Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH2:10].N1C=CC=CC=1.[Cl:17][CH2:18][CH2:19][O:20][C:21](Cl)=[O:22]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:21]([O:20][CH2:19][CH2:18][Cl:17])=[O:22]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cccc(C)c1NN
Solvent: O
Solvent: c1ccncc1
Product: Cc1cccc(C)c1NNC(=O)OCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 127 g (0.935 mol) 2,6-dimethylphenylhydrazine, 102.5 g (1.3 mol) pyridine and 400 ml water is added, at 0°-5°, 133.5 g (0.935 mol) chloroformic acid β-chloroethyl ester. After the addition is complete, the mixture is stirred for 2 hours at room temperature, the formed precipitate filtered off, washed with water and dried. The so obtained title compound is recrystallised from toluene to yield colourless crystals, m.p. 74°-75°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:15][O:11][C@@H:9]([CH3:10])[CH2:8][NH:7][C:6](=[O:12])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C)CNC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
Cool a solution of tert-butyl[(2S)-2-hydroxypropyl]carbamate (870 g, 4.96 mol) in tetrahydrofuran (10 L) to 5° C. Add sodium hydride (60% dispersion, 248 g, 6.21 mol, 1.25 eq.) in portions over 8 minutes. Stir the reaction at 5° C. for 30 minutes. Add methyl iodide (387 mL, 6.21 mol, 1.25 eq.) dropwise over 5 minutes and allow the reaction to proceed at 5-10° C. for 45 minutes. Quench the reaction with water (1 L) and extract with ethyl acetate (4 L). Obtain the organic layer and concentrate it in vacuo to obtain a residue. Co-evaporate the residue with toluene (2×1 L), dilute with dichloromethane (2 L) and filter. Rinse remaining solid with additional dichloromethane (500 mL). Concentrate the combined dichloromethane liquid filtrate in vacuo to obtain a crude intermediate of tert-butyl N-[(2S)-2-methoxypropyl]carbamate (880 g, 94%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]2
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(O)ccc2n1C
Yield: 239.9 %

Procedure:
A mixture of crude ethyl 5-(benzyloxy)-1-methyl-1H-indole-2-carboxylate (1.07 g, 3.46 mmol), 10% palladium on carbon (500 mg, 0.47 mmol) and ammonium formate (1.09 g, 17.29 mmol) in 50 mL ethanol was sparged with argon three times and heated at reflux for 1 h. The mixture was cooled, diluted with 100 mL ethanol and filtered through Celite, washed with ethanol and concentrated to give ethyl 5-hydroxy-1-methyl-1H-indole-2-carboxylate (1.82 g, 49% over two steps).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[O:10])=[CH:3][C:4]=1[F:9]
Reactant: Oc1ccccn1
Reactant: Nc1ccc(Br)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 150 °C
Reaction time: 18 h

Procedure:
4-Bromo-2-fluoroaniline (13.0 g; 68 mmol), 2-hydroxypyridine (9.11 g; 96 mmol), 8-hydroxyquinoline (1.5 g; 10 mmol) are dissolved under argon in DMSO (40 ml). To this solution K2CO3 (10.4 g; 75 mmol) and CuI (1.95 g; 10 mmol) are added and the resulting suspension is heavily stirred under argon at 150° C. for 18 h. The mixture is evaporated to dryness under reduced pressure and the final residue is chromatographed over silica gel (400 g) using dichloromethane/methanol as eluents. The obtained crude product is recrystallized with diethyl ether to yield an off-white solid. Yield: 2.80 g (20.0%), ESI-MS: m/z=205 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH:13]1[S:14][CH:15]=[C:16]2[C:22]=1[C:21](=[O:23])[NH:20][C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[NH:17]2>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:17]1[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[NH:20][C:21](=[O:23])[C:22]2=[CH:13][S:14][CH:15]=[C:16]12)=[O:4]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reaction time: 3 h
Yield: 67.2 %

Procedure:
2.2 g of chloroacetyl chloride and 2 ml of triethylamine are simultaneously added dropwise to a boiling solution of 2.2 g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 30 ml of absolute dioxane in the course of 40 minutes, and the mixture is stirred for a further 3 hours. It is then allowed to cool and is filtered; the filtrate is concentrated to dryness; the residue is chromatographed over a silica gel column by means of a mixture of petroleum ether/ethyl acetate (1:1), and the product is recrystallized from toluene to yield 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (m. 220° C.).
Reaction SMILES: Cl.C(O[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])C.C([O-])(=O)C.[NH4+:18]>C(O)C>[N+:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[NH2:18])([O-:13])=[O:12]
Reactant: [NH4+]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 4 °C
Yield: 118.2 %

