Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:16](=[O:17])[C:11]=3[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:14](=[O:28])[N:13]([CH3:29])[C:12]=3[N:30]=[CH:31][C:9]=2[O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(Cl)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a solution of 6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (470 mg, 1.06 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 2.12 mL, 4.24 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 4-chlorobenzaldehyde (298.8 mg, 2.12 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (120 mg, 19.4% yield) as an oil. LCMS: [MH+-THP] 503 and TR=1.508 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][NH2:19])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30]3([CH:33]=O)[CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:33]([C:30]4([C:26]5[CH:25]=[C:24]6[C:29](=[CH:28][CH:27]=5)[N:20]=[CH:21][CH:22]=[CH:23]6)[CH2:32][CH2:31]4)=[N:19][N:18]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1F
Reactant: O=CC1(c2ccc3ncccc3c2)CC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A mixture of methyl 2-fluoro-4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (0.17 g, 0.64 mmol) and 1-quinolin-6-ylcyclopropanecarbaldehyde (0.13 g, 0.64 mmol) in ethanol (10 mL) and acetic acid (1 mL) was stirred at RT for 2 h. The mixture was concentrated. The residue was dissolved in methylene chloride (5 mL). To the solution was added iodobenzene diacetate (230 mg, 0.71 mmol) with stirring. The mixture was stirred at RT for 2 h then concentrated. The residue was flash chromatographed on a silica gel column to give the desired product (150 mg). Analytical LCMS: (M+H)+=441.0.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH2:21][CH2:22]C.[ClH:25]>CN(C)C=O>[ClH:25].[ClH:25].[CH2:6]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCNCC1

Procedure:
To a dimethylformamide (7 ml) solution containing N-(tert-butoxycarbonyl)piperazine (1.0 g) were added potassium carbonate (742 mg) and then butyl iodide (1.09 g), and the mixture was stirred at room temperature for 15 hours to undergo reaction, thereby obtaining N-tert-butoxycarbonyl-N-butylpiperazine. This compound was acid-treated with hydrochloric acid to obtain N-butylpiperazine.dihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[NH2:1])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: Cc1cc(N)cc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N)cc(CO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of (3-amino-5-methylphenyl)methanol (prepared according to: Behrens, C.; Egholm, M.; Buchardt, O. Synthesis 1992, 12, 1235-1236, 750 mg, 5.47 mmol) in CH2Cl2 (25 mL) was added imidazole (447 mg, 6.56 mmol) then TBDMSCl (989 mg, 6.56 mmol) at room temperature. After 72 hours the mixture was diluted with H2O. The layers were separated and the aqueous extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (20% EtOAc/hexanes) gave 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-methylaniline as a clear oil. 1H-NMR (300 MHz, CDCl3) δ 6.58 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.60 (s, 2H), 3.60 (bs, 2H), 2.24 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]([C:23]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])[CH2:26][CH2:25][CH2:24]4)=[O:22])[CH2:15]3)=[CH:11][C:6]=2[O:5][CH2:4]1>CO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])[CH2:24][CH2:25][CH2:26]4)[OH:22])[CH2:15]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc4c(c3)OCO4)C2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C1(C(O)CN2CCCC(COc3ccc4c(c3)OCO4)C2)CCC1

Procedure:
2-[3-(Benzo[1,3]dioxol-5-yloxymethyl)-piperidin-1-yl]-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanol (232) was prepared according to the procedures outlined in Example 138, using sodium borohydride (17 mg, 0.453 mmol), and 2-[3-(benzo[1,3]dioxol-5-yloxymethyl)-piperidin-1-yl]-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone (100 mg, 0.227 mmol) in MeOH (1.6 mL); MS+ (440).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O>C(O)C.[Pd]>[N:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3ccncc3)c2)C1
Agent: [Pd]
Solvent: CCO
Product: c1cc(CCc2ccncc2)cc(C[C@@H]2CNCCO2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Intermediate (a) N-Boc-(R)-2-(3-(2-(4-pyridinyl)vinyl)-benzyl)morpholine (43 mg) was dissolved in ethanol (10 mL) with palladium (10% w/w on charcoal, 5 mg) and stirred at room temperature under a hydrogen atmosphere for 4.5 hrs. The reaction mixture was filtered and concentrated in vacuo. The residue (39 mg) was stirred in TFA (20% v/v in dichloromethane, 1.25 mL) at room temperature for 4 hrs. The reaction was poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 31 as a yellow oil (23.5 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)CCC>[CH:16]([NH:19][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Solvent: CCCCO
Product: CC(C)Nc1cc(C(F)(F)F)cc2nc(N)nn12
Temperature: 120 °C
Yield: 61.1 %

