Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:23])[CH:22]=1>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([C:4](=[O:14])[CH2:5][CH2:6][C:7]([CH3:12])([CH3:13])[C:8]([O:10][CH3:11])=[O:9])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: COC(=O)C(C)(C)CCC(=O)N(C)OC
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-[methoxy(methyl)amino]-2,2-dimethyl-5-oxopentanoate from Step C (4.68 g, 21.6 mmol) in THF (46.8 mL), cooled to 0° C., was added 3,5-difluorophenyl magnesium bromide (65 mL, 0.5 M in THF, 32.3 mmol) over 30 minutes. The reaction was allowed to stir at ambient temperature for 2 h, after which time no additional reaction progress was observed. Additional 3,5-difluorophenyl magnesium bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added over 30 minutes. After 3 h at 0° C., the reaction was quenched by the rapid addition of a cold (0° C.) solution of EtOH (71 mL) and conc. HCl (5.0 mL). The reaction was then diluted with water (200 mL) and diethyl ether (400 mL). The organics were washed with water (200 mL×3) and brine (100 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:hexanes-50:50 to 100:0, to give the title compound. MS: m/z=239 (M−31(MeO−)).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[C:20](=O)[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH2:29])[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(C)=O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cncn23)CC1
Temperature: 65 °C
Yield: 87 %

Procedure:
A mixture of 1-[5-(4-acetylpiperazin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethanone (12.6 mg, 0.0393 mmol) (10010-158P) and ammonium acetate (30.3 mg, 0.393 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed vial for 1 hour. The mixture was cooled to room temperature and sodium cyanoborohydride (7.40 mg, 0.118 mmol) was added. The reaction was heated at 65° C. overnight. The mixture was diluted with methanol and purified on preparative LCMS using pH 10 buffer to give the desired compound (11 mg, 89%). LCMS calculated for C15H21ClN5O (M+H)+: m/z=322.1. found: 321.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]#[N:23]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1)[O:13][CH2:21][C:22]#[N:23]
Reactant: N#CCCl
Reactant: CC(C#N)Oc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C#N)Oc1ccc(Cl)cc1OCC#N
Reaction time: 3.5 h

Procedure:
A mixture of 3-chloro-6-(1-cyanoethoxy)-phenol (34.6 g., 0.175 mole), finely powdered anhydrous potassium carbonate (37.2 g., 0.27 mole) and acetone (250 ml.) is stirred under reflux while chloroacetonitrile (9.8 g., 0.13 mole) is added over a period of about 5 minutes. The mixture then is heated under reflux with vigorous stirring for 1.5 hours, whereupon more potassium carbonate (12.5 g., 0.09 mole) and chloroacetonitrile (3.4 g., 0.045 mole) are added. Stirring and heating are continued for 3.5 hours, then the mixture is filtered and the filter-cake washed with acetone. Evaporation of the combined filtrate affords 3-chloro-6-(1-cyanoethoxy)-phenoxyacetonitrile which is recrystallized from aqueous alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[CH:9][C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4].[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:22][CH:21]=[CH2:20])=[CH:9][C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc(COc2ccccc2)cc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1cc(COc2ccccc2)cnc1C(=O)OC
Temperature: 125 °C
Reaction time: 20 h
Yield: 83.4 %

Procedure:
Tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.046 mmol) was added to a stirred solution of 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (130 mg, 0.47 mmol) and allyltri-n-butyltin (0.25 mL, 0.79 mmol) in degassed toluene (1.5 mL) under nitrogen. The mixture was stirred at 125° C. for 20 h. Then further tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.046 mmol) and allyltri-n-butyltin (0.25 mL, 0.79 mmol) were added and the mixture was stirred at 125° C. for 16 h. The mixture was diluted with EtOAc, filtered through a diatomaceous earth pad. The filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-allyl-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (111 mg, 84% yield) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:7][C:6]=2[CH:22]=1.C([Li])CCC.[B:28](OC)([O:31]C)[O:29]C.Cl>CCCCCC.C1COCC1>[C:16]1([C:8]2[O:7][C:6]3[CH:22]=[C:2]([B:28]([OH:31])[OH:29])[CH:3]=[CH:4][C:5]=3[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Temperature: -40 °C
Yield: 60 %

