Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:25](=[O:26])[CH:24]2[CH:19]([CH:20]3[O:27][CH:23]2[CH2:22][CH2:21]3)[C:18]1=[O:28].C(N(CC)CC)C>ClCCl>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:26][C:25]1[CH:24]2[CH:19]([C:18](=[O:28])[C:17]=1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])[CH:20]1[O:27][CH:23]2[CH2:22][CH2:21]1)=[O:6]
Reactant: Cc1cc(C)c(C2C(=O)C3C4CCC(O4)C3C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)C3C4CCC(O4)C3C2=O)c(C)c1
Reaction time: 0.03 h

Procedure:
A solution of pivaloyl chloride (0.055 g, 0.57 mmol) in dichloromethane (2 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.12 g, 0.42 mmol) in dichloromethane (2 ml) at room temperature and the reaction mixture is stirred for 2 minutes. A solution of triethylamine (0.08 ml) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-5-oxo-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-3-en-3-yl 2,2-dimethylpropionate as a colourless oil.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:18](OCC)=[O:19])[N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]2=[O:27].[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:48])[N:34]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:35]2[CH2:38][C:39](OCC)=[O:40])=[CH:31][CH:30]=1>C(O)C>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:48])[N:34]([CH2:44][CH:45]([CH3:46])[CH3:47])[CH:35]2[CH2:38][C:39]([NH:5][C:4]([NH2:6])=[NH:3])=[O:40])=[CH:31][CH:30]=1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:18]([NH:5][C:4]([NH2:6])=[NH:3])=[O:19])[N:12]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]2=[O:27]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(Cl)cc2C(=O)N1CC(C)C
Reactant: CCOC(=O)CC1c2cc(Cl)ccc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(Cl)ccc2C1CC(=O)NC(=N)N
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h

Procedure:
N-[(5-Chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine and N-[(6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.35 g of sodium, 1.46 g of guanidinium chloride and 3.1 g of ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 15 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 15 cm3 of water and 45 cm3 of diethyl ether and then stirred at a temperature in the region of 0° C. for 4 hours. The precipitate obtained is filtered off, washed with twice 20 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 1 g of N-[(5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine and N-[(6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a white powder. (Analysis: C15 H19 Cl N4 O2, % calculated C, 55.81; H, 5.93; Cl, 10.98; N, 17.36; O, 9.91%. found C, 55.67; H, 6.18; Cl, 11.32; N, 17.05). Mass spectrum: DCI: m/e 323 (M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=O.[Cl:11][C:12]1[CH:20]=[CH:19][NH:18][C:17]2[C:13]=1[CH:14]=[CH:15][N+:16]=2[O-].COS(OC)(=O)=O.[NH3:29]>C(C#N)(C)=O.CCO>[Cl:11][C:12]1[CH:20]=[C:19]([NH2:29])[N:18]=[C:17]2[NH:16][CH:15]=[CH:14][C:13]=12
Reactant: N
Reactant: [O-][n+]1ccc2c(Cl)cc[nH]c1-2
Agent: CC(=O)C#N
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCO
Solvent: COS(=O)(=O)OC
Product: Nc1cc(Cl)c2cc[nH]c2n1
Temperature: 57.5 °C
Reaction time: 8 h

