Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:32]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([C:19]([F:32])=[O:20])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a suspension of 4.91 g (14.85 mmol) of the product prepared in step 11.1 in 75 mL of dichloromethane are added 2.07 g (14.85 mmol) of triethylamine and then 1.88 mL (22.28 mmol) of cyanuric fluoride. The mixture is stirred at room temperature for 2 hours and the solution is diluted with 100 mL of dichloromethane. The organic phase is washed three times with 100 mL of ice-cold aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. 4.56 g of the expected product are obtained, and are used directly in the following step. Yield=98%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][CH2:12][N:13]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:18])[NH:16][C:14]1=[O:15])[CH3:10].[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[O:32]1CC[CH2:34][CH2:33]1>>[C:33]([O:31][CH:24]([C:20]1[N:13]([CH2:12][O:11][CH2:9][CH3:10])[C:14](=[O:15])[NH:16][C:17](=[O:18])[C:19]=1[CH:21]([CH3:22])[CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:34]
Reactant: CCOCn1cc(C(C)C)c(=O)[nH]c1=O
Reactant: O=Cc1ccccc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOCn1c(C(OC(C)=O)c2ccccc2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An 1N lithium diisopropylamide solution (357 ml) in tetrahydrofuran was cooled to -10°--15° C. in a stream of nitrogen and a solution of 1-ethoxymethyl-5-isopropyluracil (22.2 g) in tetrahydrofuran (100 ml) was added dropwise thereto at an appropriate rate to keep the temperature of reaction mixture at -10°--15° C. Stirring was continued for another 1 hr at -10°--15° C. after the completion of addition. To the mixture was added dropwise benzaldehyde at an appropriate rate to keep the temperature of reaction mixture at -10--15° C. The mixture was stirred for 1 hr at the same range of temperature. The reaction was quenched by the addition of acetic acid (40.8 ml) and the reaction solution was warmed up to room temperature. The resultant mixture was washed and partitioned with semi-saturated saline (100 ml). The organic layer was combined with hexane (220 ml) and extracted with 1N sodium hydroxide solution (150 ml) (×2). The aqueous layer was neutralized with hydrochloric acid and extracted with toluene (200 ml). The extract was concentrated under reduced pressure to remove toluene and the residue dissolved in pyridine (100 ml). To the solution was added acetic anhydride (270 g) and the mixture allowed to stand for 16 hr at room temperature. After addition of cooled water (100 ml), the mixture allowed to stand for another 16 hr at room temperature. After the aqueous pyridine solution was concentrated under reduced pressure, some crystals precipitated, which were collected by filtration yield 6-(α-acetoxybenzyl)-1-ethoxymethyl-5-isopropyluracil (13.3 g). M.p., 158° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH:11]=2)[CH2:5][CH2:4]1.[Cl:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)[CH:31]=1>>[ClH:28].[ClH:28].[ClH:28].[ClH:28].[CH3:1][N:2]([CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH:11]=2)[CH2:7][CH2:8]1)[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)[CH:31]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Product: COc1cc(-c2cc(CN3CCC(N(C)Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (2.67 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.12 g) were condensed in the same manner as described in Example 2. The title compound was obtained after converting a free base to a tetrahydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.CC(C1C=CC=C(Cl)C=1)=O.[NH2:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[C:33]#[N:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]3[CH:30]=[N:31][C:32]([C:33]#[N:34])=[C:28]3[N:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(Cl)c1
Reactant: N#Cc1[nH]cnc1N
Agent: CC(=O)c1cccc(Cl)c1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3cccc(Cl)c3)nc12
Yield: 41.2 %

Procedure:
