Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[C:29]3[C:30]([OH:34])=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH:26]=2)=[CH:19][CH:18]=1)#[N:16].Cl>C(OCC)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[C:29]3[C:30]([OH:34])=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH:26]=2)=[CH:21][CH:22]=1)(=[NH:3])[NH2:16]
Reactant: N#Cc1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(CCc2coc3cccc(O)c23)cc1
Reaction time: 0.17 h

Procedure:
A suspension of 3-[2-(4-bromophenyl)ethyl]-4-hydroxybenzofuran (0.5 g), sodium cyanide (0.23 g), tetrakis(triphenylphosphine)palladium (0) (91 mg) and copper (I) iodide (30 mg) in acetonitrile (5 mL) was heated for reflux for three days. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.14 g). To a solution of hexamethyldisilazane (0.35 mL) in diethyl ether (2 mL) was added n-butyl lithium (2.46 mol/L n-hexane solution 0.7 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a solution of the 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.13 g) in diethyl ether (3 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was washed with diethyl ether twice. The aqueous layer was basified by addition of 2 mol/L aqueous sodium hydroxide solution, and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with a mixed solvent of dichlorometane and methanol (5/1) (three times), and the extract was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[2-(4-carbamimidoylphenyl)ethyl]-4-hydroxybenzofuran (0.11 g). This material was dissolved in 1,4-dioxane (5 mL)-1 mol/L aqueous sodium hydroxide solution (5 mL). To the solution was added benzyl chloroformate (0.1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid (5 mL), and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH:24]([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH:24]([CH3:26])[CH3:25])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[F:20]
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C(C)C)c(OC)c1
Yield: 23.1 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 2-iodopropane (0.20 mL, 2.00 mmol) to give the title compound (0.080 g) as a white solid.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Br:19])[CH:32]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1ccccc1-c1cccc(C)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1cccc(CBr)c1

Procedure:
3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 3′-Methyl-biphenyl-2-carboxylic acid ethyl ester (4.3 g, 17.89 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.82 g, 21.47 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.15 g, 0.89 mmol, 5 mol %). When complete, the reaction was worked up as described leaving a tan oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(Cl)c1Cl
Yield: 87.9 %

Procedure:
A solution of 4.0 grams (0.013 mole) of N-(2,3-dichloro-4-methylphenyl)phthalimide, 2.3 grams (0.013 mole) of N-bromosuccinimide and 0.3 gram of benzoyl peroxide in 200 ml of carbon tetrachloride was heated under reflux for 22 hours. The cooled reaction mixture was poured into 500 ml of ethyl acetate. The solution was washed with three 100 ml portions of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using ethyl acetate:heptane (1:4). The appropriate fractions were combined and concentrated under reduced pressure to yield 4.4 grams of N-(4-bromomethyl-2,3-dichlorophenyl)phthalimide as a solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[NH:12][CH2:13][CH:14](OC)OC)=[CH:7][CH:6]=1)(=O)C.[CH3:20][S:21](O)(=[O:23])=[O:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CCOC(C)=O>[CH3:20][S:21]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:19][CH:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:23])=[O:22]
Reactant: COC(CNC(=O)c1ccc(OC(C)=O)cc1)OC
Reactant: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(-c2ncco2)cc1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
