Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>C(#N)C.C(N(CC)CC)C>[CH2:49]([CH:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:48][CH2:47]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCCN1CCC(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCCN1CCC(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a suspension of 2.19 g (6.86 mM) of 1-(4-aminobutan-1-yl)-4-benzylpiperidine dihydrochloride and 3.87 ml (27.8 mM) of triethylamine m in acetonitrile (5 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50%) to provide the title compound as red-purple amorphous substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C.CC1(C)O[C@H](CO)CO1>>[CH3:1][C:2]1([CH3:21])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: CCc1cc(C#N)cc(C)c1O
Agent: CC1(C)OC[C@@H](CO)O1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol; LC-MS**: tR=0.46 min, [M+H]+=309.23; 1H NMR (D6-DMSO): δ1.17 (t, J=7.5 Hz, 3H), 1.33 (s, 3H), 1.38 (s, 3H), 2.25 (s, 3H), 2.57-2.69 (m, 2H), 3.73-3.84 (m, 3H), 4.12 (t, J=7.0 Hz, 1H), 4.39-4.45 (m, 1H), 5.76 (s br, 2H), 7.34 (s, 1H), 7.36 (s, 1H), 9.47 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]I)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[C:9]2=[O:35])=[CH:4][CH:3]=1.[CH3:36][NH:37][CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:35])[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:37]([CH3:36])[CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CNCCS(=O)(=O)O
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCI)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(CCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CCS(=O)(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
64.5 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4-iodobutoxy)phenyl]azetidin-2-one are dissolved in 3 ml of methanol. 60.7 mg of 2-methylaminoethanesulfonic acid are then dissolved in 1 ml of water, and 30.4 mg of potassium carbonate are added. The reaction solution is stirred at 50° C. for 8 h. After concentration using a rotary evaporator at 40° C., the residue is passed over a reverse-phase cartridge (methanol). The resulting crude product is dissolved in hot methanol. The precipitate formed on cooling is filtered off, and the mother liquor is concentrated using a rotary evaporator. The product is obtained as an oil.
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][S:7][C:8]1[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:9]=1[CH2:10][N:11]([CH3:13])[CH3:12]>C(OCC)C>[BrH:1].[CH3:13][N:11]([CH2:10][C:9]1[C:8]([S:7][CH3:6])=[C:17]([OH:18])[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: COc1cccc(CN(C)C)c1SC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CSc1c(O)cccc1CN(C)C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
30% Hydrogen bromide in acetic acid (7 mL, 34 mmol) was added to (2-methylsulfanyl-3-methoxybenzyl)-dimethylamine (1.44 g, 6.8 mmol) and heated with stirring at 100° C. After 17 h, the reaction was complete by LC/MS analysis and was then allowed to cool to room temperature. Diethyl ether (100 mL) was added with stirring. After 20 min, the orange diethyl ether solution was decanted off. This was repeated until a tan solid precipitated. 3-Dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 90%) was filtered off as a brown solid.
Reaction SMILES: O=[C:2]([C:9]1([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:27]([BH3-])#[N:28].[Na+].[Cl:31][C:32]1[N:37]=C(Cl)[C:35]([F:39])=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>CCO>[Cl:31][C:32]1[N:37]=[C:27]([NH:28][CH:2]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:35]([F:39])=[CH:34][N:33]=1
Reactant: [BH3-]C#N
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CC(=O)C1(C(F)(F)F)CCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C(F)(F)F)CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-oxo-3-(1-(trifluoromethyl)cyclopentyl)propanoate, 195a, (0.500 g, 1.982 mmol) and ammonium acetate (0.458 g, 5.946 mmol) in EtOH (20 mL) was warmed to reflux for 3 hours. The crude reaction was concentrated in vacuo to a residue and redissolved in EtOAc (20 mL). The new mixture was cooled to 0° C., and acetic acid (0.338 mL, 5.946 mmol) and sodium cyanoborohydride (0.498 g, 7.928 mmol, 4 equiv) were added to the mixture. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with aqueous saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2×20 mL). The organic phase was concentrated in vacuo and redissolved in EtOH (20 mL). To the solution was added 2,4-dichloro-5-fluoro-pyrimidine (0.496 g, 2.973 mmol) and N,N-diisopropylethylamine base (2.0 mL). The reaction was refluxed for 12 hours and then concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc) yielding 84 mg of the desired product as a yellow oil: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.54 minutes (M+H) 384.40.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCCCCCl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN(CCCCCCO)c1ccccc1
Reaction time: 96 h

Procedure:
A mixture of 153 g (1.43 mol) freshly distilled N-methylaniline, 200 g (1.46) 6-chlorohexanol, 200 g (1.45 mol) potassium carbonate, 6 g potassium iodide, and 750 mL n-butanol was heated at reflux under nitrogen with vigorous mechanical stirring for 4 days. The solution was cooled, filtered, and the solvent was removed at reduced pressure. The residue was distilled in vacuo to produce a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Cl[S:10]([OH:13])(=O)=[O:11].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:11])[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: Oc1ccc(Br)cn1
Reactant: O=S(=O)(O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1O
Yield: 14.6 %

