Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4C(=O)C5C(=CC=CC=5)C4=O)[N:17]=[C:13]3[N:12]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[C:11]([CH3:39])=[C:10]2[C:40]#[N:41])=[C:5]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:4]=1)#[N:2].O.NN.Cl>C(O)C>[NH2:18][C:16]1[N:17]=[C:13]2[N:12]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)[C:11]([CH3:39])=[C:10]([C:40]#[N:41])[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[S:42]([CH3:45])(=[O:44])=[O:43])[N:14]2[N:15]=1
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
In a pressure-proof glass tube, (rac)-7-[4-cyano-2-(methylsulfonyl)phenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (10 mg, 16 μmol) was initially charged in abs. ethanol (3 ml). Hydrazine hydrate (1.3 μl, 27 μmol, 1.7 eq.) was added, and the mixture was heated at 85° C. for 1 h. The reaction mixture was concentrated under reduced pressure, the residue was taken up in DMF (1 ml), 1 N hydrochloric acid (32 μl, 2 eq.) was added and the product was purified by preparative HPLC (Reprosil C18 column, 10 μm, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (7.9 mg, quant.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][O:14][CH3:15].CN(C=O)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COCCNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
Potassium carbonate (262 mg) and bis(2-methoxyethyl)amine (840 mg) were added to a DMF (2 ml) solution containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 5 hours. Water (15 ml) was added to the reaction solution, followed by stirring at room temperature for 1 hour. Insoluble matter was collected by filtration, and a white solid of N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine (117 mg) was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[C:34]1[CH:33]=[C:32]([CH2:31][O:30][CH3:29])[CH:37]=[CH:36][CH:35]=1
Reactant: COCc1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2cccc(COC)c2)c(OC)c1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a solution of Ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) (2 g, 5.8 mmol) in DME (36 mL) and water (9 mL) was added potassium carbonate (1.61 g, 11.6 mmol) and 3-(methoxymethyl)phenylboronic acid (962 mg, 5.8 mmol) and the mixture was degassed using argon stream for 30 minutes. Pd[PPh3]4 (330 mg, 0.29 mmol) was added and the mixture was heated at 80° C. under argon overnight. The solvents were removed under reduced pressure and the residue extracted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% EtOH/hexanes) to yield 1.38 g (76%) of ethyl 2-(2-methoxy-5′-(methoxymethyl)biphenyl-4-yl)acetate. 1H NMR(400 MHz, dMSO): δ 1.16-1.20 (t, 3H), 3.27 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 4.06-4.11 (q, 2H) 4.41 (s, 2H) 6.89 (d, 1H), 7.00 (s, 1H) 7.19-7.24 (m, 2H), 7.34-7.36 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:14]([CH:23]([CH3:25])[NH2:24])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:24][CH:23]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)[CH3:25])=[O:5])=[C:7]([Cl:11])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1c(Cl)ccnc1Cl
Reactant: CC(N)c1ncc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1c(Cl)ccnc1Cl)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
2,4-Dichloronicotinoyl chloride (0.40 g), made as in Example 1, Step C, was added to a solution of the amine intermediate from Step A (0.66 g) and triethylamine (0.70 g) in 30 mL of methylene chloride at room temperature followed by stirring overnight. The reaction mixture was distilled under vacuum to remove the solvent, giving an oil that was filtered through silica gel using 100% methylene chloride as the eluent. The solvent was then removed under vacuum to give the title compound, a compound of the invention, as a red oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1(C)C=CC=C[CH:13]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cc(F)cnc1Cl
Temperature: 95 °C
Reaction time: 14 h

