Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: NCCCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)c(NCCCc2ccccc2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
500 mg of dimethyl 5-bromo-pyridine-2,4-dicarboxylate (from Example 3) are dissolved in 10 ml of toluene. 0.26 ml of phenylpropylamine are added dropwise and the mixture is stirred at 120° C. for 10 hours. After cooling, the solvent is evaporated off, the residue is taken up in ethyl acetate and the organic phase is washed with 2 portions each of citric acid, sodium bicarbonate solution and water. After drying over magnesium sulfate, the solvent is evaporated. Chromatography on silica gel gives 117 mg of product with a melting point of 102°-104° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (1.826 g, 5.00 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.200 g, 5.00 mmol) dissolved in water (2.000 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.306 mL, 5.00 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown semi-solid. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.141 g, 68%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.15 (m, 4H), 2.58-2.67 (m, 1H), 2.77-2.86 (m, 1H), 2.93-3.03 (m, 1H), 3.10-3.21 (m, 1H), 3.63 (s, 3H), 3.96-4.05 (m, 1H), 4.22-4.32 (m, 1H), 5.73 (s, 1H), 6.81-6.95 (m, 3H), 7.18-7.27 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [O:1]1C[CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17]>>[OH:1][CH:2]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N+:16]([O-:18])=[O:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Product: O=C1c2ccccc2C(=O)N1CC(O)n1ccnc1[N+](=O)[O-]

Procedure:
According to the General Reaction Scheme, N-(2,3-epoxypropyl)phthalimide (1) is reacted with 2-nitro-imidazole (2) to obtain 2-[2-Hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3). This product is then reacted with N-hydroxyphthalimide, preferably in the presence of a tertiary amine such as triphenylphosphine, to obtain the intermediate of Formula II, 2-{2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione (4). This intermediate is then reacted with hydrazine to obtain 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H-imidazole dihydrochloride (5), which is then reacted with the compound of Formula III to yield the compound of Formula I. A preferred compound of Formula III is 3-chloro-3-methyl-2-nitrosobutane, which, when used contacted with 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H-imidazole dihydrochloride (5), yields 3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime (7).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)=[O:6].[CH3:26][C:27]1[CH:28]=[CH:29][C:30](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH:34]=1)[C:32]#[N:33].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:32]([C:31]1[CH:34]=[C:27]([CH3:26])[CH:28]=[CH:29][C:30]=1[C:2]1[CH:18]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=2)=[O:6])[CH:3]=1)#[N:33]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: Cc1ncc(CNC(=O)c2cc(Br)cc(C(=O)N3CCCC3)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCC3)c2)c(C#N)c1
Temperature: 90 °C

Procedure:
Into a Parr pressure reactor were charged 3-bromo-N-((2-methylpyrimidin-5-yl)methyl)-5-(pyrrolidine-1-carbonyl)benzamide (240 mg, 0.48 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (160 mg, 0.58 mmol) (WO 2008/130481), toluene (5 mL), ethanol (1 mL), cesium carbonate (170 mg, 0.52 mmol), and water (0.5 mL). The mixture was degassed and purged with nitrogen several times and then tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) was added. The tube was sealed and the mixture was heated at 90° C. overnight. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified via flash chromatography and then preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[H-].[Na+].Cl>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]1=[O:19])[CH2:10]2
Reactant: ClCc1ccccn1
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1Cc1ccccn1

Procedure:
1—This material was obtained as described in example 23 from 1-adamantan-2-yl-4-isopropyl-1,3-dihydro-imidazol-2-one (obtained in example 8, 100 mg) by alkylation with 2-chloromethylpyridine hydrochloride (73 mg) with the following modification: 2.5 equivalents of NaH dispersion (42 mg) was used such as to compensate for the HCl content in the alkylating agent. 1-Adamantan-2-yl-4-isopropyl-3-pyridin-2-ylmethyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow gum (64 mg). MS (ESI): 352.2 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)=[O:16]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 50 °C

