphenyl)sulfonyl]-aniline (142 mg, 0.43 mmol) in anhydrous tetrahydrofuran (3 mL) and add triphenylphosphine (168 mg, 0.645 mmol). Stir under a nitrogen atmosphere and add bis(3-hydroxypropyl)-t-butylcarboxamide (83.6 mg, 0.215 mmol) followed by diethyl azodicarboxylate (0.083 mL, 0.530 mmol). Stir at room temperature for several hours and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=O)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50](O)=O)[CH:48]2[CH2:53][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50]2[NH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([B:27]4[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]4)=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:48]2[CH2:53][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1

Procedure:
This compound was synthesized using the same procedure as [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester using 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester. LCMS-ESI+: calc'd for C26H36BN3O4: 465.28 (M+); Found: 466.41 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:6]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](C(OC(C)(C)C)=O)[CH:27]=[CH:28][C:21]=34)[CH:18]=[N:19][C:5]=2[NH:4][CH2:3]1>Cl>[NH:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:17]3[N:16]=[C:6]4[N:7]([CH2:8][CH2:9][CH:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[C:2](=[O:1])[CH2:3][NH:4][C:5]4=[N:19][CH:18]=3)=[C:21]2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cnc4c(n3)N(CCC3CCOCC3)C(=O)CN4)ccnc21
Agent: Cl
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Yield: 63 %

Procedure:
7-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(tetrahydro-pyran-4-yl)-ethyl]-3,4-dihydro-1H-pyrazino[2,3-b]pyrazin-2-one. A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris(dibenzylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. Tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (ESI): m/z 379.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH4+:16].[OH-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:16])=[O:8]
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2sc(C(N)=O)c(Cl)c2c1

Procedure:
To a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride (1.52 g, 5.82 mmol) [Connor D. T., et al., J. Med. Chem. 35, 935 (1992)] in 80 mL of toluene at 50° C. is added dropwise 10 mL of aqueous NH4OH. The resulting precipitate is collected by filtration and recrystallized from methanol to provide 3-chloro-5-methoxybenzo[b]thiophene2-carboxamide; mp=220°-222° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH3:13])[C:7]2=[O:14].Cl.[CH3:17][C:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:18]1([CH3:17])[CH2:21][CH2:20][CH2:19]1)[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: CC1(N)CCC1
Reactant: Cn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(NC2(C)CCC2)nc2c(Br)c(F)ccc2c1=O
Yield: 43 %

Procedure:
A solution of 8-bromo-2-chloro-7-fluoro-3-methylquinazolin-4(3H)-one (720, 239 mg, 0.820 mmol), 1-methylcyclobutanamine hydrochloride (Oakwood Products, Inc., West Columbia, S.C., 199 mg, 1.640 mmol), and N-ethyl-N-isopropylpropan-2-amine (314 μL, 1.804 mmol) in DMSO (8.2 mL) was stirred at 80° C. for 1 h. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-40% EtOAc in hexanes to give 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502a, 0.120 g, 0.353 mmol, 43% yield) as a brown amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.74 (s, 3H) 1.89-2.00 (m, 2H) 2.26-2.36 (m, 2H) 2.38-2.49 (m, 2H) 3.46 (s, 3H) 4.72 (br. s., 1H) 6.90 (t, J=8.51 Hz, 1H) 8.06 (dd, J=8.80, 6.06 Hz, 1H). 19F NMR (377 MHz, CDCl3) δ ppm −96.60 (s, 1F). MS (ESI, pos. ion) m/z: 340.0/341.9 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([CH:27]=C)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:29]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([CH:27]=[O:29])=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: C=Cc1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C=O)nn1
Reaction time: 2 h
Yield: 41 %

Procedure:
t-Butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-vinylpyridazin-3-yl)carbamate (3.4 g, 8.84 mmol) was added as a dioxane (100 mL) solution to a mixture of sodium periodate (10.8 g, 50.5 mmol) and 4% osmium tetraoxide solution (6.5 mL) in H2O (30 mL) at 0° C. The reaction was stirred for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with satd. aq. NaHCO3, brine and dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a colorless oil (1.4 g, 41%), (m/z [M+H]=387.2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[N:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[CH2:35]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[CH2:35][N:8]([C:9]1[N:14]=[N:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nn1
Reaction time: 2 h

Procedure:
A mixture of ethyl 6-(tert-butoxycarbonylamino)-3-pyridazine carboxylate (2.4 g), 1-(benzyloxy)-2-bromomethyl-4-bromobenzene (3.2 g) and sodium hydride (0.5 g of a 50% W/W dispersion in oil) in DMF was stirred for 2 hours. The mixture was diluted with diethyl ether and washed with water. The organic solution was dried (MgSO4), filtered and evaporated. Ethyl 6-[N-(2-benzyloxy-5-bromobenzyl)-N-(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylate was isolated by flash chromatography, eluting with 2% ethyl acetate in CH2Cl2. Yield: 1.7 g.
Reaction SMILES: I[C:2]1[CH:7]=[C:6](I)[C:5](I)=[CH:4][C:3]=1I.[CH2:11]([OH:16])[CH2:12][CH2:13][C:14]#[CH:15].[OH2:17]>CN(C=O)C.CCN(CC)CC.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.[Cu]I>[C:2]1([C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16])[CH:7]=[C:6]([C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16])[C:5]([C:7]#[C:2][CH2:3][CH2:4][CH2:5][OH:17])=[CH:4][C:3]=1[C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16]
Reactant: O
Reactant: C#CCCCO
Reactant: Ic1cc(I)c(I)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cc(C#CCCCO)c(C#CCCCO)cc1C#CCCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a degassed solution of 1,2,4,5-tetraiodobenzene (5.81 g, 0.01 mol) in DMF-Et3N (100 mL, 1:1) were added Pd(PPh3)2Cl2 (350 mg. 0.5 mmol), CuI (200 mg, 1.2 mmol), and 4-pentyn-1-ol (4.2 g, 0.05 mol) was added drop-wise. The mixture was stirred under N2 at room temperature for 24 h. The solution was poured into water (400 mL). The mixture was extracted with CH2Cl2 (3×200 mL). The combined organic phases were washed with 5% HCl and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1, v/v) as eluent to afford tetramer (3.34 g, 82%): 1H NMR (300 MHz, CD3Cl+CO3OD δ ppm), 7.30 (s, 2H), 3.72 (t, J=6.3 Hz, 8H), 2.52 (t, J=7.2 Hz, 8H), 1.80 (p, J=6.6 Hz, 8H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Cl)c(C(F)(F)F)c4)ncnc32)CC1

Procedure:
4-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-chloro-5-hydroxybenzotrifluoride (available from Alfa Aesar, Ward Hill, Mass., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.96-2.05 (m, 4H), 2.96-3.04 (m, 2H), 4.08-4.11 (m, 2H), 4.99-5.04 (m, 1H), 7.73-7.76 (m, 1H), 7.86-7.89 (m, 1H), 7.96-7.98 (m, 1H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=498.