Procedure:
Into a 5 L four-necked flask, the salt (1,000 g) of 2-chloro-5-fluoronicotinic acid obtained in Example 5-1 was put and dissolved by adding toluene (3,000 mL), thionyl chloride (617 g) and N,N-dimethylformamide (0.95 g). The flask was heated by dipping it in an oil bath set at 80° C. Six hours later, after confirming by the HPLC analysis that 2-chloro-5-fluoronicotinic acid became at most 5%, ethanol (2,173 g) was added. The temperature of the oil bath was raised to 95° C., and the reaction was carried out for 14 hours. Then, concentration under reduced pressure was carried out, and to the obtained crude liquid, ethyl acetate (4,000 mL) and a 7.5% sodium carbonate aqueous solution (4,000 mL) were added, followed by stirring. After confirming that the pH of the aqueous layer was at least 8, filtration and separation were carried out, and an organic layer was recovered. An aqueous layer was extracted with ethyl acetate (2,000 mL), and the extract was put together with the previous organic layer, followed by washing with water (2,000 mL) and then with a 5% sodium chloride aqueous solution (2,000 mL). The organic solvent was distilled off under reduced pressure to obtain a reddish brown oil (1,234.7 g). It was purified by distillation under reduced pressure to obtain ethyl 2-chloro-5-fluoronicotinate (624.8 g). The yield from 2,6-dichloro-5-fluoronicotinic acid was 66%. As a result of the HPLC analysis, the purity of ethyl 2-chloro-5-fluoronicotinate was 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[CH:8][C:7]2=[O:14])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[CH:8][C:7]2=[O:14]
Reactant: O=c1ccoc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2occc(=O)c2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 6-nitrochromone (2.0 g, 10.5 mmol) in methanol/ethyl acetate (100 mL/20 mL) purged with argon, was added 5% Pd/C (Degussa-wet, 0.5 g) catalyst. Hydrogen gas was bubbled through the slurry with stirring until (2 hrs.) LCMS and TLC showed complete conversion of starting material to product. The spent palladium catalyst was filtered off through a celite, and the solid was washed with methanol. The combined filtrate and washings were evaporated to produce 6-amino-chromen-4-one (1.58 g, 94%) as a light yellow solid. LCMS m/z (%)=162 (M+H, 100), 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J=5.96 Hz, 1H), 7.38 (d, J=2.86 Hz, 1H), 7.29 (d, J=8.88 Hz, 1H), 7.01 (dd, J=8.80 Hz, 2.8 Hz, 1H), 6.26 (d, J=5.96 Hz, 1H), 5.29 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].O>CS(C)=O>[CH:2]([O:3][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]([F:17])([F:18])[F:19])([CH3:4])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 41 g of sodium isopropoxide in 300 ml of dimethyl sulfoxide was added drop-by-drop to a chilled (5° C.) solution of 118 g of 2-chloro-5-nitrobenzotrifluoride in 100 ml of dimethyl sulfoxide. The resulting mixture was stirred at room temperature for one hour, poured into water, and the resulting mixture was extracted with ether. The extract was washed with water, dried, and the solvent was evaporated. The liquid residue was taken up in hexane and the solution was chilled to give a solid, which on recrystallization from hexane gave 2-isopropoxy-5-nitrobenzotrifluoride (2A), as a white crystalline solid, mp: 34°-36° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([C@H:29]2[CH2:33][O:32]C(C)(C)[O:30]2)([CH3:28])[CH3:27])[N:12]=1>C(Cl)Cl.C(=O)([O-])O.[Na+].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([CH3:28])([CH3:27])[C@H:29]([OH:30])[CH2:33][OH:32])[N:12]=1
Reactant: CC1(C)OC[C@H](C(C)(C)Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product from step iii) 0.34 g) in DCM (9 mL) was added iron (III) chloride hexahydrate (0.61 g) and the mixture was stirred at ambient temperature for 35 min. The reaction mixture was diluted with sat. sodium hydrogencarbonate solution and extracted with DCM (×3). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white foam. Yield: 0.20 g
Reaction SMILES: O=C([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])O.CN[C@@H](CC1C=C(O)C(O)=CC=1)C(O)=O.C(=O)(O)[O-].[Na+].C1C2C(=CC(C(C=2)=O)=O)NC1C(O)=O.OC(C1NC2C(C=1)=CC=CC=2)O>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[OH:13][C:12]1[CH:14]=[C:7]2[C:8](=[CH:9][C:10]=1[OH:11])[NH:5][CH:4]=[CH:6]2
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: CC(=O)[O-]
Agent: CN[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
The Bu'Lock et al article discloses oxidation often 2-3', 4'-dihydroxyphenylethyl amine derivatives, including dopa. For methyl dopa (described at page 2251), a 4.735×10-2M concentration of methyl dopa was reacted with a 0.1974M concentration of potassium ferricyanide, in the presence of sodium bicarbonate buffer at a 0.238M concentration. After 10 minutes 8 cc of a 20% zinc acetate solution was added to effect rearrangement of the dopachrome to the dihydroxymethylindole. The article indicates that a similar procedure was used for dopa. The reported 5,6-dihydroxyindole yield of one experiment, after purification, was 30%. However, the Bu'Lock article states that this yield could not be repeated. According to the article the solid light-brown residue obtained in subsequent experiments appeared to be polymeric. At page 2249 Bu'Lock et al hypothesized that their inability to repeat the sole successful experiment was attributable to the diluteness of the reaction medium. This later article by Bu'Lock et al supplements their prior article in Nature, 166:1036-7 (1950), which reported "an excellent yield" of 5,6-dihydroxyindole, and essentially negates their original findings.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[C:13]([O-])([O-])(OC)[CH3:14].CO>C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NNc1ccc2ccccc2n1
Reactant: COC(C)([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: Cc1nnc2ccc3ccccc3n12

