Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2ccc(S)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(SCC(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 4.30 g of 4′-methoxy-biphenyl-4-thiol and 3.34 g of ethyl 2-bromo-acetate in 10 ml of ethanol was added over 5 min a solution of 1.12 g of potassium hydroxide in 20 ml of ethanol. The reaction mixture was stirred at 20° for 4 h and then, 1.68 g of potassium hydroxide and 3 ml of water were added and stirring was continued for 15 h at 20°. The mixture was poured onto 150 ml of ice/water and the pH of the mixture set to 2 by the addition of 3N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give 4.21 g of 2-(4′-methoxy-biphenyl-4-ylsulfanyl)-acetic acid as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13](O)=[O:14].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:18]([O:17][C:11](=[O:16])[CH2:12][C:13]([NH:10][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])=[O:14])[CH3:19]
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a magnetically stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.51 g, 2.55 mmol) in anhydrous CH2Cl2 under argon and cooled to 0° C., were added ethyl hydrogen malonate (0.4 g, 3.06 mmol) EDC.HCl (0.58 g, 3.06 mmol) and HOBt (0.41 g, 3.06 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and residue partitioned between EtOAC and 1 N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (40% EtOAc in hexanes) to provide the desired product (0.57 g, 71%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.CCOC(C)=O.[CH3:33][NH:34][CH3:35]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])[CH2:10][N:34]([CH3:35])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cccc(Cl)c1F
Reactant: CNC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
A solution of methanesulfonic acid (S)-2-tert-butoxycarbonylamino-2-(3-chloro-2-fluoro-phenyl)-ethyl ester (690 mg, 1.88 mmol) in 33% dimethylamine in EtOH (5.6 M, 7.5 mL, 42 mmol) was heated at 80° C. for 2 h in a sealed tube. The reaction mixture was concentrated and the crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give a pale yellow oil. TLC, Rf (EtOAc): 0.60; MS (UPLC/MS): 317.3/319.3 [M+H]+; tR (HPLC conditions a): 3.19 min.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[Br:17][C:18]1[CH:19]=[C:20]([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C