Procedure:
A 50 ml 3-neck round bottom flask fitted with a condenser, thermometer and mechanical stirrer was charged with 3.0 g (14.66 mmol) of 4-ethoxy-3-nitropyridine hydrochloride, 6.1 g (79.9 mmol) of ammonium acetate and 6.7 ml of absolute ethanol. The reaction mixture was refluxed for approximately 24 hours and cooled to about 4° C. The pH of the solution was adjusted to 8.0 with base and the precipitated solid was collected by filtration. The product was rinsed with chilled ethanol and dried in vacuo at 50° C. to afford 2.41 g of 3-nitro-4-aminopyridine (and a small amount of ammonium acetate). The identity of the product was verified by NMR comparison to an authentic sample.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:2][C:1]#[N:4]
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)NC(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of diisopropylamine (8.65 ml, 61.8 mmol) in dry THF (100 ml) at −20° C. under nitrogen was added a 2.5M solution of nBuLi in hexanes (23.7 ml, 59.2 mmol) dropwise. The solution was allowed to warm to 0° C. over 20 min, and then-cooled to −70° C. A solution of methyl-2-(4-chlorophenyl)acetate (9.5 g, 51.5 mmol) in THF (5 ml) was added dropwise over 5 min, and the whole then stirred for 30 min. lodoacetonitrile (5.03 ml, 69.5 mmol) was then added slowly, and the combined solution allowed to warm to room temperature over 72 h. Saturated aq. NaHCO3 solution (20 ml) was added, the mixture was concentrated to about 50 ml under vacuum, and then treated with 1 N HCl (100 ml). The mixture was extracted with EtOAc (120 ml) which was dried (MgSO4) and evaporated to give a dark brown oil, which was purified by column chromatography using 2:1 DCM:pentane as eluant to give the title product (8.6 g, 75%); 1HNMR (400 MHz, CDCl3) δ: 2.80 (dd, 1H), 3.00 (d, 1H), 3.73 (s, 3H), 3.92 (dd, 1H), 7.22 (d, 2H), 7.37 (d, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:13][CH2:11][OH:12])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCO
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCO)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a pressure tube containing 1-fluoro-4-nitrobenzene (10.6 mL) and absolute ethanol (20 mL) under an atmosphere of argon gas is added ethanolamine (7.2 mL). The reaction is tightly capped and heated to 90° C. After 1 hour, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is dried in vacuo. The solid is crystallized from 95% ethanol to give 4.1 g of 2-(4-nitroanilino)-1-ethanol as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23]OS(C)(=O)=O.[C-:29]#[N:30].[K+]>CN(C)C=O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23][C:29]#[N:30]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(COS(C)(=O)=O)c3)C[C@@H]21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(CC#N)c3)C[C@@H]21
Temperature: 60 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
The product of Example 66A (0.300 g, 0.630 mmol) in N,N-dimethylformamide (5 mL) was treated with KCN (61 mg, 0.945 mmol). The mixture was warmed to 60° C. and allowed to stir for 20 hours. The mixture was then concentrated under reduced pressure and the residue purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (0.100 g, 0.246 mmol, 39% yield). MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:4]1=[O:19])[CH3:2].CS([C:24]1[N:25](COCC[Si](C)(C)C)[C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O.[H-].[Na+]>CO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:24]3[NH:32][C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:16][CH:17]=2)[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 200 °C
Yield: 14.7 %

Procedure:
The mixture of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (281 mg), 2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine (240 mg) and NaH (35.2 mg) in DMF(dry) (3 mL) was heated at 200° C. for 3 h under microwave irradiation. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was diluted with 6N HCl. The mixture was neutralized with aq. NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH2:12][CH2:11]2)=[N:2]1.O.NN.Cl>CO>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)[CH2:11][CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
A mixture of N-[4-{4-(1,2-benzisothiazol-3-yl)-1-piperazinyl}butyl]phthalimide (1 g; 2.38 mmol), hydrazine hydrate (0.2 g; 3.57 mmol) and methanol (10 ml) was refluxed for 2.5 hours. After cooling, the reaction mixture was combined with a 10% aqueous hydrochloric acid solution (20 ml) and stirred. The precipitated crystals were removed by filtration, and the filtrate was neutralized with a 10% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the objective compound as an oily substance. IR νmaxfilm (cm-1): 3360, 3280, 3070, 1590, 1560, 1490.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: CO
Reactant: Cc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1C
Yield: 92 %