Reaction of 1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 3-chloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (133 mg, 41%). MS (ISP) 323.1 [(M+H)+]; mp 221° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](C(OC)=O)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1C(OC)=O.[Cl-].[Na+].O>CN(C=O)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC(C(=O)OC)(C(=O)OC)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
A 55 g (0.2 mole) portion of trimethyl 4-oxocyclohexane-1,1,3-tricarboxylate is dissolved in 240 ml DMF and to this is added 26 g (0.445 mole) of sodium chloride and 16 ml (0.89 mole) of water, under nitrogen. This mixture is heated to reflux and maintained for 48 hours, under nitrogen. The reaction is then stripped to dryness under reduced pressure, the residue added to water and the crude product extracted into dichloromethane (3×100 ml). The combined extracts are dried over MgSO4 and stopped to dryness, giving a yellow oil. This crude product is vacuum-distilled to obtain methyl 4-oxocyclohexane-1-carboxylate (b.p. 82°-108° C. at 1.0 mm Hg) which is used directly in the next step.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].O>CC(C)=O>[Cl:18][CH2:19][C:20]([O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)=[O:21]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(Cl)CCl
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Paracetamol [1] (15.117 g, 50 mmol) and pyridine (7.910 g, 50 mmol) were suspended in anhydrous acetone (200 ml) and chilled to 0° C. under an atmosphere of dry nitrogen. Chloroacetylchloride (11.29 g, 50 mmol) was added dropwise (violent reaction) and the resulting solution was stirred for additional 2 hours at room temperature. Water (300 ml) was added and the mixture was heated until a clear solution was obtained. The product [2] precipitated upon cooling and was collected via filtration, washed with water and dried under reduced pressure (0.01 mbar, 50° C.) to yield [2] as colourless needles in 72% yield. The product was pure according to 1H NMR and directly subjected to the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[OH:25][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(C(F)(F)F)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(C(F)(F)F)cc3)sc2c1O
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 7-hydroxy-2-(4-trifluoromethyl-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (40 mg, 0.11 mmol) and glycine (162 mg, 2.16 mmol) in 0.5 M sodium methoxide/methanol (4.1 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) and 1N HCl (1.5 mL) was added and the mixture was extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (1.5 mL). The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (34 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.48 (br s, 1H), 8.94 (s, 1H), 8.35 (d, 2H), 7.96 (d, 2H), 4.03 (d, J=5.8 Hz, 2H); MS: (+) m/z 329.9 (M+1)
Reaction SMILES: [O:1]=[C:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH:14]=[O:15])[CH3:13])=[CH:3]1.O1CCCC1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[OH:15][CH2:14][C@@H:12]([C@@H:11]1[C@:16]2([CH3:24])[C@H:8]([C@H:7]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C:4](=[CH:3][C:2](=[O:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:13]
Reactant: C[C@@H](C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution of (20R)-3-oxopregn-4-ene-20-carboxaldehyde (100 g, 305 mmol, commercially available from Upjohn) in 1500 ml ethanol and 250 ml tetrahydrofuran cooled to approximately 5° C. was added sodium borohydride (3.35 g, 89 mmol) portionwise to keep the temperature below 15° C. After 20 minutes, acetic acid (100 ml) was added and the mixture was concentrated to a slush on a rotary evaporator. The residue was then taken up in chloroform, successively washed with water and brine, then dried over sodium carbonate and concentrated to yield (20R)-20-hydroxymethyl-4-pregnen-3-one as a white solid (100 g, 100%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19](=[N:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:17][O:16][C:13](=[O:15])[CH2:14][C@@:19]([CH3:18])([NH:25][S@:26]([C:28]([CH3:30])([CH3:29])[CH3:31])=[O:27])[CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23]
Reactant: CC[C@H](C)CC(C)=N[S@@](=O)C(C)(C)C
Reactant: COC(C)=O
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[C@H](C)C[C@@](C)(CC(=O)OC)N[S@@](=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 62.1 %

