Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:9].O1CCOCC1.CN(C)C=O>CO>[CH2:8]([NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH3:9]
Reactant: O=C1CCC(=O)O1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)CCC(=O)O

Procedure:
500 mg of succinic anhydride was added to a solution of 500 mg of alanyl proline ethylamide in form of dioxane (10 ml) and 0.25 ml of dimethylformamide and the reaction solution heated under reflux for 30 minutes. Then the solution was evaporated and the residue crystallized from 10 ml of acetone and 30 ml of ether. 510 mg of a product having a melting point of 139 to 141 degrees C. was obtained. [α[D20 -129.2 degrees (c 0.3; 50% methyl alcohol).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].[CH3:31][N:32]([CH3:37])[C:33](=[O:36])[CH2:34]Cl>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:34][C:33]([N:32]([CH3:37])[CH3:31])=[O:36])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(=O)N(C)C)CC4)cc2OCC3)n(C(C)C)n1
Yield: 37.5 %

Procedure:
A suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (310 mg, 0.72 mmol) in DCM (6 mL) and TEA (0.3 mL, 2.16 mmol) was sonicated and stirred before adding N,N-dimethyl-2-chloroacetamide (98 mg, 0.8 mmol) and TBAI (28 mg, 0.072 mmol) and the reaction mixture stirred for 72 h at RT before being concentrated in vacuo. The resultant residue was partitioned between water and DCM and the aqueous extracted five times with DCM, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatpgraphy (SiO2, gradient 0 to 10% methanol in DCM) then triturated in diethyl ether to give 329 as a white solid (129 mg, 38%). LCMS: RT=2.71 min, [M+H]+=478. 1H NMR 400 MHz (CDCl3) δ: 8.44 (1 H, d, J=8.30 Hz), 7.61 (1 H, s), 7.04 (1 H, d, J=8.43 Hz), 6.91 (1 H, s), 5.91 (1 H, t, J=6.63 Hz), 4.45 (4H, d, J=14.92 Hz), 3.39 (2 H, m), 3.11 (2 H, m), 3.10 (3 H, s), 2.99 (1 H, m), 2.98 (3 H, s), 2.54 (2 H, m), 2.41 (3 H, s), 1.90 (4 H, s), 1.57 (6 H, d, J=6.65 Hz)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][C@H:49]2[CH3:54])[N:44]([CH2:55][C:56](O)=[O:57])[CH2:43][C@H:42]1[CH3:59])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:60][C:61]([C:66]1[CH:67]=[C:68]2[NH:74][CH2:73][C:72]([CH3:76])([CH3:75])[C:69]2=[N:70][CH:71]=1)([F:65])[CH2:62][CH2:63][CH3:64]>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][C@H:49]2[CH3:54])[N:44]([CH2:55][C:56]([N:74]2[C:68]3[C:69](=[N:70][CH:71]=[C:66]([C:61]([F:65])([F:60])[CH2:62][CH2:63][CH3:64])[CH:67]=3)[C:72]([CH3:75])([CH3:76])[CH2:73]2)=[O:57])[CH2:43][C@H:42]1[CH3:59])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Reactant: CCCC(F)(F)c1cnc2c(c1)NCC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOC[C@H]1C)CC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
HATU (3.8 g, 9.9 mmol) and DIPEA (2.4 mL, 13.3 mmol) were added to a solution of (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 6.7 mmol) and 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.6 g, 6.7 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 16 h and then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was separated, washed with brine (3×), dried over MgSO4 and concentrated in vacuo. Chromatography (70% EtOAc in Petrol) gave the title compound (2.1 g) as a yellow solid. MS: [M+H]+=594.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[Cl:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=1[CH2:57][C:58]([OH:60])=O>>[Cl:56][C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([Cl:49])[C:51]=1[CH2:57][C:58]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:60]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2c(Cl)cccc2Cl)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,6-dichlorophenylacetic acid, mp 203°-205° C.
Reaction SMILES: [OH:1][CH:2]([CH2:23]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12].[BrH:25].[C:26]([OH:29])(=O)[CH3:27].C(=O)(O)[O-]>ClCCl.O>[C:26]([O:1][CH:2]([CH2:23][Br:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=[O:29])[CH3:27]
Reactant: Br
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Reactant: CC(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A mixture of 1-(8,9-dihydroxynonyl)-3,7-dimethylxanthine and 30% hydrogen bromide in acetic acid (0.8 mL, 3.90 mmol) was stirred for 90 minutes. The solution was poured into a mixture of water (10 mL), sodioum bicarbonate (1.35 g, and dichloromethane (10 mL). After 10 minutes of vigorous stiring, the layers were separated and the aqueous portion extracted with dichloromethane (3×15 mL). The combined organic phases were dried over sodium sulfate and the solvent evaporated under vacuum, yielding 550 mg (96%) 1-(8-acetoxy-9-bromononyl)-3,7-dimethylxanthine as a yellow oil. Without further purification, the oil was dissoved in methanol (5 mL) and then a 1 M solution of sodium methoxide in methanol (1.4 mL) was added. After 30 minutes, the reaction mixture was poured into water (30 mL) and was extracted with dichloromethane (3×40 mL). The combined organic portions were dried over sodium sulfate and the solvents evaporated under vacuum. The solid residue was recrystallized (dichloromethane-petroleum ether) to yield 380 mg (91% yield) 1-(8,9-oxidononyl)-3,7-dimethylxanthine (inventive compound no. 1560).
Reaction SMILES: [CH3:1][C:2]([NH:21][C:22](=O)OC(C)(C)C)([CH3:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1.[ClH:29].C([O:33][CH2:34][CH3:35])(=O)C>CO>[ClH:29].[CH3:20][C:2]([CH3:1])([NH:21][CH2:22][C@H:34]([OH:33])[C:35]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(Cc1ccc(NC(=O)Cc2ccccn2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(Cc1ccc(NC(=O)Cc2ccccn2)cc1)NC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 490 mg of tert-butyl N-[1,1-di-methyl-2-[4-[[2-(2-pyridyl)acetyl]amino]phenyl]ethyl]-carbamate in 10 ml of methanol was added 30 ml of a 4N hydrochloride-ethyl acetate solution. After the reaction solution was stirred at room temperature for eight hours, the solvent was evaporated in vacuo. To the residue were added an aqueous solution of sodium hydrogen carbonate and potassium carbonate to adjust to pH about 12. The resulting aqueous phase was extracted with a mixed solvent of chloroform and tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated, the resulting residue was dissolved in 2 ml of 2-propanol and 2 ml of methanol, and 120 mg of (R)-styrene oxide was added thereto. After the reaction solution was heated to reflux for 24 hours, the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1→15/1) and dissolved in methanol, 0.1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, and the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=5/1) and a reversed phase column chromatography (eluent: water/methanol=2/1→1/1) to give 35 mg of (R)-4′-[2,2-dimethyl-2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl)acetanilide hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Mg].II.[CH3:14][C:15]([CH3:35])([CH3:34])[CH2:16][C:17]([NH:19][C:20]1[C:21]([CH3:33])=[C:22]([CH3:32])[C:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25](=[O:30])[C:24]=2[CH:31]=1)=[O:18]>C1COCC1>[OH:30][C:25]1([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:8]([CH3:10])[CH3:9])[CH:2]=2)[C:24]2[CH:31]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][C:15]([CH3:35])([CH3:34])[CH3:14])[C:21]([CH3:33])=[C:22]([CH3:32])[C:23]=2[O:27][C:26]1([CH3:28])[CH3:29]
Reactant: CC(C)c1ccccc1Br
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C(C)C)c1
Yield: 16.2 %

