Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Cl[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]>>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][N:13]1[C:12]([S:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:21]
Reactant: Fc1ccc(CCCl)c(F)c1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-chloro-ethyl)-2,4-difluoro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. LC-MS [M+H]+ 444.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH3:14][CH:15]([NH2:23])[CH2:16][CH2:17][CH2:18][C:19](O)([CH3:21])[CH3:20].Cl>CO>[NH2:23][CH:15]([CH2:16][CH2:17][CH2:18][C:19]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([CH3:21])[CH3:20])[CH3:14]
Reactant: Cc1ccccc1C
Reactant: CC(N)CCCC(C)(C)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1ccc(C(C)(C)CCCC(C)N)cc1C

Procedure:
21.2 Parts of o-xylene, 128 parts of 98% w/w sulphuric acid, 24 parts of methanol, and 36.3 parts of heptaminol hydrochloride were stirred at room temperature for 3 days. The work up was carried out as described in Example 2 and gave on distillation 36.2 parts of 2-amino-6-(3,4-dimethylphenyl)-6-methylheptane b16 164°-8° with the following percentage composition by weight.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (638 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (495 mg, yield: 82%). This was recrystallized from ethanol-hexane. Melting point: 114–115° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@H:15]([CH2:19][CH3:20])[CH2:16][C:17]#[N:18])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:6][C:7]([F:21])([F:22])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C@H:15]([CH2:19][CH3:20])[CH2:16][C:17]([NH2:18])=[O:2])=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: CC[C@H](CC#N)Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
Aqueous sulfuric acid (8.2 L sulfuric acid and 1.1 L water premixed and cooled to 35° C. or less) was added to the crude toluene solution of (3R)-3-(4-trifluoromethyl-phenylamino)-pentanenitrile from Example 1. The resulting bilayer was stirred well and heated to 35° C. for 17 hours. The lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95 L water and 10.7 kg sodium hydroxide) and diisopropyl ether (IPE) (40 L). After extraction and removal of the aqueous layer, the organic layer was combined and extracted with saturated aqueous NaHCO3 (10 L). The organic phase from the resulting bilayer was concentrated by distillation to a volume of 19 L. The solution was then cooled to room temperature and seeded with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide and allowed to granulate for 3 hours while stirring. To the heterogenous mixture was added cyclohexane (38 L) and the mixture was granulated for an additional 11 hours. The solids were filtered, rinsed with cyclohexane (4 L), dried under vacuum at 40° C. to afford 3021 g (75%) of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][CH3:30])[N:23]=2)=[CH:19]\[CH2:20][NH2:21])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].Cl>N1C=CC=CC=1>[C:8]([C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][CH3:30])[N:23]=2)=[CH:19]\[CH2:20][NH:21][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc(/C(=C/CN)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1nc(/C(=C/CNC(C)=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic anhydride (21 μL) was added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-amine in pyridine (1 mL), and the mixture was stirred at room temperature for 1.5 hours. 1 M hydrochloric acid was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give N-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]acetamide as a pale yellow amorphous (50 mg, 67% (two steps)).
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>C1COCC1>[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH3:10]
Reactant: CCC[C@@H](C)CCC(=O)O
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 25 °C

Procedure:
To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0° C. was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followed by (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) (30 g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution concentrated under reduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave (4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one as an oil. 31.5 g; 79%. [α]D=+5.5 (c 1 in CHCl3). MS, m/z (relative intensity): 304 [M+H, 100%]; 1H NMR (400 MHz; CDCl3) δ 7.4–7.2 (m, 5H), 5.6 (d, J=7.32 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 1.62 (m, 1H), 1.43 (m, 1H), 1.25 (m, 4H), 1.12 (m, 1H), 0.85 (m, 9H); 13C NMR (100 MHz; CDCl3) 6173.70, 153.23, 133.81, 133.59, 128.92, 128.88, 128.92, 128.88, 125.83, 79.12, 54.93, 39.24, 33.66, 32.32, 31.47, 27.18, 26.52, 20.25, 19.57, 14.75, 14.52.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:16][CH2:17][C:18]([OH:20])=O>ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:21](=[CH:22][C:23]=1[F:24])[C:18](=[O:20])[CH2:17][CH2:16]2
Reactant: O=C(O)CCc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
Oxalyl chloride (1.12 mL) and DMF (78.2 mg) were added to a solution of 3,4-difluorohydrocinnamic acid (2.00 g) in dichloromethane (3.0 mL) at 0° C., and the reaction solution was stirred at room temperature overnight. After confirming that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. Next, a solution of the resulting residue in dichloromethane (10 mL) was added to a solution of aluminum chloride (2.13 g) in dichloromethane (20 mL) at −30° C. The reaction solution was stirred at room temperature for 1.5 hours. After confirming that the raw materials disappeared, the reaction solution was poured into ice water. The solution was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain 535 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>CN(C=O)C>[C:1]([N:5]([CH3:25])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(C#Cc2ccccc2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(C#Cc2ccccc2)cn1)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
(74 mg, 266 μmol) 5-Phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 2) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (14 mg, 319 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (22 μl, 346 μmol, 1.3 equiv.) was added, and the mixture was then stirred for 1 hour at room temperature. The reaction mixture was evaporated and treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 g, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (48 mg, 62% yield) was obtained as a light yellow solid, MS: m/e=293.0 (M+H+).
