Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([NH2:14])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[N:15]1[N:16]=[N:17][N:18]2[CH:23]=[C:22]([C@@H:24]3[CH2:26][O:25]3)[CH:21]=[CH:20][C:19]=12>C(O)C>[CH3:1][C@@H:2]([NH:14][CH2:26][C@@H:24]([C:22]1[CH:21]=[CH:20][C:19]2[N:18]([N:17]=[N:16][N:15]=2)[CH:23]=1)[OH:25])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: C[C@@H](N)CCc1c[nH]c2ccccc12
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: C[C@H](CCc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 16 g of 1-(1H-indol-3-yl)-3-butanone, 10.3 g of R(+)-1-phenylethylamine and 0.2 g of TsOH.H2O in 80 ml of benzene is heated at reflux with water removal (Dean-Stark trap) for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue redissolved in 80 ml of methanol. To this solution 8 g of Ra(Ni) catalyst is added and the mixture hydrogenated under positive hydrogen pressure for 32 hours. The reaction mixture is filtered through celite and the filtrate concentrated. The residue is chromatographed on silica gel to afford the (R,R,)-diastereomer. This material (6.2 g) is converted into its hydrochloride salt and dissolved in 50 ml of ethanol and hydrogenated over 1.6 g of 5% Pd(C) for 18 hours. The reaction mixture is then filtered and the filtrate concentrated under reduced pressure to dryness. The residue is chromatographed on silica gel to give 1(R)-methyl-3-(1H-indol-3-yl)propyl amine. This amine (650 mg) is condensed with 650 mg of (R)-2-(tetrazolo-[1,5-a]pyrid-6-yl)oxirane in 15 ml of absolute ethanol at reflux for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue purified by chromatography on silica gel to give (R)-α-[[(1(R)-methyl-3-(1H-indol-3-yl)propyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol. This tetrazole (0.6 g) in 15 ml of methanol is treated with 0.6 g of SnCl2.2H2O and the reaction mixture heated at reflux for 18 hours. The reaction solution is partially concentrated under reduced pressure. This concentrated solution is added to a mixture of CH2Cl2 (20 ml) and 12 ml of 2N NaOH solution. The mixture is stirred for twenty minutes and then the layers are separated. The aqueous layer is further extracted with CH2Cl2. The combined organic extracts are backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solution is concentrated and the residue chromatographed on silica gel to give the titled compound after conversion to its hydrochloride salt with ethanolic HCl.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[CH2:21]([O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CI>C1COCC1>[CH2:21]([O:28][CH:29]1[CH2:30][CH2:31][C:32]([CH3:2])([C:35]([OH:37])=[O:36])[CH2:33][CH2:34]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCC(OCc2ccccc2)CC1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CC1(C(=O)O)CCC(OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of LDA (made by dropwise addition of nBuLi (2.38M, 13.45 ml, 32.01 mmol) to a −78° C. solution of diisopropyl amine (4.5 ml, 32.0 mmol), in THF (160 ml), in THF, at −78° C.), was added 4-benzyloxy-cyclohexanecarboxylic acid (3.75 g, 16.0 mmol) (Eur. Pat. Appl. (1984), 33 pp. EP 123238A2) dissolved in THF (24 ml). After complete addition, the reaction mixture was stirred at 50° C. for approximately 2 hours. The reaction mixture was cooled to room temperature and MeI (filtered through basic alumina) was added to the reaction mixture, dropwise. After stirring at room temperature for overnight, the reaction mixture was quenched with ice water containing ether, and the aqueous layers were collected. The organic layer was washed one time with water, and the aqueous layer was combined with previous aq. layers. The combined aqueous layers were acidified with 2N HCl (pH=1), and extracted four times with ether. The ether extracts were brined, dried over MgSO4, filtered, and concentrated giving 3.3 g (83%) of 4-benzyloxy-1-methyl-cyclohexanecarboxylic acid as an off white solid. M−H=247.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.C1(C)C=CC=CC=1.[CH3:15][NH:16][NH2:17]>C1COCC1>[CH3:15][NH:16]/[N:17]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CNN
Reactant: CCOC(=O)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=N/NC
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
47% ethyl glyoxylate in toluene (polymer type) (467.84 g, 2.15 mol) was dissolved in THF (620 ml), to the solution was slowly added methylhydrazine (103 g, 1.02 eq) under ice-cooled. After the addition was complete, the mixture was stirred at 0° C. for 30 minutes and at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in toluene (400 ml), and concentrated under reduced pressure. The resulting solid was washed with tert-butyl methyl ether (200 ml), and allowed to stand at 0° C. for 30 minutes. Then, the mixture was filtered, and washed with cooled tert-butyl methyl ether (100 ml) to give 223.91 g of Compound (XVI-1) (yield: 78.8%) as solid.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:19]([N:21](CC)CC)C.C(C1C=CC(CCCCCCCCCCC)=CN=1)#N>C(#N)C>[C:19]([C:13]1[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:21]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCc1ccc[n+]([O-])c1
Agent: CCCCCCCCCCCc1ccc(C#N)nc1
Solvent: CC#N
Product: CCCCCCCCCCCc1cccnc1C#N
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a solution of 10.0 g (40 mmol) of 3-n-undecylpyridine N-oxide and 8.10 g (80 mmol) of triethylamine dissolved in 40 ml of acetonitrile was added 15.8 g of trimethylsilyl anilide, while stirring, at room temperature. After the dropwise addition, the mixture was refluxed for 66 hours and concentrated under a reduced pressure, followed by silica gel column chromatography (ethyl acetate:hexane=15:85), to give two kinds of solids A (4.40 g) and B (4.10 g). From the data of NMR, A was determined to be 2-cyano-5-n-undecylpyridine, and B the desired 2-cyano-3-n-undecylpyridine (yield 38.8%).
Reaction SMILES: [OH-].[Na+].C1COCC1.[C:8]([C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=3)[C:32]([O:34]C)=[O:33])=[O:25])[CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].Cl>O>[C:8]([C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=3)[C:32]([OH:34])=[O:33])=[O:25])[CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C#N)c3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(CCC2CCN(C(=O)Oc3cncc(C(=O)O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
An aqueous 1 M sodium hydroxide solution (0.69 ml) was added to a THF (5 ml)/water (4 ml) solution of methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (272 mg), followed by stirring overnight at room temperature. 1 M hydrochloric acid (0.69 ml) was added to the reaction liquid, and the crystal precipitated was collected by filtration. The crystal was washed with a hot methanol/water solution, and dried to obtain 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (240 mg).
Reaction SMILES: [Br:1]Br.[CH:3]1[C:19]2=[C:20]3[C:10]([C:11]([C:13]4[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:12])=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.O>C(O)(=O)C>[Br:1][C:5]1[CH:4]=[CH:3][C:19]2[C:18]3[C:13]([C:11](=[O:12])[C:10]4[C:20]=2[C:6]=1[CH:7]=[CH:8][CH:9]=4)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2-c2ccc(Br)c3cccc1c23
Yield: 68.1 %

