Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Br)cn2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Br)cn4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(224) where 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30-1.90 (brm, 8H), 2.00-2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.75 (m, 2H); 2.90 (m, 2H), 3.50 (m, 3H), 6.64 (d, J=5.26 Hz, 1H), 6.70 (d, J=5.26 Hz, 1H), 7.00 (s, 1H), 8.75 (s, 1H), 9.19 (s, 1H). Anal. Calcd. For C26H29O4N4Br C, 57.68; H, 5.40; N, 10.35. Found: C, 57.50; H, 5.50; N, 10.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:17])[C:9]2[CH:10]=[N:11][C:12]([O:15]C)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(#N)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]2[CH:10]=[C:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:17])[CH:14]=[CH:13][C:12]2=[O:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(N(C)c2ccc(F)cc2)cn1
Reactant: Clc1ccc(CBr)cc1
Solvent: CC#N
Product: CN(c1ccc(F)cc1)c1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Yield: 33.7 %

Procedure:
According to Scheme 22 Step 2: The title compound was prepared from N-(4-fluorophenyl)-6-methoxy-N-methylpyridin-3-amine (1 eq, 86 μmol, 20 mg) and 4-chloro-benzylbromide (1.7 eq, 0.15 mmol, 30 mg) according to the procedure described for Example 6 Step 2. Reaction conditions: 12 hours at 80° C. in acetonitrile. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt 50/50 as eluent to afford 1-(4-chlorobenzyl)-5-((4-fluorophenyl)(methyl)amino)pyridin-2(1H)-one (29 μmol, 10 mg, 34%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30](C(OC(C)(C)C)=O)[CH3:31])[N:25]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:5]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1.O1CCCC1.O.C(=O)([O-])O.[Na+]>Cl.O1CCOCC1>[Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=2)=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[NH:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccnc(N(C)C(=O)OC(C)(C)C)n2)c1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nccc(-c2c(Br)c[nH]c2-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
472 mg (0.782 mmol) of 4-bromo-3-[2-(N-t-butoxycarbonyl-N-methylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step (vi) above] were dissolved in 10 of ml tetrahydrofuran, 0.98 ml (3.91 mmol) of a 4N solution of hydrogen chloride in dioxane were added to the solution, and the resulting mixture was stirred for 3 hours at 50° C. At the end of this time, water was added to the reaction mixture and then it was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. This was extracted with ethyl acetate, and the organic extract was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 7:3 by volume mixture of hexane and ethyl acetate as the eluant to afford 202 mg (yield 74%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: [C:1]([OH:7])(=O)/[CH:2]=[CH:3]/[CH2:4][CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>O1CCCC1.C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:1](=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH3:5])=[CH:26][CH:25]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CC/C=C/C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC/C=C/C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
A solution of trans-2-pentenoic acid (7.62 g, 76.2 mmol) in tetrahydrofuran (350 mL) was stirred at −15° C. and treated with N-methylmorpholine (8.37 mL, 76.2 mmol). After 10 minutes, isobutyl chloroformate (9.87 mL, 76.2 mmol) was added. After 10 minutes, a precipitate had formed. A solution of 2-(4-fluorophenyl)ethylamine (10.6 g, 76.2 mmol) in tetrahydrofuran (50 mL) was added slowly, and the mixture was stirred at room temperature, and the residue was dissolved in ethyl acetate. The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane to provide white crystals (11.69 g, 69%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.88 (dt, J=15, 7 Hz, 1H), 5.72 (dt, J=15, 2 Hz, 1H), 5.61 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 2.20 (m, 2H), 1.05 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 221.9 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][CH:33]=[O:34])([CH3:31])[CH:27]=1.C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([OH:36])=[O:34])([CH3:31])[CH:27]=1
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC=O)CC1)C(=O)OC2
