Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7](Cl)(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)Cl
Reactant: Brc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCCCC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Bromothiophene (1.63 g, 10.0 mmol) and heptanoyl chloride (1.78 g, 12.0 mmol) were dissolved in dry benzene (15 mL) and AlCl3 was added in portions with stirring over 10 min. The resulting dark brown solution was refluxed for 1 hr and left to cool down to room temperature. The mixture was quenched with 2M HCl (15 mL) carefully while stirred. The organic layer was separated, washed with 2M HCl, 2M NaOH, and water, and passed through silica column (d=3 cm, I=8 cm). The solution was dried over MgSO4, and concentrated in vacuo (2.40 g, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:2]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:15][C:16]3[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C

Procedure:
In a 250 mL round-bottomed flask was added 4-(pyridin-3-yl)benzaldehyde (4 g, 21.83 mmol), methyl 2-aminothiazole-5-carboxylate (3.45 g, 21.83 mmol), and acetic acid (0.375 ml, 6.55 mmol) in toluene (109 ml). The mixture was heated at reflux under Dean-Stark conditions for 3 hours, cooled, concentrated and redissolved in methanol. The mixture was cooled to 0° C. and sodium borohydride (1.322 g, 34.9 mmol) was carefully added. The mixture was warmed to room temperature and the resulting suspension was filtered with water washes to provide the title compound after drying.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C>CO>[N:15]1([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), piperidine (5.84 g, 68.7 mmol) and acetic acid (2.75 g, 45.8 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (400 g) eluting with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the desired intermediate as a clear oil (2.48 g, 54%). MS (APCI+) m/z: 201 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][NH:8][C:7](=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].CCCCCC.CCOC(C)=O.O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([C:5]1[CH:6]=[C:7]([Cl:32])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1cc(=O)[nH]nc1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCc1cc(Cl)nnc1-c1ccccc1
Temperature: 85 °C

