Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[Li]CCCC.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:30][CH3:31])=[C:24]([CH:29]=1)[C:25](OC)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:30][CH3:31])=[C:24]([C:25]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:26])[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cncs1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCc2ccccc2)cc1C(=O)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
To a stirring mixture of 5-methylthiazole (3.80 g, 38.2 mmol) in dry THF (200 mL) was added n-BuLi (2.5 M in hexane, 15.3 mL, 38.2 mmol) drop wise over 20 minutes at −78° C. under nitrogen atmosphere. The mixture was stirred between −78° C. and −60° C. for 1.5 h and then cooled to −78° C. A solution of methyl 5-(benzyloxy)-2-methoxybenzoate (10.4 g, 38.2 mmol) in THF (50 mL) was added drop wise over 30 minutes. The resulting mixture was stirred at −78° C. for 30 minutes and warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL). The resulting mixture was adjusted to pH around 6 with HCl (1N). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (3:1) to afford (5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.5 g, 19%) as a yellow gel. 3.0 g of starting material methyl 5-(benzyloxy)-2-methoxybenzoate was recovered.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>[C].[Pd].C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=C1CCCc2c(F)cccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2c(F)cccc21

Procedure:
Ethyl (5-fluoro-3,4-dihydro-2H-naphthalen-1-ylidene)acetate, 10% palladium carbon catalyst (3 g) and ethanol (150 ml) were stirred under a hydrogen atmosphere for 4 hr. The reaction mixture was filtered through celite, and concentrated to give ethyl (5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[CH2:17][Cl:26])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: ClCc1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-benzylpiperidin-4-ylamino)nicotinic acid (311 mg, 1.0 mmol, 1.0 eq) prepared in Preparation Example 16, and thionyl chloride (1.5 mmol) in 5 ml of methylene chloride was stirred for 1 hr under reflux. The reaction mixture was cooled to room temperature and immediately used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])([O-])=O.[OH-].[Na+:23]>O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)[C:11]([O-:13])=[O:12].[Na+:23]
Reactant: O=C(O)C(=Cc1ccc(Br)cc1)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1C(=Cc1ccc(Br)cc1)C(=O)[O-]
Temperature: 80 °C