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: [F:1][C:2]1([F:41])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:40])([CH2:37][CH2:38][OH:39])[CH3:36])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC1(F)OC2C=CC(C3(C(NC4C=C5C(=CC=4F)NC(C(C)(CCO)C)=C5)=O)CC3)=CC=2O1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[F:41][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:36])([CH2:37][CH2:38][OH:39])[CH3:40])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CCO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: CC(C)(CCO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(CCO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@@H](O)CO
Temperature: 80 °C
Yield: 31 %

Procedure:
To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide containing some 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (315 mg, 0.55 mmol) in methanol (3 mL) and water (0.3 mL) was added p-TsOH.H2O (21 mg, 0.11 mmol). The mixture was heated at 80° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated. NaHCO3 solution and brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-80% ethyl acetate-hexanes) to provide (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (92 mg, 31%). ESI-MS m/z calc. 534.2, found 535.5 (M+1)+. Retention time 1.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.53 (d, J=1.0 Hz, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.97-4.92 (m, 2H), 4.41 (dd, J=2.4, 15.0 Hz, 1H), 4.23 (t, J=5.0 Hz, 1H), 4.08 (dd, J=8.6, 15.1 Hz, 1H), 3.87 (s, 1H), 3.48-3.44 (m, 1H), 3.41-3.33 (m, 1H), 3.20 (dd, J=7.4, 12.7 Hz, 2H), 1.94-1.90 (m, 2H), 1.48-1.45 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15-1.12 (m, 2H) ppm.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[C:8](=O)([O-])[O-].[K+].[K+].[C:14]([C:16]1[C:22]([C:23]#[N:24])=[C:21]([OH:25])[CH:20]=[CH:19][C:17]=1O)#[N:15]>CC(=O)CC>[CH3:8][O:25][C:21]1[CH:20]=[CH:19][C:17]([O:6][CH3:7])=[C:16]([C:14]#[N:15])[C:22]=1[C:23]#[N:24]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(OC)c(C#N)c1C#N
Temperature: 25 °C

Procedure:
Dimethyl sulfate (15 mL, 0.16 mol) and anhydrous potassium carbonate (24 g, 0.17 mol) are added to a solution of 2,3-dicyanohydroquinone (3.0 g, 0.019 mol) in 100 mL 2-butanone. The reaction mixture is refluxed for 18 hr. under a stream of argon, cooled to room temperature and the resulting solid is collected by filtration. The residue is added to water (100 mL) to dissolve the potassium carbonate and the resulting insoluble material is collected by filtration and dried under vacuum to yield 3.10 g (88%), m.p. 276°-280° C., 1H NMR (DMSO-d6) in ppm, δ=7.63 (s, 2H), 3.93 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixed liquid of 1.00 g of tert-butyl piperidin-4-ylcarbamate and 20 ml of pyridine was added 0.77 ml of methanesulfonyl chloride, followed by stirring at room temperature for 18 hours. After evaporating the pyridine under reduced pressure, ethyl acetate was added thereto, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained solid was washed with diethyl ether to obtain 1.19 g of t-butyl[1-(methylsulfonyl)piperidin-4-yl]carbamate as a white solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31](O)=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8].[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38].C(N(CC)CC)C>C(#N)C>[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH:38][C:31](=[O:32])[C@H:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:19][C:17](=[O:18])[C@H:10]([CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)N1
Reactant: COC(=O)[C@@H](N)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Pyroglutamyl-L-histidyl-L-tryptophan (IV) (0.452 g) and L-serine methyl ester (V) hydrochloride (0.155 g) in dry acetonitrile (50 ml) are treated with triethylamine (0.14 ml) and DCI (0.227 g) in dry acetonitrile (5 ml) at 0°C. After stirring at room temperature for 24 hours, the reaction mixture is evaporated to dryness. The residue is dissolved in methanol and the dicyclohexylurea is removed by filtration. The filtrate is concentrated to dryness to L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine methyl ester (VI).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19](B(O)O)=[C:18]2[C:13]([N:14]([CH3:26])[C:15](=[O:25])[N:16]([CH3:24])[C:17]2=[O:23])=[CH:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].N#N.Br[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1>C(OC(=O)C)CCC.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:11]1[C:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[C:18]2[C:13]([N:14]([CH3:26])[C:15](=[O:25])[N:16]([CH3:24])[C:17]2=[O:23])=[CH:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2c(B(O)O)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Reactant: Clc1cccc(Br)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: 80 °C

