Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:18])[C:12]1C=CC=CC=1>ClCCl>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:12])=[O:18])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Reaction time: 16 h

Procedure:
4-Aminoacetophenone (1.35 g, 10.0 mmol) was dissolved in dichloromethane (10 mL) and treated with benzoyl chloride (1.74 mL, 15.0 mmol). The mixture was stirred for 16 hours at which time a white precipitate had formed. The solid was removed by filtration, washing with dichloromethane (3×20 mL) to provide 4-acetamidoacetophenone as a white sold (2.74 g). 1H NMR (200 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.92 (s, 7H), 7.54 (m, 3H), 2.50 (s, 3H).
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:12][CH2:11][C@H:9]2[O:10][C@@H:2]([S:1][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]2[OH:8])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: O[C@@H]1[C@@H](O)[C@H](Sc2ccccc2)O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1O
Yield: 98.7 %

Procedure:
Phenyl 1-thio-β-D-glucopyranoside (5) (7.01 g, 25.8 mmol) and triphenylmethyl chloride (9.33 g, 33.5 mmol) were suspended in pyridine (20 ml), and the mixture was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; dichloromethane:ethyl acetate=1:1) to give phenyl 6-O-triphenylmethyl-1-thio-β-D-glucopyranoside (6) (13.1 g, yield 99%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Cl[C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.CS(O)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O.CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-bromo-5-methylaniline (45.77 g, 246 mmol) in toluene (500 ml) were sequentially added 2-chloro-4-(trifluoromethyl)pyrimidine (53.9 g, 295 mmol) and methanesulfonic acid (28.4 g, 295 mmol). The resulting solution was heated to 105° C. overnight. The resulting mixture was cooled, diluted with water (500 mL) and adjusted to pH 14 via addition of a concentrated aqueous sodium hydroxide solution (26.6 g of a solution containing 320 mmol of sodium hydroxide). The resulting solution was extracted with MTBE (500 mL), the layers separated, and the organic layer subsequently washed with water (300 ml) then 50% saturated brine solution (200 mL). The organic layer was concentrated in vacuo to 200 ml resulting in product crystallization. To the slurry was added heptane (660 mL) over 40 minutes followed by a 2 hr aging at 20° C. The solid was isolated via filtration, washed with heptane (200 mL) and dried in a vacuum oven at 40° C. overnight to provide the title compound (69.5 g, 209 mmol) as a light yellow solid. MS ESI: [M+H]+ m/z 334.0. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H); 7.79 (s, 1H); 7.30 (s, 2H); 7.10-7.06 (m, 2H); 2.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:14]([N:3]1[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]1)[CH2:15][CH3:16]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 55 °C
Yield: 67.4 %

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (25 g, 92 mmol) in DMF (120 ml) was added over 45 minutes to a suspension of NaH (4.0 g, 10 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (200 ml) with stirring and under an inert atmosphere. After stirring for 30 minutes, a solution of 1-bromopropane (13.6 g, 111 mmol) in DMF (40 ml) was added over 10 minutes. The reaction mixture was heated at 50-60° C. for 3 hours (monitored by TLC) and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (300 ml, 1/5) was added and the organic phase was then extracted with water (2×50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude reaction product was obtained as a black oil (19.4 g, 70%), which was used without further purification in the amination step.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([O:25]C)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Br:34][CH2:35][Br:36].Cl>C(OCC)(=O)C.O.C1COCC1>[CH2:27]([C@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:16])[CH3:17])[C:23](=[O:25])[CH:35]([Br:36])[Br:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: BrCBr
Agent: CCCC[Mg]Cl
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Br)Br
Reaction time: 2 h
Yield: 57.8 %

