Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[Br:19][C:17]1[CH:18]=[C:13]([C:21]2([CH:22]=[CH:23][CH:24]=[CH:25][CH2:26]2)[CH2:20][OH:27])[CH:14]=[N:15][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCC1(c2cncc(Br)c2)C=CC=CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
n-Butylmagnesium chloride (3.49 mmol) in 2.05M tetrahydrofuran solution (1.70 mL) was added to ice-cooled n-butyllithium (6.99 mmol) in 1.52M hexane (4.60 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. The suspension was added to a tetrahydrofuran solution (25 mL) containing 3,5-dibromopyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more, while keeping the temperature below −5° C., to give an orange suspension. The suspension was stirred at −10° C. for one hour, and benzaldehyde (1.35 mL, 13.3 mmol) was added thereto. The resultant mixture was stirred at 0° C. for 30 minutes, and then 1M acetic acid solution (15 mL) was added. The reaction mixture was extracted twice with ethyl acetate (20 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate and was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (5:1, v/v) to give the title compound (1.647 g, 59% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Br:17][C:18]1[CH:19]=[C:20]([S:28](Cl)(=[O:30])=[O:29])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:28]([C:20]3[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:18]([Br:17])[CH:19]=3)(=[O:30])=[O:29])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of ((R)-4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (446 mg, 2.0 mmol) and 3-bromo-5-trifluoromethyl-benzenesulfonyl chloride (970 mg, 3.0 mmol) in tetrahydrofuran (5 mL) was added a solution of dimethyl-pyridin-4-yl-amine (489 mg, 4.0 mmol) in tetrahydrofuran (5 mL) dropwise. After being stirred at room temperature overnight, the mixture was concentrated. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (750 mg, 63.6%) as a white solid. MS calcd. for C18H19BrF3N3O4S 509, obsd. (ESI+) [(M+H)+] 510.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[C@@H:25]([CH3:27])O.CO>C(Cl)Cl>[C:30]([O:29][C:24](=[O:28])[C@@H:25]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Yield: 62 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 and (+)-tert-butyl d-lactate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-7% methanol in DCM) to give (S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester as a yellow solid (70 mg, 62%). LCMS: RT=3.76 min, [M+H]+=440.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 74.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.242 g, 1.22 mmol) was reacted with 2-azidoethanamine (0.105 g, 1.22 mmol) and triethylamine (0.246 g, 2.43 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-butylbenzamide (0.224 g, 75%). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.39 (t, 1H), δ 7.17 (d, 2H), δ 3.55 (q, 2H), δ 3.45 (t, 2H), δ 2.60 (t, 2H), δ 1.56 (m, 2H), δ 1.30 (m, 2H), δ 0.90 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.2, 131.7, 128.8, 127.4, 50.9, 39.7, 35.7, 33.5, 22.5, 14.1 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1481. Found 246.1476.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:3])[CH3:2].[NH2:18][CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=3)[CH:26]=2)[O:21]1.[OH-].[Na+]>C(O)(C)C>[CH:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:5]=1[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:18][CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[CH:26]=2)[O:21]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1OC[C@@H]1CO1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)c1cccc(C(C)C)c1OC[C@@H](O)CNC[C@H]1CCc2cc(-c3ccc(C(=O)O)cc3)ccc2O1
Temperature: 80 °C
Reaction time: 72 h
Yield: 41.8 %

Procedure:
Crude (2S)-2-[(2,6-diisopropylphenoxy)methyl]oxirane (Example 17, 0.55 mmol), was diluted in 2 mL of isopropanol (10% water), and treated with methyl 4-[(2R)-2-(aminomethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 39, 88 mg, 0.26 mmol). This mixture was stirred at 80° C. for 72 hours, then 1N sodium hydroxide (2 mL) was added to the solution at room temperature, and stirred for another 0.5 hour. The product was then purified by preparative HPLC (Gradient 0-70% Acetonitrile/0.1% aq. TFA) to obtain 56.3 mg of product (as a TFA salt) MH+518.3 (free base).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:35])[C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH2:27][CH2:28][NH:29][S:30](=[O:33])(=[O:32])[NH2:31])[CH:17]=2)=[C:4]([O:36][CH3:37])[CH:3]=1.[OH:38]OS([O-])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O.[OH2:57]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:35])[C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([S:26]([CH2:27][CH2:28][NH:29][S:30](=[O:32])(=[O:33])[NH2:31])(=[O:38])=[O:57])[CH:17]=2)=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: O
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(N)(=O)=O)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCNS(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To an ice-cold solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(2-(sulfamoylamino)ethylthio)-5-(trifluoromethyl)benzamide (0.058 g, 104 μmol, example 261) in MeOH (2 mL) and water (0.5 mL) was added oxone (160 mg, 260 μmol) and the white suspension was stirred at room temperature for 3.5 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The crude product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.047 g; 76%). MS (ESI): m/z=591.10 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(CCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
89.1 mg (0.50 mmol) of diphenylacetylene (1), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 89.4 mg (0.49 mmol) of 1,2-diphenylethane (2). The yield was 98%.