Procedure:
To 2-hydrazinoquinoline (15.9 grams; 0.1 mole) in 70 milliliters xylene was added 13.0 grams (0.11 mole) methyl orthoacetate (13.0 grams; 0.11 mole). The stirred solution was refluxed for four hours, during which the methanol that distilled from the reaction was collected. The reaction mixture was cooled overnight, and filtered to separate the desired 1-methyl-s-triazolo(4,3-a)quinoline product. It was recrystallized from 1-butanol, yield, 9.0 grams, m.p., 166°-7°C.
Reaction SMILES: [C:1]12([C:11]3[O:15][C:14]([C:16](O)=[O:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:19]([O:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:16]([C:14]2[O:15][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:12][CH:13]=2)=[O:17])[CH:26]=1)[CH3:20]
Reactant: O=C(O)c1ccc(C23CC4CC(CC(C4)C2)C3)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)o2)c1

Procedure:
5-Adamantan-1-yl-furan-2-carboxylic acid (50 mg, 0.20 mmol) was coupled to aniline (60) (43 mg, 0.22 mmol) using Method D to give the title compound.
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:14]([NH:16][CH2:17][CH:18]=[O:19])[CH3:15]>C1C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH:18]=[O:19])[C:12]([NH:11][C:9]1[S:10][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:7][N:8]=1)=[O:13])[CH3:15]
Reactant: CCCCCc1nnc(N=C=O)s1
Reactant: CCNCC=O
Solvent: c1ccccc1
Product: CCCCCc1nnc(NC(=O)N(CC)CC=O)s1

Procedure:
A mixture of 5-pentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-pentyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([OH:8])[CH3:7])[CH3:2].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([O:8][C:13](=[O:14])[CH2:12][C:10]#[N:11])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)O
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(C)OC(=O)CC#N
Reaction time: 8 h

Procedure:
A mixture of 194.0 g of ethyl-3-hydroxybutyrate, 149.83 g of cyanoacetic acid, and 10.76 g of 4-dimethylaminopyridine (DMAP) was stirred in 1500 ml of CH2Cl2 in a 3 L three-neck round bottom flask equipped with a mechanical stirrer. About 75 ml of N-N′-dimethylformamide (DMF) was added to the above mixture to make a clear solution. The above solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (363.45 g in 600 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9]O.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:11][CH2:9][CH2:8][CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: OCCC1CC2CCC1C2
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: BrCCC1CC2CCC1C2
Yield: 95.3 %

Procedure:
2-Bicylco[2.2.1]hept-2-yl-ethanol (13.0 g, 93 mmol) was dissolved in acetonitrile (200 mL) and treated with dibromotriphenylphosphorane (47.0 g, 0.11 mol). After 1.5 hours the mixture was quenched with water (10 mL), diluted with diethyl ether (400 mL), and washed with water (2×400 mL). The organic phase was dried (MgSO4) and concentrated to yield an oil. The product was passed through a pad of silica gel to yield 2-(2-bromo-ethyl)-bicyclo[2.2.1]heptane as a colorless oil (18 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 3.37 (t, 7.4 Hz, 2H), 2.22 (m, 1H), 1.97 (m, 1H), 1.86 (m, 1 H), 1.7-1.4 (m, 5H), 1.3-0.9 (m, 5H); MS (FAB) m/z 203 (MH+).
Reaction SMILES: S([O-])([O-])(=O)=O.[NH4+].[NH4+].[C:8]([NH:11]/[C:12](=[C:18](/[NH:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)\[CH3:19])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH3:9].C[Si](C)(C)N[Si](C)(C)C>>[CH:21]1([N:20]2[C:18]([CH3:19])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=[C:8]2[CH3:9])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)/C(NC(C)=O)=C(/C)NC1CCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C)n(C2CCCC2)c1C
Temperature: 150 °C
Yield: 71.7 %