In a similar manner as described in Pandit, C. R. et al., “Preparation of 2-Substituted Oxazoles”, Synth. Commun. 32, 2427-2432 (2002), 4-(2,2-dimethoxyethylcarbamoyl)phenyl acetate (43 g, 160.88 mmol) was stirred and treated with Eaton's reagent (380 ml; 7.7 wt. % phosphorus pentoxide in methanesulfonic acid, Aldrich #38,081-4). After 15 minutes, the internal temperature of the reaction was raised to about 130° C. and held for about 3 hours. The reaction was followed by TLC analysis (2:1 EtOAc:Hex) with only a single new UV active spot observed. The reaction mixture was allowed to cool to about 40° C. and was then cooled in an ice bath to about 3° C. The reaction was poured into 2 L of ice water and extracted with ethyl acetate (1.4 L). The organic layer was washed with water (1 L). The combined aqueous layers were extracted with ethyl acetate (2×1 L). The combined organic layers were washed with water (2×) and brine, dried, treated with silica gel and charcoal, and concentrated. The residue was dissolved in methylene chloride and treated with hexane until a precipitate was seen. The mixture was treated with charcoal, filtered, and concentrated to give 53.3 g of 4-(oxazol-2-yl)phenyl methanesulfonate (>100% th.; 90% pract.) which contained 1.2 equivalents of methyl methanesulfonic acid; 1H NMR (CDCl3) δ 8.07 (d, 2H), 7.71 (d, 1H), 7.36 (d, 2H), 7.22 (d, 1H), 3.16 (s, 3H) ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:14]=1[N:28]([C:36]1[CH:41]=[C:40]([N:42]([CH3:64])[C:43]([N:45]([C:52]2[C:57]([Cl:58])=[C:56]([O:59][CH3:60])[CH:55]=[C:54]([O:61][CH3:62])[C:53]=2[Cl:63])C(C(C)(C)C)=O)=[O:44])[N:39]=[CH:38][N:37]=1)C(=O)OC(C)(C)C)(=[O:11])[CH:9]=[CH2:10]>C(Cl)Cl>[Cl:58][C:57]1[C:56]([O:59][CH3:60])=[CH:55][C:54]([O:61][CH3:62])=[C:53]([Cl:63])[C:52]=1[NH:45][C:43](=[O:44])[N:42]([C:40]1[N:39]=[CH:38][N:37]=[C:36]([NH:28][C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[O:20])=[CH:18][C:13]=2[NH:12][C:8](=[O:11])[CH:9]=[CH2:10])[CH:41]=1)[CH3:64]
Reactant: C=CC(=O)Nc1cc(C(=O)N2CCN(C)CC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(C(=O)C(C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cc(C(=O)N2CCN(C)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 153 %

Procedure:
TFA (0.2 mL) was slowly added to a stirred solution of tert-butyl (2-acrylamido-4-(4-methylpiperazine-1-carbonyl)phenyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-3-tert-butylcarbonyl-1-methylureido)pyrimidin-4-yl)carbamate (0.060 g, 0.0711 mmol) in dry DCM (2 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 18 h. Reaction progress was monitored by LCMS, after completion of the reaction, excess solvents were removed under reduced pressure. The resulting residue was diluted with DCM and quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was separated and extracted with DCM (3×10 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to get a crude residue. The residue was purified by silica gel column chromatography to afford 70 mg of desired product with HPLC purity 35% which was then purified by preparative HPLC (Conditions: Column: Gemini NX C18 (21.2 mm×150 mm particle size 5 μm); (Mobile Phase: A; 0.1% Ammonium bicarbonate in Water, B; ACN) to afford the desired compound. The compound was then diluted with dichloromethane and water. The aqueous layer was separated and extracted with DCM (3×10 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (0.005 g, yield: 11%) as a white solid. 1H-NMR (CD3OD, 400 MHz): δ 8.41 (s, 1H), 7.79-7.76 (m, 2H), 7.36 (dd, 1H), 6.82 (s, 1H), 6.47-6.42 (m, 3H), 5.82 (d, 1H), 3.96 (s, 6H), 3.81-3.55 (m, 8H), 2.54 (s, 3H), 2.37 (s, 3H); MS (ESI): 643.1 [M+H]+; HPLC: 97.26%, rt: 6.19 min.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[CH:3][N:4]([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cnnc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnnc1)c1csc(N)n1)C(=O)O
Yield: 9.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((4H-1,2,4-triazol-4-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (77 mg, 0.117 mmol), DCM (3 mL) and TFA (1 mL, 13.0 mmol) for 2 h. The crude residue purified by reverse phase prep HPLC (XBridge, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 ml/min), affording the title compound (5.6 mg, 10%) as a white powder. LCMS: m/z=500.8 (M−1); 1H NMR (400 MHz, D2O): δ 8.52 (s, 2H), 6.90 (s, 1H), 5.30 (d, J=5.6 Hz, 1H), 4.56 (m, 2H), 4.42 (q, 1H), 1.30 (s, 6H).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[CH3:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][CH:18]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[N:22]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: Cc1cccc(OCCN2CCNCC2)n1
