Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:26]([F:29])([F:28])[F:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:26]([F:29])([F:27])[F:28])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Solvent: C1CCOC1
Product: OCCc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A 50-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetate (0.165 g, 0.40 mmol) and THF (10 mL) at rt. Borane-dimethylsulfide complex (0.154 mL, 1.62 mmol) was added and the resulting solution was stirred at 55° C. for 3 h. After this time, the reaction was quenched with methanol then treated with 2N aqueous HCl (5 drops), and concentrated under reduced pressure. The residue was diluted with methanol and then concentrated under reduced pressure. The residue was purified by column chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as the eluent followed by column chromatography on silica using hexanes/dichloromethane (10:0 to 0:10) as the eluent to afford the title compound (0.064 g, 18%) as a colorless gum. MW=391.81. 1H NMR (DMSO-d6, 500 MHz) δ 8.33 (s, 1H), 8.17-8.15 (m, 1H), 8.11-8.06 (m, 1H), 7.77 (d, J=0.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.28 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 4.58 (t, J=5.0 Hz, 1H), 4.12 (s, 2H), 3.59-3.54 (m, 2H), 2.67 (t, J=5.0 Hz, 2H); APCI MS m/z 392 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6](=[CH:13][C:14]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Pd:24]>>[CH:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:14](/[CH:13]=[CH:6]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:23][CH:22]=1.[CH:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:14](/[CH:13]=[CH:6]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:23][CH:22]=1.[CH:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:14](/[CH:13]=[CH:6]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:23][CH:22]=1.[Pd:24].[Pd:24]
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Temperature: 55 °C

Procedure:
An example of such a catalyst complex has the structure Pd2DBA3.CHCl3, in which DBA is dibenzylideneacetone. This complex is formed by the addition of palladium (II) chloride to a methanol solution containing sodium acetate and dibenzylideneacetone. The reaction mixture was warmed to 55° C. for one hour to form a precipitate, noting that excessive heating causes decomposition of the complex to palladium metal. The precipitate and catalyst precursor is filtered from the methanol and redissolved in chloroform to produce a dark purple solution, which is stripped under reduced pressure to produce a dark purple-black solid of Pd2DBA3.CHCl3. This solid is redissolved and added to a solution of diene polymer or copolymer.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O[C@H]1CNC[C@@H]1O
Product: Cn1ncc([N+](=O)[O-])c1N1C[C@H](O)[C@@H](O)C1
Yield: 91 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (3S,4S)-pyrrolidine-3,4-diol gave (3S,4S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidine-3,4-diol as a bright yellow solid (258 mg, 91%). 1H NMR (400 MHz, d4-MeOD) δ 8.04 (s, 1H), 4.27-4.22 (m, 2H), 3.98 (dd, J=10.0, 4.4 Hz, 2H), 3.84 (s, 3H), 3.31-3.25 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12].Cl[C@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: OCCCc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)Oc1ccc(F)c(CCCO)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a mixture of 4-fluoro-3-(3-hydroxypropyl)phenol (1.5 g), methyl (2R)-2-chloropropanoate (1.30 g) in DMSO (7.5 mL) was added Cs2CO3 (3.45 g) at ambient temperature. The mixture was stirred at 60° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed successively with water (30 mL) two times and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=4:1-2:1) to give methyl(2S)-2-[4-fluoro-3-(3-hydroxypropyl)phenoxy]propanoate (1.51 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])=[CH:11][CH:10]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-c3ccsc3)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
To a solution of 4-{[4-(2-Hydroxymethyl-pyrrolidin-1-ylmethyl)-phenylamino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione (200 mg, 0.40 mmol) in N,N-dimethylformamide (10 mL) were added 3-thienylboronic acid (120 mg, 0.94 mmol) and Na2CO3 (216 mg, 2.0 mmol). Pd2(dba)3.CHCl3 (20 mg, 0.02 mmol) and P(tBu)3.HBF4 (19 mg, 0.06 mmol) were then added. The mixture is then degassed and heated at 100° C. for 1 h. The N,N-dimethylformamide is then evaporated under reduced pressure and the residue is taken up in EtOAc and H2O. The EtOAc layer is dried and evaporated. The residue, which resulted, is subjected to chromatography to provide the desired product (90 mg, 49%). MS (ESI): 460.2 (M+1)+1
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=1>C1(C)C=CC=CC=1.O>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCOCc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(OCCOCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (900 mg, 60% dispersion in mineral oil, 22.5 mmol) was added portionwise to an ice-cold solution of 2-(benzyloxy)ethanol (3.0 g, 20.0 mmol) in toluene (100 ml), and the solution stirred for 30 minutes. 2,6-Dibromopyridine (4.75 g, 20.0 mmol) was added, and the reaction heated under reflux for 2 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C2(O)CCCN(Cc3ccccc3)C2)cc1OC
Reactant: [H][H]
Solvent: CCO
Product: COc1ccc(C2(O)CCCNC2)cc1OC
Temperature: 100 °C
Reaction time: 32 h
Yield: 74.6 %