Procedure:
To a solution of diisopropylamine (3.1 mL, 22.2 mmol) in THF (40 mL) at −78° C. was slowly added butyllithium (14.4 mL, 1.6 M, 23 mmol). The mixture was stirred at 0° C. for 25 minutes and subsequently cooled down to −78° C. Methyl acetate (1.76 mL, 22.2 mmol) in THF (7 mL) was added. After Stirring for 20 minutes, chlorotitaniumtriisopropoxide (11 mL, 46.2 mmol) in THF (10 mL) was added and the resulting mixture was stirred at −78° C. for 20 minutes. (S)-2-Methyl-propane-2-sulfinic acid ((3S)-1,3-dimethyl-pentylidene)-amide (1.9 g, 8.9 mmol) in THF (10 mL) was added. The mixture was stirred at −78° C. overnight. The reaction was quenched by NH4Cl solution (50 mL). The mixture was filtered. The filtrate was extracted by EtOAc (3×70 mL). The EtOAc phase was reduced under reduce pressure and the residue was purified by a silica gel column (Hexane/EtOAc 1:1) to give the titled compound (1.61 g, 62% yield) as a colorless oil: 1H NMR (CDCl3) δ 3.64 (s, 3H), 2.60 (m, 2H), 1.47 (m, 2H), 1.44 (m, 1H), 1.36(s, 3H), 1.27 (m, 2H), 1.19 (s, 9H), 0.90 (d, J=6.4 Hz, 3H), 0.81 (t, J=7.6 Hz, 3H); MS (APCl) (M+1)+ 292.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[C:37](CO)[CH:36]=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>C(Cl)Cl>[Br:24][CH2:20][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:38]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Triphenylphosphine (970 mg, 3.7 mmol) and carbon tetrabromide (1.5 g, 4.6 mmol) were added to a solution of (2-tert-butoxycarbonylaminopyridin-4-yl)methanol (Reference compound No. 4-1, 690 mg, 3.1 mmol) in methylene chloride (20 mL) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and brine (20 mL), and then dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting solid was filtered off with ethyl acetate to give 550 mg of the title reference compound as a colorless solid. (Yield 62%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22]C)=[C:5]([OH:14])[C:6](=[O:13])[NH:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22])=[C:5]([OH:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(Cl)cc1-c1c(O)c(=O)[nH]c2cc(Cl)cc(Cl)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(-c2cc(Cl)ccc2O)c1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a suspension of 5,7-dichloro-4-(5-chloro-2-methoxyphenyl)-3-hydroxy-2(1H)-quinolinone (2.22 g, 6.0 mmol) [prepared in Example 1] in methylene chloride was added BBr3 (30 mL, 1.0M solution in methylene chloride, 5.0 equiv.) at -78° C. and the suspension became a clear solution. The solution was stirred under an argon atmosphere at -78° C. for 3 hours then at room temperature for an additional 20 hours. Distilled water (0.5 mL) was added dropwise and stirring continued for 10 minutes. The reaction mixture was evaporated under vacuum and the solid residue was suspended in water (100 mL), sonicated for 5 minutes then stirred for 10 minutes, filtered, washed with water (3×30 mL) and dried to yield 2.15 g (≈100%) of the title compound as a white solid: mp=297°-299° C.;
Reaction SMILES: [Zn](CC)CC.[CH3:6][O:7][C:8](=[O:29])[N:9]([C@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH3:21])[CH2:10][CH2:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].ClCCl>ClCCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:12]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10][N:9]([C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH3:21])[C:8]([O:7][CH3:6])=[O:29]
Reactant: COC(=O)CBr
Reactant: COC(=O)N(CCC(=O)c1ccccc1)[C@@H](C)c1ccc(Cl)cc1
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CC(O)(CCN(C(=O)OC)[C@@H](C)c1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Et2Zn (1 M in hexane, 55 mL) was added dropwise to [(S)-1-(4-chloro-phenyl)-ethyl]-(3-oxo-3-phenyl-propyl)-carbamic acid methyl ester (3.80 g) dissolved in 1,2-dichloroethane (30 mL) and chilled to 0° C. under argon atmosphere. Then, (Ph3P)3RhCl (0.50 g) was added followed by the dropwise addition of methyl bromoacetate (1.0 mL) dissolved in 1,2-dichloroethane (10 mL). The resulting solution was stirred at 0-5° C. for 1 h and at ambient temperature for another 1.5 h. The solution was poured into ice-cold half-saturated aqueous NH4Cl solution (150 mL). After addition of dichloromethane, the mixture was filtered through Celite that was extracted with an additional portion of dichloromethane. The organic phase was separated and washed with water and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 85:15→70:30) to give the title compound as a mixture of two diastereomers.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23]O>>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 7.5 °C

