Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH:15](O)=O>[Pd]>[CH3:11][C:10]1[C:2]2[NH:1][CH:15]=[N:12][C:3]=2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=1
Reactant: O=CO
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1N
Agent: [Pd]
Product: Cc1ccc(C(=O)O)c2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-methyl-2-nitrobenzoic acid (16) (6.883 g, 35.10 mmol), 10% Pd/C [0.3 g, 10% dry Pd/C] and 75% aqueous formic acid (60 mL) is heated to reflux for about 15 hours. The reaction mixture is then cooled to ambient temperature and filtered through a pad of Celite, and the resulting filtrate concentrated in vacuo to a beige solid. The solids are triturated in hot methanol (50 mL), cooled slowly to ambient temperature, and filtered to give 7-Methyl-1H-benzimidazole-4-carboxylic Acid (22), as beige solid (5.26 g, 85% Yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].O1CCCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C(OCC)(=O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:31])[CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cc(NC(C)=O)ccc1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(C)=S)ccc1OC
Reaction time: 18 h

Procedure:
Combine methyl 2-methoxy-5-acetamidobenzoate (2.23 g, 10 mmol) and tetrahydrofuran (1000 mL). Add Lawesson's reagent (2.02 g, 5 mmol). After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 12% ethyl acetate/dichloromethane to give methyl 2-methoxy-5-thioacetamidobenzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][N:5]([C:7]([NH:21][CH2:22][CH3:23])=[N:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)(=[O:11])=[O:10])[N:4]=[CH:3]1.C(O)(=O)C>CCO.O.[Fe]>[NH2:18][C:14]1[CH:13]=[C:12]([S:9]([N:8]=[C:7]([N:5]2[CH2:6][C:2]([CH3:1])([CH3:24])[CH:3]=[N:4]2)[NH:21][CH2:22][CH3:23])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: CCNC(=NS(=O)(=O)c1cccc([N+](=O)[O-])c1)N1CC(C)(C)C=N1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCNC(=NS(=O)(=O)c1cccc(N)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
In a mixture of 50 mL EtOH and 25 mL water, 1.11 g N-[(4,4-Dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-3-nitro-benzenesulfonamide was dissolved. Subsequently, 1.05 g iron and 1.08 mL acetic acid were added, and the mixture was refluxed for 4 h. After cooling to room temperature, the mixture was filtered over Hyflo and the Hyflo was rinsed with MeOH. The alcohols were evaporated from the filtrate, and 5% aqueous NaHCO3 and DCM were added. The material insoluble in these phases was filtered off, the organic phase was separated and the aqueous phase extracted once more with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness to give 1.02 g (100%) of 3-amino-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide as a brown foam. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.19 (s, 6H), 3.42-3.51 (m, 2H), 3.73 (s, 2H), 3.93 (br.s., 2H), 6.71-6.79 (m, 2H), 6.90 (br.s., 1H), 7.20 (t, J=7.83 Hz, 1H), 7.24-7.31 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([CH3:15])[C:13]#[CH:14].N1CCCCC1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:14]#[C:13][C:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)([CH3:15])[CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N)nc(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Yield: 95.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step C of Example 3, using 1.3 grams (0.005 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 1.6 grams of (0.008 mole) of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne (prepared as in Step F of Example 17), 0.3 gram of bis(triphenylphosphine)palladium(II) chloride, 0.05 gram of copper iodide, and 8 mL of piperidine in 20 mL of N,N-dimethylformamide, yielding 1.6 grams of 2,4-diamino-6-methyl-5-[3-(4-trifluoromethylphenyl)-3-methyl-1-butynyl]pyrimidine, mp 153°-157° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Na].C([O:5][CH2:6][CH2:7][O:8][C:9]1[C:13]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)=[C:12]([N:23](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:11]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:10]=1)(=O)C.Cl>C(O)C.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:13]3[C:9]([O:8][CH2:7][CH2:6][OH:5])=[N:10][N:11]([CH2:50][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:12]=3[NH:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CC(=O)OCCOc1nn(Cc2ccccc2)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 95.6 %