Procedure:
To a suspn. of 4-chloro-7-azaindole-N-oxide m-chlorobenzoic acid salt [J. Org. Chem. 1980, 45, 4045] (1.60 g, 4.92 mmol) in AcCN (10 ml) was added dimethylsulfate (0.50 ml, 1.05 eq.) at RT. The suspn. was stirred under N2 at 55-60° C. overnight. After cooling to RT, a solution of NH3 in dry EtOH (2M, Aldrich, 20 ml) under cooling in an ice bath. The greenish mixture was stirred in a sealed vial at RT for 4 h, then at 45° C. for 60 h. After evaporation of the solvent and aq. workup as in the previous examples, the crude was purified by silica gel chromatography to give a yellowish-tan cryst. solid. HR-MS calculated for [MH]+: 168.03230, found: 168.03218.
Reaction SMILES: [Cl:1]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O[CH2:23][CH:24]1[C:28]2=[C:29]3[C:33](=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=[C:27]2[N:26]([C:43]([C:45]2[NH:46][C:47]4[C:52]([CH:53]=2)=[CH:51][C:50]([O:54][CH3:55])=[C:49]([O:56][CH3:57])[C:48]=4[O:58][CH3:59])=[O:44])[CH2:25]1)[NH:32][C:31]([C:39]([O:41][CH3:42])=[O:40])=[CH:30]3.O>N1C=CC=CC=1>[Cl:1][CH2:23][CH:24]1[C:28]2=[C:29]3[C:33](=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=[C:27]2[N:26]([C:43]([C:45]2[NH:46][C:47]4[C:52]([CH:53]=2)=[CH:51][C:50]([O:54][CH3:55])=[C:49]([O:56][CH3:57])[C:48]=4[O:58][CH3:59])=[O:44])[CH2:25]1)[NH:32][C:31]([C:39]([O:41][CH3:42])=[O:40])=[CH:30]3
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CO
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CCl
Temperature: 20 °C
Yield: 63.6 %

Procedure:
Dichlorotriphenylphosphorane (1.65 g, 5.1 mmol) was added to a solution of 56 (1.34 g, 2.55 mmol) in pyridine (75 mL) and the solution stirred at 20° C. After 10 min more dichlorotriphenylphosphorane (2.06 g, 6.4 mmol) was added, and after a further 10 min the solution was poured into H2O and the mixture stirred for 5 min. The precipitated solid was filtered off, washed with H2O, and redissolved in CH2Cl2 (400 mL). This solution was filtered through Celite, eluting with CH2Cl2, and the filtrate was dried (Na2SO4) and evaporated. The resulting orange solid was recrystallized from CH2Cl2 giving methyl 1-(chloromethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (31) as an orange powder (0.88 g, 64%), mp 246-247.5° C. The mother liquor was evaporated onto silica and purified by chromatography (50% EtOAc-petroleum ether) to give further 31 (0.50 g, 36%). 1H NMR (CDCl3) δ 10.39 (s, 1 H, NH), 9.42 (s, 1 H, NH), 9.39 (s, 1 H, H-4), 7.31 (d, J=2.2 Hz, 1 H, H-8), 6.97 (d, J=2.4 Hz, 1 H, H-3'), 6.86 (s, 1 H, H-4'), 4.80 (t, J=10.0 Hz, 1 H, H-2), 4.69 (dd, J=10.8, 4.4 Hz, 1 H, H-2), 4.32-42.3 (m, 1 H, H-1). 4.09 (s, 3 H, OMe), 4.05 (dd, J=11.4, 3.9 Hz, 1 H, CH2Cl), 4.02 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.77 (dd, J=11.4, 8.8 Hz, 1 H, CH2Cl); 13C NMR [(CD3)2SO] δ 160.5, 160.0, 149.2, 140.0, 139.0, 137.5, 133.6, 132.1, 131.3, 130.2, 127.7, 126.1, 125.5, 123.2, 111.3, 107.5, 106.4, 97.9, 61.1, 60.9, 55.9, 54.1, 52.3, 47.0, 42.0. Anal. Calculated for C25H23ClN4O8 : C, 55.3; H, 4.3; N, 10.3. Found: C, 55.4; H, 4.1; N, 10.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH3:24]O>>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([O:17][CH3:24])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
15 g (0.06 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid, 150 ml of methanol and 1.6 ml of concentrated sulfuric acid were introduced into a round-bottomed flask. The mixture was heated at reflux for 4 hours, the reaction medium evaporated, taken up in water, and extracted with ethyl acetate. The organic phase was decanted off and dried over magnesium sulfate. 15.9 g (99%) of the expected ester of melting point 83°-85° C. were recovered.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)=O.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:20]3[N:19]([C:18]([CH3:17])=[N:22][CH:21]=3)[CH2:2][CH2:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:16])[CH3:15]
Reactant: Cc1ncc[nH]1
Reactant: CC(=O)Nc1ccc(C(=O)CCCCl)cc1
Product: CC(=O)Nc1ccc(C2=CCCn3c2cnc3C)cc1