Procedure:
A suspension of 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 183.00 mg; 0.77 mmol; 1.00 eq.) and isopropylamine (664.58 μl; 7.74 mmol; 10.00 eq.) in n-butanol (1.50 mL) was heated at 120° C. for 1 h30 under MW irradiation. The reaction mixture was then concentrated under vacuum till dryness. The solid obtained was triturated in water/MTBE and filtered. The solid which precipitated in mother liquor was finally filtered, washed with water and dried under vacuum at 40° C. to give the title compound as an off-white solid (122 mg, 61%). HPLC, Rt: 2.64 min. (purity 86.5%). LC/MS, M+(ESI): 259.9, M−(ESI): 257.9.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.N1CCOCC1.COC1C=CC(C[N:62](CC2C=CC(OC)=CC=2)[C:63]2[N:68]=[CH:67][C:66]([C:69]3[C:70]4[CH2:83][CH2:82][N:81]([C:84]5[CH:89]=[CH:88][C:87]([CH2:90][N:91]6[CH2:96][CH2:95][O:94][CH2:93][CH2:92]6)=[CH:86][CH:85]=5)[C:71]=4[N:72]=[C:73]([N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[N:74]=3)=[CH:65][N:64]=2)=CC=1>>[N:75]1([C:73]2[N:74]=[C:69]([C:66]3[CH:67]=[N:68][C:63]([NH2:62])=[N:64][CH:65]=3)[C:70]3[CH2:83][CH2:82][N:81]([C:84]4[CH:89]=[CH:88][C:87]([CH2:90][N:91]5[CH2:92][CH2:93][O:94][CH2:95][CH2:96]5)=[CH:86][CH:85]=4)[C:71]=3[N:72]=2)[CH2:76][CH2:77][O:78][CH2:79][CH2:80]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CN4CCOCC4)cc3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C=O)cc3)cn2)cc1
Solvent: C1COCCN1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(CN3CCOCC3)cc2)cn1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzaldehyde (70 mg) and morpholine (14 μl) instead of 1-methylpiperazine, in the same manner as Step B in Example 1-D-26, a crude product of bis-(4-methoxy-benzyl)-{5-[2-morpholin-4-yl-7-(4-morpholin-4-ylmethyl-phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-126) as a pale brown powder (26 mg, 50%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1.[C:13](O)(=[O:15])[CH3:14].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:9]1([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:10][CH2:11]1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: OC1(COC2CCCCO2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(COC2CCCCO2)CC1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (172 mg, 1 mmol) and acetic acid (120 mg, 2 mmol, Shantou Xilong chemical factory) in 2 mL of DCM was added DMAP (12 mg, 0.1 mmol, aladdin) at rt. After stirring for 30 min, DCC (840 mg, 4 mmol, Aldrich) was added at 0° C. The reaction was quenched with water after all of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol disappeared (monitored by TLC) (about 4 hours). The solid formed during the reaction was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give the desired compound as yellow oil (130 mg, 60.7%).
Reaction SMILES: C(O)(=O)C.O.[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24](C2CCCCO2)[N:23]=[CH:22]3)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CN2CCN(c3ccc4c(cnn4C4CCCCO4)c3)CC2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(CN2CCN(c3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 47.6 %

Procedure:
Acetic acid (2.6 ml) and water (0.7 ml) were added to a solution of 5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (100 mg, 0.266 mmol) in tetrahydrofuran (1.3 ml) at room temperature and stirred 80° C. for 7 hours. Then, the reaction solution was concentrated and the resulting residue was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a thin-layer chromatography (eluent: chloroform/methanol=95/5) to obtain 5-(4-benzyl-1-piperazinyl)-1H-indazole (37 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](OC)=[O:34])=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:37]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][OH:34])=[CH:29][CH:30]=3)[S:7][C:6]=2[CH:37]=1
Reactant: COC(=O)COc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cc2c(-c3ccc(OCCO)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To 6-hydroxy-2-[4-(2-methoxy-2-oxoethoxy)phenyl]-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiophene (36 mg) in THF (2 mL) was added lithium aluminum hydride (16 mg) and the mixture was stirred under argon at ambient temperature for 1 h. The reaction was quenched with water (1 mL) and sodium hydroxide solution (1.0 M, 1 mL) while stirring continued for 30 min. The mixture was then diluted with brine (50 mL) and extracted with dichloromethane (30 mL×3). The combined organic layers were dried with sodium sulfate and concentrated in vacuo. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the product (29 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)[C@H](NC(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](NC(=O)c1ccccc1N)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.8 %

