Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]1([CH3:31])[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:31][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 35.4 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (197 mg), 4-(4-toluoyl)benzyl bromide (336 mg) and 1N-sodium hydroxide/water (1 ml) in DMF (10 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=5:1:1) and crystallized from methanol to provide the title compound as colorless solid (140 mg).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([CH2:11][C:12]#[N:13])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[C:4]1([N:1]2[C:12]([NH2:13])=[CH:11][C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Yield: 178.7 %

Procedure:
To a solution of 1.08 g hydrazine in 10 ml 5N hydrochloric acid was added 1.45 g benzoylacetonitrile (prepared according to the procedure of Example 2), under stirring. The mixture was refluxed for 3 hrs. After cooling, the solution was neutralized with Na2CO3. The yellow precipitate was filtrated, washed with H2O, and dried to get 2.1 g 1,3-diphenyl-5-aminopyrazole.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[CH3:20][CH:19]([CH3:21])[C:18]([C:14]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1)([C:23]1[N:24]=[CH:25][N:26]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=1)[OH:22]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)c2)cc1
Yield: 72.3 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using p-tolylboronic acid (0.45 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.03 g), the title compound (0.76 g) was obtained as a colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=1.CO.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:14]1[CH:13]=[N+:12]([O-:9])[CH:17]=[CH:16][CH:15]=1)[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 124.9 %

Procedure:
m-Chloro perbenzoic acid (6.2 g, 36.06 mmol) in CHCl3 (30 mL) was added drop wise to a solution of ethyl 2-(pyridin-3-yl)acetate (3.5 g, 21.21 mmol) in CHCl3 (30 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was stirred at room temperature for 5 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was basified using aqueous NaHCO3 solution to pH 7 and extracted using CHCl3. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 4.8 g of the crude product. LCMS: 60.09%, m/z=182.0 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH:10][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)[C:7]([NH2:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cnc(N)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a solution of 5,6-Diamino-nicotinic acid methyl ester (4) (3.22 g, 19 mmol) in dry pyridine (100 ml) was added 4-nitrobenzoyl chloride (3.5 g, 19 mmol) and the mixture stirred for 18 h. The mixture was poured into H2O and the resulting solid collected by filtration, dried in vacuo to give the product as a yellow solid (4.05 g, 13 mmol, 66%). 1H NMR (500 MHz, DMSO-d6) δ9.98 (s, 1H), 8.47 (s, 1H), 8.36 (d, J=8.7 Hz, 2H), 8.23 (d, J=8.7 Hz, 2H), 8.0 (s, 1H), 6.92 (s, 2H), 3.79 (s, 3H), EIMS m/z M−1 315.4.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4].[Se](=O)=[O:20]>O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH:17]=[O:20])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4]
Reactant: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reactant: O=[Se]=O
Solvent: O
Product: O=Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reaction time: 8 h
Yield: 18 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and argon-filled balloon, 7-chloroacetamido-2-methylquinoline-5,8-dione (28) (prepared as described in Example 28) (0.529 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and allowed to go to completion (29.5 hours). The selenium was allowed to settle, and the supernatant solution was pipetted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml.). All filtrates were combined and stored at 4EC overnight. Solid precipitate from the chilled mixture was filtered yielding 0.0985 g. of crude product (yield of 18%). This was purified by recrystallization from ethyl acetate/dichloromethane. The original remaining filtrate was diluted with 50 ml of dichloromethane and washed with 3% sodium bicarbonate solution (2×50 ml.). The aqueous layer was then extracted with dichloromethane (2×20 ml.) The organic layers were dried with magnesium sulfate and rotoevaporated to give a dark orange solid. The product was dried under vacuum overnight and 0.2941 g. of product was obtained (yield of 52%, total 70%). This product could be further purified by flash chromatography and recrystallization from ethyl acetate/dichloromethane: mp 190-192EC; 1H NMR (CDCl3)*4.26 (2H, s, C-7NHCOCH2Cl), 8.04 (1H, s, C-6H), 8.33 (1H, d, J=8.1 Hz, C-3H), 8.62 (1H, d, J=8.1 Hz, C-4H), 9.54 (1H, br. s, C-7NH), 10.28 (1H, s, C-2CHO); IR (KBr) vmax 3310, 3089, 2950, 2852, 1731, 1720, 1678, 1644, 1521, 1118 cm−1; EIMS, m/e (relative intensity) 278/280 (M+, 2.7/1, 95), 243 (33), 229 (33), 215 (55), 202 (base), 175 (61), 146 (17); HRMS, m/e for C14H9ClN2O3 calculated 278.009435, found 278.008764; analysis for C14H9ClN2O3 calculated C, 51.72; H, 2.53; Cl, 12.72; N, 10.05; Found C, 51.81; H, 2.9; Cl, 12.79; N. 9.86.