Procedure:
To a flask (1000 mL), 120 g of 2-methylphenylacetic acid and 400 mL of anhydrous methanol were added, and then 24 mL of concentrated sulfuric acid was further added with stiffing. The mixture was heated with an oil bath and refluxed. The reaction was monitored with thin layer chromatography (TLC) until the reactants were basically consumed. Subsequently, the solvent was removed by vacuum distillation. The residue was dumped into 400 mL of water and extracted with 400 mL of ethyl acetate. The organic layer was washed with water (2×200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A light yellow oily product was obtained. The light yellow oily product was further distilled under vacuum condition to yield 117.3 g of a colorless oily product (135-140° C., 16 mmHg) with a yield of 92%.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:15](=[O:17])[C@H:10]([CH2:11][C:12](=[O:13])[OH:14])[NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)c1ccccc1
Reaction time: 7 h
Yield: 64.2 %

Procedure:
The procedure of Example 9 was followed excepting that: the quantity of N-benzoyl-L-aspartic acid was 2.85 g (10 mmol) and of the L-phenylalanine methyl ester was 2.69 g (15 mmol), in place of polyethylene glycol 600, polyethylene glycol 200 was used, the reaction time was 7 hours. N-benzoyl-L-aspartyl-L-phenylalanine methyl ester was obtained in the yield of 64.2%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1)[CH3:2].[O:10]1CCC[CH2:11]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:11]=[O:10])[C:6]([F:9])=[N:7][CH:8]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1ccc(F)nc1
Product: CCc1cnc(F)c(C=O)c1
Reaction time: 0.5 h

Procedure:
A solution of diisopropylainine (1.01 mL, 7.19 mmol) in tetrahydrofuran (20 mL) was treated in ice-bath with n-butyllithiuin (2.5M, 2.9 mL, 7.19 mmol) and stirred for 30 min. The resulting solution was reacted at −78° C. with 5-ethyl-2-fluoropyridine (2-b, 0.75 g, 5.99 mmol), stirred for 4 h, and treated with N,N-dimethylforninamide (482 mg, 6.59 mmol). The reaction mixture was quenched with acetic acid (1 mL), partitioned between ethyl acetate and water. The organic layer was washed with 0.5N—HCl and then with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (30% ethyl acetate in hexanes) afforded the desired compound (2-f); 1H NMR (500 MHz, CDCl3) δ10.3 (s, 1H), 8.29 (d, 1H, J=2.0 Hz), 8.12 (dd, 1H, J=9.0, 2.5 Hz), 2.73 (q, 2H, J =7.8 Hz), 1.29 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[CH2:2].BrBr.N.[NH2-].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[CH:2]
Reactant: C=Cc1ccc2ccccc2c1
Agent: BrBr
Agent: N
Agent: [NH2-]
Solvent: ClC(Cl)Cl
Product: C#Cc1ccc2ccccc2c1

Procedure:
To a mixture of 15.5 g. of 2-vinylnaphthalene and 300 ml. of chloroform, a 5 percent bromine in chloroform solution is added at -10° C until the bromine color persists. The mixture is then added to 200 ml. of ammonia containing 15 g. of sodium amide. The mixture is allowed to evaporate, acidified with dilute hydrochloric acid, and the residue is extracted with diethyl ether. The extracts are combined, washed to neutrality with water, dried, and evaporated to yield 2-ethynylnaphthalene.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)C(C)C)(C)C.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>ClCCl.C(OCC)C>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:1]=[O:2])=[O:8])[CH2:22][CH3:23]
Reactant: CCCNCCC
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 3-formylbenzoic acid (300 mg, 2.00 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and di-n-propylamine (0.41 mL, 3.0 mmol) in 4 mL of dry dichloromethane was added 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (575 mg, 3.00 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain the title compound as a colorless oil (95 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:24]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(F)cc1)C1CCNCC1
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-((4-fluorophenyl)sulfonyl)piperidine-1-carboxylate (32.7 mg, 0.095 mmol) in dioxane (238 μL) at room temperature was treated with HCl (4 M in dioxane, 190 μL, 0.762 mmol) and the resulting reaction mixture was stirred for 4 h. The solvent was removed to give the title compound as its HCl salt (25 mg, 94%) as a white solid. ESI-MS m/z [M+H]+ 243.95.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 904.2 %

