Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc2ccccc2c1
Product: COc1ccc(/C(C#N)=C/c2ccc3ccccc3c2)cc1OC
Yield: 86.4 %

Procedure:
2-Naphthaldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (567 mg) through Method A (production step 2), to thereby yield the target product (yield: 872 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(O)(=O)C.[CH2:22]([CH2:24][NH2:25])[OH:23]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:25][CH2:24][CH2:22][OH:23])=[CH:12]/[C:13]([O:15][CH3:16])=[O:14]
Reactant: NCCO
Reactant: COC(=O)CC(=O)c1ccc(OC)cc1OC
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)/C=C(\NCCO)c1ccc(OC)cc1OC
Temperature: 83 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
To a mixture of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (3.50 g, 14.69 mmol) and acetic acid (0.17 mL, 2.94 mmol) in i-PrOH (70 mL) was added ethanolamine (0.88 mL, 14.69 mmol) and the reaction mixture was heated to 83° C. Additional ethanolamine (0.88 mL, 14.69 mmol) was added to the reaction mixture at two, four and six hours. After stirring at 80° C. for 48 hours, the reaction mixture was cooled and concentrated under reduced pressure before the residue was suspended in equal parts of a saturated sodium bicarbonate solution and water under N2. After stirring overnight, the solids were collected by vacuum filtration and dried in a vacuum oven at 30° C. overnight to afford the title compound (2.72 g, 63%) as a beige colored power.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:42]([CH2:44][C:45](O)=[O:46])#[N:43]>ClCCl>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:45](=[O:46])[CH2:44][C:42]#[N:43])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (580 mg, 1.50 mmol, 1.00 equiv), carbonyldiimidazole (365 mg, 2.25 mmol, 1.50 equiv) and 2-cyanoacetic acid (190 mg, 2.24 mmol, 1.49 equiv) in dichloromethane (100 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed with 3×100 mL of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 380 mg (56%) of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:4]12[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=O.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:2]([C:4]12[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)#[N:1]
Reactant: NC(=O)C12CCC(CC1)N2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#CC12CCC(CC1)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-(aminocarbonyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (C-36) in dichloromethane was treated at 0° C. with Et3N (2.1 eq.) and trifluoroacetic anhydride (1.1 eq.) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes. Then, it was diluted with dichloromethane, washed with saturated NaHCO3 solution, H2O, brine and dried over Na2SO4. Filtration and evaporation afforded the titled compound (C-37).
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH2:5][CH2:6][C:7](N)=[S:8])[CH3:2].[H][H]>[Co](=S)(=S)=S>[SH:8][CH2:7][CH2:6][CH2:5][Si:4]([O:13][CH2:14][CH3:15])([O:3][CH2:1][CH3:2])[O:10][CH2:11][CH3:12]
Reactant: CCO[Si](CCC(N)=S)(OCC)OCC
Reactant: [H][H]
Agent: S=[Co](=S)=S
Product: CCO[Si](CCCS)(OCC)OCC
Temperature: 195 °C

Procedure:
Into a clean, dry 300 cubic centimeter high pressure reactor were added 150 grams (0.60 moles) of beta-triethoxysilylthiopropionamide product (Example II pilot plant lot containing 5% beta-cyanoethyltriethoxysilane starting material) and 2.5 weight percent of cobalt trisulfide. The reactor was sealed, initially pressurized to 600 psig with hydrogen and placed in a rocker. The vessel was heated to 195° C. internal temperature which raised the hydrogen pressure to 1100 psig. Heating was maintained for 8 hours with agitation. Hydrogen was continuously fed into the reactor to maintain the hydrogen pressure at about 1000 psig. The pressure never exceeded 1100 psig. The pressure at the end of the reaction was 575 psig. The reaction produced the desired gamma-mercaptopropyltriethoxysilane.
Reaction SMILES: S(Cl)(Cl)=O.[H+].[CH3:6][C@H:7]([NH2:16])[C@H:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].Cl.NC(C)C(Cl)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:16][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6]
Reactant: [H][H]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Pd]
Agent: CC(N)C(Cl)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CC(N)Cc1ccccc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A 100 mL round bottom flask with a magnetic stirrer was charged with thionyl chloride (24.47 g, 15 mL) and norephedrine hydrochloride (5.38 g). The mixture was stirred and heated at reflux temperature for about 1 hour and allowed to cool to ambient temperature. The excess thionyl chloride was removed by evaporation on a rotary evaporator. The residue in the flask was triturated with ether (50 mL) and the solid collected. The crude solid product was recrystallized from methanol-isopropyl ether and the purified solid collected (2.83 g, 48%). The purified 2-amino-1-chloro-1-phenylpropane hydrochloride was then subjected to hydrogenolysis as follows. A solution of 2-amino-1-chloro-1-phenylpropane hydrochloride (2.38 g, 0.0137 mol) in a mixture of 50 mL ethanol/16 mL water was prepared and transferred to a Parr bottle. Under a nitrogen atmosphere, a portion of 10% palladium on carbon catalyst was added to the solution in the Parr bottle. The Parr bottle was then installed on a Parr shaker apparatus and an inert atmosphere produced and maintained in the bottle. The Parr bottle was then pressurized with hydrogen to about 50 psi and was shaken until the hydrogen uptake ceased. The contents of the Parr bottle was filtered to remove the catalyst and the filtrate was evaporated under reduced pressure to remove the ethanol. The remaining aqueous solution was basified with 50% sodium hydroxide solution. The oily top layer with was extracted with ether and the ether layer was separated from the aqueous layer. The ether extract was dried with drying agent and filtered to remove the drying agent. The filtrate was concentrated to obtain crude amphetamine as an oil (1.70 g, 72.3%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:35])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (774 mg) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (570 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[OH:20].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:20][C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][C:10]=2[N:9]=1
Reactant: Oc1ccc(C(F)(F)F)cc1N=Cc1ccncc1Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)nc2c1
Reaction time: 2.5 h
Yield: 19.9 %