Procedure:
(6-(2-((tert-Butoxycarbonyl)amino)ethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)boronic acid (step 4) (631 mg, 1.724 mmol), Pd-118 (commercial, CAS 95408-45-0) (51.1 mg, 0.078 mmol, 5 mol %) and potassium carbonate (433 mg, 3.13 mmol) were suspended in n-butylacetate (11.2 mL). The vessel was evacuated and back filled with N2 (×4). Under a stream of N2 was charged 1-bromo-3-chlorobenzene (commercial) (0.184 mL, 1.567 mmol) and water (0.056 mL, 3.13 mmol). The vessel was heated to 80° C. for 2 hrs under microwave irradiation. An additional amount of water (100 μL) and 1-bromo-3-chlorobenzene (0.184 mL, 1.567 mmol) was charged and the mixture heated to 80° C. for a further 2 hrs under microwave irradiation. The reaction mixture was diluted with water (40 mL) and EtOAc (20 mL) and the layers were separated. The aqueous was extracted with EtOAc (4×20 mL) and the combined organics were washed with brine (20 mL), dried (Na2SO4) and filtered under reduced pressure. Silica gel was added to the solution and the solvent evaporated under reduced pressure. The residue was purified via ISCO SiO2 80 g RediSep® Rf column eluting with 50-70% EtOAc/hexane. The fractions containing product were combined and evaporated to afford a pale tan solid, which was dried under vacuum at 50° C. for 3 hrs. This afforded the title product as a pale tan solid.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=[C:10]2[CH3:18])=[CH:5][CH:4]=1)#N.[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>>[CH3:18][C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:22]([C:21]([OH:19])=[O:23])=[CH:4][CH:5]=2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: [OH-]
Reactant: Cc1nc2cnccc2n1-c1ccc(C#N)cc1
Reactant: CCO
Agent: [Na+]
Product: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
A mixture of 1-(4-cyanophenyl)-2-methylimidazo[4,5-c]pyridine (12.0 g, 51.3 mmol) and 40% aqueous sodium hydroxide (55 ml) in absolute ethanol (55 ml) was heated at reflux for 11/2 hours. The solvent was removed under reduced pressure, and the brown residue was dissolved in water. The solution was chilled to 0° C. by the addition of ice. Glacial acetic acid (ca 33 ml) was added slowly. The buff solid which precipitated was filtered off, washed with water, and dried in vacuo at 70° C. Yield 9.14 g (70%).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)\[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[O:23]C(=O)O[CH:20]3[C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH2:37](N(CC)CC)C.[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[OH:23][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:29]=[CH:30][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:8][CH:9]=2)=[CH:14][CH:15]=1)[CH:20]([S:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:25]([O:27][CH2:28][CH3:37])=[O:26]
Reactant: Sc1ccccc1
Reactant: CO/N=C(\COc1ccc(COc2ccc(C3OC(=O)OC3C(=O)OC)cc2)cc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(Sc1ccccc1)C(O)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
To a solution of methyl 5-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}-2-oxo-1,3-dioxolane-4-carboxylate (0.8 g, 1.6 mmol) in THF was added Triethylamine (0.32 g, 3.2 mmol) and Thiophenol (0.34 g, 3.2 mmol) at 0° C. under argon then slowly warmed to RT, then stirring continued at 60° C. for 12 h. Reaction mass quenched with water and extracted with ethyl acetate, organic layer was washed with water and brine, dried over sodium sulphate and concentrated to yellow oil which was further purified by column (60-120 silica) using 20% ethyl acetate in pet ether to get the titled compound as yellow oil. (0.55 g, Yield: 61%) 1H NMR (300 MHz, DMSO): δ 7.62-7.65 (m, 2H), 7.27-7.40 (m, 8H), 7.22-7.24 (m, 2H), 7.11-7.14 (m, 2H), 6.90-6.93 (d, 4H), 5.21 (s, 2H), 5.01 (s, 2H), 4.63-4.73 (m, 1H), 4.01 (s, 3H), 3.89-3.91 (d, 1H), 3.59 (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH2:14][CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>C(O)(C)C.