Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCNC1=O.C([C@@H]1COC(=O)N1[C:20](=[O:44])[C@H:21]([C@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:31]=1)[O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH3:23])C1C=CC=CC=1>>[CH:38]1([CH2:37][O:36][C:32]2[CH:31]=[C:30]([C@H:24]([O:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C@H:21]([CH2:22][CH3:23])[CH2:20][OH:44])[CH:35]=[CH:34][CH:33]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CC[C@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O[Si](C)(C)C)c1cccc(OCC2CCCCC2)c1
Agent: O=C1NCCO1
Product: CC[C@H](CO)[C@@H](O[Si](C)(C)C)c1cccc(OCC2CCCCC2)c1

Procedure:
Oxazolidinone cleavage of (R)-4-benzyl-3-((S)-2-((R)-(3-(cyclohexylmethoxy)phenyl)(trimethylsilyloxy)methyl)butanoyl)oxazolidin-2-one following the method described in Example 45 gave (R)-2-((R)-(3-(cyclohexylmethoxy)phenyl)-(trimethylsilyloxy)methyl)butan-1-ol as colorless oil. Yield (0.273 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=7.6 Hz, 1H), 6.73-6.80 (m, 3H), 4.64 (d, J=6.5 Hz, 1H), 4.19 (t, J=5.1 Hz, 1H), 3.41-3.47 (m, 1H), 3.32-3.37 (m, 1H), 1.58-1.79 (m, 6H), 1.48 (m, 1H), 0.99-1.26 (m, 7H), 0.76 (t, J=7.6 Hz, 3H), −0.06 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][C:16](=[O:35])[N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][C:16]([N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:31])[F:32])[CH2:21][CH2:22]1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.5 %

Procedure:
TFA (13 mL) was added drop wise to {2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (2.6 g, 6.27 mmol) in DCM (15 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. Concentrating the mixture afforded a crude product, which was recrystallized from hexane to afford 2.5 g (93% yield) of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone as TFA salt.
Reaction SMILES: [CH2:1]1[CH:6]2[CH:7]3[CH:13]4[CH2:14][CH:2]1[CH2:3][CH:4]1[CH:12]4[CH2:11][CH:9]([CH2:10][CH:5]12)[CH2:8]3.S(=O)(=O)(O)[OH:16]>>[CH2:1]1[CH:6]2[CH:5]3[CH:4]4[CH2:3][CH:2]1[CH2:14][CH:13]1[CH:12]4[C:11](=[O:16])[CH:9]([CH2:8][CH:7]12)[CH2:10]3
Reactant: C1C2CC3C4CC5CC(C14)C(C2)C3C5
Reactant: O=S(=O)(O)O
Product: O=C1C2CC3C4CC5CC3C1C(C5)C4C2
Temperature: 75 °C
Yield: 70 %