Procedure:
A solution of 1-bromo-2-isopropylbenzene (1.20 g, 6.03 mmol) in THF (5 mL) was added dropwise under an argon atmosphere to a mixture of magnesium (147 mg, 6.03 mmol) and a catalytic amount of iodine, and the mixture was stirred at 70° C. for 30 minutes. To the reaction solution was added dropwise a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (350 mg, 1.15 mmol) obtained in Reference Example 65 in THF (3 mL), and the mixture was refluxed with heating for 12 hours. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 79 mg (yield: 16%) of N-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide. To a solution of the compound (79 mg, 0.19 mmol) in trifluoroacetic acid (1 mL) was added with ice-cooling triethylsilane (44 mg, 0.38 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 1 N sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([NH:24][N:25]2[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]2)=[O:23])=[N:10]1.[C:33]([CH2:35][CH2:36][C:37]#[CH:38])#[N:34].[Cl-].[NH4+]>N1CCCC1.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:33]([CH2:35][CH2:36][C:37]#[C:38][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]([C:22]([NH:24][N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:23])[C:12]=2[CH3:21])=[CH:15][CH:16]=1)#[N:34]
Reactant: C#CCCC#N
Reactant: Cc1c(C(=O)NN2CCS(=O)(=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: Cc1c(C(=O)NN2CCS(=O)(=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C#CCCC#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
To a stirred solution of amide obtained from step E (2 g, 3.3 mmol) in pyrrolidine (40 ml), under an argon atmosphere, tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.3 mmol) was added. The reaction mixture was stirred for 5 min at room temperature, and subsequently 4-cyano-1-butyne (0.78 g, 9.9 mmol) in pyrrolidine (1.5 ml) was added over 5 minutes. The resulting mixture was heated at 80-85° C. for 10 h. The reaction was hydrolyzed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extract was dried over MgSO4 and the solvent was removed in vacuo. Purification by flash column chromatography on silica gel (eluant ethylacetate) gave compound 15 as a white solid (0.8 g, 43.7%)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 95 %

