Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCCCCCC[CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH:45]1CCN[CH2:47][CH2:46]1>>[CH3:44][O:43][C:39]1[CH:38]=[C:37]([NH:36][C:25]2[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=[C:22]([S:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([N:10]5[CH2:47][CH2:46][NH:45][CH2:8][CH2:9]5)=[O:12])[CH:14]=4)(=[O:21])=[O:20])[CH:23]=3)[N:28]=[CH:27][C:26]=2[C:33]([NH2:35])=[O:34])[CH:42]=[CH:41][CH:40]=1
Reactant: C1CNCCN1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCNCC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using piperazine in place of 8-aminooctanol. ES/MS calcd. for C29H30N5O5S+ 560.2. Found m/z=560.2 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([O:12][C:13](OCC)=[CH2:14])[CH3:11].CCO>[O-]CC.[Na+].CCOC(C)=O>[C:3]([C:2](=[C:10]([O:12][CH2:13][CH3:14])[CH3:11])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=C(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(C)=O)=C(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A 5 L 4-neck flask equipped with a mechanical stirrer, condenser, thermowell, addition funnel and N2 inlet was charged with ethyl acetoacetate (493.1 g, 483 mL, 3.7931 mol, 1.0 equiv) and sodium ethoxide (3.1 g, 0.046 mol, 1.2 mol %). Ketene diethylacetal (880.0 g, 1000 mL, 7.5862 mol, 2.0 equiv) was added over 1 hr maintaining the reaction temperature at <22° C. by external cooling. When addition was complete, the reaction mixture was heated at 85° C.±5° C. for 7.5 hr. The yellow brown reaction mixture was cooled to room temperature and stirred overnight. Much of the lower boiling components [EtOH, EtOAc, Me(OEt)3] were stripped on a roto-evaporator (bath temperature ˜65° C.). The residual yellow-orange oil was distilled, collecting the fraction with by 100-107° C. (1.8-2.1 Torr) to give 675.2 g (89%) of product as a yellow liquid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2>C(Cl)(Cl)(Cl)Cl>[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:15][C:7]1=2
Reactant: CC1(C)OB(O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To 100% fuming nitric acid (10 mL) at −40° C. was added dropwise a solution of 3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVI) (1.37 g, 0.0085 mol) in carbon tetrachloride (40 mL), maintaining the temperature below −40° C. Stirring was continued for 20 min at −40° C. The yellow solution was poured onto ice and was stirred for 10 min at room temperature. The mixture was extracted with EtOAc. To the organic layer was added 1M aqueous NaOH to pH=7. The organic layer was separated, and washed with water, dried over MgSO4 and filtered, and the solvent was removed in vacuo to give an orange viscous oil. The oily residue was triturated with hexane to give pure 3,3-dimethyl-6-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (XCVII) as a yellow solid (1.20 g, 5.8 mmol, yield 68%). 1H NMR (CDCl3) δ ppm 1.61 (s, 6H), 7.42 (s, 1H), 8.35 (d, J=8 Hz, 1H), 8.56 (d, J=8 Hz. 1H). ESIMS found for C9H10BNO4 m/z 206.3 (M−H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.C(O)(=O)C>C(O)C.[Pt]=O>[CH:1]1([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C1CCC(C2CCCCC2)CC1
Yield: 99.9 %

Procedure:
A solution of biphenyl-4-carboxylic acid (9.9 g, 50 mmol) in 500 ml of ethanol and 150 ml of glacial acetic acid containing 1.0 g of platinum oxide was hydrogenated overnight at 40 psi. Upon filtering the solution and concentrating the filtrate under reduced pressure, 10.5 g of bicyclohexyl-4-carboxylic acid was obtained as a white solid (m.p. 122°-125° C.).
Reaction SMILES: [O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C:18]2=[O:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123.C(O)C.[BH4-].[Na+].Cl>O>[O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C@@H:18]2[OH:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 0.105 g (0.237 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3one and 6 ml of ethanol was added 9 mg (0.237 mmole) of sodium borohydride at a temperature of 0° C. and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture were added water and 1N-hydrochloric acid in the order mentioned and the mixture was extracted with methylene chloride. The aqueous layer was further extracted with methylene chloride and the extract was pooled with the previous methylene chloride extract. The mixture was washed successively with cold saturated sodium hydrogen carbonate solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 0.084 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-ol (yield: 80%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[CH3:19][C:20]([O-])=[O:21].[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][C:20](=[O:21])[CH3:19])[CH:2]=[CH2:3]
Reactant: CC(=O)[O-]
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C=CCc1cc(OCc2ccccc2)ccc1OC(C)=O
Temperature: 80 °C
Yield: 650 %

