Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)c(Cl)c([N+](=O)[O-])c1C

Procedure:
31.6 g of 2-chloro-4,5-dimethylbenzoic acid are initially introduced into 94 ml of H2SO4. 19 g of KNO3 are added in portions, while cooling with ice. The mixture is subsequently warmed to 50° for a further 2 hours and then poured onto ice. The product is isolated and recrystallized from toluene. Yield: 25.3 g, melting point: 160°-63°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].B(F)(F)F.CCOCC>C(O)(=O)C>[CH2:14]1[O:15][CH:4]([C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[F:1])[O:5][CH2:13]1
Reactant: OCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(C2OCCO2)c1
Temperature: 45 °C

Procedure:
A solution of 2-fluoro-5-nitro-benzaldehyde (25.0 g, 148 mmol), ethylene glycol (160 mL, 2.87 mol) in acetic acid (625 mL) was heated to 55° C. for 15 min. The temperature was then adjusted to 45° C., at which time BF3 --Et2O (20 mL, 20 mmol) was added dropwise (30 min). After an additionl 60 min at 45° C. the solution was cooled to room temperature, and poured onto ice (1 L). The resulting solid was filtered, pressed dry, and dried in vacuo to afford the title compound as white flakes (18.81 g, 60%). MS(ES) m/e 213 [M+H]+.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.Cl.[CH3:10][O:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:23])=[NH:20])=[CH:14][CH:13]=1>C(O)C>[ClH:7].[CH3:3][C:4]1([CH3:6])[N:20]=[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:35][CH:34]=2)[NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:23]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccc(OC)cc2)N1

Procedure:
100 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 2.0 g (4.6 mmol) of N1-(4-methoxyphenethyl)-N5-nonyl-biguanide dihydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure to give a residue, which was dissolved in hydrous ethanol. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7)) to obtain 1.2 g of a colorless resinous solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaidehyde (66 g) and sulfamic acid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during 1 hour with a solution of sodium chlorite (35 g) in water (150 mL). The mixture is stirred at 20° C. during 1 hour and then it is treated with water (500 mL) dropwise during 30 minutes. The resulting solid is filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of white crystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1; H,6.8%].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[C:10](Cl)=[N:11][CH:12]=[N:13][CH:14]=2)=O)=[CH:4][C:3]=1[C:18]#[N:19].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[S:29][C:10]3[N:11]=[CH:12][N:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: N#Cc1cc(C(=O)Nc2cncnc2Cl)ccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2nc3cncnc3s2)ccc1Cl
Temperature: 25 °C
Yield: 130.3 %

Procedure:
The above-obtained 4-chloro-N-(4-chloro-5-pyrimidinyl)-3-cyanobenzamide (7.98 g, 27.2 mmol) and Lawesson's reagent (8.25 g, 20.4 mmol) were suspended in toluene (150 mL). The suspension was refluxed with heating for 8 hours, and cooled to room temperature to filtrate precipitated crystals. The crystals were washed with chloroform (75×2), and air-dried to obtain 7.25 g (yield: 98%) of the subject compound as pale yellow crystals.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[C:15](=O)(O)[O-].[Na+]>CO>[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1
Reactant: O=C([O-])O
Reactant: NC1CCC(C(=O)O)CC1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C1CCC(N)CC1
Reaction time: 14 h

Procedure:
Thionyl chloride (4.15 g, 34.92) was added to a cold (0° C.) stirred solution of 4-aminocyclohexane carboxylic acid (1 g, 6.98 mmol) in MeOH (10 mL). The reaction mixture was stirred under reflux conditions for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with ice cold water, basified with aqueous sodium bicarbonate solution and extracted with DCM. The DCM layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 650 mg of the title compound as a brown liquid. MS (ESI): m/z 158 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][NH2:35].C(N(C(C)C)CC)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][NH:35][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=1)=[O:23]
Reactant: CON
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CONC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Yield: 99.7 %