Procedure:
Chiral hydrogenation of acetophenone was carried out (see formula (7) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using acetophenone (150 mg; 1.25 mmol) as the substrate and 2-propanol (1.5 mL) as the solvent. However, the hydrogen pressure was set to 1 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 12 hours. As a result, (R)-1-phenylethanol was obtained at a conversion rate of 99%, isolation yield of 95% (293 mg; 1.19 mmol), and enantiomeric excess of 97%.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.Cl>ClCCCl>[CH3:3][CH2:2][C:1]([C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCC(=O)Cl
Reactant: c1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCCl
Product: CCC(=O)c1cccc2ccccc12
Temperature: 47.5 °C
Yield: 79 %

Procedure:
The foregoing 1,2-dichloroethane solution of a propionyl chloride.aluminum chloride complex was added dropwise to a solution consisting of 128.2 g (1.0 mol) of naphthalene and 300 mL of 1,2-dichloroethane at 35 to 40° C. over one hour. After completion of addition, the resulting mixed liquid was heated at 45 to 50° C. for 2 hours and after cooling to room temperature, was poured into, ice water. 200 mL of concentrated hydrochloric acid was further added thereto, and the mixture was stirred and mixed. The product as formed in this reaction mixture was extracted with chloroform together with 1,2-dichloroethane, dried over magnesium sulfate, and concentrated in vacuo. A concentrated liquid was distilled in vacuo to obtain 145.3 g (yield: 79%, boiling point: 139 to 142° C./4 mmHg) of 1-propionaphthone as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[I:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1O.CC(C)([O-])C.[Na+]>O1CCCC1.ClCCl>[Br:1][C:2]1[C:3]([CH2:8][O:9][C:28]2[CH:27]=[C:26]([Cl:29])[CH:25]=[CH:24][C:23]=2[I:22])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1Br
Reactant: Oc1cc(Cl)ccc1I
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1ccc(I)c(OCc2ncccc2Br)c1
Temperature: 0.6000000238418579 °C
Yield: 65.9 %

Procedure:
(3-Bromo-pyridin-2-yl)-methanol (7.39 g, 39.30 mmoles), and triethylamine (7.15 mL, 51.3 mmoles) are combined in tetrahydrofuran (70 mL) under nitrogen. The solution is chilled to 0.6° C. with an ice bath. Methanesulfonyl chloride (3.35 mL, 43.28 mmol) is added dropwise over 20 min, controlling the exotherm such that the internal temperature does not exceed 5° C. Following the addition, the reaction is stirred over an ice bath. After 20 min HPLC analysis shows that the (3-Bromo-pyridin-2-yl)-methanol is fully consumed. Triethylamine hydrochloride is filtered using a fitted glass funnel, washing with cold THF (50 mL). The THF filtrate containing the mesylate is placed under nitrogen and chilled in an ice bath. 2-Iodo-5-chlorophenol (10.00 g, 39.30 mmoles) is added, followed by addition of sodium t-butoxide (4.10 g, 41.38 mmol) in two equal portions with a mild exotherm of about 5° C. for each addition. The ice bath is removed and the reaction allowed to stir overnight. The reaction is quenched with water (50 mL) and the lower aqueous layer allowed to slowly separate. The organic portion is washed with brine (25 mL), and then the brine and aqueous portions back-extracted with THF (10 mL). The organic portions are combined and dried over sodium sulfate, filtered, and concentrated to afford a rusty orange solid. The solid is dissolved in dichloromethane (25 mL) and chromatographed on an AnaLogix Inc., Intelliflash 180 automated chromatography instrument, version 1.8.0. using a gradient of 10- 20% ethyl acetate/hexanes over 35 min to afford 11.0 g (65%) of the product as a yellow solid. 1H NMR (DMSO) δ 5.31 (2H, s), 6.85 (1H, dd), 7.25 (1H, m), 7.39 (1H, dd), 7.77 (1H, d), 8.17 (1H, d), 8.59 (1H, d).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@H:4]1[O:8][C:7](=[O:9])[N:6]([NH:10]C(=O)OC(C)(C)C)[CH2:5]1.O1CCOCC1.C(OC(C)C)(C)C.[ClH:31]>C1COCC1>[ClH:31].[NH2:10][N:6]1[CH2:5][C@@H:4]([CH2:3][S:2][CH3:1])[O:8][C:7]1=[O:9]
Reactant: CSC[C@@H]1CN(NC(=O)OC(C)(C)C)C(=O)O1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CSC[C@@H]1CN(N)C(=O)O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
To a solution of (S)-tert-butyl 5-(methylthiomethyl)-2-oxooxazolidin-3-ylcarbamate (374 mg, 1.426 mmol) in THF (2 mL), 4M HCl in dioxane (1.25 mL, 4.99 mmol) was added. The reaction was stirred at r.t. for 4 days and a white solid precipitated. The obtained product was filtered and triturated with hot diisopropyl ether affording the title compound (240 mg, 1.208 mmol). Yield=85%.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12](F)[CH:11]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][C:12]2[CH:13]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:15]=[C:10]([Br:9])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Product: Cc1ccc(Sc2cc(Br)cc(C(F)(F)F)c2)cc1
Yield: 63 %

