Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:14]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[N:8][NH:9]2.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.O>[N:27]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:14]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[N:8][NH:9]2)=[N+:28]=[N-:29]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cccc(OCCCl)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.2 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles).
Reaction SMILES: OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)=O)CC1.[BH4-].[Na+]>CO>[CH3:25][C:20]([C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)([CH3:24])[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1

Procedure:
A mixture of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetic acid, and 300 mg of NaBH4 in 25 ml, of CH3OH was stirred overnight at room temperature. The mixture was then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous portion was treated with concentrated HCl until pH 6, then extracted with EtOAc. The organics were concentrated in vacuo. The residue was dissolved in EtOAc, filtered, and concentrated in vacuo to an oil. The oil was dissolved in CH3OH and concentrated to a solid. The solid was slurried with EtOAc, filtered, and rinsed with EtOAc to afford 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[CH:24](=[O:26])[CH3:25]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:24]([OH:26])[CH3:25])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: CC=O
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To a 250-mL 3-neck flask was added a THF solution (20 mL) of 2-bromo-5-fluoropyridine (8.80 g, 50 mmol). At −78° C., to the solution was added LDA (25.0 mL, 50 mmol, 2.5 M in THF) dropwise. After stirring for 5 min, diisopropylamine (7.0 mL, 50 mmol) was added dropwise via a syringe and the mixture was stirred at −78° C. for 4 h. A THF solution of acetaldehyde (11 mL, 55 mmol, 5M in THF) was added dropwise via a syringe. The contents were removed from the cold bath and stirred with warming to room temperature overnight. The mixture was diluted with water (150 mL) and vigorously stirred for 5 min. The contents were concentrated under reduced pressure and the residue was extracted with ethyl ether (3×150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford yellow oil, which was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 5:1) to afford 325b (8.0 g, 72.7%) as a yellow solid. MS-ESI: [M+H]+ 220.1. 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=1.5 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 5.17 (d, J=6.5 Hz, 1H), 2.18-2.16 (m, 1H), 1.52 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[Na+].[Na+].[F:7][CH2:8][CH2:9][NH:10][C:11](=[O:14])[O:12][CH3:13]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.C([N+](CC)(CC)CC)C.CO>[F:7][CH2:8][CH:9]([NH:10][C:11](=[O:14])[O:12][CH3:13])[O:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)NCCF
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC(CF)OC
Reaction time: 1 h
Yield: 251.4 %

Procedure:
An undivided electrochemical flow cell was constructed from two 150 cm2 graphite block electrodes separated with a 6 mm Viton® gasket and plumbed to a 500 ml jar reservoir, a Teflon® lined pump and a refrigerated cooling system so that the contents of the reservoir could be continuously recirculated through the cell and cooling system. The electrodes were connected to a power source and a voltage meter. The system was flushed with chromatography grade methanol to remove any contaminants. The reservoir was charged with 10-20 g of molecular sieves to keep the system dry, 290 g of chromatography grade methanol, 12 g (0.039 mol) of tetraethylammonium p-toluenesulfonate, 2 g (0.02 mol) of sodium carbonate, and 27.5 g of 91 percent purity (0.227 mol) of methyl 2-fluoroethylcarbamate and the resulting solution was circulated through the electrochemical cell while maintaining the current at 10 amperes and the temperature at 12°-16° C. After 1 hour gas chromatographic analysis indicated about 2 percent conversion. The current was increased to 12 amperes and the conversion went up to about 8 percent during the next hour and 39 percent after 6 hours. The process was continued overnight to increase the conversion to about 95 percent based on starting material and 81 percent based on product. The volatiles were removed under reduced pressure and the residue was dissolved in 200 ml of methylene chloride. The resulting solution was extracted with 100 ml of water, 100 ml of saturated aqueous sodium bicarbonate, and 100 ml of saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the volatiles under reduced pressure left 22.0 g of an oily residue which was found to be the title compound of about 81 percent purity by gas chromatography. The aqueous extracts were combined and extracted with methylene chloride to obtain another 7.6 g of the title compound of about 85 percent purity. The total yield recovered was about 85 percent of theory.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[CH:26]=[CH:27][C:4]([NH:3][C:41]([CH:38]3[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]3)=[O:42])=[CH:5][CH:6]=2)=[N:14][CH:13]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (1.0 g, 2.24 mmol) in DMF (15 mL) were added, piperidine-1,4-dicarboxylic acid mono-t-butyl ester (510 mg, 2.22 mmol), triethylamine (0.94 mL, 6.74 mmol), 1-hydroxybenzotriazole monohydrate (350 mg, 2.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (514 mg, 2.68 mmol) under ice cooling. The resulting solution was then stirred under ice cooling for 1 hour, and at room temperature for 17 hours. This reaction solution was concentrated under reduced pressure. The residue was diluted with water and ethyl acetate, whereupon a white powder was precipitated. The white powder was filtered, then washed with water, and subsequently washed with ethyl acetate, to thereby yield 1.04 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[CH:28]1([CH2:31][NH:32][C:33](=[O:49])[C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([C:33]([NH:32][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[O:49])=[CH:35][CH:36]=3)[C:26]([CH3:27])=[CH:25][CH:24]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(C)c(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)cc1
Temperature: 85 °C