Procedure:
A mixture of (R)-cyclohexyl-(2-nitro-benzoylamino)-acetic acid methyl ester (1.16 g, 3.62 mmol), 10% Pd/C (250 mg) in EtOH (25 mL) are stirred under H2 atmosphere at room temperature for 16 hours. The reaction mixture is filtered and the organic layer is concentrated to give (R)-(2-amino-benzoylamino)-cyclohexyl-acetic acid methyl ester (1.08 g, 98%).
Reaction SMILES: C([O:4][C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2occc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Ethyl 7-(Acetyloxy)-1-benzofuran-5-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (7 g, 50 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (2:1) to give the desired product 2.8 g (13 mmol, 38%) as a cream solid. 1H NMR (DMSO-D6): δ ppm 1.35 (s, 3H), 4.20 (qt, 2H), 7.15 (m ,1H), 7.39 (m, 1H), 7.77 (m, 1H), i8.04 (m, 1H); MS (APCI, pos): 241.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[NH:12][N:11]=1.[CH3:25]I>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:25])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])[N:14]=1
Reactant: Fc1ccccc1-c1n[nH]c(-c2ccccc2C(F)(F)F)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.19 g of sodium hydride is placed in 10 ml of N,N-dimethylformamide. A solution of 2.3 g of 3-(o-fluorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole in 15 ml of N,N-dimethylformamide is allowed to drop in while stirring during 10 minutes. After stirring for a further 45 minutes the solution, which has meanwhile become brown, is treated dropwise with 1.17 g of methyl iodide while cooling with ice. The reaction mixture is stirred for a further one hour and thereafter poured on to ice-water, and the aqueous mixture is extracted three times with ethyl acetate. The combined extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. In this manner there is obtained a mixture of isomeric N-methyltriazoles which can be separated by chromatography on silica gel. By elution with n-hexane/ethyl acetate (19:1) there is obtained pure 5-(o-fluorophenyl)-1-methyl-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole as a resinous product, 1H-NMR(CDCl3): 3.93 (d, CH3, coupling with F).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:15]([O:17]C)=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2]>[OH-].[Na+].Cl>[N+:1]([C:4]1[C:5]([C:15]([OH:17])=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Methyl 4-nitro-1-phenyl-1H-pyrazole-3-carboxylate (1.14 g, 4.63 mmol) was suspended in 1N sodium hydroxide (11 mL), and the solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The precipitates formed upon addition of IN hydrochloric acid (12 mL) were collected by filtration, washed with water and dried to obtain the title compound (1.00 g, 93.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])[S:26][CH:27]=1)[CH3:35]
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCO2
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)n1

Procedure:
The title compound, MS (ISP)=492.0 (M−H)−, was produced as described in example 1, steps 1-6. Step 3 was performed using 3-chlorobenzenesulfonyl chloride, furnishing 4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5 and yielded (2-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CCc2ccccc2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
15.73 g (82.5 mmol) of p-toluenesulphonyl chloride are added at room temperature while stirring to a solution of 13.36 g (75 mmol) of 2-(2-hydroxyethyl)chroman in 90 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. After stirring for a further 3 hours at room temperature, the reaction mixture is poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. There are obtained 8.68 g (34.7%) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman which melts at 57°-59°.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[OH:20].Br[C:22]1C(O)=C(C)C=C2C=1C=CC=N2>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[C:3]([OH:20])=[C:2]([CH3:22])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:18][CH:17]=1
Reactant: Cc1cc2ncccc2c(Br)c1O
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(Cl)cc2n1
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1O

Procedure:
Compound 3E was prepared following the procedure used to prepare compound 1E of Example 1, except that 5-bromo-7-methylquinolin-6-ol (3D) was used instead of compound 1D.
Reaction SMILES: COCCOC.[CH3:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1B1OC(C)(C)C(C)(C)O1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH:43]=[C:42]([C:44]3[CH:45]=[N:46][C:47]([NH2:51])=[C:48](Br)[CH:49]=3)[CH:41]=[N:40]2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(Cl)Cl.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH:43]=[C:42]([C:44]3[CH:45]=[N:46][C:47]([NH2:51])=[C:48]([C:9]4[O:10][C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[C:8]=4[CH3:7])[CH:49]=3)[CH:41]=[N:40]2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)oc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(Br)c3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)oc2ccccc12
Temperature: 100 °C

Procedure:
To the DME solution of 3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (2.3 mL, 0.58 mmol, 2 eq.) from the previous step were added 4-[4-(6-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (BB3) (120 mg, 0.29 mmol, 1 eq.), potassium carbonate (120 mg, 0.87 mmol, 3 eq.), water (0.5 mL), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium DCM (10 mg, 0.01 mmol, 0.05 eq.). The mixture was evacuated and filled with nitrogen (3×) and heated in a microwave reactor to 100° C. for 30 min. The crude was passed through Thiol-SPE to remove Pd. The clear solution was purified with the MDPS. 1H NMR (400 MHz, CD3OD): δ=1.48 (s, 9H), 1.96 (dq, J=4.3, 12.3 Hz, 2H), 2.09 (br. s., 2H), 2.35 (s, 3H), 2.96 (br. s., 2H), 4.21 (br. s., 2H), 4.33-4.43 (m, 1H), 7.29 (dt, J=0.8, 7.4 Hz, 1H), 7.34 (dt, J=1.4, 7.2 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.59-7.65 (m, 1H), 7.82 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 8.07 (s, 1H), 8.26 (d, J=2.3 Hz, 1H). MS (ES+): m/z=474.38 (100) [MH+]. HPLC: tR=0.94 min (UPLC-ACQUITY, Analytical).