Procedure:
An aqueous solution of sodium hydroxyde (2N, 75 ml) was added at room temperature to a solution of 2-{[4-(1,3-benzodioxol-5-yl)-1-benzyl-5-(bis{[4-(tert-butyl)phenyl]sulfonyl)amino)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 52) (24 g) in ethanol (300 ml) and left overnight. The reaction mixture was then diluted with water (1000 ml), acidified with an aqueous solution of HCl (1N) and extracted with ethyl acetate (3×500 ml). The combined organic phases were washed with brine (500 ml) and concentrated under reduced pressure. The yellow oil was purified by column chromatography (silica, 500 g) eluted with hexane:ethyl acetate (1:1) yielding the title compound as a pale beige solid (16 g).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]=1[NH:11][CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:10][C:8]1[CH:7]=[N:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:4]([CH:9]=1)[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNc1ncc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-nicotinic acid methyl ester (0.16 g, 0.36 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.075 g, 1.78 mmol). The reaction was stirred at ambient temperature overnight, concentrated in vacuo, diluted with dichloromethane and passed through a glass frit. The filtrate was treated with diethyl ether saturated with hydrogen chloride gas, and the white precipitate thus formed was collected by filtration to give the title compound as its hydrochloride salt (0.13 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH2:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(CC)CC>CCO>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([NH:23][C:29]2[CH:30]=[C:25]([Cl:24])[N:26]=[CH:27][N:28]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 140 °C
Yield: 57.2 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (0.400 g, 1.11 mmol) in EtOH (3.0 mL) was added 4,6-dichloro-pyrimidine (0.199 g, 1.33 mmol) and Et3N (0.310 mL, 2.22 mmol). The reaction was heated to 140° C. for 1 h in a sealed tube using microwave irradiation then concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash chromatography (CH2Cl2) to afford the title compound (0.300 g, 57%).
Reaction SMILES: O.[OH-].[Na+].[C:4]1([CH2:10][C:11](=[O:13])[CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([CH2:10][CH:11]([OH:13])[CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)Cc1ccccc1
Temperature: 80 °C

Procedure:
In a 4 liter three-necked flask fitted with a mechanical stirrer and a reflux condenser, were placed 1500 ml of water, 150 g of sodium hydroxide (pellets), 190 ml of ethanol and 180 g of phenylacetone. The mixture was stirred and heated to 80° C., and 150 g of Raney alloy was added very cautiously by small amounts over about 1 hour. During the addition, heating was discontinued and the temperature was maintained at 85°-87° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2.[C:19]([O-])([O-])=O.[K+].[K+].CI>>[CH3:19][O:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2
Reactant: CC1(C)C=Cc2c(O)c(C=O)cc([N+](=O)[O-])c2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c(C=O)cc([N+](=O)[O-])c2c1C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde (2.34 g, 10 mmol), K2CO3 (4.12 g, 29.8 mmol) and MeI (2.13 g, 0.94 mL, 15 mmol in Me2CO (40 mL) is refluxed for 4 h and stirred at room temperature overnight. The mixture is concentrated, treated with water (15 mL) and extracted with dichloromethane. The combined organic layers are washed with water, dried over Na2SO4, and the solvent is removed in vacuo to afford an oil, which is chromatographed with 3% Me2CO in hexane to afford 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[C:4](Cl)[N:3]=1.C(O)=[O:20]>>[OH:17][CH2:16][CH2:15][CH:12]([CH2:13][OH:14])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(Cl)c2ncn(CC(CO)CCO)c2n1