Procedure:
To a stirred suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 113 μmol) and O-methylhydroxylamine hydrochloride (11.3 mg, 136 μmol) and diisopropylethylamine (79 μL, 453 μmol) in DMF (2 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate (58.6 mg, 136 μmol) at 20° C. for overnight. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl solution. The organic layer was then washed with saturated sodium bicarbonate and brine then dried (sodium sulfate), filtered and concentrated in vacuo to give the crude 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid methoxy-amide (53 mg) as a white solid. This was used directly in the next step without further purification. MS (M+H)+=471.
Reaction SMILES: [O:1]=[C:2]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:3]([C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)[C:4]#[N:5].[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1(C)C(C)=CC=CC=1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:1]/[C:2](/[C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=[C:3](\[C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)/[C:4]#[N:5])=[O:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Solvent: Cc1ccccc1C
Product: CCc1nn(-c2ccccc2)nc1/C(C#N)=C(\OC(=O)C(C)(C)C)c1c(C)c(C)nn1C
Temperature: 70 °C
Yield: 93 %

Procedure:
In a 3 L-reaction flask, 156.8 g (0.45 mol) of 3-oxo-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 900 g of xylene were added, the temperature was raised to 70° C., and 162.7 g (1.35 mol) of pivaloyl chloride was added dropwise under reflux over 10 hours while removing hydrogen chloride under a reduced pressure at 68 to 71° C./10 to 13 kPa. After reacting as such for 5 hours, 740 g of a mixture of pivaloyl chloride and xylene was distilled off at 70° C. under a reduced pressure in order to remove excess pivaloyl chloride. After adding 156 g of warm water of 70° C., 70 g of 2.7% sodium hydrogen carbonate aqueous solution was added dropwise. After separating the resulting aqueous phase, the resulting organic phase was washed with 156 g of warm water of 70° C., the resulting aqueous phase was separated to obtain a xylene solution containing 181 g (yield 93.0%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trim ethylpyrazol-5-yl) acrylonitrile. After distilling off most of xylene at 90° C. under a reduced pressure, 540 g of acetonitrile was added, and crystallization was carried out by gradually cooling from 70° C. After stirring at 0° C. for 1 hour, the resulting crystal was filtered, and dried to obtain 163.5 g (yield 84%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trim ethylpyrazol-5-yl) acrylonitrile (melting point: 119° C.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][OH:16].[F:17][C:18]1[C:26](O)=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[F:17][C:18]1[C:26]([O:16][CH2:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[CH3:1])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: Cc1sc(-c2ccccc2)nc1CCCO
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1CCCOc1ccc(F)c(C(N)=O)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
3-(5-Methyl-2-phenyl-thiazol-4-yl)-propan-1-ol To a solution of 3-(5-methyl-2-phenyl-thiazol-4-yl)-propan-1-ol (0.219 g, 1.0 mmol) in 5 ml of anhydrous DMF, 2,6-difluoro-3-hydroxybenzamide (0.173 g, 1.0 mmol), PPh3 (0.262 g, 1.0 mmol) and diisopropyl azodicarboxylate (0.202 g, 1.0 mmol) was added. The reaction mixture was stirred at 80° C. for overnight under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (35:65) as the eluent to provide the title compound as white solid (0.050 g, 13%). 1H NMR (DMSO-d6, 400 MHz): δ 2.44 (broad s, 3H), 3.14 (t, 2H, J=6.4 Hz), 4.35 (t, 2H, J=6.4 Hz), 7.04 (dt, 1H, J=9.2 Hz (o-coupling), 7.22-7.28 (m, 1H), 7.43-7.49 (m, 3H), 7.83-7.86 (m, 3H), 8.10 (s, 1H); MS ES+(375.15), HPLC (method 5) Rt=10.67 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(C(=O)O)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2
Temperature: 40 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To solution of 3-(4-methoxyphenyl)-2-phenylpropionic acid (4.6 g) in dry methylene chloride (26 ml) was added two drops of dry DMF. Thionylchloride (3 ml) was added and reaction mixture was stirred at 40° C. for 4 h. Solvent was evaporated under vacuum. Precipitate was dissolved to methylene chloride. Solution was cooled to 0-3° C. This solution and aluminium chloride (2.5 g) were mixed slowly over 4 hours keeping temperature under 4° C. After mixing reaction mixture was stirred at room temperature for 2 h. Reaction was quenched by pouring to dilute ice cold hydrochloric acid. Layers were separated and water solution was extracted with methylene chloride. Combined organic layers were washed with water, dried and evaporated. Crude product was triturated to give 2.9 g of 6-Methoxy-2-phenylindan-1-one. 1H-NMR (400 MHz, d6-DMSO): 7.56 (d, 1H), 7.35-7.23 (m, 4H), 7.18-7.13 (m, 3H), 4.02 (dd, 1H, J 3.9, 8.0 Hz), 3.82 (s, 3H), 3.61 (dd, 1H, J 8.0, 17.2 Hz), 3.11 (dd, 1H, J 3.9, 17.2 Hz).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCO
Reactant: CCCCCCCCCCOc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(C(=O)OCCCCCCCC)ccc3o2)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
In a 30 ml round-bottom flask, 0.30 g (0.76 m mole) of 2-(4-decyloxyphenyl)-5-carboxybenzooxazole, 0.11 g (0,84 m mole) of octanol and 8 ml of dichloromethane were placed. To the mixture solution 0.16 g (0.78 m mole) of N,N'-dicyclohexycarbodiimide and 0.04 g of 4-pyrrolidinopyridine were added in order under stirring at room temperature, followed by stirring for 8 hours at room temperature to precipitate N,N'-dicyclohexylurea. The resultant N,N'-dicyclohexylurea was filtered off and the filtrate was dried under reduced pressure. The resultant was purified by silica gel column chromatography (eluent: toluene) and recrystallized twice from acetone to obtain 0.19 g of 2-(4-decyloxyphenyl)-5-octyloxycarbonyl benzooxazole (Yield: 49.3%). ##STR89##
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[S:12][N:11]=[C:10](SC)[N:9]=1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)(Cl)Cl>[CH3:16][S:26]([C:10]1[N:9]=[C:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])[S:12][N:11]=1)(=[O:29])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nsc(C2CCCCC2C)n1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CCCCC1c1nc(S(C)(=O)=O)ns1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
500 mg of 5-(2-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole was dissolved in 6.5 ml of chloroform, 1.62 g of 3-chloroperoxybenzoic acid (content>65%) was added thereto taking for 20 minutes, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1.5 hours under room temperature. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 466 mg of 3-methylsulfonyl-5-(2-methylcyclohexyl)-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:10]Br>>[Br-:10].[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH2:2][N+:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: BrBr
Reactant: CC(=O)c1ccccn1
Product: O=C(C[n+]1ccccc1)c1ccccn1
Product: [Br-]
Temperature: 25 °C