Procedure:
The synthesis of 3-diamantanol (22) from diamantane follows Gund et al, J. Org. Chem., 39, 2987 (1974), incorporated herein by reference. To diamantane (2 g), prepared as in Example 3, Procedure 6, is added 96.6% sulfuric acid (100 ml); the reaction mixture is then heated for four hours at 75° C. with vigorous stirring. Stirring is continued at room temperature for one additional hour. The black reaction mixture is poured over ice and steam distilled. The steam distillate is extracted with ether, and the combined ether extracts are washed with water and dried over MgSO4. Evaporation of the solvent leaves 1.4 g (70% yield) of crude diamantanone. The product may be further purified by chromatography on alumina. The second fraction, eluted with benzene-ether (1:1) contains pure diamantanone (0.8 g, 37%). Recrystallization from petroleum ether gives white crystals, mp 249°-250° C.; IR (Nujol oil) 1745, 1720, 1295, 1245, 1045 cm-1.
Reaction SMILES: [OH:1][C@@:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH2:20])=[O:8])=[O:4].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>CCO>[OH:1][C@@:2]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH:20][CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[O:8])=[O:4]
Reactant: C[C@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CCN)c1ccccc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCNCCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@](C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 1-((2R)-2-hydroxy-2-phenylpropanoyl)-N-(2-(2-aminoethyl)-5-chlorobenzyl)-L-prolinamide (90 mg, 0.21 mmol) in EtOH (2 mL) was added ethyl acrylate (25 microliters, 0.22 mmol). The mixture was stirred at ambient temperature for 48 h. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography using a gradient elution of 5% to 7.5% MeOH in CH2Cl2. The product-containing fractions were combined to give the title compound as an amorphous solid upon removal of the solvents in vacuo (TLC Rf=0.4 (95:5 CH2Cl2:MeOH); HPLC RT=2.95 min, method A; LC-MS m/z=530).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: OCCOCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,2,2-trifluoroethoxy)ethanol (intermediate BR) (12.7 g) was dissolved in anhydrous pyridine, then TsCl (1.3 eq) was added, and the mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. Then the mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was removed and the residue purified by column chromatography to obtain intermediate BS (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:17])([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:26][C:27](Br)=[O:28]>CCOCC>[CH2:13]([C:8]1([C:9]([F:10])([F:11])[F:12])[C:7]2[CH:6]=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][O:17]1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C(Br)CBr
Reactant: CCCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 185 mg of 6-amino-3-chloro-α-butyl-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of cry pyridine and 0.060 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 8 mL of dry DMF and was treated at room temperature with 40 mg of 100% sodium hydride for 16 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried, and evaporated. The crude product was purified first by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3), and then by preparative silica gel TLC. (elution with 2.5% methanol in methylene chloride) affording 32 mg of the title compound as an amorphous solid: HRMS: Calcd. for C14H16NO2ClF3 (M+H)+ : 322.082166. Found: 322.080685.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:24]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CS(=O)(=O)NC(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1)S(=O)(=O)NC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
11.2 g (0.05 mol) of ethyl 2-(tert.butylaminosulfonyl)acetate (see J. Org. Chem. 43, p. 4535 (1978)) are dissolved in 50 ml of benzaldehyde, 2 g of ammonium acetate and 2 ml of glacial acetic acid are added, and the mixture is stirred for 2 hours at 60° C. under a water pump vacuum (20 mm). The excess aldehyde is subsequently distilled off, and the residue is digested using n-hexane and recrystallized from isopropanol. 11.2 g (72% of theory) of ethyl 3-phenyl-2-(tert.butylaminosulfonyl)prop-2-enoate of melting point 111°-113° C. are obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[OH-].[K+].Br[C:9]([CH3:23])([CH3:22])[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:15][N:14]=1)=[O:11]>C(O)C>[C:18]([C:16]1[O:15][N:14]=[C:13]([NH:12][C:10](=[O:11])[C:9]([S:4][CH2:3][CH:2]([CH3:5])[CH3:1])([CH3:22])[CH3:23])[CH:17]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CC(C)CS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CSC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a stirred solution of 82 μL (1.31 mmol) of 2-methyl-1-propanethiol in ethanol (2 mL) were added 37 mg (0.65 mmol) of KOH pellets, followed by 190 mg (0.65 mmol) 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in step 2, method B). The reaction mixture was heated to reflux for 18 h. The reaction was cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (15 mL). The filtrate was concentrated under reduced pressure to yield 160 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-isobutylsulfanyl-2-methyl-propionamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]3[CH2:16][CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:18][N:19]([CH3:23])[CH2:20][C:21]#[CH:22]>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]12[N:11]([C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:22]#[C:21][CH2:20][N:19]([CH3:23])[CH3:18])[CH:3]=3)[CH:12]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2
Reactant: C#CCN(C)C
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1[N+](=O)[O-]
Yield: 79.4 %

Procedure:
To 7-(3-bromo-4-nitro-phenyl)-7-azabicyclo[2.2.1]heptane 25 (500 mg, 1.683 mmol), Pd(PPh3)2Cl2 (59 mg, 0.08 mmol), and cuprous iodide (9.616 mg, 1.708 μL, 0.05049 mmol) was added a solution of N,N-dimethylprop-2-yn-1-amine (420 mg, 538 μL, 5.05 mmol) in degassed DMF (5 mL) and triethylamine (5 mL). The reaction mixture was microwaved under N2 for 10 min at 100° C. The reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4 and filtered, leaving a red solid. Purification by silica gel chromatography (0-50% dichloromethane in ethyl acetate) yielded 3-[5-(7-azabicyclo[2.2.1]heptan-7-yl)-2-nitro-phenyl]-N,N-dimethyl-prop-2-yn-1-amine 26 (400 mg, 79% yield). LC/MS m/z 300.5 [M+H]+, retention time 1.11 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1F)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a mixture of 6-(2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.21 g) and aminoguanidine hydrochloride (95 mg) were added ethanol (17 ml) and 6N hydrochloric acid (0.074 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-fluorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 40) (0.19 g).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[O:19][C:20]([CH3:22])=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1coc(C)c1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2oc(C)cc2c1
Yield: 81 %