Procedure:
3-Bromo-N-[3-t-butyl-1-(4-methylphenyl)-pyrazol-5-yl]-4-methylbenzamide (Intermediate 2 2, 43 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (33 mg), tetrakis(triphenylphosphine)palladium (2 mg) and aqueous sodiumhydrogen carbonate (1M, 0;5 ml) were mixed in propan-2-ol (2 ml) and heated at 85° C. under nitrogen for 96 hrs. The cooled reaction was absorbed onto silica and applied to a SPE cartridge (Si, 5 g) and eluted with an ethyl acetate/cylohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum to give N3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N4′-(cyclopropylmethyl)-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].[Al+3].[Cl-].[Cl-].[Cl-].[C:35](Cl)(=[O:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([N:12]2[C:13]3[CH:1]=[CH:2][C:3]([C:35](=[O:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([C:8]4[CH:9]=[CH:10][C:11]5[N:12]([C:14]6[CH:15]=[CH:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][CH:19]=6)[C:13]6[C:5]([C:6]=5[CH:7]=4)=[CH:4][C:3]([C:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[O:29])=[CH:2][CH:1]=6)=[O:45])=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[C:8]([C:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:29])[CH:7]=3)=[CH:19][CH:18]=1)(=[O:22])[CH3:21]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccc(C(=O)CCCCCCCCC(=O)c4ccc5c(c4)c4cc(C(=O)c6cccs6)ccc4n5-c4ccc(C(C)=O)cc4)cc3c3cc(C(=O)c4cccs4)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-carbazol-9-yl-phenyl)-ethanone (5.00 g) in CH2Cl2 (200 mL) is added thiophenecarbonyl chloride (2.56 g) and AlCl3 (4.74 g) at 0° C. After stirring overnight at room temperature, sebacoyl chloride (2.09 g) and AlCl3 (2.57 g) are further added at 0° C. and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated to give the residue, which is purified by washing with hot ethyl acetate. The structure of the product, which is obtained as an orange solid, is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.38-1.51 (m, 8H), 1.82 (quint, 4H), 2.73 (s, 6H), 3.11 (t, 4H), 7.23 (t, 2H), 7.47 (d, 2H), 7.51 (d, 2H), 7.70-7.77 (m, 8H), 8.06 (d, 2H), 8.13 (d, 2H), 8.27 (d, 4H), 8.79 (s, 2H), 8.82 (s, 2H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.CCCCCC>CCO>[Br:26][C:27]1[CH:28]=[N:29][C:30]([N:9]2[CH2:10][CH2:11][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:8]2)=[N:31][CH:32]=1
Reactant: CCOC(=O)C1(S(C)(=O)=O)CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1(S(C)(=O)=O)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of ethyl 4-(methylsulfonyl)piperidine-4-carboxylate hydrochloride (0.20 g, 0.74 mmol) in EtOH (7.0 mL) was added DIPEA (0.03 mL, 1.86 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.12 g, 0.62 mmol). The reaction was then heated up to 70° C. for 1 h. After completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 15% EtOAc:hexane to obtain the desired product as a yellow solid (0.108 g, 45% yield). 1H NMR (DMSO-d6): δ 1.20 (t, J=7.20 Hz, 3H), 1.62 (m, 2H), 2.07 (m, 2H), 2.69 (m, 2H), 3.69 (s, 3H), 4.62 (q, J=7.20 Hz, 2H), 4.86 (m, 2H) and 8.46 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[OH2:30].Cl(O)(=O)(=O)=O>C(#N)C>[ClH:1].[NH2:9][CH2:10][CH2:11][O:30][CH2:5][C:7]([N:9]([CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[CH2:12]1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])=[O:8]
Reactant: O
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Product: Cl
Product: NCCOCC(=O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1