Procedure:
To a mixture of FeSO4.7H2O (163 g, 0.586 mol) in 180 ml of water was added 720 ml of 2.5N NaOH and the mixture was stirred and heated at 80° C. A solution of cinnamic acid derivative 1 (20.40 g, 0.05859 mol) in 180 ml of 0.5N NaOH was added dropwise. After the addition was complete, the temperature was increased to 100° C. and maintained for 30 min. The mixture was filtered while hot, and the filtrate was allowed to cool gradually to room temperature. The resulting solid was isolated by filtration to yield, after drying in vacuo, 12.1 g (61%) of the title compound as a tan solid which was used in the next reaction without purification. 1H-NMR (300 MHz, 2:1 D2O/CD3CN): δ 6.95-7.15 (m,3H), 7.18 (d,J=7.3 Hz,2H), 7.39 (t, J=7.6 Hz, 1H), 7.53 (d, J=7.3 Hz,2H), 7.72 (s, CH=C, 1H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[C:15]([O:7][CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCSCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Tetrahydrothiopyran-4-ol (4.81 g, 40.7 mmol) and triethylamine (6.2 mL, 44.5 mmol) were dissolved in anhydrous dichloromethane (60 mL) and cooled to 0° C. Methacryloyl chloride (4.0 mL, 45.0 mmol) then was added slowly, dropwise. The reaction then was warmed slowly to room temperature. After stirring overnight, the reaction was washed with DIW (20 mL), 1 M NaOH (2×20 mL), DIW (20 mL), 1 M HCl (20 mL), DIW (20 mL) and brine (20 mL). The organic layer then was dried over sodium sulfate, filtered, and then concentrated by rotary evaporation and dried in vacuo to afford tetrahydro-2H-thiopyran-4-yl methacrylate as a pale yellow liquid (4.85 g, 61%). 1H NMR (600 MHz, CDCl3, ppm) δ 6.07 (s, 1H), 5.52 (s, 1H), 4.88 (m, 1H), 2.77 (m, 2H), 2.55 (m, 2H), 2.07 (m, 2H), 1.90 (m, 5H). 13C NMR (150 MHz, CDCl3, ppm) δ 166.29, 166.23 (minor), 136.55, 13.70 (minor), 125.40 (multiplet: 126.58, 126.31, 125.72, 125.28, 125.07, 124.65, 124.19), 70.86, 69.86 (minor), 32.33 (multiplet: 32.59, 32.44, 32.21, 32.04), 25.71 (multiplet: 26.66, 26.19, 25.71, 25.44, 24.95), 18.26 (multiplet: 18.43, 18.09).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:31])[CH2:29][OH:30])[C:18]2=[O:32])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])C.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:31])[CH2:29][OH:30])[C:18]2=[O:32])[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CO)c3C2=O)ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)C[C@H](c1ccc(O)c(O)c1)N1C(=O)c2cccc(NC(=O)CO)c2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)—N-{2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-hydroxy-acetamide (0.55 mmol) in anhydrous CH2Cl2 is added AlCl3 (2.20 mmol) at room temperature. After stirring for 1 hour, water is added. The product is extracted into CH2Cl2. The solvent is removed in vacuo to give crude (S)—N-{2-[1-(3,4-dihydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-hydroxy-acetamide. The product is purified by column chromatography or recrystallization.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=O)=[C:7]([NH:15][C:16]([C:18]3[CH:19]=[N:20][O:21][C:22]=3[CH3:23])=[O:17])[C:6]=2[CH:24]=1.[CH2:25](N(CC)CC)C>O>[C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=2[C:7]=1[NH:15][C:16](=[O:17])/[C:18](/[C:19]#[N:20])=[C:22](\[OH:21])/[CH3:23])(=[O:12])[CH3:25]
Reactant: CCOC(=O)c1oc2ccc(Br)cc2c1NC(=O)c1cnoc1C
Reactant: CCN(CC)CC
Solvent: O
Product: CC(=O)c1oc2ccccc2c1NC(=O)/C(C#N)=C(/C)O
Temperature: 68 °C
Yield: 449.5 %

Procedure:
To a solution (30 ml) of ethyl 5-bromo-3-[(5-methylisoxazole-4-carbonyl)amino]benzofurane-2-carboxylate (compound of Example 67 described below) (0.2 g, 1.8 mmol) produced according to Example 65 in water-free THF was added triethylamine (2.4 ml, 0.18 mmol), and the reaction mixture was heated at 68° C. for 6 hr and the solvent was evaporated. The residue was poured into ice water, and the mixture was acidified 30 with 5% aqueous hydrochloric acid solution and extracted with CHCl3. The extract was washed with saturated brine and dried. The solvent was evaporated. The residue was recrystallized from acetonitrile to give (Z)-N-(2-acetylbenzofuran-3-yl)-2-cyano-3-hydroxy-2-butenamide as colorless crystals (0.23 g, yield 22.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.C(N(CC)C(C)C)(C)C.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 25 °C