Reactant: O=CO
Product: Nc1nc2c(ncn2CC(CO)CCO)c(=O)[nH]1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A solution of (-)-2-(2-amino-6-chlorpurin-9-ylmethyl)-1,4-butanediol (11.5 mg, 0.0423 mmol) in 50 % aqueous formic acid (0.75 ml) was kept at 100° C./2 h and then evaporated to dryness, dissolved in 2 ml of water and lyophilized. The product was dissolved in 1 ml of water, 2 drops of conc. aqueous ammonia was added and the solution kept at 100° C. for 10 min, flushed with nitrogen to remove ammonia, and lyophilized. The residue was dissolved by warming with 1.2 ml of 20% aqueous methanol and the solution filtered and kept in open air to allow for slow partial evaporization of solvent. Crystalline needles were formed. Filtration, washing with 3 drops of water and drying yielded 6.4 mg (60%) of (-)-9-(4-hydroxy-2-hydroxymethylbutyl)guanine.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:11]=O.[CH:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([C:23]([NH:25][C:26](=[O:27])[C:19]3=[CH:18][CH:17]=[CH:16]2)=[O:24])[CH:22]=1>CN(C)C=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][N:25]1[C:26](=[O:27])[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:20]=2[C:21](=[CH:22][CH:13]=[CH:14]3)[C:23]1=[O:24]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: C=O
Reactant: c1ccc2c(c1)CCNC2
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CN1CCc2ccccc2C1

Procedure:
An equimolar mixture of 1,2,3,4-tetrahydroisoquinoline, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[(3,4-dihydro-2(1H)-isoquinolinylmethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[F:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Cc1cnc(F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)cnc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
To a solution of 2-fluoro-5-methylnicotinic acid (4.9 g, 31.6 mmol), N,O-dimethylhydroxylamine hydrochloride (4.01 g, 41.08 mmol), diisopropylethylamine (12.6 ml, 72.68 mmol) in dichloromethane (150 ml) at 0° C. was added TBTU (11.16 g, 34.76 mmol) portionwise over 30 minutes. The solution was stirred at 0° C. for a further 10 minutes then, at room temperature for 18 hours. The reaction mixture was washed with a 10 wt % solution of citric acid and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 80 g column, 0-20% EtOAc/Petrol) to afford the title compound as a colourless solid (5.44 g, 87% yield).
Reaction SMILES: [O-:1]O.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].C=CC>>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:1])[CH3:4].[C:5]1([OH:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCc1ccccc1
Reactant: [O-]O
Solvent: C=CC
Product: CC(=O)c1ccccc1
Product: Oc1ccccc1

Procedure:
Referring to FIG. 4, 8 g of the same catalyst as that in Example 1 is charged in a single catalyst bed, and 10 g/hour of the same solution as that in Example 1 containing 30% by weight of ethylbenzene hydroperoxide and 15 g/hour of the same propylene as that in Example 1 are fed thereto. The pressure at the catalyst bed is adjusted to 7.0 MPa, and the temperature at the inlet of the catalyst bed is adjusted such that the conversion of the fed ethylbenzene hydroperoxide becomes 99%. The results of reaction in this case are shown in Table 2, indicating that the yield of propylene decreases and produced amount of acetophenone and phenol formed by thermal decomposition of ethylbenzene hydroperoxide increases.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a mixture of 2-piperazinone (0.46 g, 4.59 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (1.5 mL, 10.76 mmol) in CH2Cl2 (20 mL) at 0° C. was added 6-chloropyridine-3-sulfonyl chloride (0.974 g, 4.59 mmol, Organic Process Research & Development 2009, 13, 875). The resulting slurry was stirred at room temperature for 30 min and then was concentrated. The residue was mixed with saturated aqueous NaHCO3 (10 mL) and was stirred at room temperature for 1 d. The slurry was filtered, washed with water (3×5 mL), and dried under reduced pressure to give 4-((6-chloro-3-pyridinyl)sulfonyl)-2-piperazinone as a white solid (1.12 g).