Procedure:
Thionyl chloride (60 ml; 0.83 mol) was added drop-wise to a mixture of (4-benzyloxy-phenyl)acetic acid (100 gm; 0.4132 mol) and methanol (300 ml) under constant stirring while maintaining the temperature at 5-10° C. After complete addition, the reaction mixture was stirred for 5-6 hours at room temperature. After completion of the reaction, white crystalline solid was isolated by filtration to yield (4-benzyloxy-phenyl)-acetic acid methyl ester. Yield: 104 g, Efficiency: 98.31%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]=2[CH:18]=1.Cl[C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:21]1.[Cl-].[Na+].[CH3:38]CCCCC>CS(C)=O.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH2:38][C@H:23]3[CH2:24][CH2:25][CH2:20][CH2:21][N:22]3[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:8]=2[CH:18]=1
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reactant: Fc1ccc2c(c1)Nc1ccccc1OC2
Reactant: CCCCCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCN2CCCC[C@@H]2CN2c3cc(F)ccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (44 mg, 1.1 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (5 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 3-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (0.22 g, 1.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (R)-3-chloro-1-(4-methoxyphenethyl)piperidine (0.25 g, 1.0 mmol, prepared by a method disclosed in International Patent No. 9733885A1) in dimethyl sulfoxide (2 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 6 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (7:3) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-fluoro-5,11-dihydro-5-[1-(4-methoxyphenethyl)piperidine-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (0.30 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:35][C:36](=[O:38])[CH3:37])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:35]/[C:36](=[O:38])[CH3:37])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.00 g (7.37 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10 mmole) of 1-triphenylphosphoranylidene-2-propanone. The mixture was stirred at room temperature under nitrogen for 5 hours, during which time some product precipitated from solution. The solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ(2 H); doublet 7.6 δ(1 H); doublet 7.5 δ(2 H); doublet 7.4 δ(2 H); doublet 6.95 δ(1 H); doublet 6.6 δ(1 H); multiplet 4.5 δ(1 H); doublet of doublets 4.0 δ(1 H); multiplet 4.2 δ(3 H); singlet 2.45 δ(3 H); singlet 2.4 δ(3 H).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH:7]([O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:31]([NH:30][C@H:29]([C:28]([O:27][CH:7]([CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:6]([OH:45])=[O:5])=[O:44])[CH:41]([CH3:42])[CH3:43])([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of t-butyl -2,3-bis-(N-CBz-L-valyloxy)-propionate (7.2 g, 11.4 mmole) in dichloromethane (25 ml) was added trifluoroacetic acid (25 ml) and the solution was stirred for five hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 5.9 g=90%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[C:4]([CH3:9])[N:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Cc1nc(N)ccc1Br
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Product: Cc1nc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-methylpyridine and 4-(N -piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2-chloro-4-trifluoromethylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.21 (1 H, d, J 10 Hz, Ar CH ortho to SO2NH), 7.61-7.45 (5 H, m, Ar CH's), 6.96 (2 H, d, J 9 Hz, Ar CH's), 6.76 (1 H, d, J 11 Hz, Ar CH), 2.86-2.78 (4H, m, CH2NCH2), 2.34 (3H, s, CH3), 1.53-1.41 (4 H, m, CH2CH2CH2CH2CH2), 1.33-1.20 (2 H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.47 minutes. LC/MS rt=7.04 minutes, 606 (MH+).