Procedure:
Under nitrogen gas, diisopropylamine (17.4 g, 157.5 mmol) was added to n-butylmagnesium chloride (1.8 mol/kg, 79.6 g, 143.2 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8 mmol), dibromomethane (12.45 g, 71.6 mmol) and THF (20 mL) (liquor B). To this liquor B was added said liquor A over 1 hour at an internal temperature of about 5° C., and the reaction was further conducted for 1 hour. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (34.5 g), water (50 g) and ethyl acetate (100 mL) over 15 minutes for hydrolysis. After phase separation, the organic layer was washed with 2 portions of water (50 mL) and partially concentrated and the residue was precipitated from hexane to provide white crystals of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (8.709 g, 95.5 area %, yield 55%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[C:15]([O:18][CH:19]1[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:20]1[NH2:21])(=[O:17])[CH3:16].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:21][C@@H:20]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:33][CH:19]1[O:18][C:15](=[O:17])[CH3:16])=[O:7]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)c1cccc(I)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](NC(=O)c2cccc(I)c2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 65 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
A mixture of m-iodobenzoic acid (1.6 g; 6.45×10-3 mol) and thionyl chloride (10 ml) was stirred at 65° C. for 24 hours, benzene was added thereto, and excessive thionyl chloride was removed by distillation under reduced pressure. The thus prepared m-iodobenzoyl chloride was dissolved in benzene (2 ml), and a solution of 1,3,4,6-tetra-O-acetyl-D-glucosamine (2 g; 5.76×10-3 mol) in benzene (10 ml) and pyridine (2 ml) was added thereto, followed by stirring for 48 hours. The resulting mixture was neutralized with 0.1N hydrochloric acid and extracted with chloroform, followed by crystallization from methanol to give N-(m-iodobenzoyl)-1,3,4,6-tetra-O-acetyl-D-glucosamine (ABGA) (1.50 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:18]C3CCCCO3)[CH:14]=[C:15]([O:16][CH3:17])[C:7]1=2)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:16][CH3:17])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC)c21
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(OC)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of ethyl-2-(1-hydroxy-4-methoxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.35 g, 1.0 mmol) in THF (10 mL) was added dropwise concentrated hydrochloride acid (0.2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE=1/2) to give the title compound as a light yellow solid (180 mg, Y: 67.7%). 1H NMR (400 MHz, DMSO-d) δ 9.45 (s, 1H), 9.15 (s, 1H), 6.65-6.66 (d, J=1.2 Hz, 1H), 6.48-6.49 (d, J=1.2 Hz, 1H), 5.33-5.36 (m, 1H), 4.05-4.10 (m, 2H), 3.76 (s, 3H), 3.10-3.13 (m, 1H), 2.15-2.21 (m, 1H), 1.16-1.20 (m, 3H). MS (ESI) m/z=267 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.CCCCCC.C(OCC)(=O)C>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:20][CH2:21][CH:22]3[O:26][CH2:25][CH2:24][O:23]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: BrCCC1OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)-c1ccccc1C2CCC1OCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(9-Fluorenyl)ethyl-1,3-dioxolane was prepared from a solution of fluorene (30.0 g, 180.5 mmol) in 400 ml of dry THF cooled in a -78° C. bath under argon, to which was added 100 ml of n-butyllithium (2.0M in cyclohexane) over 15 minutes. After stirring for 0.5 hours at 78° C., 2-(2-bromoethyl)-1,3-dioxolane (22.3 ml, 190 mmol) was added dropwise, and the resulting solution stirred at room temperature for 16 hours. Concentration in vacuo yielded an orange residue which was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was then washed with brine, dried with magnesium sulfate, and concentrated in vacuo to afford an orange oil. Flash chromatography on silica, hexane:ethyl acetate 20:1 to 1:1 yielded a yellow oil (36.38 g, 76%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[N:39]=[CH:38][C:37]3[C:32](=[C:33]([F:44])[CH:34]=[C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:36]=3)[C:31]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[N:21]([CH3:27])[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:40]([C:35]1[CH:36]=[C:37]2[C:32](=[C:33]([F:44])[CH:34]=1)[C:31](=[O:45])[N:30]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH:24]5[CH2:26][CH2:25]5)[N:21]([CH3:27])[N:20]=4)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:39]=[CH:38]2)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)n(C)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)cc1C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
A mixture of 126g (100 mg, 0.16 mmol) and lithium hydroxide (72 mg, 3.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 50° C. for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by reverse-phase Combiflash to afford 126 (32 mg, 35%) as a white solid. MS-ESI: [M+H]+ 570.3. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=5.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.56-7.55 (m, 2H), 7.53-7.51 (m, 2H), 7.33 (s, 1H), 5.53 (s, 1H) 4.49-4.48 (m, 2H), 4.04-4.02 (m, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 1.69-1.65 (m, 1H), 1.43 (s, 9H), 0.97-0.94 (m, 2H), 0.68-0.65 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:20][CH2:21][O:22][CH3:23])[C:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>[Pt](=O)=O.FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:20][CH2:21][O:22][CH3:23])[C:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)O
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: COCCn1nc2c(N)nc3c(c2c1CC(C)(C)O)CCCC3
Yield: 57.1 %