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Br:18]P(Br)Br>C(Cl)Cl.C1COCC1>[Br:18][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(O)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(Br)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl 3-(1-hydroxyethyl)phenylcarbamate (5.8 g, 24.44 mmol) in CH2Cl2 (30 mL) and THF (20 mL) at 0° C. was added tribromophosphine (1 M solution in CH2Cl2, 24.44 mL, 24.44 mmol). The reaction was stirred at 0-10° C. for 1.5 h and then quenched with water. The mixture was extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound (5.7 g, 78% yield) as a colorless oil. LCMS, [M+Na]+=322.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1.[CH3:34][C:35]1[N:39]=[C:38]([NH2:40])[S:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:38]4[S:37][N:36]=[C:35]([CH3:34])[N:39]=4)(=[O:21])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1nsc(N)n1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nsc(NS(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4C)nccc3c2)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (Intermediate DDDDD; 59.9 mg, 0.120 mmol), 3-methyl-1,2,4-thiadiazol-5-amine (27.6 mg, 0.240 mmol), cesium carbonate (117 mg, 0.360 mmol), and DMF (0.6 mL). The vial was sonicated for 20 s, and the mixture was stirred further for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-5% MeOH/DCM) to give 1-(4-chloro-2-methylphenyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (38.94 mg, 0.090 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.16 (d, J=5.8 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.44-7.39 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 2.27 (s, 3H), 1.97 (s, 3H). m/z (ESI) 431.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:31][CH:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:26][CH2:27]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 16 h
Yield: 39.5 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-hydroxybenzamide (200 mg, 0.806 mmol), 1-tert-butoxycarbonylpiperidine-4-methanol (191 mg, 0.887 mmol), and triphenylphosphine (232 mg, 0.887 mmol) in THF was treated dropwise with a THF solution of diethyl diazodicarboxylate (DEAD) (0.14 mL, 0.887 mmol in 1 mL of THF). After 16 h, the mixture was treated with an additional equivalent of triphenylphosphine and DEAD. After 2 h, the mixture was concentrated, diluted with methylene chloride, and filtered. The solid collected was the desired product (128 mg, 36%). The filtrate was purified by column chromatography (SiO2; 4:1 hexanes:EtOAc) providing an additional 142 mg (40%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][N:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=3[F:34])=[CH:15][N:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc(F)cc2)CCN(C(C)c2ccc(Br)cn2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CCC1(c2ccc(F)cc2)CCN(C(C)c2ccc(-c3ccc(F)cc3F)cn2)C(=O)O1
Yield: 46 %

Procedure:
A solution of 6-allyl-3-(1-(5-bromopyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.24 mmol), 2,4-difluorophenylboronic acid (56.9 mg, 0.36 mmol), PdCl2(PPh3)2 (10 mg, 10%) and aqueous solution of Cs2CO3 (2 M, 0.2 mL) in 1,4-dioxane (3 mL) was heated to reflux overnight. After the solvents were evaporated, the crude product was purified by preparative TLC to give 6-allyl-3-(1-(5-(2,4-difluorophenyl)pyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 46%). LC-MS Method 3, tR=1.336 min, m/z=453.1. 1H NMR (CDCl3): 2.30-2.40 (m, 1H), 2.39-2.42 (d, 3H), 2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 4.10-4.20 (m, 1H), 4.50-4.65 (m, 2H), 5.55-5.70 (m, 2H), 6.40-6.50 (d, 1H), 6.80-7.00 (m, 4H), 7.10-7.15 (m, 1H), 7.22-7.30 (m, 2H), 7.30-7.40 (m, 3H).
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=O)[CH2:4][C:5]([CH3:7])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=C(F)[C:14]=1[F:23]>C1COCC1>[C:5]([CH2:4][C:3]1[C:14]([F:23])=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])(=[O:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed with pentane) in THF (100 ml) cooled at 101C was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping the temperature below 15C. After completion of addition, the mixture was further stirred for 15 minutes and cooled to 5° C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g, 113 mmol) in THF (150 ml) was added while keeping the temperature below 5C. The mixture was then left to warm up to ambient temperature and stirred for 24 hours. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was dissolved in concentrated hydrochloric acid (650 ml) and acetic acid (600 ml) and the mixture was refluxed for 15 hours. After cooling, the volatiles were removed under vacuum and the residue was partitioned between aqueous sodium hydrogen carbonate (5%) and ethyl acetate. The organic layer was washed with sodium hydrogen carbonate, water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (75/25) to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).