Reaction SMILES: ClC1C=C[C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34](OC(F)(F)F)[CH:33]=2)=NC=1>C(O)=O.CC(=O)OCC.O.[Zn]>[CH2:8]([C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]=[O:25])[C:15](=[O:30])[N:14]([CH3:31])[C:13]=2[N:12]=[CH:11][C:10]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=1[CH:10]([CH3:32])[CH3:11])[CH2:5][CH:8]([CH3:9])[CH3:5]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cn3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 80 °C
Yield: 276.8 %

Procedure:
To a solution of 5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.048 mmol) in HCOOH (1 mL) was added Zn dust (30 mg, 0.48 mmol). The reaction was heated at 80° C. for 30 min, cooled to RT then diluted with EA (2 mL) and water (2 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-isopentyl-6-(2-isopropyl phenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propylformate (30 mg, 90% yield) as a an oil. LCMS: MH+ 549 and TR=2.286 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24]([O:26]CC)=O)=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].C1COCC1.[NH4+:41].[OH-]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:30])[CH3:31])[C:21]([C:24]([NH2:41])=[O:26])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(C(N)=O)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
To a vial containing Ethyl 5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate (59 mg, 0.1 mmol) was added THF (0.6 mL) and NH4OH (0.2 mL). The solution was stirred at room temperature for 16 h. EtOAc (30 mL) was added. The organic phase washed with water (2×10 mL) and dried over Na2SO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (4.0 mg, 8% yield). HPLC retention time=2.76 minutes. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.0, 1H), 8.16 (d, J=2.0, 1H), 8.05 (d, J=2.4, 1H), 7.85 (dd, J=2.4, 8.4, 1H), 7.53 (d, J=8.4, 1H), 5.75 (sept, J=6.8, 1H), 1.52 (d, J=6.8, 6H). MS (ES) [M+H]+ expected 523.0. found 522.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:30][CH2:31][CH2:32][CH3:33].Cl.Cl.[CH3:36]OC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.C(OC1C=C(C=CC=1OC)C=O)C(C)C>>[CH2:31]([O:30][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:3]=1[O:2][CH3:1])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[CH:32]([CH3:36])[CH3:33]
Reactant: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1OC
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: COc1ccc(C=O)cc1OCC(C)C
Agent: Cl
Product: COc1ccc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)cc1OCC(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide (example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3-isobutoxy-4-methoxy-benzaldehyde (intermediate E12) in a yield of 15.1 mg (21%). MS (ISP): 482.4 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2C(=O)[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[CH:20]1([NH:19][N:16]2[C:29](=[O:30])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:21][CH2:22][CH2:8][CH2:7][CH2:6][CH2:11]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.06 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.10 mL, 0.2 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.35 (m, 4 H) 1.50 (m, 4 H) 1.64 (m, 3 H) 1.86 (m, 1 H) 2.56 (m, 1 H) 5.62 (d, J=2.94 Hz, 1 H) 7.12 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.09 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.53 (m, 1 H) 7.64 (d, J=7.72 Hz, 1 H) 7.72 (d, J=5.15 Hz, 1 H) 15.92 (s, 1 H). MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][C:15](=[O:20])[CH:16]([CH3:19])[CH2:17][NH2:18].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:13][O:14][C:15](=[O:20])[CH:16]([CH3:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COC(=O)C(C)CN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CNc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-nitropyridine (3 g, 15.91 mmol) in tetrahydrofuran (20 mL) was added methyl-3-amino-2-methylpropanoate (2.05 g, 17.50 mmol) and potassium carbonate (4.40 g, 31.82 mmol). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated in vacuo and washed with water (20 mL), extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 100:1→80:1) to give methyl-3-((6-methoxy-3-nitropyridin-2-yl)amino)-2-methylpropanoate (4.2 g, 97%) as a yellow oil.