Procedure:
2-Acetylpyridine (100 mmol) is treated with bromine (6.2 mL, 0.12 mol) at reflux in 200 mL of CHCl 3 for 45 min. The solution is cooled to room temperature then washed with dilute aqueous NaHCO3 /Na2S2 O3. The organic phase is dried over Na2SO4, filtered, and evaporated. The residue is dissolved in 200 mL of tetrahydrofuran (THF) and 30 mL of pyridine is added. The resulting solution is refluxed for 30 min. The mixture is cooled and filtered to give the desired product. The nuclear magnetic resonance (NMR) and infrared (IR) spectra are consistent with the assigned structure and the product is homogeneous by TLC.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.[Li]CCCC.[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:32][C:27]3([CH2:30][C:29](=O)[CH2:28]3)[CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]>C1COCC1>[CH2:16]([CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]2[CH2:32][C:27]3([CH2:30][C:29](=[C:3]4[S:8][CH2:7][CH2:6][CH2:5][S:4]4)[CH2:28]3)[CH2:26]2)[CH2:23][CH2:24]1)[CH2:17][CH3:18]
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CCCC1CCC(C2CC3(CC(=O)C3)C2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1CCC(C2CC3(CC(=C4SCCCS4)C3)C2)CC1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
15.5 g (80.3 mmol) of 2-trimethylsilyl-1,3-dithiane are dissolved in 150 ml of THF, and 51 ml (80.3 mmol) of n-BuLi (15 percent in hexane) are rapidly added dropwise at −70° C. The batch is subsequently allowed to thaw to 0° C. over the course of 4 hours, stirred for 10 minutes without cooling and re-cooled to −70° C., and a solution of 17.0 g (72.5 mmol) of 6-(4-n-propylcyclohexyl)spiro[3.3]heptan-2-one 5 in 50 ml of THF is added drop-wise. The batch is left to stir overnight at room temperature, hydrolysed using saturated sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic phases are washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure, and the crude product is recrystallised from n-heptane. The dithioacetal 6 is obtained as colourless flakes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.Cl.[Br:24][C:25]1[C:26]([O:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35])=[N:27][C:28](Cl)=[N:29][CH:30]=1>C(#N)C.O1CCOCC1>[Br:24][C:25]1[C:26]([O:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35])=[N:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])(=[O:12])=[O:13])=[O:9])=[CH:4][CH:3]=2)=[N:29][CH:30]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(CCO)c1ccc(N)cc1
Reactant: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(CCO)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of 205 mg (0.56 mmol) of (RS)-S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide in 2 ml of acetonitrile is mixed with 0.15 ml of a 4N solution of HCl in dioxane. 175 mg (0.62 mmol) of (2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml of acetonitrile is added, and the batch is stirred for 24 hours at 70° C. Then, it is stirred for another 24 hours at 85° C. The solvent is removed, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 110 mg (0.18 mmol, corresponding to 32% of theory) of the product is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20](=[O:47])[CH:21]([NH:34][C:35](=[O:46])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].N#N>C(#N)C>[C:15]([O:19][C:20](=[O:47])[CH:21]([NH:34][C:35](=[O:46])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])=[CH:12][CH:11]=1)[CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(CCC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)NC(CCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Yield: 110.6 %

