Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([OH:13])[CH:4]=1.C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CCOCC>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:13][C:5]1[CH:4]=[C:3]([CH2:2][Cl:1])[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=1
Reactant: Oc1cc(CCl)nc(C(Cl)(Cl)Cl)n1
Reactant: CN(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc(CCl)nc(C(Cl)(Cl)Cl)n1
Yield: 60.1 %

Procedure:
A solution of 1.3 g (0.005 mole) 6-chloromethyl-4-hydroxy-2-trichloromethylpyrimidine, 0.55 g (0.005 mole) triethylamine, 0.55 g (0.005 mole) dimethylcarbamoyl chloride and 25 ml ether was refluxed 20 hours. The solvent was rotary evaporated and the residue extracted with refluxing ligroin. The extract was cooled to yield 1.0 g (60% yield) of pure product as a thick oil. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:17][CH2:18][C:19](O)=[O:20].[NH2:22][C:23]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:24]=1[C:25](=[N:32][CH:33]([CH3:36])[CH2:34][OH:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O.O.O1CCCC1>[NH2:17][CH2:18][C:19]([NH:22][C:23]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:24]=1[C:25](=[N:32][CH:33]([CH3:36])[CH2:34][OH:35])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:20]
Reactant: CC(CO)N=C(c1ccccc1)c1cc(Cl)ccc1N
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)N=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)CN
Yield: 32.9 %

Procedure:
To a solution of 4.5g of N,N'-dicyclohexylcarbodimide in 100ml of dimethylformamide is added a solution of 2.2g of glycine hydrochloride in 2.2ml of water in a period of about 30 seconds under stirring and ice-cooling. To the reaction mixture is immediately added dropwise a solution of 3.3g of 2-[(2-amino-5-chloro-α-phenylbenzylidene)amino]propanol in 10ml of tetrahydrofuran and the mixture is stirred for further 3 hours at room temperature. After the reaction is completed, the reaction mixture is treated by the same manner as described in the Example 1 to give 1.3g of the desired product melting at 168°-172° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)O)c3)cc2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.235 mL, 0.235 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 145-(2); 39.3 mg, 0.078 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature for three days. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (26.8 mg, 70%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH3:38]>CN(C=O)C.[Cu]I>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10](/[CH:36]=[C:37](/[C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)\[CH3:38])[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=CBr)c1ccncc1
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C(C)(C)C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-tert-Butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (212 mg, 1 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. Yield: 12 mg. 1H NMR (CD3OD, freebase) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.42 (d, 1H), 7.36 (s, 1H), 7.30 (dd, 1H), 7.10 (d, 1H), 3.80 (m, 2H), 2.95 (m, 2H), 2.85 (m, 2H), 2.60 (s, 3H), 2.00 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH3:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: COc1ccccc1C(C)c1ccccc1OC
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Solvent: CI
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethane (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed. After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49°-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]2[C:17]([C:21](OC)=[O:22])=[CH:18][CH:19]=[CH:20][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BH4-].[Li+].C(=O)([O-])O.[Na+].COC(C)(C)C>O1CCCC1>[OH:22][CH2:21][C:17]1[C:7]2[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2c1N(COCC[Si](C)(C)C)C(=O)CCC2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CO)c21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of 1.500 g of methyl 2-oxo-1-(trimethylsilanylethoxymethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-9-carboxylate in 35 ml of tetrahydrofuran is admixed with 0.205 g of lithium borohydride. The reaction mixture is stirred at 50° C. over 4 hours and subsequently poured onto 300 ml of a 1:1 mixture of saturated aqueous sodium hydrogencarbonate solution and tert-butyl methyl ether. The phases are separated and the aqueous phase is extracted with 150 ml of tert-butyl methyl ether. The combined organic phases are washed with 150 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=4.38.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]3[N:15]=[N:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:18](O)[C:13]=3[C:12]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:11]2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:33]>C(Cl)Cl>[Cl:33][C:18]1[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:16][N:15]=[C:14]2[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:11]=[C:12]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCN(CCn2nc(N3CCCC3)c3c(O)c(-c4ccccc4)nnc32)CC1
Solvent: ClCCl
Product: CN1CCN(CCn2nc(N3CCCC3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 60 °C

Procedure:
A suspension of 1-[2-(4-methylpiperazin-1-yl)ethyl]-5-phenyl-3-pyrrolidin-1-yl-pyrazolo[3,4-c]pyridazin-4-ol (90 mg) in POCl3 (6 mL) and CH2Cl2 (3 mL) was heated to 60° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The layers were separated and the aqueous was extracted with CH2Cl2, the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to provide Compound Iz (12 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>ClCCl>[NH2:24][C:9]1[C:8]2[N:25]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:26][CH2:27][CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:22][CH2:23]3)=[CH:12][C:11]=2[N:10]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(=O)NC(C)C)CC4)ccc3c21
Reaction time: 16 h