Procedure:
To a mixture of 0.71 g of 2-(3-chloropyridin-4-yl)methylideneamino-4-(trifluoromethyl)phenol and 10 ml of methanol, 0.80 g of iodobenzene diacetate was added at room temperature and stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. Organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.14 g of 2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 18”).
Reaction SMILES: [NH3:1].C[O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)=O>CO>[C:4]([C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)(=[O:3])[NH2:1]
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.5 %

Procedure:
Ammonia gas was passed into a solution of tert-butyl (1S,3R)-3-(methoxycarbonyl)cyclopentylcarbamate (2.0 g, 8.2 mmol) in MeOH (20 ml) at −78° C. in a steal bomb. The reaction mixture was slowly warmed to room temperature, heated to 80° C. and stirred further for 48 h. The reaction mixture was cooled to room temperature and concentrated to afford 1.6 g (85.5%) of tert-butyl (1S,3R)-3-carbamoylcyclopentylcarbamate as brownish solid.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OCC)(=O)C.Cl>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 77.3 %

Procedure:
In ethanol (10 ml) was dissolved 465 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-methylphenyl)ethyl]piperidine. To the mixture was added 1.75 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 3 hours. The solvent was evaporated, an aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting solid was recrystallized from ethyl acetate, to give 344 mg of the title compound as white needles.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([NH:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: NCCN1CCCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(NCCN2CCCC2)c1
Temperature: 100 °C
Yield: 18.4 %

Procedure:
The mixture of 1-fluoro-3-nitrobenzene (420 mg, 3 mmol) in DMF (1.5 mL), N-(2-aminoethyl)-pyrrolidine (514 mg, 4.5 mmol) and Cs2CO3 (977 mg, 3 mmol) is heated at 100° C. under microwave radiation for 2.5 hours, then concentrated. The mixture is diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=1:99 to 10:90) to give 130 mg of the title compound as a light brown oil.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[Cl-].[CH2:15]([O:17][C:18](=[O:24])/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH3:16].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:24])[CH:19]=[CH:20][C:21](=[O:22])[N:1]([CH2:2][CH2:3][CH2:4][N:5]([CH3:6])[CH3:7])[CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH3:16]
Reactant: CN(C)CCCNCCCN(C)C
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC(=O)N(CCCN(C)C)CCCN(C)C
Temperature: 23 °C
Reaction time: 3 h

Procedure:
3,3′-Iminobis(N,N-dimethyl-propylamine) (10.66 g, 55 mmol) and DMAP (54 mg) are dissolved in toluene (60 ml). To this solution is added the solution of fumaric acid monoethyl ester mono chloride (8.15 g, 50 mmol) in toluene (20 ml) over 20 min via syringe pump. The mixture is further stirred for 3 h at 23° C., then poured on a mixture of ice and sat. aq. NaHCO3-solution. The product is extracted twice with EtOAc (100 ml) and the organic layers washed twice with brine, combined and dried over MgSO4.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(P(N(C)C)(N(C)C)=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C@H:13]([C:14]([OH:16])=[O:15])[CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
A mixture of 5 g of p-trifluoromethylaniline, 2.25 g of α-bromoisovaleric acid and 2.0 g of potassium carbonate is heated at 100° for 1 hour. After 1.5 hour, 5 ml of HMPT is added and the mixture heated at 100° for 15 hr. The mixture is then poured into water and potassium carbonate added to about pH 11. The mixture is washed with ether, methylene chloride and the aqueous phase acidified to about pH 3 and washed with ether and concentrated. The residue is recrystallized from hexane/ether to yield N-(4-trifluoromethylphenyl)valine, which is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine. MS m/e 443 (M+, 5.9).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[C:16]([F:21])[C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[F:11][C:12]1[CH:19]=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH2:8][CH2:9][CH3:10])[C@@H:2]2[CH3:1])[CH:17]=[C:16]([F:21])[C:13]=1[C:14]#[N:15]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CCC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2cc(F)c(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 2,4,6-trifluorobenzonitrile (414 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 233 mg, yield: 63%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])=[CH:9][CH:8]=2)[N:3]=1.[H-].[Na+].Br[CH2:27][CH2:28][Cl:29].O>CN1CCCC1=O>[Cl:29][CH2:28][CH2:27][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:12][CH:11]=2)[C:15]1=[O:23]
Reactant: Cc1nc(-c2ccc(Cn3c(=O)[nH]c4ccccc43)cc2)no1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(-c2ccc(Cn3c(=O)n(CCCl)c4ccccc43)cc2)no1
Reaction time: 2 h