Reaction SMILES: C(OC[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]C=1)=[CH2:8])(=O)C.S(=O)(=O)(O)O.C(OCCC(C1C=CC=CC=1)=C)(=[O:22])C.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:7]([CH:9]1[CH2:14][CH:13]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=[CH:11][O:22]1)([CH3:6])[CH3:8]
Reactant: C=C(CCOC(C)=O)c1ccccc1
Reactant: C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1CC(c2ccccc2)C=CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 ml three neck reaction flask equipped with stirrer, thermometer, reflux condenser and addition funnel is placed 72 gms (1 mole) of isobutyl aldehyde. The isobutyl aldehyde is heated to 66° C (reflux) and from the additional funnel, over a period of 1 hour, is added a mixture of 204 g (1 mole) of 3-phenyl-3-buten-1-yl acetate and 1 g concentrated sulfuric acid. During addition of the 3-phenyl-3-buten-1-yl acetate/sulfuric acid mixture, the reaction mass temperature increases to 80°-85° C. At the end of the addition of the mixture, the reaction mass is stirred for a period of three hours at 80°-85° C. The reaction mass is then cooled to room temperature and 100 ml of a 10% aqueous sodium hydroxide solution is added thereto with stirring, followed by 100 ml cyclohexane. The resulting mixture is transferred to a separatory funnel and the aqueous layer is removed. The organic layer is then washed with one 100 ml portion of 10% aqueous sodium chloride. The organic layer is then stripped of solvent and rushed over. To the rushed over material 4.5 gms Primol®, 0.5 gms triethanolamine and 0.1 gms of Ionox® is added. The resulting material is then distilled in an 8 plate vigreux column yielding the following fractions:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12](C(O)=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:22](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[NH2:22][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: CCc1nn(C2CCCC2)c2cc(N)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (258 mg) and triethylamine (0.56 mL) in t-butanol (1 ml) was added diphenylphosphoryl azide (0.33 mL). The mixture was stirred at 100° C. for 4 h, then partitioned between water (25 mL) and ether (25 mL). The ether layer was collected, dried (MgSO4), and passed through a plug of silica. The silica was washed with an additional 25 mL of ether and the mixture was concentrated in vacuo. The residue was dissolved in THF (5 mL) and 6N aq. HCL (1 mL) was added and the mixture was stirred for 18 h. Ether (25 mL) and water (25 mnL) were added and the ether layer was collected, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel to yield 0.14 g of 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (59% yield). 1H NMR (300 MHz) δ 7.45 (d, J=8.4 Hz, 1H), 6.52 (m,2H), 4.74 (p,J=7.8 Hz, 1H), 3.86 (br,2H), 2.95 (q,J=7.7 Hz, 2H), 2.3-1.8 (m,6H), 1.8-1.6 (m,2H), 1.37 (t,J=7.7 Hz, 3H).
Reaction SMILES: COC(C1C=C(Cl)C2N([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)N=2)C=1)=O.[Br:39][C:40]1[CH:41]=[C:42]([O:47][CH3:48])[C:43]([NH2:46])=[N:44][CH:45]=1>>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:46]=[C:43]4[C:42]([O:47][CH3:48])=[CH:41][C:40]([Br:39])=[CH:45][N:44]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1cc(Cl)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reactant: COc1cc(Br)cnc1N
Product: COc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12

Procedure:
This intermediate was prepared in analogy to 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-8-chloro-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester by using 5-bromo-3-methoxy-pyridin-2-ylamine from Step 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO[C@@H]1CCCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium({[(2S,5R)-2-({[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 15 (0.30 g, 0.42 mmol) in DCM (17 mL) was added trifluoroacetic acid (0.84 mL, 10.9 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-[(3R)-piperidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 3 (Table 1) (0.045 g, 29.41%) as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][CH2:35][CH2:36][OH:37].[Br:38][C:39]1[O:43][C:42]([C:44]([OH:46])=O)=[CH:41][CH:40]=1>ClCCl>[Br:38][C:39]1[O:43][C:42]([C:44]([NH:34][CH2:35][CH2:36][OH:37])=[O:46])=[CH:41][CH:40]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol), N,N-diisopropylethylamine (0.82 mL, 4.7 mmol) and 2-aminoethanol (0.14 mL, 2.4 mmol) were added to a solution of 5-bromo-2-furoic acid (0.30 g, 1.6 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, water (5 mL) was added thereto. The whole was extracted with ethyl acetate (10 mL), and the organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.18 g) as a colorless solid (yield 49%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:18]([OH:20])=O)=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].CN.