Product: Cc1cccc(OCCN2CCN(CCCC(C#N)(c3cccs3)C(C)C)CC2)n1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-methyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.C1C(=O)N([Br:40])C(=O)C1>C(Cl)Cl>[Br:40][C:19]1[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:16][C:15]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(-c2ccc(-c3ccccn3)o2)cc1OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2oc(-c3ccccn3)cc2Br)cc1OC1CCCC1
Yield: 63 %

Procedure:
A mixture of 2-(3-cyclopentyloxy-4-methoxyphenyl)-5-(2-pyridyl)furan, (0.5 g) example 2, in CH2Cl2 (3 ml) and diisopropylamine(21 ul) and NBS (0.320 g) were stirred for 20 mins. at room temperature. The reaction mixture was quenched with Na2CO3, extracted with CH2Cl2 dried with sodium sulfate and evaporated in vacuo to afford the title compound as a beige solid in 63% yield. 1H NMR (300 MHz, CDCl3): δ 1.6 (m, 2H), 2.0-1.8 (m, 6H), 3.90 (s, 3H), 4.95 (m, 1H), 7.05 (dd, 1H), 7.23 (m, 2H), 7.43 (m, 2H), 7.85 (dd, 2H), 8.5 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:10]CC)=[O:9].[OH-].[K+]>O.C(O)C>[CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1CC2C=CC1O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CC2C=CC1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g (17.8 mmol) of ethyl 7-oxabicyclo[2.2.1]hept-5-en-2-carboxylate are suspended in 10 ml of water and 20 ml of ethanol. The temperature is kept below 20° C. by cooling with ice, while 3.5 g (62.3 mmol) of potassium hydroxide are added. The mixture is stirred for 2 hours at ambient temperature, the ethanol is distilled off at a bath temperature of 30° C. and the aqueous solution is extracted with ethyl acetate. The aqueous phase is acidified to a pH of 6 while cooling with ice and shaken with dichloromethane, then the combined organic extracts are dried and evaporated down. 0.8 g (32% of theory) of the title compound are obtained as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>CCOC(C)=O.CCCCCC>[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH2:16]1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c([N+](=O)[O-])c1
Yield: 99.2 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 1-(4-bromo-3-nitro-phenyl)-ethanone (347 mg, 1.42 mmol), and 4,4-dimethylcyclohexen-1-ylboronic acid (254 mg, 1.65 mmol). Silica gel chromatography (5-15% EtOAc/hexane) afforded the title compound (385 mg, 99%) as a faint green oil. Mass spectrum (APCI, m/z): Calcd. for C16H19NO3, 274.1 (M+H), found 274.0.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].S(O)(O)(=O)=O.[S:12]([NH:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)([CH3:15])(=[O:14])=[O:13].[C:27](OC(=O)C)(=[O:29])[CH3:28]>O>[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][CH2:18][CH2:17][NH:16][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:21][CH:22]=1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)NCCNc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(NCCNS(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
0.2 mol (25.2 g) of sodium sulphite is added, at ambient temperature, to a solution of 0.1 mol (32.7 g) of N-(β-mesylaminoethyl)-para-phenylenediamine sulphate in 150 ml of water, and 0.13 mol (13.17 g) of acetic anhydride is added gradually, whilst stirring. When the addition is complete, stirring is continued for one hour and the expected acetylated derivative which has precipitated in crystalline form is then filtered off. The product is drained, washed with water and dried in vacuo. After recrystallisation from alcohol and drying in vacuo, it melts at 130° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([CH2:10][C:11]([O:13]CC)=O)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:17][NH2:18]>C(O)C>[CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([CH2:10][C:11]([NH:17][NH2:18])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CN(C(=O)C2CC2)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CC1CN(C(=O)C2CC2)C1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