Procedure:
To a mixture of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (3.0 g, 16.5 mmole) and N,N-diisopropylethylamine (9 ml, 50 mmole) in toluene (150 ml), was added POCl3 (4.7 ml, 50 mmol). The resulting reaction mixture was refluxed for 1.5 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (200 ml) and washed with cold water till pH=6-7. The organic phase was dried over MgSO4, filtrated and concentrated under reduced pressure to yield crude 4,6-dichloro-pyrido[3,2-d]pyrimidine which was not purified but used as such for further reactions.
Reaction SMILES: N12CCCN=C1CCCCC2.Br[C:13]1[CH:20]([CH:21]([OH:26])[C:22]([O:24]C)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.Cl>CS(C)=O>[C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:20]([CH:21]([OH:26])[C:22]([OH:24])=[O:23])[C:19]#1
Reactant: COC(=O)C(O)C1CCCCCC=C1Br
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: O=C(O)C(O)C1C#CCCCCC1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
150 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1 mmol) are added to a solution of methyl 2-bromocyclooctene-3-glycolate 17 (0.5 mmol) in anhydrous DMSO at 60° C. After stirring for 15 min, an additional 600 μl of DBU (4 mmol) are added and then the combined mixture is stirred overnight at 60° C. The mixture is acidified with 1M HCl and extracted with AcOEt. The organic phase is filtered through a separating filter and is concentrated under vacuum. The cyclooct-1-yn-3-glycolic acid 18 is purified on a preparative plate (CH2Cl2/MeOH 9/1) and is obtained with a yield of 55% (w=50 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[F:33][C:34]([F:50])([F:49])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1>CN(C=O)C>[F:49][C:34]([F:33])([F:50])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=2[OH:11])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Reactant: Nc1cccc(C(=O)O)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Nc1cccc(C(=O)NCc2ccc(C(F)(F)F)cc2N2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
3-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) was dissolved in 20 ml of DMF and at 0° C. EDCI (1.4 g, 1.2 equiv.), hydroxybenzotriazole (1 g, 1.2 equiv.) and amine 2c (2 g, 1.2 equiv.) were added. The mixture was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 9 as eluant gave 1.3 g of a beige solid. Yield=51% [M+1] 393.4 (C20H22F3N3O2 requires 393.4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.Cl[Sn]Cl.[Sn].[OH-].[Na+]>Cl.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1OCCO
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccccc1OCCO
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
8.9 g (48.59 mmol) 2-(2-hydroxyethoxy)nitrobenzene A2, 16.44 g (72.88 mmol) SnCl2. 2H2O and 17.3 g (145.77 mmol) tin were stirred in 30.84 ml aqueous HCl (30%) and 25 ml water at 90° C. for 8 hours. After cooling, the solution was treated with aqueous 5n sodium hydroxide solution and stirred for 3 hours at 90° C. The aqueous solution was subsequently decanted, wherein, upon cooling, the crude product crystallized out and was removed by suction. This crude product was then taken up in methanol, warmed and the suspension was filtered. The filtrate was then concentrated in vacuo. 6 g of light-brown crystals were obtained; yield 80%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (8.14 g, 53.5 g), 2-chloro-5-nitropyridine (8.08 g, 51.0 mmol), potassium carbonate (11.1 g, 80.3 mmol) and N,N-dimethylformamide (100 mL) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (14.4 g, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[OH2:11]>>[OH:11][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cnccc1Cl
Reactant: O
Product: O=C(O)c1cnccc1O
Yield: 80 %

Procedure:
Compound 3 is heated in water (see ROSS, J. Chem. Soc. (C), p. 1816-1821, 1966) to obtain 4-hydroxypyridine-3-carboxylic acid 5 as a colorless solid (>80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>[OH-].[Na+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCCCc1cccc(Br)c1
Reaction time: 48 h

Procedure:
A stirred mixture of 4-(3-bromophenyl)butan-1-ol (18 g) and 1,6 dibromohexane (48 ml) in 50% aq. sodium hydroxide (500 ml) with tetrabutylammonium bromide (1.5 g) was stirred for 2 d at 20°. The mixture was poured into water (1000 ml) and extracted into ethyl acetate (3×500 ml). The combined extracts were washed with water (1000 ml), dried (Na2SO4). The solvent was removed in-vacuo and the residual oil was purified by flash chromatography (500 g) using dichloromethane as eluent, changing to light petroleum (40–60°)-diethyl ether (9:1) to give the title compound (18 g). LCMS RT=4.34 min.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[O:14]=[C:15]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:16][CH2:17][CH2:18][CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:27]1([N:24]2[CH2:25][CH2:26][N:21]([C:15](=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]3[CH2:13][CH2:12][C:8]4[N:9]=[CH:10][S:11][C:7]=4[CH2:6]3)[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CCCCC(=O)N1CCN(c2ccccc2)CC1
Reactant: CCCNC1CCc2ncsc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCC(=O)N1CCN(c2ccccc2)CC1)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 67 %