Reaction SMILES: B(F)(F)F.CCOCC.[N+:10](=[CH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N-].C(=O)(O)[O-].[Na+].[Cl:24][CH2:25][C:26]#N>>[Cl:24][CH2:25][C:26]1[O:18][C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][N:10]=1
Reactant: CC(C)(C)C(=O)C=[N+]=[N-]
Reactant: N#CCCl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)c1cnc(CCl)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 mL (2.3 g, 16 mmol) of boron trifluoride etherate in 20 mL of chloroacetonitrile at 0° C. was added a solution of 1.33 g (10 mmol) of 1-diazo-3,3-dimethyl-2-butanone in 5 mL of chloroacetonitrile dropwise. The resulting solution was stirred at 0° C. for 0.5 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times with dichloromethane. The combined extracts was dried (sodium sulfate), concentrated and purified by flash column chromatography (Merck silica, 25×200 mm, dichloromethane) to give 1.1 g of 2-(chloromethyl)-5-t-butyloxazole as a yellow liquid (6.4 mmol, 64% overall from the acid chloride).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19]>O.CC(C)=O>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[O:3][C:4]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(=O)oc2cccc(O)c12
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(=O)oc2cccc(OC(=S)N(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
410 mg (7.3.10-3 mol) of potassium hydroxide are added under an inert atmosphere to a suspension of 1 g (5.7.10-3 mol) of 5-hydroxy-4-methyl-2H-1-benzopyran-2-one in 10 ml of water and 10 ml of acetone. After 10 minutes at room temperature, 770 mg (6.2.10-3 mol) of dimethylthiocarbamoyl chloride in 10 ml of acetone are added at 0° C. The reaction mixture is stirred for 2 hours at room temperature and then, after evaporation of the acetone, the expected derivative is precipitated in water to give 1.35 g (yield: 90%) of the expected product.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Na].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[OH:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CCC(O)C(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCC(O)C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a solution of (±)-2-hydroxybutanoic acid, sodium salt (2.54 g, 20.1 mmol) in dry DMF (30 ml) was added benzyl bromide (2.9 mL, 1.2 eq) and anhydrous KI (330 mg, 0.1 eq). The suspension was heated at 100° C. for 24 hours and the DMF was distilled off under reduced pressure. The residue was taken up in ether, washed with water and saturated Na2S2O3, dried (MgSO4), and concentrated. Distillation of the residual oil afforded 3.7 g (95%) of benzyl (±)-2-hydroxybutanoate as a colorless oil, b.p. 95° C. (0.45 Torr).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1([C:34]2[CH:35]=[C:36]([C:40]3[O:45]C(C)(C)[O:43][C:42](=O)[CH:41]=3)[CH:37]=[CH:38][CH:39]=2)[CH:33]=[CH:32][N:31]=[CH:30]1>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:42](=[O:43])[CH2:41][C:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:35]=2)=[O:45])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) (160 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous brown substance (167 mg).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>S(=O)(=O)(O)O.ClCCl>[C:17]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of benzoin with 15 ml of acetic anhydride and a few drops of sulphuric acid are added to a reactor with stirring and at room temperature (25° C.) for 15 hours. Water and dichloromethane are added to the reaction mixture. The organic phase is recovered after separating by settling, dried over sodium sulphate, filtered and then concentrated to dryness under vacuum.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:15])SCC(O)=O)=[CH:5][CH:4]=1.[OH-].[K+].O.[NH2:19][NH2:20].Cl>CO>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:19][NH2:20])=[S:15])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C(=S)SCC(=O)O)cc1