Procedure:
The methods described in Example 586 were used to hydrogenate 1-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol (1.75 g, 5.5 mmol) in the presence of platinum (IV) oxide (1.5 g) and trifluoroacetic acid (20 mL) and purify the product with the modification that before recrystallization, the product was also triturated with acetonitrile. 1-[4-Amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol (1.0 g) was obtained as white crystals, mp 163-165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH:20][OH:21])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reaction time: 6 h
Yield: 85 %

Procedure:
2-(4-Fluoro-phenyl)-1H-benzoimidazole-5-carbonitrile (1.898 g, 8 mmol; example 1), hydroxylamine hydrochloride (3.34 g, 48 mmol) and triethylamine (5.67 g, 56 mmol) were heated at reflux in 85 ml of ethanol for 6 hours. Heating was continued for further 6 hours after addition of 3 equivalents of hydroxylamine hydrochloride and triethylamine each and molecular sieve (3 Å). The molecular sieve was filtered, the solvent evaporated and the solid recrystallized from methanol. Yield: 85%. MS: m/e=271.05 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)(=[O:25])=[O:26])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CC(C)NC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Yield: 38.5 %

Procedure:
6-[(3-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (18-05) (110.0 mg, 38.2%, purified by Prep-HPLC) was synthesized as a white solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-05) (350.0 mg, 0.69 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2ccncc2)cc1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a CH3CN solution of 1-iodo-4-nitrobenzene (498 mg, 2 mmol) and 4-vinylpyridine (262 mg, 2.5 mmol) was added TEA (350 μL, 2.5 mmol) and Pd(OAc)2 (0.45 mg, 0.2 mmol). The mixture was heated to 100° C. for 48 hr in a capped Pyrex tube. It was then cooled to room temperature, quenched with 1N HCl (20 mL) and concentrated under reduced pressure. The mixture was filtered and the solid was taken up in EtOAc (30 mL) and washed with 1N NaOH (30 mL). The organic layer was concentrated, dried over Na2SO4 and concentrated to give 4-[2-(4-nitro-phenyl)-vinyl]-pyridine as yellow solid (160 mg, 37%).
Reaction SMILES: [Li]CCCC.[CH2:6]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[CH3:7].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>CCCCCC.C1COCC1>[CH2:6]([NH:8][C:9]([C:11]1[S:12][C:13]([Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:14][C:15]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])=[O:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCNC(=O)c1sc([Si](C)(C)C)cc1[Si](C)(C)C
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
A solution of 2.5M n-BuLi in hexane (18 mL) was added dropwise to a solution of N-ethyl-2-thiophenecarboxamide (3.1 g, 20 mmol) in 50 mL THF at below -65° C. under a positive nitrogen atmosphere and the resulting solution was stirred at -70° C. for 45 min. After that, TMSCl (9 mL) was added slowly at below -60° C. and stirring was continued at below -60° C. for 15 min. The solution was allowed to warm to 0° C., then poured into water and extracted with CH2 Cl2. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 5% ethyl acetate-hexane yielded 3.1 g of Example 248 as a white solid, m.p. 81°-84° C., and 1.1 g of Example 249 as a colorless oil. nD24 1.5228.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([OH:19])=[C:14]([Cl:20])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC1C=CC=CC=1C>[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:14]([Cl:20])[CH:13]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: O=C(O)c1cnccc1Oc1cc(Cl)c(Br)cc1Cl
Temperature: 120 °C