Procedure:
2-Allyl-4-benzyloxy-phenol (2.87 g, 12 mmol) was taken up in acetic anhydride (40 ml) and NaOAc (150 mg, 1.8 mmol) was added and the mixture heated 18 hr at 80° C. After cooling, the reaction mixture was evaporated to afford an oil which was partitioned between EtOAc and H2O (100 ml) and the aqueous phase was extracted with EtOAc (100 ml) and the combined organic phases were dried with MgSO4, filtered and evaporated to afford acetic acid-2-allyl-4-benzyloxy-phenyl ester as a pale yellow oil (3.30 g, 11.7 mmol, 97%), MS: m/e=282.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:20])=[CH:18][CH:17]=1)=[O:32]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2CCCCc3sc(Cl)cc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sc(Cl)cc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath) solution of 0.245 g 15 (0.8 mmol) of 2-chloro-4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 167 μl (1.2 mmol) of triethylamine in 5 ml of dichloromethane is added 140 μl (1 mmol) of 2,4-dichlorobenzoyl chloride. The solution is stirred under argon at room temperature overnight and diluted with 60 ml of dichloromethane. The mixture is washed with 20 ml each of 2N-citric acid, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue crystallized from ethyl acetate-hexane to give 0.315 g of white crystals, m.p. 187°-189° C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>CO.O>[CH:14]([C:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1)=[O:23]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCOC(=O)CNc1ccc(C)cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)CNc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
To a solution of ethyl 2-(p-tolylamino)acetate (1.69 mmol) in methanol/water (20 ml/20 ml) was added the 2,3 dichloro-5,6-dicyanobenzoquinone (2.87 mmol) and the mixture was stirred for 4 hours at room temperature. The residue was chromatographed on a silica gel column (dichloromethane/ethyl acetate 8/2 as eluent) to give 88 mg of ethyl 2-(4-formylphenylamino)acetate. (yield 25%). MS (ESI): m/z 208.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CN(C=O)C.O>[CH2:17]([N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)[CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 153.2 %

Procedure:
A solution of 4-aminophenylacetonitrile (20 g, 151.3 mmol) in dry DMF (150 ml) was treated with potassium carbonate (50.1 g, 363.1 mmol), benzyl bromide (54.4 g, 318 mmol), and potassium iodide (5 g, 0.2 30.3 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (100 ml) was added to the mixture and the organic was extracted with ether (3×200 ml). The combined organic fraction was washed with brine (200 ml), dried over sodium sulfate and concentrated. The crude product was further purified by flash chromatography (SiO2, 20% EtOAc: Hexanes) to give 36.2 g (76%) of the pure product. NMR was consistent with the proposed title structure. Field Desorption
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)[O:8][C:9](=O)[C:4]=2[CH:3]=1.[CH3:14][NH2:15]>C(O)C>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([OH:1])=[CH:3][C:4]=1[C:9]([NH:15][CH3:14])=[O:8]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1cc(O)ccc1N
Reaction time: 72 h
Yield: 60.2 %