Procedure:
A mixture of 4-tert-butyl-phenylamine (5.8 mL, 36.5 mmol), 2-amino-benzoic acid (5.0 g, 36.5 mmol), TBTU (12.9 g, 40.2 mmol) and DIEA (6.7 mL, 40.2 mmol) in 5 mL of DMF was heated (50° C.) for 12 h in a sealed tube. The mixture was diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) and crystallized from EtOH:H2O (3:1) to afford a yellow solid. MS (ES+): 269.4. (M+H)+. Calc'd for C17H20N2O-268.35.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C.[CH3:23][CH:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>C(Cl)Cl>[CH3:23][CH:24]([S:26]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-BOC-piperazine (0.617 mmol) and diisopropylethylamine (0.679 mmol) in 0.5 mL of methylene chloride was added to a 4 mL vial. Propane-2-sulfonyl chloride (0.679 mmol) was added to the vial, and the reaction mixture was shaken overnight at room temperature. When the reaction was complete, it was diluted with 1.5 mL of methylene chloride and extracted with 1 mL of 1N solution of hydrogen chloride followed by 1 mL of 10% potassium carbonate solution. The organic layer was concentrated in vacuo. The residue was dissolved in 0.5 mL of tetrahydrofuran and 4M solution of hydrogen chloride in dioxane (0.5 mL). The solution was shaken overnight at room temperature then concentrated in vacuo to give 1-(propane-2-sulfonyl)-piperazine.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][S:37]([CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:39])=[O:38])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NS(=O)(=O)Cc3ccccc3)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 39 mg (0.2 mmol) alpha-toluenesulphonylchloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 40 mg (38%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-C-phenyl-methanesulfonamide as a light yellow solid. MS ISP (m/e): 525.9 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.48 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.60 (d, 1H), 7.26-7.21 (m, 6H), 7.06 (d, 1H), 7.03 (s, 1H), 4.39 (q, 1H), 4.13 (d, 1H), 4.03 (d, 1H), 3.83 (s, 3H), 2.14 (s, 3H), 1.69 (m, 2H), 1.56 (m, 1H), 0.86 (d, 6H).
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][NH:5]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>CN(C=O)C>[NH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-L-Dab(Fmoc)-OH (132 mg, 0.3 mmol, PepTech) and piperidine (0.2 mL, 2.02 mmol) were dissolved in DMF (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and the residue was used directly in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc(C)n1
Yield: 46.8 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (102 mg, 47%). MS (ISP) 437.2 [(M+H)+]; mp 257° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:23][C:24](=O)[NH:25][C:26]2[S:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH:14][C:24]([NH:25][C:26]3[S:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=3)=[O:23])[CH2:8]2)=[CH:15][CH:16]=1
Reactant: NCCCN1CC(Cc2ccc(Cl)cc2)C1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)NCCCN2CC(Cc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of 3-[3-(4 chloro-benzyl)-azetidin-1-yl]-propylamine (0.100 mg, 0.418 mmol) and (5-ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.11 mg, 0.439 mmol) in DMSO is stirred at room temperature for 18 hours then partitioned between ethylacetate and water. The organic phase is washed with brine and dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 5% methanol in DCM as eluent to afford 1-{3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea. [M+H] 394.1
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][OH:46].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:40]2[CH2:44][CH2:43][CH2:42][C@H:41]2[CH2:45][OH:46])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC[C@H]3CO)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 68.7 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (119 mg, 0.208 mmol) was dissolved in N,N-dimethylacetoamide (1.2 mL), and the solution was treated with (S)-(+)-2-pyrrolidinemethanol (0.205 mL, 2.08 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain (S)-4-chloro-5-[3-(2-hydroxymethylpyrrolidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (91.0 mg, yield 69%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[C:20]1([CH2:26][CH2:27][CH:28]2[CH2:30][O:29]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO.O.CN(P(N(C)C)(N(C)C)=O)C>[OH2:7].[OH:29][CH:28]([CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:30][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: c1ccc(CCC2CO2)cc1
Reactant: C#CCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: O=C(O)CCCC#CCC(O)CCc1ccccc1
Reaction time: 48 h