Procedure:
5-butyl-6-phenyl-2H-pyridazin-3-one (3.6 g, 15.8 mmol)) is dissolved in POCl3 (40 mL) and the solution is heated at 85° C. for 3 hours. The excess POCl3 is evaporated in vacuo and the residue is partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL). The organic layer is washed with water (35 mL), brine (35 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatograph (silica gel, 4:1 hexane, EtOAc) provides a light yellow oil. LC-MS (M+1) 247. 1H NMR (δ, CDCl3) 7.47 (s, 5H), 7.42 (s, 1H), 2.62 (t, J=7.2 Hz, 2H), 1.43-1.53 (m, 2H), 1.18-1.31 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].O.[C:20](Cl)(Cl)=[S:21]>CCOCC>[C:8]1([C:7]2[C:2]([N:1]=[C:20]=[S:21])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ncccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOCC
Product: S=C=Nc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 G. of 2-amino-3-phenylpyridine and 7.4 g. of calcium carbonate in 500 ml. of water is added to a solution of 2.9 ml. thiophosgene in 105 ml. of ether. The reaction mixture is stirred at room temperature for 3 hours and the ether layer is separated. The water layer is extracted with ether and the combined ether extracts dried and evaporated to dryness affording 3-phenyl-2-pyridylisothiocyanate. The residue from the evaporation is allowed to stand at room temperature for 3 days. The reaction mixture is then triturated with ether and filtered affording 9-phenyl-3-(3-phenyl-2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 90°-92° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:40][CH2:39][C:15]3([O:19][N:18]=[C:17]([C:20]4[C:21]([NH:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:22]5[C:28](C)=[N:27][N:26]([CH2:30][CH3:31])[C:23]5=[N:24][CH:25]=4)[CH2:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[N-:41]=[N+:42]=[N-:43].[Na+].O>CN(C)C=O>[N:41]([CH:12]1[CH2:40][CH2:39][C:15]2([O:19][N:18]=[C:17]([C:20]3[CH:25]=[N:24][C:23]4[N:26]([CH2:30][CH3:31])[N:27]=[CH:28][C:22]=4[C:21]=3[NH:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:16]2)[CH2:14][CH2:13]1)=[N+:42]=[N-:43]
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(N=[N+]=[N-])CC4)C3)cnc21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonate (0.00090 mole) (example 39) is taken in dimethylformamide. Sodium azide (0.0027 mole) is added. The reaction mixture is stirred at 60-70° C. overnight. It is cooled and water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)=[CH2:2].C(O)(=[O:13])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:1]2[CH2:2][O:13]2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(OC)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 3-vinylanisole (5.0 g, 37.0 mmol) and acetic acid (2.1 mL, 37.0 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (7.30 g, 41.0 mmol) in three portions. The reaction was allowed to warm to R.T. and then 2M NaOH (50 ml) was added. The reaction was left to stir at RT overnight. The reaction mixture was then partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.60 g (100%) of the title compound as a slightly tinted oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:43](=[O:45])[CH3:44])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.25 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) in a dried 10 mL round-bottom flask was dissolved in 1.7 mL of methylene chloride and was charged with PS-DIEA (117.95 mg, 0.46 mmol). Acetic anhydride (Ac2O) (11 μL, 0.51 equiv) was added in one portion. After 15 min., another 5.5 μL of Ac2O (0.25 equiv) was added. After another 15 min., another 2.64 μL of Ac2O (0.12 equiv) was added. After another 15 min., another 11 μL of Ac2O (0.51 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by silica gel flash chromatography (wetted with 100% EtOAc, eluted with 5% (7N NH3) in MeOH/EtOAc) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=1.68), 8.28 (1H, d, J=8.20), 8.19 (2H, dd, J=1.51 Hz, J=1.18), 7.93 (3H, m), 7.53 (3H, m), 7.23 (1H, d, J=5.10), 7.12 (1H, d, J=5.76), 5.55 (2H, m), 4.67 (1H, d, J=13.28), 3.83 (1H, d, J=12.26), 3.06 (1H, m), 2.96 (2H, m), 2.56 (1H, m), 2.27 (1H, m), 2.10 (3H, s), 1.85 (2H, t), 1.31 (2H, m); MS (ES+): m/z 477.11/478.08 (40/20) [MH+]; HPLC: tR=2.11 min (OpenLynx, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCC1CC1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 2-bromo-3-pyridinol (500 mg, 2.83 mmol;) in dimethylformamide (3 mL) is added at 0° C. 60% sodium hydride in mineral oil (169.81 mg, 4.25 mmol). The mixture is stirred at that temperature for 15 min and bromomethylcyclopropane (329.66 μL, 3.40 mmol) is added. Then the reaction is stirred at room temperature for 1 h and quenched with water and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over magnesium sulfate and the solvent evaporated in vacuo. The crude is passed through a short silica gel plug and the compound was eluted with dichloromethane to yield 23% of the title compound. MS (m/z): 228 (M+1), 230 (M+3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17]2=[N:18][C:19]([C:24](OC)=[O:25])=[C:20]([OH:23])[C:21](=[O:22])[N:16]2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:24]([C:19]2[N:18]=[C:17]3[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:14]=[CH:15][N:16]3[C:21](=[O:22])[C:20]=2[OH:23])=[O:25])=[CH:31][CH:30]=1
Reactant: COC(=O)c1nc2c(NC(=O)OCc3ccccc3)cccn2c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C(Nc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12)OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a suspension of methyl 9-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-oxo-4-H-pyrido[1,2-a]pyrimidine-2-carboxylate in MeOH was added p-fluorobenzylamine. The suspension was stirred at 80° C. and after 16 hours the solvent was removed under reduced pressure. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as bright yellow fluffy material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: Nc1ccnc(Br)c1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2ccnc(Br)c2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
2-Bromo-pyridin-4-ylamine 2 (4.3 g; 25 mmol) and NaH 60% (1.5 g; 37 mmol) was at 0° C. stirred for 1 h in dry THF (50 ml) and then a solution of 4-Fluoro-3-nitro-benzoic acid methyl ester 1 (5 g; 25 mmol) in dry THF (50 ml) was addeddrop. The resulting cold solution was allowed to reach RT and stirred overnight for completion of the reaction. LCMS showed complete conversion to product and the reaction was quenched by addition of iPrOH and H2O. A precipitate was formed and this was filtered off, dried under educed pressure to obtain 3 as a yellow solid (7.5 g). Yield 85%. The product identity was confirmed by NMR and LCMS and taken for the next step.
Reaction SMILES: Cl.Cl[CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1.Cl.[CH3:32][NH2:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:32][NH:33][CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCC(Cl)c4ccccc4)CC3)ccc2N1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNC(CCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
One gram of 6-[4-(3-chloro-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.hydrochloride, 0.17 g of methylamine.hydrochloride and 1.2 g of potassium carbonate were dispersed in 20 ml of acetonitrile and the dispersion was stirred at 60° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water then extracted with methylene chloride. The extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. Thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =20:1), then the desired product was converted into a citrate, and recrystallized from ethanol-water to yield 0.5 g of 6-[4-(3-methylamino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. dicitrate. White powdery substance. Melting point: 150° C.-156° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:33])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (106 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (114 mg, 57%) as a white powder.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([SH:29])[CH3:28])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)([S:29][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][CH2:5]2)[CH3:28])=[CH:23][CH:22]=1
Reactant: COC(=O)COc1cccc2c1OCCN2CCO
Reactant: CC(S)(c1ccc(F)cc1)c1ccc(F)cc1
Product: COC(=O)COc1cccc2c1OCCN2CCSC(C)(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 83.2 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (200 mg) and 1,1-bis-(4-fluorophenyl)ethanethiol (450 mg) were used to obtain the colorless oily object compound (311 mg, yield 83%).
Reaction SMILES: [S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH2:20])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].O>CO>[S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21](=[O:23])[CH3:22])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1