Procedure:
A mixture of 5 g of 10% palladized carbon and a solution of 9.8 g of N-benzyl-3-(3,4-dimethoxyphenyl)-3-hydroxy-piperidine [described in French patent No. 2,310,761] in 100 ml of ethanol was placed in an autoclave and hydrogen was introduced to obtain a pressure of 50 kg/cm2. The autoclave was sealed and was heated at 100° C. and the hydrogen pressure stabilized at 65 kg/cm2. The mixture was stirred at 100° C. for 32 hours and was then cooled and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 75-20-5 chloroform-methanol-triethylamine mixture yielded 5.3 g of 3-(3,4-dimethoxyphenyl)-3-hydroxy-piperidine.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:9]([CH3:18])=[C:8]([CH3:19])[N:7]=1.[OH-].[Na+].O>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:19])=[C:9]([CH3:18])[N:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Cc1nc(O)c(-c2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nc(-c2ccccc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 71.6 %

Procedure:
Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-phenyl-5,6-dimethyl-pyrazine (10.0 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 2.5 hours. Water was added to the reaction mixture, the mixture extracted with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 130 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 109 (8.73 g, yield: 71.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])[C:12]([O:23][CH3:24])=[C:11]([C:25]([N:27]2CCS[C:28]2=S)=[O:26])[CH:10]=1)[CH3:2].CN.C(O)(C)C.CO>ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])[C:12]([O:23][CH3:24])=[C:11]([C:25](=[O:26])[NH:27][CH3:28])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1
Agent: CN
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCNC(=O)c1cc(C(=O)NC)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To a solution of compound 6B (2.3 g, 4.25 mmol) in dichloromethane, a mixture of 0.2 mL methylamine solution (40% wt in water, d=0.902) and 10 mL isopropanol was added dropwise over 24 h, the completeness of reaction was monitored by TLC. The reaction mixture was then directly applied onto a gradient flash silica column (1-5% methanol in dichloromethane). The desired product was obtained as a thick, yellow oil.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@H:7]([OH:18])[C:8]1[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=1)=[O:4].Br[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:32])[C:30]#[N:31])=[N:27][CH:28]=1>>[Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@@H:7]([C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:28]=[N:27][C:26]([CH:29]([C:30]#[N:31])[CH3:32])=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[OH:18])=[O:4]
Reactant: CC(C#N)c1ccc(Br)cn1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CC(C#N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1

Procedure:
Following the general procedure of step 3, Example 4 and using the product of step 2, Example 4 and making non-critical variations but using the product of step 1, Example 23, the title compound is obtained (85 mg): 1H NMR (300 MHz, DMSO-d6) δ 1.61 (d, 3H), 4.25 (m, 1.5H), 4.40-4.60 (m, 2H), 4.70 (m, 0.5H), 4.91 (m, 1H), 5.99 (d, 1H), 6.53 (s, 1H), 7.48 (d, 2H), 7.55 (d, 1H), 7.70 (d, 2H), 8.13 (dd, 1H), 8.62 (bd, 1H), 8.89 (m, 1H). MS (ESI+) m/z 410 [M+H].
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]([NH:10]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[C:6]([CH3:28])[N:5]1[CH3:29])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C.O.CO>[NH2:10][C:7]1[C:8](=[O:9])[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]([CH3:29])[C:6]=1[CH3:28]
Reactant: Cc1c(NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)n(C(C)C)n1C
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1c(N)c(=O)n(C(C)C)n1C