Procedure:
Sodium acetate (15 g, 0.18 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-furyl)but-3-enoic acid (14 g, 58 mmol) in 150 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 300 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) as eluent to give the desired product 12.5 g (47 mmol, 81%) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[CH2:18]([NH2:20])[CH3:19]>C1COCC1>[Cl:17][C:4]1[N:3]=[C:2]([NH:20][CH2:18][CH3:19])[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CCN
Reactant: O=C(c1cccc(Cl)c1)c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CCNc1nc(Cl)ccc1C(=O)c1cccc(Cl)c1

Procedure:
To a THF solution of 2,6-dichloro-3-(3-chlorobenzoyl)pyridine was added a 70% ethylamine aqueous solution, followed by reaction at room temperature. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 6-chloro-3-(3-chlorobenzoyl)-2-ethylaminopyridine. NMR1: 8.95 (1H, brs), 6.48 (1H, d, J=7.8 Hz), 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: C(SC1CCCCC=1)CCC.C(SC(C)=C)C.[CH2:18]([S:20][C@@:21]1([CH3:37])[CH2:24][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[C@@H:22]1[C:29]([N:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36])=[O:30])[CH3:19]>>[CH2:18]([S:20][C@:21]1([CH3:37])[CH2:24][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[C@@H:22]1[C:29]([N:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36])=[O:30])[CH3:19]
Reactant: CCS[C@@]1(C)C[C@@H](C(=O)OC)[C@@H]1C(=O)N1CCOC1=O
Agent: C=C(C)SCC
Agent: CCCCSC1=CCCCC1
Product: CCS[C@]1(C)C[C@@H](C(=O)OC)[C@@H]1C(=O)N1CCOC1=O
Yield: 70 %

Procedure:
The procedure of Example 2-1 was repeated except that the 1-n-butylthiocyclohexene was replaced with 2-ethylthiopropene. Thus a mixture of (1S,2R,3R)-1-ethylthio-3-methoxycarbonyl-1-methyl-2-(oxazolidin-2-on-3-yl)carbonylcyclobutane and (1R,2R,3R)-1-ethylthio-3-methoxycarbonyl-1-methyl-2-(oxazolidin-2-on-3-yl)carbonylcyclobutane (72:28, 70%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Ark Pharm, 5.023 g, 32.92 mmol) in DCM (150 mL), DMAP (418.1 mg, 3.422 mmol) was added, followed by triethylamine (4.984 g, 49.25 mmol) and benzenesulfonyl chloride (6.904 g, 39.09 mmol). After stirring at room temperature for 15 h, the mixture was washed with 1 M HCl (100 mL). The organic layer was washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (9.39 g, 97%). LCMS calc. for C13H10ClN2O2S (M+H)+: m/z=293.0. found 293.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 98 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 98%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.11-3.18 (m, 4H), 3.77-3.86 (m, 4H), 4.12 (s, 3H), 6.95-7.61 (m, 7H), 7.73 (d, J=8.6 Hz, 1H).
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1.[OH-].[Na+]>CCOCC.O.CN(C=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:2]([F:7])[F:6])=[C:18]([F:23])[CH:17]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OC(F)F
Temperature: 100 °C
Yield: 26.4 %