Procedure:
Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: Zorbax Extend-C18 3.5μ; temperature: 40° C.; eluent A: water+5 ml of perchloric acid/liter, eluent B: acetonitrile; flow rate: 0.7 ml/min; gradient: 0-0.5 min 98% A, 2% B; ramp 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; ramp 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]3)[CH:15]=[CH:14][N:13]=[CH:12]1>[OH-].[K+].CCO>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[C:24](=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:23][CH2:22]3)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Methylthio)benzaldehyde (0.114 g, 0.75 mmol) was added to a stirring solution of (1) (0.25 g, 0.98 mmol) in 2 mL 4% KOH in EtOH (wt/vol). The reaction stirred at room temperature for 2 hours and the resulting precipitate was collected and washed well with water and then cold iPrOH. The solid was dried in vacuo at 40° C. for 3 hours affording the title compound, 0.277 g (95%) as an off-white solid, mp 161-161.5° C.; CI-MS m/e 390 (M+), 391 (M++1);
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([C:15]1[CH:53]=[CH:52][C:18]([CH2:19][C:20]2[C:21]([CH3:51])=[C:22]([OH:50])[CH:23]=[C:24]([C:26]3([O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]3[O:29][C:30](=[O:32])[CH3:31])[OH:27])[CH:25]=2)=[CH:17][CH:16]=1)[CH3:14].[CH:54]1(O)[CH2:57][CH2:56][CH2:55]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:54]1([O:50][C:22]2[CH:23]=[C:24]([C:26]3([O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]3[O:29][C:30](=[O:32])[CH3:31])[OH:27])[CH:25]=[C:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([CH2:13][CH3:14])=[CH:53][CH:52]=3)[C:21]=2[CH3:51])[CH2:57][CH2:56][CH2:55]1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(O)c2C)cc1
Reactant: OC1CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC3CCC3)c2C)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (0.38 g) dissolved in THF (0.5 mL) is added to 3-(4-ethylbenzyl)-1-hydroxy-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.27 g), cyclobutanol (0.1 mL) and triphenylphosphine (0.56 g) dissolved in THF (2 mL). The mixture is heated with stirring at 70° C. overnight. After cooling to room temperature, the solvent is evaporated and the residue is purified by chromatography (cyclohexane/ethyl acetate 4:1->1:3) on silica gel.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)[CH3:14].[Cl:26][C:27]1[C:28]([CH2:33][S:34][CH2:35][CH2:36][NH2:37])=[N:29][CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[C:28]([CH2:33][S:34][CH2:35][CH2:36][NH:37][C:7]2[C:3]([NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]3[O:20][C:16]([CH2:15][N:13]([CH3:12])[CH3:14])=[CH:17][CH:18]=3)=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: NCCSCc1ncccc1Cl
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)N=C2NCCSCc2ncccc2Cl)o1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with 2-[(5-dimethylaminomethyl-2furyl)methylthio]ethylamine and 2-[(3-chloro-2-pyridyl)methylthio]ethylamine, the title compound is thereby produced.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH:30]=[CH2:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C=CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and allyl bromide (33 uL, 0.38 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 21 as a colorless oil (15 mg).
Reaction SMILES: B1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5]2.CCCCCC.[Br:16][C:17]1[CH:22]=CC(C=CCC)=CC=1.[OH-:27].[Na+].OO>O.C1COCC1>[Br:16][C:17]1[CH:22]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:2][OH:27]
Reactant: CCC=Cc1ccc(Br)cc1
Reactant: [OH-]
Reactant: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.4 M 9-BBN in hexane (72 mL, 28.8 mmol) was added 4-bromophenyl-1-butene (3.99 g, 18.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 h. The mixture was treated sequentially with 3.3 mL of 6N aqueous NaOH (19.8 mmol), THF (7 mL), and 30% H2O2 in H2O (7 mL), then refluxed for 2 h. The reaction mixture was then cooled to room temperature. The organic layer was washed with aqueous sodium sulfite (40 mL), H2O (20 mL), and brine (20 mL). The aqueous extracts were combined, saturated with solid K2CO3 and extracted with Et2O (3×50 mL). The combined organic extracts were dried over Na2 SO4, filtered and concentrated. The resulting crude product was purified by flash chromatography twice (33% EtOAc in hexane and 20% EtOAc in hexane) to yield 4-(o-bromophenyl)butanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:18](=[O:19])[CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:10]=1
Reactant: Brc1ccc2sccc2c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1csc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 5-bromobenzothiophene (1 g) and phenylacetyl chloride (1.1 g) in dichloromethane (50 mL) was added aluminum chloride (1.9 g) at 0° C. and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into an ice-cooled hydrochloric acid aqueous solution (2 mol/L) and the mixture was extracted with diethyl ether. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1). After the solvent was removed, the residual solid washed with hexane to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:30][C:21]2[CH:20]=[C:19]([CH3:18])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1cccc(N2CCN(CCNCc3cc(C)n(-c4ccccc4)n3)CC2)c1C
Yield: 85.6 %

Procedure:
Compound 14 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.