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH2:14][CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCc1ncc[nH]1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Twenty grams (0.123 mol) of isatoic anhydride were slowly added to a cold (0° C.) solution of 13.5 g (0.122 mol) of 2-(2-aminoethyl)imidazole in 220 ml isopropanol, under nitrogen. The reaction mixture was gradually warmed to room temperature and allowed to react. When the reaction was complete, as indicated by thin layer chromatography, the solution was reduced to dryness under reduced pressure and the resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated, the organic layer was washed with water and reduced to dryness to provide a solid. This solid was recrystallized from ethanol containing a small amount of hexane to provide 24.1 g of the desired subtitled intermediate (m.p. 180°-185° C.).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2].CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]2[N:20]=1)=O>>[CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:19]3[N:24]=[CH:23][C:22]4=[CH:25][CH:26]=[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]4[N:20]=3)=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: CCN1CCOC(c2ccc(N)cc2)C1
Product: CCN1CCOC(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)C1
Yield: 0.3 %

Procedure:
Following a procedure analogous to 251c, 4-(4-Ethyl-morpholin-2-yl)-phenylamine (0.16 g, 78 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (94 mg, 26 mmol) were converted to the title compound (35 mgs, 22%) isolated as a TFA salt. H-NMR (DMSO-d6) δ 9.89 (broad s, 1H), 9.56 (s, 1H), 9.00 (s, 1H), 7.79 (d, J=3.3 Hz, 1H), 7.69-7.66 (m, 3H), 7.59-7.58 (m, 2H), 7.20 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.8 Hz, 2H), 4.63 (d, J=11.1 Hz, 1H), 4.18 (d, J=12.9 Hz, 1H), 3.85 (t, J=8.3 Hz, 1H), 3.59-3.32 (m, 2H), 3.12-2.98 (m, 4H), 2.86 (s, 3H), 1.25 (t, J=7.8 Hz, 3H); LC/MS (ESI+): 507.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH3:14])([NH2:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:27][C:28]1[CH:29]=[C:30]([C:35]2[C:43]([C:44]([NH2:46])=[O:45])=[C:38]3[CH2:39][NH:40][CH2:41][CH2:42][N:37]3[N:36]=2)[CH:31]=[CH:32][C:33]=1[F:34]>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:13][C:16]([N:40]2[CH2:41][CH2:42][N:37]3[N:36]=[C:35]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=4)[C:43]([C:44]([NH2:46])=[O:45])=[C:38]3[CH2:39]2)=[O:18])([CH3:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNCC2
Reactant: CC1(N)CC(OCc2ccccc2)C1
Solvent: C1CCOC1
Product: CC1(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a stirred solution of 3-(benzyloxy)-1-methylcyclobutanamine (64.9 mg, 0.339 mmol) in THF (10 mL) was added TEA (0.14 mL, 1.357 mmol) followed by triphosgene (100 mg, 0.339 mmol) at 0° C. After stirring for 10 min, a solution of Intermediate 185B (100 mg, 0.34 mmol) in THF (2 mL) was added at 0° C. and the resulting solution was allowed to warm to RT and stir for 16 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (3×20 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford the crude reaction mixture which was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 260A (70 mg, 40% yield) as a pale yellow solid. MS(ES): m/z=512 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)[N:6]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].[Na+].[I-].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([N:7]1[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][NH:26][CH2:25][CH2:23][OH:24])=[N:6]1)[CH:20]=[CH:19]2
Reactant: COc1ccc2cc(-n3nc(OCCCl)cc3C)ccc2c1
Reactant: NCCO
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2cc(-n3nc(OCCNCCO)cc3C)ccc2c1
Temperature: 110 °C
Yield: 41.1 %

Procedure:
A mixture of 3-(2-chloroethoxy)-5-methyl-1-(6-methoxynaphthalen-2-yl)-1H-pyrazol (0.15 g, 0.47 mmol), ethanolamine (0.115 g, 1.89 mmol) and catalytic amount of NaI in N-methylpyrrolidone (NMP) (30 ml) was heated to 110° C., in a nitrogen atmosphere, during 20 hrs. Next, it was cooled, and water and ethyl acetate was added to the residue. The organic phase was washed with water several times, dried over Na2SO4, filtered and evaporated, thereby leaving a residue of 66 mg of 2-(2-(1-(6-Methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethylamino)etanol. The aqueous phase was extracted with dichloromethane, dried over Na2SO4, filtered and evaporated leaving a crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate/methanol, from 8/2 until 0/10) thereby obtaining additional 40 mg of desired compound. A total weight of 104 mg (yield: 65%) of 2-(2-(1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethylamino)etanol in the form of a colourless oil was obtained.