Procedure:
2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Isopropyl isocyanate was added dropwise to the slurry and the reaction was stirred for 16 hours. The reaction was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-22% CMA in chloroform) followed by recrystallization from acetonitrile yielded 0.430 g of 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamide as a white solid, mp 163-164.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: Nc1cc(CO)cc([N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a solution of 3-amino-5-nitrobenzoic acid (1.12 g, 6.16 mmol) in THF (5 mL) was added dropwise a solution of borane tetrahydrofuran complex solution (13.6 mL, 13.6 mmol) at ambient temperature and the mixture was stirred for 90 minutes. The solvent was then evaporated. Aqueous NaOH (15 mL) was added and the resulting mixture was extracted with ether. The ether solution was dried over anhydrous Na2SO4. Evaporation of ether afforded 921 mg of the title compound (89%).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20](I)=[CH:21][C:15]=3[S:14](=[O:24])(=[O:23])[N:13]=2)=[C:8]([OH:25])[C:7]2=[CH:26][CH:27]=[CH:28][N:6]12.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>[Cu]I.CN(C)C=O>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[CH:21][C:15]=3[S:14](=[O:24])(=[O:23])[N:13]=2)=[C:8]([OH:25])[C:7]2=[CH:26][CH:27]=[CH:28][N:6]12
Reactant: CC(C)(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Reactant: CS(N)(=O)=O
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccn21
Yield: 50.8 %