Procedure:
To a 100 mL flask charged with DMF (23 mL) was added sodium 2-chloro-2,2-difluoroacetate (4.79 g, 31.4 mmol), potassium carbonate (2.60 g, 18.85 mmol), 4-bromo-2-fluorophenol (3 g, 15.71 mmol). Water (5.75 mL) was added and the reaction mixture was heated to 100° C. for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with Et2O (100 mL) and a 2 N NaOH solution (100 mL). The organic layer was removed and dried over anhydrous Na2SO4. Upon filtration the organic solution was concentrated on a rotary evaporator with the water bath at 4° C. to yield the title compound as a clear oil (1 g). NMR (400 MHz, CDCl3) δ 7.35 (dd, J=9.7, 2.3 Hz, 1H), 7.27 (ddd, J=8.7, 2.3, 1.5 Hz, 1H), 7.19-7.04 (m, 1H), 6.53 (t, J=73.0 Hz, 1H); ESIMS m/z 242 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][O:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Reaction time: 12 h
Yield: 97 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (2.1 g, 9.8 mmol, 1 eq) and K2CO3 (2.4 g, 17.4 mmol, 1.8 eq) in 15 mL of DMF was added 1.3 mL of bromo-acetic acid ethyl ester (11.7 mmol, 1.2 eq) under nitrogen. After 12 h, the mixture was worked up and crude compound recrystallized to give (2-acetyl-4-bromo-phenoxy)-acetic acid ethyl ester in 97% yield (2.87 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 4.7 (s, 2 H) 6.7 (d, J=8.8 Hz, 1 H) 7.5 (dd, J=8.8, 2.8 Hz, 1 H) 7.9 (d, J=2.8 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([N:28]=[N+]=[N-])[CH2:24][N:25]=[N+]=[N-])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([NH2:28])[CH2:24][NH2:25])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@@H](CN=[N+]=[N-])N=[N+]=[N-])NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](N)CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-diazidopropylthio)propanoate (1 eq) was stirred in dry EtOH (0.05 M) under nitrogen at room temperature. Pd(OH)2 (0.5 eq) was then added in one portion. The reaction was purged with, then stirred under hydrogen atmosphere (1 atm) for 16 hours at room temperature. The crude material was then filtered twice through celite and cotton. The organics were concentrated and used in the next step without further purification.
Reaction SMILES: C(O[C:9]([C:11]1[CH:16]=[CH:15][C:14](COC(=O)C)=[CH:13][CH:12]=1)=[CH2:10])C1C=CC=CC=1.C(OC(C1C=CC=C([CH2:38][O:39][C:40](=[O:42])[CH3:41])C=1)=C)C1C=CC=CC=1.ClCC=CC1C=CC=CC=1.C>>[C:40]([O:39][CH2:38][CH:10]=[CH:9][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:42])[CH3:41]
Reactant: C=C(OCc1ccccc1)c1ccc(COC(C)=O)cc1
Reactant: C=C(OCc1ccccc1)c1cccc(COC(C)=O)c1
Agent: C
Agent: ClCC=Cc1ccccc1
Product: CC(=O)OCC=Cc1ccccc1

Procedure:
α-Benzyloxy[4-(acetoxymethyl)styrene] and α-Benzyloxy[3-(acetoxymethyl)styrene] (Formula II, R1 =CH3COOCH2C6H4 -, R2 =benzyl). (Acetoxymethyl)styrene was prepared from (chloromethyl)styrene by the method described in Polymer, 1973, 14, 330. It was converted (Method C) to the required alkoxystyrene: 1H NMR (CCl4) δ 2.02 (3H, s), 4.23 (1H, d, J 2 Hz), 4.67 (1H, d, J 2 Hz), 4.87 (2H, s), 5.00 (2H, s), 7.0-7.7 (9H, m); MS (CH4) 283 (MH+, 1%), 91 (100%); IR 1740 cm-1.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Li+]>C1COCC1.CO.O.O>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([OH:11])=[O:10])[CH2:4][CH2:5]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#CC1(c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 33 (1.56 g, 7.75 mmol) in 25 mL of THF/MeOH/H2O (3/1/1) was added lithium hydroxide (613 mg, 25.6 mmol) in water (5 mL). The mixture was stirred overnight at rt. Concentrated in vacuo and the resulting solution was acidified with 1N HCl (until pH=1). The resulting precipitate was collected and washed with water and dried to give 3-(1-cyanocyclopropyl)benzoic acid 34 (1.19 g, 82%). NMR (400 MHz, CDCl3) 1.49 (m, 2H), 1.81 (m, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.67 (m, 1H), 7.94 (m, 1H), 8.05 (m, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[C:4]=2[O:3]1>C(OCC)(=O)C.Cl>[CH3:1][C@H:2]1[CH2:8][NH:7][CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])[C:4]=2[O:3]1
Reactant: CC(c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(c1csc2c1O[C@@H](C)CNC2)C(F)(F)F
Yield: 105.8 %

Procedure:
tert-Butyl (2S)-2-methyl-8-(2,2,2-trifluoro-1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (475 mg) was stirred in 4 N hydrogen chloride-ethyl acetate solution (10 mL) for 15 min. The reaction solution was concentrated, and the residue was recrystallized from diethyl ether to give the title compound (365 mg, 93%) as colorless crystals.