Procedure:
1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl-1,3-dihydro-2H-benzimidazol-2-one (0.416 g, 1.36 mmol) was added to a suspension of 60% sodium hydride (0.06 g, 1.49 mmol, dispersion in oil) in N-methylpyrrolidinone (3 ml) and stirred for 2 hours. More N-methylpyrrolidinone (2 ml) was added followed by 1-bromo-2-chloroethane (0.203 ml, 0.351 g, 2.44 mmol). The resultant mixture was allowed to stir at room temperature for 16 h then water was added and the mixture extracted with ethyl acetate (2×30 ml). The organic layer was washed with water (4×50 ml), brine (50 ml), dried (MgSO4).filtered and evaporated in vacuo to give a light brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:33]([N:27]1[CH2:28][C@@H:11]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)c1ccccc1/C=C/C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of (E)-ethyl 2-(3-(benzyloxy)-3-oxoprop-1-enyl)benzoate (1.44 g, 4.64 mmol)) in 20 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.78 mL, 6.96 mmol) and trifluoroacetic acid (0.072 mL, 0.93 mmol). The solution was allowed to stir at ambient temperature for 18 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.5 g, 2.1 mmol) and trifluoroacetic acid (2 drops) were added and the reaction was stirred at ambient temperature for 1 h. The reaction was evaporated and purified by ISCO (elution with 0-30% EtOAc/hexane) to afford 1.97 g (95%) of the title compound as an oil. LRMS (ES)+: 444.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC.O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2ccccc2Br)cc1
Temperature: 85 °C
Yield: 55.1 %

Procedure:
To a 250-mL round bottom flask equipped with a magnetic stir bar was added water (41 mL) and 1,2-dimethoxyethane (41 mL). The solution was sparged with nitrogen for 20 minutes, then potassium carbonate (6.49 g, 46.9 mmol, 3 equiv), 2-bromophenylboronic acid (3.69 g, 18.4 mmol, 0.98 equiv) and 1-bromo-4-tert-butylbenzene (4.00 g, 18.8 mmol, 1 equiv) were added. The flask was then purged with N2 for 10 minutes before finally adding palladium(II) acetate (84 mg, 0.375 mmol, 0.02 equiv) and triphenylphosphine (394 mg, 1.50 mmol, 0.08 equiv). The reaction mixture was heated to 85° C. under a positive pressure of nitrogen for 18 hours. After cooling to room temperature, the phases were partitioned and the organic layer was collected. The aqueous layer was washed with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude yellow oil was purified by column chromatography on an Isco CombiFlash system (120-g column; eluted with 14 column volumes heptane) to afford the title compound as a colorless oil (2.93 g, 67 area % by HPLC, 54% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.68-7.64 (m, 1H), 7.48-7.42 (m, 2H), 7.39-7.31 (m, 4H), 7.21-7.15 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7](O)=[O:8])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:14]1[C:13]2[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[CH2:7][OH:8])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=C(O)C(O)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(O)c1ccc2c(c1)OCO2
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 3,4-(methylenedioxy)mandelic acid (1.5 g, 7.65 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.58 g, 15.29 mmol). The reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled (0° C.), quenched with sat. ammonium chloride solution, filtered, concentrated to yield 1.3 g of 1-benzo[1,3]dioxol-5-yl-ethane-1,2-diol
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=3[O:18][CH3:19])[C:4]=2[CH:3]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([N:9]2[CH2:8][CH2:7][O:6][C:5]3[CH:20]=[C:21]([S:23]([Cl:22])(=[O:25])=[O:24])[C:2]([F:1])=[CH:3][C:4]2=3)=[C:11]([O:18][CH3:19])[CH:12]=1)#[N:15]
Reactant: COc1cc(C#N)ccc1N1CCOc2ccc(F)cc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Temperature: -78 °C

Procedure:
To a vial charged with 4-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-3-methoxybenzonitrile (0.234 g, 0.823 mmol) was added DCM (3.29 ml). The resulting solution was cooled to −78° C. and chlorosulfonic acid (0.137 ml, 2.058 mmol) was added faster than dropwise. After 30 min the mixture was warmed to 0° C. and the mixture was allowed to stir and warm to rt over 3 hr. LC-MS indicated conversion to the desired product mass (M+23). The reaction mixture was added to ice carefully and EtOAc was used to wash reaction vial. The resulting mixture was extracted with EtOAc (2×). The layers were separated and the cloudy aqueous phase was diluted with brine and extracted once more with EtOAc. The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified with a 40 g silicycle HP column ramping EtOAc in heptane (0-50%) providing product 4-(4-cyano-2-methoxyphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.093 g, 0.243 mmol, 29.5% yield) as a light yellow solid. m/z (ESI) 405.2 (M+Na)+.