Procedure:
Combine 20 g (83.4 mmol) of N-[4-(4-chloro-1-oxobutan-1-yl)phenyl]acetamide with 50 g (0.61 mol) of 2-methylimidazole and heat to 175° C. for 18 hr. Crystallization from ethyl acetate provides the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[Cl:16])([O:3]CC)=[O:2].[OH-].[Na+]>>[ClH:16].[C:1]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[Cl:16])([OH:3])=[O:2]
Reactant: CCOC(=O)c1cccc2c(Cl)nccc12
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: O=C(O)c1cccc2c(Cl)nccc12
Yield: 200 %

Procedure:
A solution of 5-carbethoxy-1-chloroisoquinoline (German Patent DE 2816863) (1.75 g, 7.4 mmol) and NaOH (0.8 g, 20 mmol) in MeOH-H20 (50 mL, 4:1) was stirred at 23° C. for 5 h. The solvents were evaporated in vacuo and the residue partioned between CH2Cl2 and aqueous NaOH (2 M). The aqueous phase was acidified with conc HCl and extracted with copious EtOAc (×4). The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to leave 5-carboxy-1-chloroisoquinoline hydrochloride (1.8 g, 7.4 mmol) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[CH2:30]([O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reactant: CCCCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of 406 mg (1.00 mmol) of the title product of Example 1, 190 mg (1.20 mmol) of 1-decanol, and 393 mg (1.50 mmol) of triphenylphosphine in 10 ml of dimethylformamide was added 261 mg (1.50 mmol) of diethyl azodicarboxylate. After stirring overnight at room temperature, the solvent was removed under reduced pressure. Chromatography of the residue on silica gel, using 20% ethyl acetate/hexane as eluent, gave 408 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: Cn1c(C(=O)Cl)nc2ccccc21
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (1.50 g, 3.94 mmol) in pyridine (18 mL) was cooled to 0° C. and 1-methyl-1H-benzo[d]imidazole-2-carbonyl chloride (0.874 g, 3.33 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an eighteen hour time period. The solvent was removed in vacuo and the residue was suspended in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (1.90 g, 90%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.18 (s, 1H), 8.49 (d, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.85 (d, 1H), 7.76 (d, 1H), 7.46 (t, 1H), 7.39 (t, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 5.77-5.89 (b, 2H), 4.24 (s, 3H), 4.03 (s, 3H); RP-HPLC (Conditions d) Rt 11.89 min.; MS: MH+ 540.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C(O[CH:14]=[C:15]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:16](=O)[C:17]([F:20])([F:19])[F:18])C>CO>[CH:23]([C:22]([C:15]1[C:16]([C:17]([F:18])([F:19])[F:20])=[N:9][CH:8]=[N:10][CH:14]=1)=[O:26])([CH3:25])[CH3:24]
Reactant: CCOC=C(C(=O)C(C)C)C(=O)C(F)(F)F
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C(=O)c1cncnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
46 g (0.85 mol) of sodium methoxide was dissolved in 700 ml of methanol, and 76 g (0.73 mol) of formamidine acetate was added, followed by stirring at room temperature for 15 minutes. Then, 146 g (0.61 mol) of 3-ethoxymethylene-1,1,1-trifluoro-5-methyl-2,4-hexanedione was added under cooling with ice, followed by heating and refluxing for further 2 hours. The solvent was distilled off under reduced pressure, and 1,000 ml of ice water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=6:1) to obtain 89 g (yield: 67%) of 5-isopropylcarbonyl-4-trifluoromethylpyrimidine as slightly yellow liquid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:51])([CH3:50])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH2:48][CH3:49])=[CH:19][CH:18]=1>O>[CH3:51][C:14]([CH3:50])([CH3:13])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH2:48][CH3:49])=[CH:21][CH:22]=1
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.46 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.33 g, 73%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]=1[CH:10]([OH:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31]([O:33]C)=[O:32]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]=1[CH:10]([OH:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:30][C:31]([OH:33])=[O:32])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CBr