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2-isopropyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)carbamate (2.047 g, 5.23 mmol) in DMF (30 mL) was added piperidine (2.59 mL, 26.1 mmol) at room temperature. Upon completion of addition the reaction mixture was added to water (30 mL). The resulting suspension was diluted with water (100 mL) and extracted with EtOAc. The combined organics were extracted with 2M HCl (aq) and the acidic aqueous extracts were neutralised with a saturated sodium bicarbonate solution and loaded onto a C18 cartridge. The column was eluted with water and the collected aqueous was slurried with SCX-2 and filtered. The resin was rinsed with MeOH and 7M ammonia in MeOH. The MeOH and aqueous filtrate solvent was removed under reduced pressure. MeOH (150 mL) was added to the resulting mixture, sonicated, filtered and the filtrate was concentrated under reduced pressure. EtOH was added to the resulting mixture and it was filtered. The filtrate was concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography using a gradient of 0-10% MeOH in DCM afforded crude material. The crude material in MeOH was slurried with SCX-2 (30 g). The suspension was filtered and washed with MeOH. The resin was then eluted with 7M NH3 in MeOH. The methanolic ammonia was concentrated under reduced pressure to afford crude material. The crude material was then adsorbed onto silica and purification by chromatography using a gradient of 0-10% MeOH in DCM afforded the title compound;
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11]>>[CH2:1]([Si:10]([Cl:12])([Cl:11])[Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 84.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.16 g (0.40 mmol) of ethylenebis(benzyldimethylphosphonium chloride), 1.00 g (7.90 mmol) of benzyl chloride, and 3.21 g (23.7 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.51 g of benzyltrichlorosilane (yield; 85%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11]C)(OC)[CH2:7][CH2:6][N:5]([C:13]([O-:15])=[O:14])[CH2:4]1.CO.Cl.O1CCO[CH2:21][CH2:20]1>>[CH3:1][O:2][CH:3]1[C:8](=[O:11])[CH2:7][CH2:6][N:5]([C:13]([O:15][CH2:20][CH3:21])=[O:14])[CH2:4]1
Reactant: C1COCCO1
Reactant: COC1CN(C(=O)[O-])CCC1(OC)OC
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCC(=O)C(OC)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared by taking 3,4,4-trimethoxypiperidine-1-carboxylate (210 mg, 0.00085 mol) in Methanol (5 mL, 0.1 mol) and adding 4 M of Hydrogen chloride in 1,4-dioxane (5 mL). The reaction was allowed to stir for 4 h at ambient temperature. The residue obtained by removing the solvent in vacuo was used in the next step as-is (170 mg, 99%). MS calculated for C9H15NO4: (M+H) 202; found 202.1.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>C1C=CC=CC=1>[C:22]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)(=[O:24])[CH3:23]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2C=Cc2ccccc21
Reaction time: 3.5 h

Procedure:
In a 500 ml round bottom flask fitted with a stirrer, dropping funnel and calcium chloride drying tube was placed recrystallized dibenz[b,f]azepine (33.5 g, 0.173 moles), 200 ml of anhydrous benzene and pyridine (13.6 g, 0.173 moles). Acetyl chloride (~12.3 ml) was then added dropwise to the mixture. A white precipitate formed with disappearance of orange color. After 3 to 4 hours of stirring, the reaction mixture was extracted with three 100 ml portions of 10% hydrochloric acid or until the extract remained acidic. The organic phase was washed with 5% Na2CO3 in water, dried over anhydrous magnesium sulfate, filtered and concentrated. Crystallization from a hexane-chloroform mixture afforded 49 g of 5-acetyl-5H-dibenz[b,f]azepine, m.p. ~121°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30]([O-:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[Na+]>>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=2)(=[O:32])=[O:31])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Reactant: O=S([O-])c1cccc(F)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4cccc(F)c4)cc3c2C1
Yield: 37 %