Procedure:
To a stirred slurry of 4-nitro-2-cyanophenyl phenyl sulfide (13.3 g, 5.19 mmol) and 100 mL of absolute ethanol was added stannous chloride dihydrate (58.6 g, 26 mmol) in one portion. The mixture was heated to 60° C. where an exothermic reaction caused the solution to strongly reflux. The mixture was allowed to stir at ambient temperature for 30 min., poured onto ice-water and made strongly basic by the addition of 350 mL of 15% NaOH. The mixture was extracted with methylene chloride (4×275 mL), the extracts dried (MgSO4), filtered, and the solvent removed in vacuo to yield an oil which was chromatographed on 300 g of silica gel using a methylene chloride (20%, 40%, 60% 80% and 100%) in hexane gradient. The proper fractions were combined and the solvent removed to yield the 4-amino-2-cyano-phenyl phenyl sulfide (10.62 g, 91%) as a pale yellow solid; mp 73°-75° C. 1H-NMR (300 MHz, CDCl3): 4.01 (s, 2H, NH2), 6.78 (dd 1H, J=8.5, 2.6, aromatic), 6.95 (d, 1H, J=2.6, aromatic), 7.18-7.29 (m, 5H, aromatic), 7.34 (d, 1H, J=8.5, aromatic). MS (CI, CH4): 227(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[Cl:15][S:16](O)(=[O:18])=[O:17].S(Cl)(Cl)=O.C(OC(C)C)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:4][C:3]=1[S:8]([C:11]([F:12])([F:13])[F:14])(=[O:9])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=S(=O)(c1ccccc1F)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 22 h

Procedure:
EXAMPLE 13 (80 g) was charged to a reactor fitted with overhead stirrer, nitrogen inlet, condenser, scrubber, temperature probe and heating bath. Chlorosulfonic acid (307 g) was added slowly through an additional funnel. The mixture was then heated up to 120° C. and held for 22 hours at 120° C. The mixture was cooled down to room temperature. Thionyl chloride (118 g) was added to the reaction mixture in one portion at ambient temperature. The mixture was stirred at 25° C. for 24 hours. A sample was pulled and HPLC showed the reaction was completed with 1.1% of the sulfonic acid left. Isopropyl acetate (775 g) was cooled down to −50° C. Water (600 g) was charged to isopropyl acetate solution. The reaction mixture was transferred slowly to the isopropyl acetate/ice mixture through an additional funnel. The internal temperature increased to 0.8° C. during the addition. The cold reaction mixture was warmed up 15° C. and layers were separated. The organic layer was used in the next step (EXAMPLE 15) without isolation.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C(O)(C)C.[Cl-].[NH4+]>[Fe].O>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(CO)ccc1F

Procedure:
A flask equipped with overhead stirrer was charged with 4-fluoro-3-nitrobenzyl alcohol (20 g, 0.117 mol) and 200 mL of 5:1 isopropanol: water. Ammonium chloride (62 g, 1.17 mol) was added followed by iron filings (65 g, .17 mol). The mixture was stirred at 70 C for 1.5 H when it was shown to be complete by LC-MS. The liquid was decanted and the solids were washed with additional isopropanol:water. The isopropanol was removed and the residue was diluted with 0.5 N HCl and was extracted with ethyl acetate. The aqueous layer was brought to pH 12-14 with 2.5 N NaOH and was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. 3-Amino-4-fluorophenyl methanol was isolated as a brown solid (4.5 g, 27%) and was used without further purification. LC/MS, tr=2.40 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 142 (M+H). ES-HRMS m/z 142.0692 (M+H calcd for C7H8FNO requires 142.0663). Step 2 Preparation of 1-[2-fluoro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([NH:9][NH:8][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCOCC1
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (2.50 g) and tert-butyl hydrazinecarboxylate (3.47 g) in methanol (10 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in THF (25 mL), acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added thereto, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g).