Procedure:
A solution of 11.2 g of bromine in 20.5 g of acetic acid was added dropwise to a mixture of 11.5 g of benzanthrone, 184 g of acetic acid and 23 g of water with stirring. The total mixture was heated with stirring to 100° C for 5.5 hours. The precipitated crystals were filtered and washed with water and dried. The product was recrystallized from a mixture of 88.3 g of chlorobenzene and 6.3 g of methanol whereby 10.52 g of 3-bromobenzanthrone were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.Br[C:12]#N.CC#N>CO.O>[F:8][C:7]1[CH:2]=[CH:3][C:4]2[N:10]=[CH:12][NH:9][C:5]=2[CH:6]=1
Reactant: N#CBr
Reactant: Nc1cc(F)c(Cl)cc1N
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Fc1ccc2nc[nH]c2c1
Reaction time: 3 h

Procedure:
4-Chloro-5-fluoro-1,2-phenylenediamine (12a, 3.212 g, 20 mmol) was dissolved in 40 mL of MeOH and then added dropwise to a stirred solution of 4.4 mL of 5M BrCN/MeCN in 40 mL of H2O over 30 min. After the addition, stirring was continued at room temperature for 3 hr. The reaction mixture was concentrated to ~40 mL and then was washed with EtOAc (100 mL). The EtOAc phase was extracted with H2O (60 mL). The combined H2O phase was neutralized with sat. NaHCO3 solution to ~pH 8 and the resulting suspension was extracted with EtOAc (200 mL). The EtOAc phase was washed with a mixture of sat. NaHCO3 /sat. NaCl solution (20 mL/180 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with CHCl3 (20 mL×2) and then was suspended in 50 mL of CHCl3. The suspension was filtered to give 3.340 g of 12b as a grey solid. The filtrate was evaporated and coevaporated with CHCl3. The resulting solid was again suspended in a small amount of CHCl3 and the suspension was filtered to give an additional 0.235 g of 12b. The total yield of 12b was 3.575 g (96%). This product showed a single spot on TLC. MP: 194°-196° C. MS: (El) m/e 185.0156 (100%, M+ =185.0156). 1H NMR (DMSO-d6): d 10.85, (br s, 1, 1-NH), 7.16 (d, 1, 4-H, 4JF-H =7.0 Hz), 7.06 (d, 1, 7-H, 3JF-H =10.0 Hz), 6.43 (br s, 2, 2-NH2). Anal. Calcd. for C7H5ClFN3 ; C, 45.30; H, 2.72; N, 22.64. Found: C, 45.14; H, 2.67; N, 22.44.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:14][NH2:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cnc2ccc(Br)cc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cnc2ccc(Br)cc2n1
Temperature: 78 °C
Yield: 87 %