Procedure:
In one example, the primary amine group of compound B5 can optionally be acylated by contacting B5 with an excess of acetic anhydride in methanol containing a trace of water. Generally, this reaction is conducted at about 25° C. to about 30° C. for about 2 to about 24 hours to provide for 3-acetamidocycloheptyl 1-thio-β-galactopyranoside, C5.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])(=[O:4])=[O:3].[C:14](Cl)(Cl)=[O:15]>>[N:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([O:12][CH3:13])[CH:7]=1)=[C:14]=[O:15]
Reactant: COc1cc(N)ccc1S(C)(=O)=O
Reactant: O=C(Cl)Cl
Product: COc1cc(N=C=O)ccc1S(C)(=O)=O

Procedure:
4-Isocyanato-1-methanesulfonyl-2-methoxy-benzene was prepared by reaction of 4-methanesulfonyl-3-methoxy-phenylamine with phosgene following the procedure of step 6 of Example 3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].ClC1C=CC(SC)=CC=1C(O)=O.[CH3:36][N:37]([C:39](ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:38].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:36][N:37]([CH3:39])[C:38]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CSc1ccc(Cl)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(N(C)C)n1
Temperature: 150 °C
Yield: 231.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-chloro-5-(methylthio)benzoic acid (0.404 g, 2.0 mmol), HATU (1.50 g, 0.040 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.035 g (42% yield) of pure product as the undesired product: MS (ES) m/z 377 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[Si:13]([O:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1OCCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxydihydrofuran-2(3H)-one (5 g, 49 mmol) in anhydrous DMF (50 mL) was added imidazole (6.7 g, 98 mmol) and TBDMS chloride (8.1 g, 54 mmol). The reaction was allowed to stir under an N2 atmosphere at room temperature overnight. The reaction was diluted with diethyl ether and washed with 1 N aqueous HCl×2 then brine×1. The organic phase was dried over Na2SO4 and the solvent removed in vacuo to yield 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) as a clear oil. [M+H] calc'd for C10H20O3Si, 217; found, 217.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH:9]12)C1C=CC=CC=1.C=O>CCO.CC#N.[OH-].[OH-].[Pd+2]>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:9]2[CH:10]([O:11][CH2:12][CH2:13][N:8]2[CH3:1])[CH2:14]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2OCCN(Cc3ccccc3)C2C1
Agent: [Pd+2]
Agent: C=O
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CN1CCOC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
To a solution of tert-butyl 4-benzylhexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate (1.00 g) in EtOH (20 mL) was added 20% Pd(OH)2/C (0.30 g). The reaction mixture was heated to reflux for 8 h and filtered. The filtrate was evaporated in vacuo. To a solution of the residue in CH3CN (30 mL) was added formaldehyde aqueous solution (15 eq) and NaB(OCOCH3)3H (2.5 eq). The mixture was stirred at room temperature for 6 h under N2. The solvent of the mixture was removed under reduce vacuum pressure, and the residue was chromatographed with a silica gel column to give the title compound (0.33 g, 43.42%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 243.3 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH2:11]([SH:14])[CH2:12][SH:13]>C1C=CC=CC=1>[C:4]1([C:2]2[S:13][CH2:12][CH2:11][S:14][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: SCCS
Solvent: c1ccccc1
Product: C1=C(c2ccccc2)SCCS1
Reaction time: 48 h

Procedure:
By following substantially the procedure of Example 4, Step A, phenacyl bromide (95.0 g.) and ethane-1,2-dithiol (40.0 ml.) in benzene (500 ml.) is allowed to stand for 2 days at room temperature (until gas chromatography indicates the absence of starting material). Solid by-product is removed by filtration and the filtrate is washed with aqueous sodium bicarbonate solution and water. The product solution is dried over anhydrous sodium sulfate. Solvent is removed by distillation and the residual oil is distilled at reduced pressure to afford 2-phenyl-5,6-dihydro-1,4-dithiin (47.2 g.; b.p. 140°-150° C./0.25 mm.). The product solidifies on standing and is recrystallized from methanol (m.p. 58.0°-59.0° C.).