Reactant: NN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=S)NN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step c) (15.0 g) in methanol (200 ml) was added aqueous potassium hydroxide (58.0 ml, 1M) followed by hydrazine monohydrate (3.1 ml) dropwise over 30 minutes. After stirring at room temperature for 1 hour the mixture was acidified to pH 5 with concentrated hydrochloric acid. The resulting precipitate was filtered off and recrystallised from ethanol to afford the sub-title compound (9.9 g) as pale yellow plates. mp 152°-153°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.C1(=O)OC(=[O:28])C2=CC=CC=C12.C(=O)([O-])[O-].[Na+].[Na+].OO>ClCCl.O>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:28])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 81.6 %

Procedure:
To a solution of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole (11) (32.9 gm, 0.1 mole) in dichloromethane (200 ml) was added phthalic anhydride (20 gm, 0.135 mole) and cooled in an ice salt bath. This was followed by addition of sodium carbonate (18 gm, 0.17 mole) and water (20 ml). Hydrogen peroxide (12 ml, 45%, 0.16 mm mole) was added dropwise at −5 to 0° C. and the reaction mixture was stirred at the same temperature. When the reaction was complete as indicated by TLC, water (200 ml) was added, cooling bath was removed and the reaction mixture was stirred for 10 mins. The organic layer was separated and washed with 5% sodium carbonate solution. The separated dichloromethane solution was charcolised and filtered through celite. The filtrate was concentrated to 100 ml and ethyl acetate 100 ml was added thereto. The separated solid was filtered, washed with ethyl acetate and dried in vacuum oven to yield 28.20 gm of Omeprazole. Yield 82.4% of theoretical. Melting Point was 158-160° C. (dec.)
Reaction SMILES: [F:1][CH2:2][CH:3]([CH2:7][CH:8]([F:10])[F:9])[CH:4]([F:6])[F:5].FCC(O)CO>>[F:1][CH2:2][C:3]([CH:7]=[C:8]([F:10])[F:9])=[C:4]([F:6])[F:5]
Reactant: FCC(CC(F)F)C(F)F
Agent: OCC(O)CF
Product: FCC(C=C(F)F)=C(F)F

Procedure:
As another example, 2-methyl-1,1,3-trifluoropropane may be prepared by reacting commercially available fluoroacetone with a CF2 carbene to form 2-fluoromethyl-1,1-difluoro-1-propene which may then be hydrogenated to form 2-methyl-1,1,3-trifluoropropane. As another example, 2-fluoromethyl-1,1,4,4-tetrafluorobutane may be prepared by oxidizing commercially available 3-fluoro-1,2-propanediol to form a product which may then be reacted with a CF2 carbene to form 2-fluoromethyl-1,1,4,4-tetrafluoro-1,3-butadiene; the 2-fluoromethyl-1,1,4,4-tetrafluoro-1,3-butadiene may then be hydrogenated to form 2-fluoromethyl-1,1,4,4-tetrafluorobutane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.O[CH2:25][CH2:26][N:27](C)[C:28](=O)OC(C)(C)C.Cl>CO>[CH3:28][NH:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and tert-butyl 2-hydroxyethyl(methyl)carbamate except that the crude product was deprotected with a mixture of MeOH (1 mL) and conc. HCl (1 mL) before purification. MS (ESI) m/z 361.12 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.29 (1H, d, J=8.85 Hz), 8.16 (1H, s), 8.11 (2H, d, J=7.02 Hz), 7.54 (2H, t, J=7.78 Hz), 7.44 (1H, t, J=7.32 Hz), 7.21 (1H, d, J=2.14 Hz), 6.98 (1H, dd, J=8.70, 2.29 Hz), 4.25 (2H, t, J=5.19 Hz), 3.05 (2H, t, J=5.19 Hz), 2.51 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1.CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-3-nitrobenzaldehyde (5.00 g, 29.9 mmol) in tetrahydrofuran/DMF (300 mL/120 mL) was added NaH (60%, 1.32 g, 32.9 mmol), followed by ethyl bromoacetate (5.49 g, 3.65 mL, 32.9 mmol). The mixture was heated at reflux for 20 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), acidified to pH 2 with 1N HCl, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL), the organic extracts were combined and washed with saturated NaHCO3 (2×50 mL), brine (1×50 mL), dried over MgSO4, and concentrated to an amber oil. Purification of the residue by silica gel flash chromatography (25% ethyl acetate/hexanes) afforded the title compound. 1H NMR (DMSO-d6) δ 1.91 (t, J=7.08 Hz, 3H), 4.16 (q, J=7.08 Hz, 2H), 5.15 (s, 2H), 7.50 (d, J=8.79 Hz, 1H), 8.12–8.14 (m, 1H), 8.42 (d, J=1.95 Hz, 1H), 9.93 (s, 1H) ppm. MS: M+−1=252.1 Da.