Procedure:
To the solution of 7-bromo-2-chloroquinoxaline (2 g, 8.2 mmol) in ethanol (20 mL) was added hydrazine hydrate (85%, 4.5 mL, 32.8 mmol). The mixture was heated to 78° C. for 2 h. After cooling to r.t., the precipitate was collected by filtration to afford 7-bromo-2-hydrazinylquinoxaline as white solid in 87% yield (1.7 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1.C(OCC)(=O)C>C(N(CC)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]2[NH:8][C:7]3[C:9]([CH:19]=2)=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)c1ccccc1
Product: Cc1ccc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)cc1
Temperature: 165 °C

Procedure:
To a stirred solution of 5.3 g (30 mmol) of 4-trifluoromethoxyaniline in 8 ml of N,N-diethylaniline was added dropwise at 165° C. a solution of 4.3 g of 4-methylphenacyl bromide in 7.5 ml of xylene. It was heated at 165° C. for 3 h. The mixture was cooled followed by addition of 50 ml of ethyl acetate. It was washed with 2N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via repeated column chromatography on silica gel using a hexane dichloromethane gradient (100:0 to 50:50). The title compound thus obtained was recrystallized from hexane.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(N(C(C)C)CC)(C)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:28][CH2:27][N:29]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro- 1 -methyl-2-oxo-quinoline-3-carboxylic acid (15 gm) and methylene chloride (105 ml) was cooled to 5-10° C. under nitrogen atmosphere. Diisopropylethyl amine (26.7 gm) was added to the resulting mass for 5 minutes at 5-10° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (7.8 gm) in one portion at 5-10° C. and then thionyl chloride (9.1 gm) was added at 5-10° C. The resulting mixture was stirred for 7 hours followed by evaporation of methylene chloride under vacuum. The resulting residue was dissolved in ethyl acetate (200 ml) followed by washings with 5% sodium hydroxide solution (65 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (25 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 19.3 gm of laquinimod (HPLC Purity: 98.41%).
Reaction SMILES: [OH:1][C@H:2]([CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C([CH2:18][C:19]([O-])=[O:20])=C>O1CCCC1>[C:19]([O:14][CH2:13][C@@H:12]([OH:15])[CH2:11][C@@H:2]([OH:1])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])(=[O:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO
Reactant: C=CCC(=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred 11 round bottom flask 700 ml tetrahydrofuran and 70.7 g (0.32 mol) of (3R,5S) t-butyl 3,5,6-trihydroxyhexanoate, 41 ml (0.46 mol) vinylacetate and 6.3 g of the supported lipase Chirazyme L2™ were charged. After 3 hours stirring at ambient temperature the lipase was removed by screening and the volatiles removed by distillation under vacuum. The mass of crude oil was 78.7 g and the major component was determined to be (3R,5S) t-butyl 6-acetoxy-3,5-dihydroxyhexanoate. This material was used directly in the next stage.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[OH:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=Cc1ccc(F)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(Cl)ccc1C(O)c1ccc(F)cc1

Procedure:
The title compound was prepared starting from 1.00 g (4.87 mmol) of 2-bromo-5-chlorotoluene and 0.72 g (5.84 mmol) of 4-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 0.64 g (52% of theory) of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.C1(C)C=CC=CC=1.[SH-].[Na+]>O>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 100 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone in 400 parts of toluene, 1000 parts of toluene-containing mother liquor and a solution of 8.8 parts of sodium bisulfide in 400 parts of water are charged simultaneously to a tube reactor (volume: 100 ml) with static mixing elements. The average residence time is c. 3 minutes. The feed temperature of the components is regulated such that the reaction mixture leaves the reactor at 160° C. and is separated continuously in a separating vessel under pressure (10 bar) into an aqueous and an organic phase. The pressure is relaxed in the working up reactor containing the organic phase, which is cooled to room temperature. The product is isolated by filtration, washed with toluene and dried under vacuum at 80° C. The aqueous phase is extracted with the mother liquor, a portion of which is recycled to the reactor. In stationary operation, 86 parts of 1-aminoanthraquinone are obtained per hour in 99% purity (layer chromatography), corresponding to a yield of 98% of theory, based on 5-nitrotetrahydroanthraquinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:37]([CH:40]1[CH2:49][N:43]2S(=O)(=O)O[CH2:46][C@H:42]2[CH2:41]1)([CH3:39])[CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:46][C@H:42]1[CH2:41][CH:40]([CH:37]([CH3:39])[CH3:38])[CH2:49][NH:43]1
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)C1C[C@@H]2COS(=O)(=O)N2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C1CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.3 %