Procedure:
A solution of 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine and 781 mg (3 mmol) 5-oxo-5-(4-phenylpiperazin-1-yl)pentanal in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20]>O>[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20].[C:6]([C@H:4]([C@@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
A solution of D-(−)-tartaric acid (204 mg, 1.359 mmol) in deionized water (2.0 mL) was added into the solution of isofagomine (200 mg, 2.0 equivalents) dissolved in deionized water (2.0 mL) at room temperature. The solution was stirred for 10 min and lyophilized overnight. The residue was further dried under vacuum at 45° C. for three days to afford the desired salt (396.9 mg, 98%). m.p. 73-74° C., 1H NMR (300 MHz, D2O): δ 4.41 (s, 2H), 3.71 (dd, J=12, 3.3 Hz, 1H), 3.66-3.59 (m, 2H), 3.44-3.36 (m, 3H), 2.84 (t, J=12 Hz, 1H), 2.75 (t, J=12 Hz, 1 H), 1.84 (m, 1H) (FIG. 8C)
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][CH2:17][NH:16][C:2]2[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=23)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: NCCN1CCOCC1
Product: Cc1nnc(NCCN2CCOCC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 4-(2-aminoethyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride salt (MeOH/ethereal HCl/diethyl ether), mp 310° C. (dec).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][C:15]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:14][C:13]=2[C:24]=1[CH3:25])(C(C)(C)C)(C)C.C(O)(=O)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][C:15]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:14][C:13]=2[C:24]=1[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(C)(c1ccccc1)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)SC(C)(c1ccccc1)O2

Procedure:
3.0 g of 5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2-phenyl-1,3-benzoxathiole were dissolved in 30 ml of tetrahydrofuran. Under a stream of nitrogen, 4.5 g of acetic acid and 12.9 g of tetrabutylammonium fluoride trihydrate were then added to the mixture. The reaction mixture was then allowed to react for 2 hours at room temperature. At the end of this time, the reaction mixture was poured into water, and the resulting precipitate was extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The resulting crude oily substance was subjected to silica gel column chromatography. The title compound was obtained from the portion eluted with a 1.1 by volume mixture of cyclohexane and benzene. It melted at 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([F:30])[CH:21]=2)([NH:13]C(=O)C(C)(C)C)[CH2:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.Cl.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CO.C(#N)C.CO.O>[NH2:13][C@:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([F:30])[CH:21]=1)[CH2:9][C:10]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:12]
Reactant: CC(C)(C)C(=O)N[C@@](CC(=O)O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: Nc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CO
Product: N[C@@](CC(=O)Nc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
(S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-pivalamidopropanoic acid (0.10 g, 0.21 mmol) was dissolved in MeOH (2 mL) and 4M HCl in dioxanes added (2 mL). The resulting solution was stirred at RT for 30 mins then the solvents were removed under reduced pressure yielding a pale yellow oil (crude quantative) LCMS: 1.31 min [M+1] 363.2 (2 min gradient, MeOH/H2O 0.1% TFA). The residue was dissolved in acetonitrile (5 mL) and TEA, (0.3 mL, excess), aniline (0.030 g, 0.32 mmol) and PyBrOP (0.11 g, 0.24 mmol) added at RT. The RM was stirred for 14 h, concentrated to 1.5 mL, filtered and purified by prep HPLC: YMC ODSA30×100 mm, 40ml/min, 20-100% MeOH (0.1% TFA) over 10 min. The product (S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-N-phenylpropanamide with a retention time of 7.52 min was isolated as a pale yellow oil, (0.054 g, 58% yield). LCMS: 1.48 min [M+1] 438.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C)C=O>[CH2:30]([CH:14]1[C:10]2[N:11]3[CH:12]=[CH:13][C:4]4[C:5]3=[C:6]([CH2:1][CH2:2][CH:3]=4)[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]=2[CH:17]=[CH:16][C:15]1=[O:18])[CH:29]=[CH2:28]
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC1C(=O)C=CC2=C1n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (2.5 g) was dissolved in dimethylformamide (50 ml). Potassium carbonate (0.5 g) was added followed by allyl bromide (2.2 g). The reaction mixture was stirred at 95° C. overnight, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (2% methanol/dichloromethane) to yield 1.9 g (65.9%) of product. Recrystallization from methanol gave the analytical sample, mp 109°-110° C.