Procedure:
Using a similar procedure to that described in the 1st paragraph of Note a. above 4-toluenethiol was reacted with 1-bromo-3-fluoro-5-trifluoromethylbenzene to give 3-bromo-5-trifluoromethylphenyl 4-tolyl sulphide in 63% yield as an oil.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[SH:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27].ClC(Cl)(Cl)C(O)=O>O>[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])[CH2:1][CH2:2][O:3]1
Reactant: O=S(=O)([O-])CCS
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 72 h

Procedure:
5.6 g (20 mmol) of 4-hydroxycyclophosphamide (i.e., 2-(bis (2-chloroethyl)-amino)-4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.8 g (20 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 100 ml of distilled water, mixed with some trichloroacetic acid and left to stand in a refrigerator for 3 days at 0° C. The solvent was then removed under high vacuum, the residue was taken up in acetone, re-concentrated, crystallised from acetone and recrystallised from isopropanol.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>>[CH:20]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1=CCCCCCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1C=CCCCCC1
Temperature: 87.5 °C
Yield: 17.4 %

Procedure:
A mixture of 15.0 g (0.09 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 126.6 g (1.15 mol) of cyclooctene is heated under a nitrogen atmosphere at 87-88° C. for 40 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 5% ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is crystallized from heptane to give 4.40 g (36% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:17][C:18]([F:26])(S(F)(=O)=O)C(O)=O.O>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:18]([F:26])[F:17])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)OCc1ccc(Br)cc1
Temperature: 45 °C
Yield: 37.1 %

Procedure:
To a solution of 4-bromobenzyl alcohol (5.6 g) in acetonitrile (15 ml), sodium sulfate (0.28 g) was added. While warmed to 45° C., 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.78 g) was slowly dropwise added, and the mixture was heated and refluxed at 45° C. for 4 hours. The reaction solution was poured into water, the mixture was extracted with diethyl ether and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo and the residue obtained was purified with silica gel column chromatography (hexane:ethyl acetate=19:1 to 17:3) to afford the above-identified compound (0.88 g).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.O.[NH4+].[Cl-]>C(O)C.C1COCC1.[Fe]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:3]2[C:4]3[C:9]([NH2:10])=[N:8][CH:7]=[N:6][C:5]=3[S:11][C:2]=2[CH3:1])=[CH:17][CH:16]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
A suspension of Example 1D (1.01 g, 3.53 mmol) in ethanol (60 mL), THF (20 mL), and water (10 mL) was treated with NH4Cl (0.19 g, 3.53 mmol) and iron powder (1.18 g, 21.2 mmol), and stirred at 70-80° C. for 1 hour. The mixture was diluted with ethanol (40 mL) and filtered through a pad of diatomaceous earth (Celite®) while still hot. The pad was washed with ethanol and the filtrate was concentrated. The concentrate was diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 1 g of the desired product. MS (CI) m/e 257 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H); 7.01 (d, J=8.4 Hz, 2H); 6.70 (d, J=8.4 Hz, 2H); 5.39 (s, 2H); 2.27 (s, 3H); Anal. Calcd. for C13H12N4S.0.2C4H8O2.0.2H2O: C, 59.72; H, 5.08; N, 20.19. Found: 59.64; H, 4.99; N, 20.22.