Procedure:
A solution of 5-bromopyridin-2-ol (1.00 g, 5.75 mmol) in chlorosulfonic acid (15.0 mL, 224 mmol) was heated to 150° C. for 14 h. The reaction mixture was added dropwise to tert-butyl amine (25 mL) in THF (25 mL) at 0° C. and was evaporated under reduced pressure to give a brown residue. The residue was dissolved in water (100 mL) and acidified with saturated citric acid solution (pH=6) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 60% EtOAc/hexanes) to obtain 5-bromo-N-(tert-butyl)-2-hydroxypyridine-3-sulfonamide (0.260 g, 14.6%). LCMS Condition B-24: retention time 1.10 min, [M+2]=309.0.
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:13]=1[CH2:14]O.O>ClCCl>[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:13]=1[CH2:14][Cl:9]
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1ccc(CO)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1ccc(CCl)c(Cl)c1
Reaction time: 1 h
Yield: 106483.8 %

Procedure:
Pyridine (0.5 ml) and thionyl chloride (0.18 mg) were successively added to a solution of 2-chloro-4-isopropoxybenzylalcohol (401 mg) in dichloromethane (2 ml) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the resulting product was extracted three times with hexane. The organic layers were combined, washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the objective compound (353 mg) as a yellow oil.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][NH2:17])=[O:15])[CH:8]=[CH:9][CH:10]=1.[C:24](=S)=[S:25]>CO>[F:3][C:4]([F:22])([F:23])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]2[O:15][C:24](=[S:25])[NH:17][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2ccccc2-c2n[nH]c(=S)o2)c1
Yield: 68.8 %

Procedure:
Potassium hydroxide (123.0 mg, 1.87 mmol) is added to a 020 C. solution of 2-[(3-trifluoromethylphenyl)amino]-benzoic acid, hydrazide (515.8 mg, 1.75 mmol) and carbon disulfide (250 μl, 3.96 mmol) in 15 ml of methanol. The mixture is heated at reflux overnight. The solution is concentrated in vacuo and the residue dissolved in water. The resulting aqueous solution is acidified with 1N hydrochloric acid and the resulting solids extracted into a 1:1 mixture of ether and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed, eluting with hexane:ethyl acetate (1:1), providing a white solid. Drying in vacuo at 65° C. overnight gives 406.4 mg (69%) of product, mp 211°-213° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].Br[CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: CN1CCNCC1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(CN5CCN(C)CC5)cc4)cc3)n(C)c(=O)c12

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)quinazolinone (1.03 g), 4,4'-bis (bromomethyl)benzophenone (1.75 g), N-methylpiperazine (500 ml) and 1N-sodium hydroxide/water (5.5 ml) in DMF (35 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia=40:1:0.1) to provide the title compound as colorless amorphous solid (180 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1

Procedure:
The title compound was prepared according to the procedure for Example 102 using 4-chloro-N-[4-(dipropyl phosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine Compound 198A, (75.0 mg, 0.185 mmol) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (48.1 mg, 0.185 mmol). The reaction mixture was concentrated in vacuo purified on an ISCO Combiflash unit (0-5% MeOH/DCM) to isolate the desired product as 66 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14](NC)=[O:15]>>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[C:14]([NH:13][CH3:12])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)NC
Reactant: OCCNCc1ccccc1
Product: CNC(=O)N(CCO)Cc1ccccc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzyl ethanolamine (3 g, 0.0198 mol) and N,N′-dimethyl urea was stirred at 130° C. overnight. The reaction mixture was cooled to RT and the crude product was purified by column chromatography over silica gel using 3% methanol in dichloromethane as eluent to yield 3.5 g of the sub-title compound as a liquid.
Reaction SMILES: [OH-].[K+].[CH3:3][SH-:4][C:5](=[N:7][OH:8])[CH3:6].C1C=CC=CC=1.[CH3:15][N:16]([S:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:17](F)=[O:18]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.O>[CH3:15][N:16]([S:20][N:21]([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:26])[CH3:27])[C:17]([O:8][N:7]=[C:5]([S:4][CH3:3])[CH3:6])=[O:18]
Reactant: CC(C)N(SN(C)C(=O)F)C(C)C
Reactant: C[SH-]C(C)=NO
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CSC(C)=NOC(=O)N(C)SN(C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Powdered potassium hydroxide (2.5 g), 4.7 g. 10.045 mole) of S-methyl-N-hydroxythioacetimidate, 0.11 g dicyclohexyl-18-crown-6, and benzene (200 mol) were combined and stirred 0.5 hr. at room temperature. Then 9.4 g (0.045 mole) of N-methyl-N-(diisopropylaminosulfenyl)carbamoyl fluoride were added. The mixure was stirred at room temperature for 1 hr., and then was water washed four times, dried (MgSO4), and the benzene solvent was removed under vacuum. The residue was recrystallized from diisopropyl ether to give 9 g (67.3 percent yield) of S-methyl N-[N'-methyl-N'-(diisopropylaminosulfenyl)carbamoyloxy]thioacetimidate, m.p. 79°-80° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12
Yield: 94 %