Procedure:
Under an argon atmosphere, 400 mL of anhydrous THF were added to 40.2 g of 6-bromo-2,3-diphenylbenzo[b]furan, and the mixture was stirred at −40° C. During the stirring, 72 mL of a 1.6-M solution of n-butyllithium in hexane were added to the mixture. The reaction solution was stirred for 1 hour while being heated to 0° C. The reaction solution was cooled to −78° C. again, and a solution of 54.0 g (250 mmol) of trimethyl borate in 50 mL of dry THF was dropped to the solution. The reaction solution was stirred at room temperature for 5 hours. 200 mL of 1N hydrochloric acid were added to the reaction solution, and the mixture was stirred for 1 hour. After that, the water layer was removed. The organic layer was dried with magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resultant solid was washed with toluene, whereby 21.7 g of 2,3-diphenylbenzo[b]furan-6-boronic acid were obtained (60% yield).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1)#[C:21][CH3:22]>>[CH3:17][C:13]1[C:14]([NH2:16])=[N:15][C:11]2([C:18]3[C:5](=[CH:4][CH:3]=[C:2]([C:25]4[CH:26]=[N:27][CH:28]=[C:23]([C:20]#[C:21][CH3:22])[CH:24]=4)[CH:19]=3)[CH2:6][C:7]32[CH2:10][CH2:9][CH2:8]3)[N:12]=1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC2)C3)c1
Yield: 67.7 %

Procedure:
The title compound (60 mg, 68% yield) was prepared by the method described in Example 55, starting from 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54) (80 mg, 0.25 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 53 mg, 0.33 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.59 (m, 4 H) 1.83 (d, 1 H) 2.09 (s, 3 H) 2.16 (d, 1 H) 2.21 (s, 3 H) 3.23 (m, 2 H) 6.60 (s, 2 H) 6.89 (d, 1 H) 7.41 (d, 1 H) 7.54 (dd, 1 H) 7.91 (t, 1 H) 8.52 (d, 1 H) 8.67 (d, 1 H). MS (ES+) m/z 355 [M+H]+.
Reaction SMILES: [Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5]CC)=[O:4].Cl>C(O)(=O)C>[Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)c1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C(Cl)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 52.5 g. (0.167 moles) of the ethyl α,3-dichloro-4-cyclohexylphenylacetate and 160 ml. of glacial acetic acid containing 40 ml. of 37% hydrochloric acid is refluxed for 20 hours. The mixture is concentrated under reduced pressure to give a gummy residue. The latter material is dissolved in 300 ml. of n-hexane, washed with ice-cold water (100 ml. total), dried over sodium sulfate and filtered. The hexane is removed to give α,3-dichloro-4-cyclohexylphenylacetic acid.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(O)C.[N+]([NH:31][C:32](N)=[O:33])([O-])=O>O>[NH2:31][C:32]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:33]
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
A mixture of 4.89 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, 50 ml of 95% ethanol and 2.1 g of nitrourea was refluxed at 70° C. until the evolution of gas had ceased. After refluxing for an additional 30 minutes, the mixture was cooled, treated with 200 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 3.5 g (64.81%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 155°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:15][CH2:16][N:17]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:18][CH2:19]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
The crude 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 6) (1.23 mmol) was suspended in dichloromethane (20 mL) and treated with triethyl amine (0.856 mL, 6.15 mmols), and ethane sulfonyl chloride (0.175 mL, 1.85 mmols) at 0° C. After 2 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (25 mL), and extracted with dichloromethane (100 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified by combiflash (column 10 g, eluting with 100% dichloromethane, 5% ethyl acetate/dichloromethane, 30% ethyl acetate/dichloromethane) to give the title compound (0.161 g, 32%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1.[OH:21]O.O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1)=[O:21]
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a slurry of 10.0 g (0.0350 moles) of 2-(4-(methylthio)phenoxy)-5-nitrobenzonitrile in 100 ml of glacial acetic acid was added a solution of 4.0 g of aqueous 30 percent (30%) hydrogen peroxide (0.0350 moles) dissolved in 20 ml of glacial acetic acid over 5 minutes. The reaction mixture was stirred at room temperature for 16 hrs and heated at 50° C. for 3 hrs. The reaction mixture was poured into water and the product collected by filtration, washed well with water and dried to obtain 9.8 g of product (92.8% yield). Recrystallization from ethanol afforded purified 2-(4-(methylsulfinyl)phenoxy)-5-nitrobenzonitrile, mp 159°-160° C.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH:15]=[C:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29])[CH3:4].[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][C@@H:15]([CH3:1])[C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29])[CH3:4]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4C[C@@H](C)[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reaction time: 0.5 h