[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:18]([NH:28][CH3:27])=[O:20])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(NC(C)C)nncc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoic acid (0.22 g, 0.7 mmol) in DMF (2 mL) at RT was treated with a 2 M solution of methylamine (2 mL, 3 mmol), and HATU (0.4 g, 1 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4, concentrated in vacuo and purified by column eluting with 2-3% 2M ammonia MeOH/DCM to give the title compound. MS (ES+): 335 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]Br)=[CH:26][C:25]=1[F:34])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:15][CH:14]=3)[CH2:13][CH2:12]2)=[CH:26][C:25]=1[F:34]
Reactant: Fc1cc(OCCBr)ccc1OCc1ccccc1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc(OCCN2CCC(Cc3ccc(F)cc3)CC2)cc1F

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine hydrochloride (344 mg, 1.50 mmol), 2-(4-benzoxy-3-fluorophenoxy)ethyl bromide (487 mg, 1.50 mmol), potassium carbonate (518 mg, 3.75 mmol) in two steps as white-off solid (277 mg), mp 184-186° C. 1H NMR (CD3OD) 1.40 (m, 2 H), 1.709 (m, 3 H), 2.424 (d, J=4.8 Hz, 2 H), 2.850 (m, 2 H), 3.319 (m, 2 H), 3.443 (d, J=12.0 Hz, 2 H), 4.087 (s, 2 H), 6.50 (m, 1 H), 6.642 (m, 2 H), 6.833 (m, 2 H), 7.021 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:24][CH2:25][CH2:26][C:27]#[N:28])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCBr
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester 1 (2.00 g, 6.70 mmol), 4-bromobutyronitrile (0.70 mL, 6.70 mmol), and potassium carbonate (1.00 g, 7.4 mmol) in DMF (10 mL), was stirred at 65° C. for 16 h. Solvent was removed by rotary evaporation and the residue was taken up in ethyl acetate, washed with water and brine, and concentrated under vacuum. The crude product was purified by flash silica gel column chromatography eluting with ethyl acetate/CH2Cl2 (1:9, v/v) to give the desired product 2 as a white solid (1.80 g, 75% yield). 1H NMR (300 MHz, CDCl3) δ 1.56 (m, 4H), 2.15 (m, 2H), 2.55 (m, 4H), 3.15 (m, 2H), 4.00 (m, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H), 7.30 (m, 5H). m/z (ESI): 367 [C22H26N2O3+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH:17]([C:20]1[N:24]2[N:25]=[CH:26][C:27]3[C:32]([C:23]2=[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]=1/[CH:39]=[CH:40]/[CH:41]=[O:42])=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH3:19])[CH3:18]>O1CCCC1.CCCCCC>[OH:42][CH:41](/[CH:40]=[CH:39]/[C:21]1[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[N:25][N:24]2[C:20]=1[CH:17]([CH3:19])[CH3:18])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)c1c(/C=C/C=O)c(-c2ccccc2)c2c3ccccc3cnn12
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A stirred suspension of sodium hydride (80% dispersion in oil, 112 mg; 3.7 mmol) in dry tetrahydrofuran (15 ml) was treated with ethyl acetoacetate (0.43 g) under an atmosphere of argon, maintaining the temperature at -10° C. The mixture was stirred for 30 minutes and then it was treated with a solution of butyl lithium in hexane (2.5M; 1.38 ml), still maintaining the temperature at -10° C. The mixture was stirred for a further period of 20 minutes and then it was treated dropwise with a solution of (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)propenal (0.56 g) in tetrahydrofuran (5 ml) at -10° C., and the resulting mixture was stirred at -10° C. for 1 hour. The reaction mixture was then quenched at -10° C. by treatment with saturated aqueous ammonium chloride solution (15 ml). The mixture was allowed to warm to the ambient temperature and then it was partitioned between water (20 ml) and diethyl ether (50 ml). The organic layer was separated and the aqueous layer was extracted with diethyl ether (50 ml). The combined organic layers were dried over magnesium sulphate, evaporated and subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (3:1 v/v), to give ethyl (E)-5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-3-oxohept-6-enoate (0.33 g) in the form of an orange oil. [NMR (in a mixture of CDCl3 and D2O): 1.27 (3H, t, J=7 Hz), 1.54 (6H, d, J=7 Hz), 2.52-2.62 (2H, m), 3.44 (2H, s), 3.78 (1H, septet, J=7 Hz), 4.21 (2H, q, J= 7 Hz), 4.50-4.62 (1H, m), 5.3 (1H, dd, J=16 Hz, 7 Hz), 6.65 (1H, dd, J=16 Hz, 1 Hz), 7.22-7.62 (9H, m), 8.24 (1H, s)].