Procedure:
Acridine-9-carboxylic acid (1.730 g, 10 mmol) was dissolved in thionyl chloride (25 ml) and the solution was refluxed for 6 hours. The solution was concentrated in vacuo and hexane was added slowly to precipitate the product. The mixture was filtered to give a yellow solid (1.721 g, 94%), mp 218–9° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[CH2:8]1[CH2:12][O:11][CH2:10][CH2:9]1.C(Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC>[CH2:6]([N:4]1[C:3]2[CH2:12][CH2:8][CH2:9][C:10](=[O:11])[C:17]=2[C:16]2[C:5]1=[CH:18][CH:19]=[CH:14][CH:15]=2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C1CCCc2c1c1ccccc1n2Cc1ccccc1
Reaction time: 4 h
Yield: 79 %

Procedure:
Sodium hydride (60% in oil; 0.207 g, 5.18 mmol) is washed three times with hexane. DMF (3 mL) is added, followed by 36B added in portions. A moderate exotherm ensued; THF (3 mL) is added. After ten minutes benzyl bromide (1.047 g, 6.12 mmol) is added. After stirring for 4 h, an additional 0.1 g of benzyl bromide is added. The mixture is stirred overnight and then the solvents are removed; the residue is partitioned between CH2C2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate. Chromatography on silica gel (150 mL) using CH3OH—CH2Cl2 (1/99) as eluent, followed by re-chromatography of mixed fractions using EtOAc-hexane (30/70), gave 1.023 g (79%) of the title compound; mp 157.0-157.5° C.; IR (drift) 2940, 1636, 1610, 1530, 1484, 1464, 1445, 1399, 1357, 1187, 1133, 749, 742, 731, 698 cm−1; 1H NMR (CDCl3) δ2.23, 2.60, 2.88, 5.34, 7.03, 7.2-7.3, 8.30. Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.51; H, 6.21; N, 5.13.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]=O)[CH:19]=[C:20]2[C:25]=1[O:24][CH2:23][CH2:22][CH2:21]2.FC(F)(F)C(O)=O.[C:35](C1C=CC(NC(C2C=C(OC)C(OC)=CC=2F)C2NC(=O)N(C3C=CC=CC=3C(O)=O)N=2)=CC=1)(=N)[NH2:36].C[Si](C#N)(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:35]#[N:36])[CH:19]=[C:20]2[C:25]=1[O:24][CH2:23][CH2:22][CH2:21]2
Reactant: COc1cc(C=O)cc2c1OCCC2
Reactant: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCCC2

Procedure:
After adding 700 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 770 mg of 8-methoxychromane-6-carbaldehyde [CAS No. 81258-23-3], 1g of MS3A and 1.1 ml of trimethylsilyl cyanide to a solution of 250 mg of Yb(OTf)3 in 5 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1.[BrH:16]>>[BrH:16].[Br:16][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:15])=[N:12][CH:11]=1
Reactant: Cc1ccccc1-c1ccc(CO)cn1
Agent: Br
Product: Cc1ccccc1-c1ccc(CBr)cn1
Yield: 95 %

Procedure:
A solution of 4.49 g (22.5 mmol) of (6-o-tolylpyridin-3-yl)methanol in 75 mL of 48% hydrobromic acid was heated to reflux for 64 h. The reaction mixture was partially cooled and excess hydrobromic acid was removed by vacuum distillation (110° C. @ 2 Torr) until a tan solid residue remained in the flask. Distillation was carried out using a large KOH pellet trap placed between the distillation apparatus and the vacuum pump. The solid residue was slurried in diethyl ether, filtered and dried under a nitrogen stream to give 7.38 g of product, 95% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:28])[F:27])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[NH2:38][CH2:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH2:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:4](=[N:5][OH:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:27])[F:28])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[CH3:1])[CH3:44]
Reactant: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: CCNC(=O)CN
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)CNC(=NO)c1ccc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C
Temperature: 75 °C
Yield: 55.4 %

Procedure:
To a solution of 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (250 mg) in DMF (8 mL) was added N-chloro succinimide (84 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-amino-N-ethyl-acetamide (61 mg) and triethylamine (0.15 mL, 0.11 g) in THF (8 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (171 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:16])[C:6]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc2c1OCCN2
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)cc2c1OCCN2C
Temperature: 70 °C
Yield: 72.7 %

Procedure:
To a solution of 9.2 g of methyl 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate and 6.7 g of potassium carbonate in 100 ml of dimethylformamide was added 6.4 g of methyl iodide with cooling and stirring. The resulting mixture was heated at 70° C. for 2 hours with stirring. The liquid reaction mixture was added to 200 ml of water, and the resulting insoluble substance was filtered off, washed with water, and dried, thereby obtaining 7.1 g of methyl 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate. Melting point: 91°-92° C.