Reaction SMILES: [Mg].[CH3:2][Si:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(Cl)Cl.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1.C=CC=C>CCOCC.C(O)(C)C>[CH3:2][Si:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14][CH:13]=[CH:12][CH2:16]1
Reactant: C[Si](Cl)(Cl)c1ccccc1
Reactant: C1CCOC1
Agent: C=CC=C
Agent: [Mg]
Solvent: CC(C)O
Solvent: CCOCC
Product: C[Si]1(c2ccccc2)CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed magnesium powder (9.6 g, 0.4 mol), methylphenyldichlorosilane (38.2 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Isopropyl alcohol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. These were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. The expected compound (boiling point 85°-87° C. at 4 mm Hg, 22.6 g, 65 % yield) was collected.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C.O>[CH3:19][CH:18]([CH3:20])[CH:17]([O:16][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[O:21][C:22]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:23]
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: NC1(C(=O)O)CC1
Solvent: CC#N
Solvent: O
Product: CC(C)C(OC(=O)NC1(C(=O)O)CC1)OC(=O)c1ccccc1
Yield: 23.2 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.726 g, 7.15 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (2 g, 5.96 mmol) were reacted in the acetonitrile/water mixture to provide 0.445 g (25% yield) of the title compound (12) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.02 (d, 2H), 7.59 (t, 1H), 7.42 (t, 2H), 6.82 (d, 1H), 5.56 (br s. 0.3H), 5.44 (s, 0.7H), 2.21 (m, 1H), 1.61 (m, 2H), 1.39 (m, 2H), 1.02 (dd, 6H). MS (ESI) m/z 344.19 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[F:37][C:38]1[C:39]([NH:48][CH:49]2[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]2)=[C:40]([CH:44]=[C:45](I)[CH:46]=1)[C:41]([OH:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC(N(C)C)=O.O>[F:37][C:38]1[C:39]([NH:48][CH:49]2[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]2)=[C:40]([CH:44]=[C:45]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[CH:46]=1)[C:41]([OH:43])=[O:42]
Reactant: O=C(O)c1cc(I)cc(F)c1NC1CCC(O)CC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC4CCC(O)CC4)c(C(=O)O)c3)cc12
Temperature: 100 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.24 g, 3.27 mmol), 3-Fluoro-2-(4-hydroxy-cyclohexylamino)-5-iodo-benzoic acid (1.65 g, 3.27 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (66 mg, 0.08 mmol) in dimethylacetamide (20 mL) and aqueous solution of sodium carbonate (2M, 4.9 mL) was stirred at 100° C. for 14 h. The cooled reaction mixture was poured into 150 mL of water acidified with 6 N hydrochloric acid and filtered. The solids were redissolved in a mixture of dichloromethane and ethanol and filtered again. The filtrate was concentrated and the brown residue was purified by flash silica gel chromatography using a gradient of a solution of 90 parts ethyl acetate, 10 parts methanol, and one part acetic acid and hexanes afforded 1.5 g of a light brown solid (2.38 mmol, 76% yield). MS: m/z 630 [MH+]