Procedure:
Ammonium sulfate (100 mg) was added to a solution of (E)-ethyl 2-acetamido-3-(cyclopentylamino)but-2-enoate (compound 18, 1.5 g, 5.9 mmol) and hexamethyldisilazane (15 mL) and refluxed overnight at 150° C. The reaction mixture was evaporated and extracted with EA and water. The organic layer was evaporated and the residue was purified with 20% methanol in CH2Cl2 to produce as a light brown solid (1.0 g, 71.4% yield).
Reaction SMILES: O.[OH-].[Na+].[C:4]([C:6]1([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5]>CO>[C:4]([C:6]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)CC1(C#N)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suitable reactor is charged 120 L of water, 32 kg of 50% aqueous sodium hydroxide solution, 21 L of methanol, and 70 kg of ethyl 1-cyanocyclohexaneacetate. This mixture is stirred at 50° C. for 1 hour, after which 40 to 60 L of solvent is removed by vacuum distillation while maintaining a temperature of below 50° C. After cooling to 20° to 25° C., the reaction mixture is filtered through a 0.45 micron Pall filter. The filtered solution is then diluted with 70 L of water and extracted with 20 L of methylene chloride, followed by a second extraction with 15 L of methylene chloride. The aqueous solution is charged to a pH of 8 with 37% hydrochloric acid solution. About 6 to 8 kg of 37% hydrochloric acid solution is required. The solution is then extracted two times with 20 L each of methylene chloride. After the final extraction, the aqueous solution is stirred under full vacuum at 20° to 30° C. for 30 minutes minimum, then cooled to 3° to 10° C. While maintaining this temperature, 37% hydrochloric acid solution is charged to a pH of 3. About 32 to 36 kg of 37% hydrochloric acid solution is required. After the addition is complete, the product slurry is stirred at 3° to 10° C. for 30 minutes. The product is then collected on a centrifuge and washed with 300 to 400 L of water which is prechilled to 5° C. or less. The product is spun as dry as possible on the centrifuge and is then removed from the centrifuge and stored as a wet cake in a cold room at 5° C. or less. After vacuum drying at 40° C. for 24 hours 1-cyanocyclohexaneacetic acid is obtained; mp 103°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)C.[Pd].[H][H]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: [H][H]
Reactant: COc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)cc1N

Procedure:
Reduction of 1-fluoro-3-nitro-4-methoxybenzene (34 g) in 400 ml of ethanol was carried out with 2 g of 10% palladium/carbon catalyst in hydrogen. The mixture was filtered, concentrated and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][O-].[Na+]>>[CH3:20][O:8][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: C[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(C)n1

Procedure:
Successive treatment of 6-methyl-2-pyridone with a mixture of phosphoryl chloride and phosphorus pentachloride, and sodium methoxide gives 6-methoxy-2-methylpyridine which may be converted into 2-bromomethyl-6-methoxypyridine with N-bromosuccinimide. Substitution of 2-bromomethyl-6-methoxypyridine for 2-chloromethyl-3-methoxypyridine in the general procedure of Example 1(iii)-(v) leads to the preparation of N-cyano-N'-methyl-N"-[2-((6-methoxy-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: COC(=O)[C@@H](C1C=CC=[CH:8][C:7]1([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[O:12][C:13]([O:16][CH3:17])([CH3:15])[CH3:14])O.[BH4-].[Na+].C[OH:29]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:7]([O:12][C:13]([O:16][CH3:17])([CH3:14])[CH3:15])[CH2:8][OH:29])=[CH:23][CH:22]=1
Reactant: CO
Reactant: COC(=O)[C@H](O)C1C=CC=CC1(OC(C)(C)OC)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COC(C)(C)O[C@@H](CO)c1ccc(Cl)cc1

Procedure:
Into methanol (20 ml) were added (R)-2-(4-chlorophenyl)-2-(1-methoxy-1-methylethyloxy)mandelic acid methyl ester obtained in 2) above (6.0 g) and further, under ice-cooling, sodium borohydride (4.35 g). The resulting mixture was stirred at the same temperature, neutralized and the reaction mixture was concentrated. Ethyl acetate and water were added to the resulting residue and the organic layer was collected by layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (5.2 g, 96.7%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cncc(Cl)n1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of 6-chloropyrazin-2-amine (1.00 g, 7.72 mmol) in DCM (20 mL) was added acetyl chloride (0.659 mL, 9.26 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by CombiFlash (REDISEP®, silica gel, 12 g, 25% EtOAc/petroleum ether) to give N-(6-chloropyrazin-2-yl)acetamide (0.700 g, 52.9%). LCMS Condition B-39: retention time 1.67 min, [M+1]=170.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 8.47 (s, 1H), 9.29 (s, 1H), 11.09 (br s, 1H).