In a round bottom flask equipped with reflux condenser under nitrogen, a solution of ethyl [1-(cyclopropylcarbonyl)-3-azetidinyl]acetate (0.433 g, 2.097 mmol) and hydrazine monohydrate (1.3 mL, 41.9 mmol) in ethanol (10 mL) was stirred at 80° C. for 16.5 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was then concentrated down from methanol and then toluene. The residue was dissolved in dichloromethane, filtered through sodium sulfate, and concentrated in vacuo to a colorless oil. The oil still looked wet and was too heavy, so it was dissolved again in dichloromethane and filtered through sodium sulfate, rinsing with additional dichloromethane. The combined organics were concentrated in vacuo and then concentrated under high vacuum pressure to yield the crude title product as a yellow oil (0.316 g, 86% pure, 66% yield). MS(ES)+ m/e 198.1 [M+H]+, 395.1 [2M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:20][C:21]([O:23]C)=[O:22].C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:50][CH2:49][CH2:48]3)=[CH:43][CH:42]=2)O1>C1(C)C=CC=CC=1>[C:54]([O:53][C:52]([NH:51][C:47]1([C:44]2[CH:45]=[CH:46][C:41]([C:2]3[N:6]4[C:7]5[CH:19]=[CH:18][CH:17]=[N:16][C:8]=5[NH:9][C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[C:5]4=[N:4][C:3]=3[CH2:20][C:21]([OH:23])=[O:22])=[CH:42][CH:43]=2)[CH2:50][CH2:49][CH2:48]1)=[O:58])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: COC(=O)Cc1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a suspension of methyl 2-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.15 g, 1 eq.) in a mixture of toluene (8 mL), ethanol (8 mL), and saturated sodium bicarbonate (2 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.219 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.045 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (30 mL). The aqueous phase was extracted with dichloromethane (2×30 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-100% ethyl acetate in hexanes) gave 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 19%). LCMS: 538 [M+H].
Reaction SMILES: [CH:1]1[N:2]=[C:3]([CH2:10][C:11](OC)=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[BH4-].[Na+].O>CO>[CH:1]1[N:2]=[C:3]([CH2:10][CH2:11][OH:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)Cc1ncc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCCc1ncc2ccccn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Methyl 2-(imidazo[1,5-a]pyridin-3-yl)acetate (1.85 g) was dissolved in methanol (30 ml). To the solution was added sodium borohydride (3.68 g), and the mixture was stirred for one hour at 60° C. To the reaction mixture was added water (20 ml), which was concentrated under reduced pressure. The concentrate was subjected to extraction twice with ethyl acetate (40 ml). The organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration to afford the title compound (1.39 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][O:17][C:18]4[C:27]5[C:22](=[CH:23][C:24]([C:28]#[N:29])=[CH:25][CH:26]=5)[N:21]=[CH:20][CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:31]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][O:17][C:18]4[C:27]5[C:22](=[CH:23][C:24]([C:28]([NH2:29])=[O:31])=[CH:25][CH:26]=5)[N:21]=[CH:20][CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc2c(OCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc2c(OCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 90 °C

Procedure:
A mixture of 4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline-7-carbonitrile (0.300 g, 0.793 mmol) and SULFURIC ACID (3.00 ml, 56.3 mmol) was heated at 90° C. for 30 min. Quenched onto ice and sodium bicarbonate. Isolated solid by filtration and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles. Product crashed out and was isolated by filtraton. MS m/z=397.1 [M+1]+. Calc'd for C22H16N6O2: 396.4.