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(-c2ccc(OCC(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4'-[(2-butyl-benzofuran-3-yl)-hydroxymethyl]-biphenyl-4-ol, and methyl bromoacetate in substantially the same manner, as described in Example 4, and was obtained as a yellow solid, mp 111-113° C.; MS m/e 430 (M+);
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.Cl[CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:26]([NH:25][C:23](=[O:24])[CH2:22][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[O:27])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: O=C=NC(=O)CCl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(CC(=O)NC(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A solution of Example A2 (0.15 g, 0.561 mmol) in THF (3 mL) was treated with TEA (0.114 g, 1.122 mmol) and 2-chloroacetyl isocyanate (0.107 g, 0.898 mmol), stirred at RT for 2 h, treated with N-methylpiperazine (0.112 g, 1.122 mmol) and stirred at RT for 4 h. The mixture was diluted with EtOAc, stirred for several minutes, the solids removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (NH4OH/MeOH/DCM). The material was suspended in 2:1 EtOAc/DCM and the solid was removed via filtration and discarded. The filtrate was concentrated to dryness and treated with 3:2 EtOAc/Hex. The mixture was briefly sonicated. The solid was collected via filtration, dissolved in MeCN/H2O, frozen and lyophilized to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-(4-methylpiperazin-1-yl)acetamide (76 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 10.48 (br s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27-8.24 (m, 2H), 8.07-8.00 (m, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.22 (s, 2H), 2.51 (m, 4H), 2.35 (m, 4H), 2.15 (s, 3H); MS (ESI) m/z: 451.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: OC1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)CC3)s2)noc1C(F)(F)F
Yield: 78 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxypiperidine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (141 mg, 78%). 1H NMR (CDCl3) 1.58-1.69 (m, 2H), 1.93-2.00 (m, 2H), 2.26 (br s, 1H), 2.37 (s, 3H), 3.44-3.52 (m, 2H), 4.00-4.12 (m, 3H), 7.33 (d, J=4.0, 1H), 7.46 (d, J=3.5, 1H). 13C NMR 7.9, 34.4, 42 (br), 66.9, 114.8, 118.7 (q, J=271), 128.0, 129.2, 131.2, 140.1, 155.2 (q, J=40), 158.1, 162.8. 19F NMR −63.1. LC/MS 5.71 min, [M+1]+ 361.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[C:18]([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[CH:32][CH:33]=3)[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2sc(CC)cc2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate (200 mg, 0.8 mmol), 4-(2-t-butoxycarbonylphenyl)benzyl bromide (300 mg, 0.9 mmol) and cesium carbonate (650 mg, 2.0 mmol) in DMF (10 ml) was stirred at 60° C. for 3 hours and further at 100° C. for an additional hour. After cooling, the reaction mixture was poured into water followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting residue was purified by flash column chromatography on silica gel to give 258 mg (62%) of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([O:25][CH3:26])[CH:18]=1.[C:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:20]=1[CH:21]=[N:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(OCCBr)ccc1C=O
Reactant: c1ccc(C2CCCCN2)cc1
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Product: COc1cc(OCCN2CCCCC2c2ccccc2)ccc1C=NNC(=O)c1ccc(O)c(Cl)c1

Procedure:
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin—[building block 1]) (2 g, ˜2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 2-phenylpiperidine ([building block 3]) (3.0 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was purified by column chromatography on silica gel (28 g) eluting with a mixture of methanol and dichloromethane (1:13). This afforded 0.24 g of the title compound.