Procedure:
To a stirred suspension of 6.0 g (38.08 mmol) 4-chloronicotinic acid (commercially available; CAS RN 10177-29-4) in 200 mL o-xylene were added 10.13 g (41.89 mmol) 4-bromo-2,5-dichlorophenol (commercially available; CAS RN 1940-42-7) and 2.84 g (7.62 mmol) tetrakis-(acetonitrile)-copper hexafluorophosphate (commercially available; CAS RN 64443-05-6). Then 31.31 g (95.20 mmol) cesium carbonate were added and the resulting dark brown suspension as heated to 120° C. for 16 hours. After cooling to room temperature, the sovent was evaporated, the residue dissolved in 1.25 l water, extracted four times with 250 mL ethyl acetate and filtered. The pH of the green filtrate was adjusted to 6 using 25% aqueous hydrochloric acid. The formed precipitate was filtered off to give a first batch of the desired compound. The pH of the filtrate was adjusted to pH 3 using 25% aqueous hydrochloric acid, the suspension stirred for 0.25 hours at room temperature and then kept in the fridge for 64 hours. The suspension was filtered and washed with water to yield another batch of compound. Brown solid (overall yield 5.63 g (41%)). MS (ESI): m/z=363.9 [M+H]+.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1.CCOCC>[CH2:17]([O:16][C:14](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(F)ccc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Magnesium (0.644 g, 26.5 mmol) was added wit THF (4 mL) and a small amount of iodine. After the mixture was stirred, the mixture was added dropwise with a solution of 1-bromo-4-fluoro-2-methylbenzene (5.00 g, 26.5 mmol) in THF (50 mL). The mixture was stirred at room temperature for 30 minutes, and then cooled at −78° C. and added dropwise with a solution of ethyl chloroformate (3.80 mL, 39.8mmol) in THF (40 mL). The mixture was warmed slowly up to room temperature and stirring was continued at room temperature for 2 hours. The reaction mixture was diluted with ether and washed with water, saturated aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated, and the resulting oily substance was purified by silica gel column chromatography (hexane/ether) to obtain the title compound (3.65 g, yield: 76%).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]([CH2:26][C:27]2[N:28]=[C:29]([NH2:32])[S:30][CH:31]=2)[CH3:25])[N:20]=[C:19]([Cl:33])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[ClH:41]>CO.O1CCOCC1>[ClH:33].[ClH:41].[ClH:33].[NH2:32][C:29]1[S:30][CH:31]=[C:27]([CH2:26][N:24]([CH3:25])[C:21]2[NH:20][C:19]([Cl:33])=[N:18][C:17](=[N:9][NH2:8])[C:22]=2[F:23])[N:28]=1
Reactant: CN(Cc1csc(N)n1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(Cc1csc(N)n1)c1[nH]c(Cl)nc(=NN)c1F
Yield: 83 %

Procedure:
Tris(1,1-dimethylethyl)2-{6-[[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (220 mg, 0.36 mmol) was dissolved in 10 mL of methanol and stirred. To this solution, 5 mL of 4M HCl in dioxane was slowly added. The mixture was stirred for 3 days and was evaporated to provide 6-[[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4(1H)-pyrimidinone hydrazone trihydrochloride (150 mg, 83%). LCMS: (M+H)+: 303.9.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH2:15]([OH:17])[CH3:16].[H-].[Na+].O>C1COCC1>[CH2:15]([O:17][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1)[CH3:16]
Reactant: CCO
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (500 mg, 2.207 mmol) in THF (10 mL) was added ethanol (0.155 mL, 2.65 mmol) and NaH (132 mg, 3.31 mmol). Then the mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 16 h. The mixture was added to H2O and extracted with EA (2×50 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated to yield a brown oil of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7% yield): 1H NMR (400 MHz, CD3OD) δ 9.27 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J=7.0 Hz, 3H).