Procedure:
In a dry flask under N2 was placed 200 ml of HMPA (distilled over NaH) and 24.4 g (0.218 mole) of 5-hexynoic acid, the product of 1b. The solution was stirred at 0° and was added a solution of n-BuLi in hexane (256 ml, 0.436 mole) dropwise. After 2 hours stirring, 2-phenylethyloxirane (33.9 g. 0.229 mole) was added and stirring was continued at RT for 2 days. The reaction mixture was cooled to 0° and 200 ml of H2O was added. The aqueous solution was acidified with 6N HCl and then extracted with Et2O three times. The ether solution was washed once with H2O and was extracted with aqueous NH4OH solution. The aqueous NH4OH solution was reacidified with 6N HCl and then extracted with ether. Removal of the solvent yielded the crude product. The crude product was converted to the corresponding methyl ester via reaction with MeOH in the presence a catalytic amount of BH3 ·Et2O (0.2 ml). The methyl ester was purified by flash column chromatography (Silica gel, EtOAc-petroleum ether(1:4)) and subsequently was hydrolyzed to the acid in the mixture of K2CO3 -MeOH-H2O at RT. The acid was distilled through a Kugelrohr adaptor to give the title compound, bp 190°-195°/0.01 nmmHg (pot temperature).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+]=[N-].[Na+].CP(C)C>CN(C=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:21])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: CP(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure E using 8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.685 g, 2.12 mmol) and sodium azide (1.10 g, 17 mmol, 8 eq) in DMF (10 mL). The resulting intermediate was submitted to trimethyl phosphine (1.0M) in THF (2.5 mL, 2.5 mmol, 1.2 eq) in THF (8 mL) and water (2 mL). (8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine was obtained as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1 H, s), 8.05 (1 H, dd, J=8.6, 1.2 Hz), 8.00 (1 H, dd, J=7.4, 1.2 Hz), 7.63-7.73 (2 H, m), 7.47-7.62 (3 H, m), 3.90 (1 H, s), 3.75 (1 H, s) Mass Spectrum (ESI) m/e=303.1 and 305.0 (M+1)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCCO)C.O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2[N:29]1[CH2:30][CH2:31][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1cc(Cl)c2cc(NCc3ccccc3)ccc2n1
Solvent: O
Solvent: CCOCCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(NCc3ccccc3)ccc2n1

Procedure:
Benzyl-(4-chloro-2-methylquinolin-6-yl)amine (0.041 g; see Preparation 4 above) and 3-phenylpyrrolidine in 2-ethoxyethanol (1 mL) were heated in a microwave to 240° C. for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated and the sample evaporated to dryness. Trituration from ether gave the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11](I)([F:16])[C:12]([F:15])([F:14])[F:13].CCCCCC>C(Cl)Cl>[C:2]1([C:1]([C:11]([F:16])([F:10])[C:12]([F:15])([F:14])[F:13])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1ccccc1)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
Under protective gas, 35 g (0.25 mol) of benzoyl chloride in 150 ml of CH2Cl2 are initially introduced at about -20° C. into a round-bottomed flask. 67 g (0.27 mol) of pentafluoroethyl iodide are first condensed in and 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide are then metered in. The reaction mixture is subsequently stirred at 0° C. for 5 hours more. After addition of the same volume of hexane to the reaction mixture, 2 phases are formed. After phase separation, the lower phase is carefully extracted using hexane; the combined hexane phases are concentrated and distilled under reduced pressure. 20.8 g (58% yield) of pentafluoroethyl phenyl ketone of b.p. 76-77/40 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1)(=[O:26])[CH3:25]
Reactant: COc1ccc(-c2nc(N)n3nc(-c4ccco4)nc3n2)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc(NC(C)=O)n3nc(-c4ccco4)nc3n2)cc1

Procedure:
A solution of 7-amino-2-(2-furyl)-5-[4-methoxyphenyl][1,2,4]triazolo[1,5-a][1,3,5]triazine (0.23 g) in acetic anhydride (10 ml) was heated on the steam-bath for 18 hours. The solvent was then evaporated in vacuo and the residue was purified by chromatography on silica-gel eluting with dichloromethane containing ethyl acetate (5% v/v). The solid obtained from the chromatography was crystallised from ethanol and gave 7-acetylamino-2-(2-furyl)-5-[4-methoxyphenyl][1,2,4]triazolo[1,5-a][1,3,5]triazine m.p. 243°-6° C.; microanalysis, found: C, 58.0; H, 4.0; N, 23.9% C17H14N6O3 requires C, 58.3; H, 4.0; N, 24.0%; NMR 2.50 (s, NHCOCH3), 3.87 (s, 3H, CH3O), 6.75 (d of d, 1H, furyl-4H), 7.12 and 8.42 (A2B2 pattern, 4H, phenyl-H), 7.32 (d, 1H, furyl-3H), 7.98 (d, 1H, furyl-5H) and 11.42 (s, H, NHCOCH); m/e 351 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[O:6]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([N:17]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: OC(CCl)CN(CC(O)CCl)c1ccc(Oc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To a four-necked flask equipped with a thermometer, a dropping funnel, a cooling tube, and a stirrer was charged with 610.6 g (6.6 mol) of epichlorohydrin, and then the inside of the four-necked flask was purged with nitrogen. In 1018.5 g of ethanol was dissolved 203.7 g (1.1 mol) of 4-phenoxyaniline powder. The temperature of the epichlorohydrin was raised to 70° C. and the ethanolic solution of 4-phenoxyaniline was dropped over 4 hours. Moreover, the reaction was continued at 70° C. for six hours under stirring to produce 4-phenoxy-N,N-bis(2-hydroxy-3-chloropropyl)aniline.