Procedure:
A solution of 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.79 mmol) in ethanol (20 mL) was cooled to 0° C. and methylamine solution (33% in ethanol, 2.92 mL, 27.9 mmol) added and the reaction stirred for 3 days. The solvent was removed under reduced pressure and the product purified by silica chromatography, eluent 5% methanol in dichloromethane to yield 2-amino-5-hydroxy-N-methylbenzamide (280 mg, 1.68 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:19])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:19])[C:4]=1[F:20])=[O:28]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1ccc(Oc2c(Cl)ccc(CN)c2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3ccc(C#N)cc3F)c2F)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
To a solution of 4-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile (40.0 mg, 0.136 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (21.79 mg, 0.136 mmol) and HATU (51.6 mg, 0.136 mmol) in DMF (3 ml) was added diisopropylethyl amine (0.047 ml, 0.271 mmol) and the reaction mixture was stirred at rt for 15 minutes. The reaction mixture was purified via reverse phase HPLC and neutralized to give 4-chloro-N-({4-chloro-3-[(4-cyano-2-fluorophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (13 mg, 0.030 mmol, 22% yield) 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (d, 1H), 7.47 (d, 1H), 7.29-7.42 (m, 2H), 6.87 (t, 1H), 4.52-4.73 (m, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 437.11, [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[C:15]=1[O:24]C.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[C:15]=1[OH:24]
Reactant: COc1ccc(C(=O)Nc2cccc3cc(Br)cnc23)c(OC)c1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cccc2cc(Br)cnc12)c1ccc(O)c(O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 3-bromo-8-(2,3,4-trimethoxybenzoylamino)quinoline (700 mg) in dichloromethane (10 ml) was added 1M solution of boron tribromide in dichloromethane (5.5 ml) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. To the mixture was added ice-water, and the mixture was stirred for 1.5 hours. The mixture was adjusted to pH 4 with IN sodium hydroxide solution, and ethyl acetate was added thereto. The mixture was stirred at ambient temperature overnight, and the insoluble material was filtered off. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (methanol-dichloromethane) to give 3-bromo-8-(2,3,4-trihydroxybenzoylamino)quinoline (110 mg).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>C1COCC1>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccccc1CBr
Reactant: N#CC1CCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1CC1(C#N)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (0.018 mol, 7.2 ml, 2.5M) was added to a solution of diisopropylamine (1.7 g, 0.017 mol) in THF (15 mL) at −78° C. After 5 minutes neat cyclobutancarbonitrile (1.2 g, 0.015 mol) was added and the mixture was stirred at −78° C. for 1 hour. Then a solution of 1-(bromomethyl)-2-methylbenzene (3.3 g, 0.018 mol) in THF (3 mL) was added and the mixture was stirred at −78° C. for 1 hour. The mixture was quenched with water and extracted with EtOAc. The organic phase was concentrated and the residue was directly used to the next step without further purification. MS: m/z 186 (M+H)
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[CH:7]=1>C(O)(=O)C>[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[C:7]=1[N:1]=[O:3]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
157.6 ml of 4N sodium nitrite was added over 45 minutes to a suspension of 165 g of 6-amino-1-(4-chlorobenzyl)-uracil in 825 ml of acetic acid at 65-70° C. After a further 15 minutes at 70° C. the reaction mixture was cooled to room temperature, the pink solid collected and washed with 80% acetic acid and water to give the title compound (150.9 g) mp >320° C.
Reaction SMILES: C([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])C1C=CC=CC=1.C(O)C>[Pd].O1CCCC1>[OH:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A mixture of 9-benzyloxy-6-phthalimidopurine (11.0 g, 29.5 mmol), 10% palladium on charcoal (2.2 g), ethanol (300 ml) and tetrahydrofuran (500 ml) was stirred at 25° C. for 1 hour under an atmosphere of hydrogen. The suspension was then filtered and the catalyst washed with ethanol. The filtrate was evaporated under reduced pressure and the resulting solid triturated with ether. The solid was collected and then dried to afford the title compound (6.93 g; 83%). IR: νmax (KBr). 2607, 1794, 1735, 1603, 1582, 1467, 1401 cm-1 ; 1H NMR δH [(CD3)2SO] 8.15(4H, s, Ar), 8.95(1H, s, H-2), 9.15(1H, s, H-8), 12.80(1H, br.s, D2O exchangeable, OH). Found: C, 55.34; H, 2.58; N, 24.56%. C13H7N5O3 requires: C, 55.51; H, 2.51; N, 24.91%.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([N:36]4[CH:40]=[CH:39][CH:38]=[N:37]4)[CH:33]=[CH:32][C:24]=3[C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([N:36]4[CH:40]=[CH:39][CH:38]=[N:37]4)[CH:33]=[CH:32][C:24]=3[C:25]([OH:27])=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2cccn2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-n2cccn2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrazol-1-yl)benzoate (68 mg), followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and methanol was added to the obtained residue. The solid substance was collected by filtration to obtain 53 mg of 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrazol-1-yl)benzoic acid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:48])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[C:23]([F:46])[C:22]=2[F:47])=[CH:14][C:13]=1[C:49]([F:52])([F:51])[F:50])C1C=CC=CC=1>CO.[Pd]>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([C:49]([F:52])([F:50])[F:51])[CH:14]=3)=[O:48])=[C:22]([F:47])[C:23]=2[F:46])[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2F)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCO)c(C(F)(F)F)c3)c(F)c2F)c[nH]c1=O
Yield: 44.2 %

Procedure:
To a solution of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide (10 mg, 0.014 mmol) in MeOH (3 mL) stirred under N2 at 20° C. was added Pd/C (0.147 mg, 1.384 μmol) in one charge. The solution was stirred under a H2 atmosphere. The reaction mixture was stirred at 10° C. for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a light yellow solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,3-difluorophenyl)-N-(4-(2-hydroxy ethoxy)-3-(trifluoromethyl)phenyl)acetamide (3.17 mg, 6.19 μmol, 44.7% yield). TLC (DCM/MeOH=5:1, Rf=0.4): 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J=2.4 Hz, 1H), 7.75 (dd, J=2.2, 8.8 Hz, 1H), 7.37-7.12 (m, 5H), 4.20-4.07 (m, 4H), 3.90 (t, J=5.0 Hz, 2H), 3.85 (s, 2H), 1.48 (t, J=7.0 Hz, 3H); ES-LCMS m/z 513.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cc(C)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Cl)c(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (50 mg, 0.088 mmol) in 4N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography to afford 4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzene sulfonamide (29.5 mg) in 64% yield. ESMS m/z (relative intensity): 522.9 (M+H)+ (30), 544.9 (M+Na)+ (50).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[CH3:9][N:10]([CH3:14])[C:11](=O)[CH3:12].[Br:15][C:16]1[CH:17]=[C:18]([C:22]2C=C([CH:26]=[CH:27][CH:28]=2)N)[CH:19]=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:12]=[C:11]([CH:26]=[CH:27][CH:28]=2)[N:10]([CH3:14])[CH3:9])[CH:19]=[N:20][CH:21]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1cccc(-c2cncc(Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN(C)c1cccc(-c2cncc(Br)c2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (83 mg) and methyl iodide (62 W) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at 80° C. for 4 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and a white solid of 3-(5-bromopyridin-3-yl)-N,N-dimethylaniline (7.1 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1nc(N)sc1C
Product: COC(=O)Cc1nc(NS(=O)(=O)c2ccc(Cl)cc2)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 4-chlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (29.2 mg) with purity >90%. LCMS (pos) m/z 361.2.