Procedure:
1-(3,3-Dimethyl-butyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 4d, 0.065 g, 0.120 mmol), potassium triphosphate (0.128 g, 0.60 mmol), sarcosine (0.006 g, 0.072 mmol), and copper (I) iodide (0.006 g, 0.03 mmol) were combined. Anhydrous N,N-dimethylformamide (2 mL) was added followed by methanesulfonamide (0.114 g, 1.2 mmol). The solution was degassed while stirring under vacuum and the flask was purged with nitrogen. The mixture was stirred at 100° C. for 2 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with 1.0 M aqueous hydrochloric acid solution (3×50 mL) and dried over magnesium sulfate. The entire organic layer was passed through a plug of silica gel. The filtrate was concentrated in vacuo to afford a solid. The solid was triturated with a 1:1 mixture of ethyl acetate and hexanes, collected by vacuum filtration, triturated with methanol and collected by vacuum filtration. The solid was dried in vacuo for 16 h to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.031 g, 0.061 mmol, 51% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.01 (9H, s), 1.57-1.62 (2H, m), 3.07 (3H, s), 4.39-4.43 (2H, m), 6.70-6.72 (1H, m), 7.03 (1H, d, J=3.8 Hz), 7.53 (1H, dd, J1=8.7 Hz, J2=2.8 Hz), 7.60 (1H, d, J=2.3 Hz), 7.67 (1H, d, J=8.4 Hz), 7.75 (1H, s), 10.20 (1H, s), 13.72 (1H, bs). LC-MS (ESI) calcd for C21H25N5O6S2. found 507.12. found 508.36 [M+H+].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@H:16]([N:17]([CH3:34])[C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:15][CH2:14][N:13]([C:35](=[O:44])[CH2:36][NH:37][CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[C:45](O)(=[O:47])[CH3:46]>>[ClH:3].[C:45]([N:41]1[CH2:40][CH2:39][CH:38]([NH:37][CH2:36][C:35]([N:13]2[CH2:14][CH2:15][C@@H:16]([N:17]([CH3:34])[C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C@H:11]([C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)[CH2:12]2)=[O:44])[CH2:43][CH2:42]1)(=[O:47])[CH3:46]
Reactant: CC(=O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)CNC2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(=O)N1CCC(NCC(=O)N2CC[C@@H](N(C)C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in step 2 and acetic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH:12]2[C:17](=O)[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)=[CH:5][CH:4]=1.O.NN.[OH-].[K+]>C(O)COCCO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH:16]3[CH2:15][CH2:14][N:13]2[CH2:20][CH2:19]3)=[CH:5][CH:4]=1
Reactant: O=C(CCC1C(=O)C2CCN1CC2)c1ccc(Cl)cc1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: Clc1ccc(CCCC2CC3CCN2CC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 15.06 g (0.046 mole) 2-[3-(4-chlorophenyl)-3-oxopropyl]-1-azabicyclo[2.2.2]octane-3-one hydrochloride, 45 ml (0.93 mole) hydrazine monohydrate, 50.6 g (0.9 mole) potassium hydroxide and 75 ml diethylene glycol and heat to 100° C. After 3 hours, fit the reaction flask with a distillation head and heat reaction in an oil bath until oil bath temperature reaches approximately 190° C. Heat at this temperature for 5 hours. Cool the reaction mixture to room temperature. Quench the cool mixture with 500 ml H2O. Adjust the pH with concentrated hydrochloric acid to pH=1. Wash the aqueous layer 1×250 ml diethyl ether. Adjust pH of the aqueous layer to pH=11 with ammonium hydroxide. Extract with 3×250 ml methylene cloride. Dry the extracts over potassium carbonate, filter and remove the solvents in vacuo to obtain 2-[3-(4-chlorophenyl)propyl]-1-azabicyclo[2.2.2]octane as an oil. Dissolve this oil in 50 ml ethanol and acidify with HCl gas. Remove the solvents in vacuo to obtain an oil. Triturate the residue in diethyl ether to obtain the title compound. Recrystallize product from 2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[NH:18][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[O:34]=[C:35]1[NH:39][C:38]2[CH:40]=[CH:41][C:42]([S:44](Cl)(=[O:46])=[O:45])=[CH:43][C:37]=2[S:36]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[N:18]([S:44]([C:42]3[CH:41]=[CH:40][C:38]4[NH:39][C:35](=[O:34])[S:36][C:37]=4[CH:43]=3)(=[O:46])=[O:45])[CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19]
Reactant: COc1ccc(OCCN2CCC3CCCC(N3)C2=O)cc1OC
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCN2CCC3CCCC(C2=O)N3S(=O)(=O)c2ccc3[nH]c(=O)sc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (15 mg, 0.05 mmol) in 3 ml DCM was treated with DIPEA (12 mg, 0.09 mmol) and stirred for 30 min at room temperature followed by addition of 2-oxo-2,3-dihydrobenzo[d]thiazole-6-sulfonyl chloride (22 mg, 0.09 mmol). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-HPLC in 55-65% buffer B in 16 mins.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:24])[CH:23]=1)[C:20](=[O:25])[N:19]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29]C(=O)C)[N:18]=[CH:17]2)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:24])[CH:23]=1)[C:20](=[O:25])[N:19]([C:26]1[C:27]([CH2:28][OH:29])=[C:33]([C:2]3[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=3)[CH:34]=[CH:35][CH:36]=1)[N:18]=[CH:17]2)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: NC(=O)c1csc(Br)n1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4nc(C(N)=O)cs4)c3CO)ncc2c1
Yield: 10 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 2-bromothiazole-4-carboxylic acid amide (intermediate-2) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 5). The desired compound was prepared in two steps (10% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J=2.4 Hz, 1H), 8.46 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.88-7.79 (m, 2H), 7.66-7.63 (m, 2H), 4.61-4.52 (m, 2H), 1.46 (s, 9H). LC-MS calcd for C23H21FN4O3S 452.13, obsd 453 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].O>C(O)=O>[CH:25]([NH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2)=[O:26]
Reactant: COC(=O)CC/C(C)=C/Cc1c(N)c2c(c(C)c1OC)COC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O=CO
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(NC=O)c2c(c(C)c1OC)COC2=O
Yield: 66.4 %

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.32 g, 1 mmol) in 3 ml formic acid was cooled to 0° C. and treated with 0.45 g of carbonyldiimidazole. After 1 hour water was added and the precipitate collected by filtration. This material was recrystallized from isopropanol to give 0.24 g of methyl (E)-6-[1,3-dihydro-4-formamido-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, as a white solid, mp 187°-189° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[NH:5][N:4]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([N:5]2[C:6]([C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=3)=[CH:7][C:3]([C:2]([F:1])([F:15])[F:16])=[N:4]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(-c2cc(C(F)(F)F)n[nH]2)cc1
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2)cc1

Procedure:
This compound was isolated by silica gel chromatography following arylation of 3-trifluoromethyl-5-(p-tolyl)-1H pyrazole using iodobenzene as described in Example 1.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C=CC=CC=1.[C:32](Cl)(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH:25][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH3:24])[CH3:23])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(N)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C)(C)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 4 h

Procedure:
In a 500 ml, three-neck, round-bottom flask equipped with a thermometer, stirrer and dropping funnel were placed 26 g (0.75 mole) of 2-amino-2-methylpropyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, 200 ml of benzene and 8.2 g of triethylamine. To this stirred mixture was added 22.5 g (0.075 mole) of stearoyl chloride, and the mixture stirred for 4 hours. The triethylamine hydrochloride was removed by filtration and the solvent was stripped off. The residue was dissolved in hot hexane. After crystallization, filtration and drying, the title compound melted at 46°-48° C.