Procedure:
A solution of methyllithium in ether (c. 2M 4 ml.) was added to a stirred slurry of cuprous iodide (630 mg.) in dry ether (60 ml.) under dry nitrogen until the initially formed yellow precipitate redissolved. A solution of 2β-ethoxy- 3α-hydroxy-5α-pregn-16-ene11,20-dione (420 mg.) in dry tetrahydrofuran (35 ml.) was added to the stirred solution at 0° and stirring was continued, at 0°, for 30 minutes. The mixture was then poured into saturated ammonium chloride solution (150 ml.), more ether (150 ml.) was added, the organic layer separated, washed with saturated ammonium chloride solution (150 ml.) and water (150 ml.) and dried (Na2 SO4). The solution was then evaporated. The residue was purified by preparative TLC (CHCl3 × 4). The least polar component was recrystallised from acetone/petrol to give title compound (130 mg.) as white needles; m.p. 178°-179°; [α]D + 112° (c 0.3).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[C:10]([C:19]([NH:21][C:22]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][C:23]=2[C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1>C(Cl)Cl>[OH:8][C:9]1[C:10]([C:19]([NH:21][C:22]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc2c(cc1O)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc2c(cc1O)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A trifluoroacetic acid (4 mL) solution of the obtained tert-butyl 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carboxamido)-4-phenylbenzoate (0.37 g) was stirred at room temperature for 15 minutes. Methylene chloride (10 mL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour and 15 minutes. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the obtained residue. The solid substance was collected by filtration to obtain 0.30 g of 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carboxamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([CH:9]1[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1C=CC=CC=1.O>[O:15]=[C:14]1[NH:13][CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]1[CH:1]1[O:8][CH2:23][CH2:24][O:25][C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=2
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1C(=O)c1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1C1OCCOc2ccccc21

Procedure:
A mixture of 2.0 g (6.5 mmole) of 27d, 1.25 g (20.0 mmole) of ethyleneglycol, and 1.0 g of p-toluenesulfonic acid monohydrate is refluxed in 50 ml of benzene in a Dean-Stark apparatus until the collection of water ceases. The reaction mixture is cooled, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and filtered. The filtrate is stirred with 2.2 g (10 mmole) of di-t-butyldicarbonate at reflux temperature and then concentrated to a solid residue and recrystallized from benzene/hexane to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14](=O)C1C=CC=CC=1.CI>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CI
Solvent: CCO
Product: CNCCc1ccc(OC)c(OC)c1
Yield: 74.3 %