Procedure:
To a solution of 3,5-dichloropyridine (228 mg, 1.542 mmol) in THF (2.6 mL) at −78° C. was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (0.976 mL, 1.953 mmol) dropwise. After stirring for 45 min, a solution of (3aR)-5-isopropyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (211 mg, 1.028 mmol) in THF (3.0 mL) was added dropwise at −78° C. The resulting mixture was allowed to warm to room temperature and then stirred for 3 h. After evaporation of the solvent, the resulting brown solid was treated with 2 N HCl (3 mL) and EtOH (3 mL) and heated at 80° C. for 2 h. The reaction mixture was concentrated to remove the EtOH. The resulting mixture was treated with ice and basified with 2 N NaOH to pH-10 and extracted with EtOAc (2×10 mL). The extracts were dried, evaporated and purified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% MeOH (with 2 M NH3) in DCM to give 3,5-dichloro-4-(((2R)-4-isopropylpyrrolidin-2-yl)methyl)pyridine (102 mg, 0.373 mmol, 36.3% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 3.35-3.51 (m, 1H), 2.84-3.08 (m, 3H), 2.35-2.44 (m, 1H), 1.80-1.93 (m, 1H), 1.55-1.69 (m, 1H), 1.31-1.49 (m, 2H), 1.02-1.17 (m, 1H), 0.85 (t, J=6.7 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:14][CH2:15][O:16][CH3:17]>>[CH3:17][O:16][CH2:15][CH2:14][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COCCBr
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Product: COCCn1ncc2cc(CO)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-1 and step 2 of Example 13 from 1H-indazole-5-carboxylic acid and 1-bromo-2-methoxyethane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])([CH3:16])([CH3:15])[CH3:14].[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[Cl:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][C:19]([CH3:21])([CH3:20])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])[CH:27]=[CH:26][C:25]=1[Cl:32]
Reactant: CC(C)C(=O)OC(C)(C)C
Reactant: Clc1ccc(CBr)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(Br)c1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 4.0 ml (28.8 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 11.5 ml (28.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 2.77 g (19.2 mmol) of tert-butyl-2-methylpropanoate in 20 ml of THF was then added, the temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 6.0 g (21.1 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, the reaction temperature once more being kept below −60° C. The reaction mixture was stirred overnight slowly warming to RT, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 5.6 g (84% of theory) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.[CH:16]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:16]1([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][NH2:5])[CH2:25][CH2:26]2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCCCN1CCN(C2CCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of N-(3-bromopropyl)phthalimide (0.8 g, 3.0 mmol), 1-cyclopentylpiperazine (0.46 g, 3.0 mmol), and K2CO3 (1.66 g, 12.0 mmol) in CH3CN (30 mL) was heated to reflux for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The filtrate was concentrated, treated with 6N HCl (9.0 mL) and acetic acid (18.0 mL), heated to reflux overnight, and concentrated. The residue was treated with potassium carbonate (1.66 g) in CH3CN (30 mL) for 1 hour. After filtration of the solid, the solvent was evaporated to provide the desired product. MS (DCI/NH3) m/e 212 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.04 (br s, 2H), 3.68 (m, 4H), 3.41 (m, 4H), 3.21 (m, 2H), 2.91 (m, 2H), 2.0 (m, 4H), 1.84-1.73 (m, 4H), 1.55 (m, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:21](O)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:32]>C1C=CC=CC=1>[ClH:32].[C:21]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1)OCCN1CCNCC1
Yield: 53 %

Procedure:
In 150 ml of absolute benzene there were dissolved 1.95 g of 1-piperazineethanol and 14.2 g of p-toluene sulfonic acid. To the solution 2.89 g of cinnamic acid was added. The system was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline followed by extraction with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to give a colorless transparent liquid. The liquid was converted into the hydrochloride thereof. Upon recrystallization from ethanol, 1-piperazineethanol cinnamate hydrochloride was obtained. The melting point of the product was 184°-187° C. The yield was 53%.