Procedure:
4-Hydroxy-benzoic acid tert-butyl ester (0.65 g, 3.08 mmol) was dissolved in acetonitrile (7.5 ml) and added to 2-(10-Bromodecanoylamino) pentanedioic acid 5-benzyl ester 1-tert-butyl ester (1.62 g, 3.08 mmol). Acetonitrile (90 ml) and K2CO3 (0.64 g, 4.62 mmol) was added and the mixture was refluxed for 16 h under a flow of N2. The solvent was removed under vacuum. AcOEt (100 ml) was added and the solution was washed with water (2×50 ml) using sat. NaCl and methanol to aid phase separation, dried over MgSO4, and concentrated to yield a light brown oil (2.18 g). The oil was purified by flash chromatography (silica, 95:5 DCM/AcOEt) to yield an oil (160 mg, 8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=O)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>O=P(Cl)(Cl)Cl.C(Cl)Cl>[CH:14]1([CH:12]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:9][CH2:10][N:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(CCN(C(=O)C2CCCCC2)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A stirred solution of cyclohexanecarboxylic acid [2-(3-methoxy-phenyl)-ethyl]-phenyl-amide in POCl3 under an atmosphere of N2 was heated at reflux for 14 hours. The solution was allowed to cool to rt and concentrated in vacuo. The residue was taken up in CH2Cl2 (30 ml) and washed with sat. NaHCO3 until CO2 evolution ceased. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (20 ml), cooled to 0° C., and NaBH4 (0.105 g, 2.77 mmol) was added in a portionwise manner. The reaction was stirred for 2 hours at 0° C., then additional NaBH4 (0.105 g, 2.77 mmol) was added. The reaction was stirred at rt overnight, diluted with CH2Cl2 (50 ml), and washed with sat. NaHCO3 solution (1×50 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo, to give the desired compound as a yellow oil (0.234 g, 0.729 mmol, 73% yield).