Procedure:
The product of Example 44, step B and sodium 3-fluorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 80:20 hexane/ethyl acetate) provided tert-butyl 6-chloro-8-((3-fluorophenyl)sulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (172 mg, 37%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.91 (m, 1H), 7.83 (s, 1H), 7.80-7.73 (m, 1H), 7.70-7.62 (m, 1H), 7.60-7.45 (m, 2H), 4.57 (s, 2H), 3.84 (s, 2H), 2.91 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Br[C:19]1[C:20]2[C:21]3[CH:34]=[CH:33][S:32][C:22]=3[C:23](=[O:31])[NH:24][C:25]=2[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:31])[C:22]3[S:32][CH:33]=[CH:34][C:21]=3[C:20]=2[C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 49.3 %

Procedure:
Following General Procedure E, tert-butyl 1-(4-bromophenyl)ethylcarbamate (3.0 g, 10 mmol) was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.8 g, 9.0 mmol) to afford the desired product (2.0 g, 50%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([CH:10](Cl)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].[C:39]1([P:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([C:10](=[P:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of crude diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]-α-chloroacetate (2.251 g) in anhydrous methylene-chloride (20 ml) is added triphenylphosphine (1.50 g), and the mixture is refluxed for 4 hours under nitrogen atmosphere. The reaction mixture is poured into ice water, mixed with 5% aqueous solution of sodium hydrogen carbonate (20 ml), and extracted with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the residue by chromatography over silica gel containing 10% water (100 g) using a mixture of benzene and ethyl acetate (1:2) as eluting solvent gives the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]=[C:18]([CH3:20])[CH3:19].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])[CH3:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 95 h

Procedure:
A solution of N-[(4-fluorophenyl)sulfonyl]-D-alanine from Example 3a (8.00 g, 32.4 mmol), isobutene (120 mL), and concentrated sulfuric acid (0.5 mL) in 1,4-dioxane (20 mL) and CH2Cl2 (60 mL) was added to a 500 mL high pressure bottle and sealed. The mixture was shaken at room temperature for 95 hours at a pressure of 18 psi. The mixture was poured into an aqueous solution containing 20 g of sodium bicarbonate, which was cooled by an ice bath. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed successively with water and brine, dried with MgSO4, and concentrated to a clear, yellow oil (6.06 g). Chromatography on silica gel (20% ethyl acetate in hexane) afforded N-[(4-fluorophenyl)sulfonyl]-D-alanine, 1,1-dimethylethyl ester, as a white solid (5.00 g, 51% yield): Anal. calc'd for C13H18NO4FS: C, 51.47; H, 5.98; N, 4.62. Found: C, 51.39; H, 5.82; N, 4.53.
Reaction SMILES: CC(C)([O-])C.[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:47]([N:50]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61](Br)[CH:62]=2)[C:52]2([CH2:55][S:54](=[O:57])(=[O:56])[CH2:53]2)[CH2:51]1)(=[O:49])[CH3:48]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:47]([N:50]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH:62]=2)[C:52]2([CH2:53][S:54](=[O:56])(=[O:57])[CH2:55]2)[CH2:51]1)(=[O:49])[CH3:48]
Reactant: CC(=O)N1CC2(CS(=O)(=O)C2)c2ccc(Br)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(=O)N1CC2(CS(=O)(=O)C2)c2ccc(N3CCOCC3)cc21
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
To a microwave vessel was added sodium tert-butoxide (0.045 g, 0.466 mmol), morpholine (0.030 mL, 0.350 mmol), XPhos, Pd2(dba)3 (0.021 g, 0.023 mmol), and 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′thietane]1′,1′-dioxide (0.077 g, 0.233 mmol) in 1,4-dioxane (2.3 mL). The suspension was deoxygenated with argon for 5 min and stirred at 110° C. for 90 min under microwave irradiation. The crude mixture was loaded directly onto a silica gel column (eluting with a gradient of 0-10% MeOH in DCM) to give 1-acetyl-6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide as a tan oil. Mass Spectrum (ESI) m/e=337.1 (M+1).