Procedure:
3,4-Dimethoxybenzeneethanamine (100 g) was mixed with benzaldehyde (59 g), and rotoevaporated to give an oil. Methyl iodide (69 ml) was then added and the mixture was heated for 48 h at 40° and then boiled with 80% ethanol (500 ml) for 3 h. After half of the ethanol had evaporated, the solution was treated with ether (1 liter) to give a solid that was filtered, washed with ether, treated with dilute sodium hydroxide and extracted with ether to give the title compound (80 g) as an oil that was distilled under reduced pressure, b.p. 0.1 mm; 92°-95°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.[BH4-].[Na+]>CO>[CH:11]1([NH:14][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(CNC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5.25 g (30 mmol) of 2,4-dichlorobenzaldehyde was introduced into 140 ml of methanol and, at room temperature, a solution of 1.71 g (30 mmol) of cyclopropylamine was added. The mixture as stirred at room temperature for 40 min and then 1.42 g (37.5 mmol) of NaBH4 was added in portions. After standing overnight, the solvent was removed and the residue was taken up in 2 N HCl. Two extractions with ethyl acetate were carried out. The aqueous phase was made alkaline with NaOH and again extracted twice with ethyl acetate. The organic phases were dried with MgSO4 and concentrated. The crude product obtained in this way, in the form of a slightly yellowish oil, was reacted further without further purification.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][CH2:35]O)=[CH:26]1>C1CCCCC1>[Br:1][CH2:35][CH2:34][C:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:25][CH:26]=1
Reactant: OCCc1coc2ccccc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CC#N
Product: BrCCc1coc2ccccc12
Reaction time: 12 h
Yield: 83.8 %

Procedure:
Triphenylphosphane dibromide (5.52 g, 14.4 mmoles) was suspended in abs. acetonitrile (15 ml) under argon, the suspension was brought to 19° C. in a water-bath and 2-(benzofuran-3-yl)ethanol (2.11 g, 13.1 mmoles) in abs. acetonitrile (7 ml) was added in the course of 15 min. During the addition the temperature of the reaction mixture was kept between 19 and 21° C. The mixture was then left to stand for 12 hours without further cooling. The reaction mixture was filtered and the filtrate obtained was concentrated. The residue obtained was taken up in cyclohexane (20 ml), and the mixture was filtered over a silica gel layer (15 g) about 3 cm thick. The silica gel was washed with cyclohexane (5×20 ml) and the filtrate obtained was concentrated. 2.47 g 3-(2-bromoethyl)benzofuran were obtained as a yellowish oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21].Cl[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([O:22][CH2:24][CH2:25][O:26][CH3:27])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCCl
Reactant: COCCOCCOCC(O)COCCOCCOC
Agent: [Na+]
Agent: [OH-]
Product: COCCOCCOCC(COCCOCCOC)OCCOC
Temperature: 60 °C
Yield: 84.6 %

Procedure:
20.4 g (0.51 mol) of NaOH pellets were added to 100 g (0.34 mol) of 1,3-bis[2-(2-methoxyethoxy)ethoxy]-2-propanol resulting from Step 1. 48.2 g (0.51 mol) of 2-chloroethylmethylether was dropwise added in small portions while stirring at 60° C. After the completion of dropwise addition, the mixture was stirred for about 2 hours and a precipitated salt was filtered off, the filtrate was condensed and purified by a vacuum distillation to give 102 g of 1,3-bis[2-(2-methoxyethoxy)ethoxy]-2-(2-methoxyethoxy)propane (E) (yield: 85%). The distillation temperature was from 155 to 161° C./0.2 mmHg.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.O[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CCn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.500 g, 2.58 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.593 g, 2.58 mmol) and 2-(tributylphosphoranylidene)acetonitrile (0.746 g, 3.09 mmol) were stirred together in toluene (10 ml) at 85° C. overnight. The reaction was concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C1CCNCC1
Product: CC(=O)c1ccc(N2CCCCC2)cc1

Procedure:
without solvents (e.g. B. G. Kresze and H. Goetz, Chem. Berichte 90, 2161, 2174 (1957)), reaction of p-bromoacetophenone with piperidine under reflux with 19% yields of 1-(4-piperidinophenyl)ethanone; or