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH:33]=O>CS(C)=O.O1CCCC1>[Cl:2][CH:3]=[CH:33][C:32]1[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(C=CCl)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a suspension of 11.94 g of (chloromethyl)-triphenylphosphonium chloride in 85 ml of absolute dimethylsulfoxide and 170 ml of absolute tetrahydrofuran were added dropwise at 0° C., while stirring in an atmosphere of dry nitrogen, 21.5 ml of n-butyllithium solution. After stirring for 30 minutes a solution of 5.48 g of 3,4,5-trimethoxybenzaldehyde in 20 ml of absolute tetrahydrofuran was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then allowed to warm to room temperature. After about 4 hours the reaction mixture was worked up in the manner described in Example 5e. Column chromatography of the raw product with petroleum ether/ether (2:1) yielded 4.64 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]N)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:20]([N:22](CC)CC)[CH3:21].C(Cl)(=[O:29])C.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(Cl)Cl.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:21][C:20]([NH2:22])=[O:29])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)CCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.56 g, 9.7 mmol) and triethylamine (1.45 g, 14.5 mmol) in DCM (50 ml) was treated with dropwise addition of acetyl chloride (1.0 g, 12.7 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The crude oil was purified by flash chromatography over a silica gel column (SiO2, 20 g; eluted with (0-2%) CH3OH in DCM). The pure product thus obtained weighed 1.36 g (46%). It was converted to a fumarate salt by treatment with fumaric acid (517 mg) in ethanol. Recrystallization from ethanol gave white crystals; weight: 1.53 g, m.p.=132°-133° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C=O)[CH:2]=1.[CH2:9]([NH2:11])[CH3:10]>C(Cl)(Cl)Cl>[N:1]1[CH2:2][C:3](=[N:11][CH2:9][CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: CCN
Reactant: O=Cc1cccnc1
Solvent: ClC(Cl)Cl
Product: CCN=C1C=CC=NC1
Yield: 101.2 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (1 g, 9.3 mmol) and ethylamine (661 mg, 10.2 mmol, 70% wt in water) was strirred at room temperature for 18 h. The reaction mixture was diluted with chloroform (20 mL) and dried over anhydrous K2CO3. The solution was filtered and the solvent was evaporated to afford N-(3-pyridylidene)-ethylamine (XVII) 1.15 g (92%), which was used immediately without further purification. 1H NMR (CDCl3): δ 8.82 (s, 1H), 8.60 (d, 1H), 8.28 (s,1H), 8.10 (m, 1H), 7.4-7.3 (m, 1H), 3.78-3.62 (q, 2H), 1.38-1.22 (t, 3H).
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:28])([CH3:27])[C:14]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17](OCC)=[O:18])=[O:15])=[CH:9][CH:8]=1.O>CCCCCCC>[Cl:6][C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][CH:8]=1)[C:13]([CH3:27])([CH3:28])[C:14](=[O:15])[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]2[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
Concentrated H2SO4 (5.0 mL, 18.0M) was cooled to −4° C. and treated with diethyl 2-(2-(4-chlorophenyl)-2-methylpropanoyl)malonate (1.00 g, 2.93 mmol). The resulting green solution was warmed to room temperature and allowed to stir for 1 hour. The solution was then poured into a 0° C. chilled mixture of water (10 mL) and heptane (5 mL). The resulting precipitate was collected by vacuum filtration, washed with cold water (10 mL) and heptane (1 mL). The product was dried at 40° C. overnight under vacuum to give 0.69 g of the title compound. MS m/e=295.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)(=[O:3])[CH3:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A mixture of 2-acetyl-benzaldehyde (1 g, 6.75 mmol), N-methyl piperazine (878 mg, 8.76 mmol) and NaBH(OAc)3 (2.14 g, 10.12 mmol) in DCM (50 ml) was stirred at room temperature for 1 h and then acetic acid (526 mg, 8.76 mmol) was added. The resulting solution was stirred at room temperature overnight and then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) to give 1.06 g of 1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:24]
Reactant: O=C=NCCCl
Reactant: CCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 91.7 %

Procedure:
3.6 g of D-glucose, 2.1 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 6.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-glucopyranosylurea are thereby obtained as brownish caramel.