Procedure:
Dibenzo[b,d]thiophen-4-yl-boronic acid (10.00 g, 43.8 mmol), 1,3-dibromobenzene (20.69 g, 88 mmol) and Pd(PPh3)4 catalyst (0.507 g, 0.438 mmol) were dissolved in 200 mL of toluene, and potassium carbonate (18.18 g, 132 mmol) in 50 mL of water was added, and the mixture was refluxed overnight under N2. The mixture was cooled to room temperature, and the organic layer was separated, filtered and evaporated. The residue after evaporation was purified by column chromatography on silica gel (eluted with hexane/DCM 95/5 v/v mixture), followed by recrystallization from hexane. 4-(3-bromophenyl)dibenzo[b,d]thiophene was obtained as white solid (12 g, 81% yield).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[O:8]([C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:15])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc(Oc2ccccc2)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=c1cc(Oc2ccccc2)cn[nH]1
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-phenoxy-2H-pyridazin-3-one (1.76 g, 7.90 mmol), water (29.6 mL), and a 2N aqueous sodium hydroxide solution (4.26 mL) was treated with 10% palladium on carbon (174 mg, 10% weight of 4-chloro-5-phenoxy-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 24 h. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL), filtered through a pad of diatomaceous earth, and rinsed. The layers were separated, and the organics were concentrated in vacuo. The aqueous layer was then acidified to pH 1-2 with a 2N aqueous hydrochloric acid solution. The resulting mixture was extracted with 90/10 methylene chloride/methanol (3×100 mL). These organics were combined, dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo to afford 5-phenoxy-2H-pyridazin-3-one (1.44 g, 96%) as a white solid; ES+-HRMS m/e calcd for C10H8N2O2 [M+H+] 189.0659, found 189.0658.
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([CH:35]3[CH2:37][CH2:36]3)[O:33][CH:34]=2)=[CH:26][CH:25]=1)[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].C(N(CC)CC)C.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](Cl)=O>C1(C)C=CC=CC=1>[CH:35]1([C:32]2[O:33][CH:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:5]([C:2]4[N:1]=[C:50]([C:49]5[CH:53]=[CH:54][CH:55]=[C:47]([C:46]([F:45])([F:56])[F:57])[CH:48]=5)[O:4][N:3]=4)[CH2:6][CH2:7][C:8]4[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=4)=[CH:29][CH:28]=3)[N:31]=2)[CH2:36][CH2:37]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)/C(N)=N/O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a cooled solution of ethyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.108 g, 0.21 mmol) in toluene (2 ml) was added triethylamine (0.028 mL, 0.20 mmol) dropwise. After 5 min, 3-(trifluoromethyl)benzoyl chloride (0.031 ml, 0.20 mmol) in toluene (0.1 ml) was added dropwise. The mixture was allowed to warm to rt over 2 h and then heated to 110C for 2 hr. Upon cooling, the mixture was filtered, and the solid was washed with EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc and a solution of 0.5N aqueous HCl. The organic phase was washed with 0.5N aqueous HCl (1×), 0.5N aqueous NaOH (2×), and brine (1×), dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexanes, 10:90 to 20:80) to yield ethyl 2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate (76 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[C:10]1[N:14]([CH2:15][CH2:16][CH2:17][OH:18])[C:13]2[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:21]([F:23])=[CH:22][C:12]=2[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:20]=[C:21]([F:23])[CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17][O:18]1
Reactant: CCN(CC)c1cc(F)cc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)c1cc(F)cc2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Reaction time: 90 h
Yield: 23.8 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-5-fluoro-1H-benzimidazol-1-yl}propan-1-ol (Reference example 212, 44.0 mg, 0.100 mmol) and triphenylphosphine (26.2 mg, 0.100 mmol) in tetrahydrofuran (2 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 68.3 μL, 0.150 mmol) at room temperature. After 90 h, the reaction mixture was concentrated in vacuo, and purified by column chromatography on NH silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give colorless oil (10.1 mg, 0.0238 mmol, 24%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl>[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:7]2[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: O=C1c2ccccc2NCc2cccn21
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3C(=O)c3ccccc32)cc1
Reaction time: 6 h

Procedure:
To a stirred solution of 107 mg of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one in 3 ml of methylene chloride containing 0.084 ml of triethylamine is added 165 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride and stirring continued for 6 hours. The volatiles are removed in vacuo to a residue which is purified on thick layer chromatography plates with 7:3 hexane-ethyl acetate to afford the desired product as a foam.
Reaction SMILES: CN[C@H](CC=CC1C(O)=NC(O)=NC=1)C.[CH3:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]([CH2:20][CH:21]=[CH2:22])[CH3:19].[CH3:30][O:31][CH:32]1[N:37](I)[C:36]([O:39][CH3:40])=[CH:35][CH:34]=[N:33]1>[Pd]>[CH3:16][N:17]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:18]([CH2:20][CH:21]=[CH:22][C:35]1[C:36]([O:39][CH3:40])=[N:37][C:32]([O:31][CH3:30])=[N:33][CH:34]=1)[CH3:19]
Reactant: COC1=CC=NC(OC)N1I
Reactant: C=CC[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CN[C@@H](C)CC=Cc1cnc(O)nc1O
Product: COc1ncc(C=CC[C@H](C)N(C)C(=O)OC(C)(C)C)c(OC)n1

Procedure:
Scheme I shows the synthesis of (S)-N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine. In this synthesis, the previously described (S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is subjected to Heck-type coupling conditions by reaction with a 2,4-dimethoxy-3-iodopyrimidine in the presence of a palladium catalyst to form (S)-N-methyl-N-(tert-butoxycarbonyl)-5-(2,4-dimethoxy-5-pyrimidinyl)-4-penten-2-amine. The methoxy groups can be converted to hydroxy groups, concurrent with the cleavage of the amine protecting group, by reaction with trimethylsilyl iodide in methanol/dichloromethane to yield the desired N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine compound as a hydroiodide salt. Alternately, the tert-butoxycarbonyl protecting group can be selectively removed by trifluoroacetic acid, as described previously, to give the (S)-N-methyl-5-(2,4-dimethoxy-5-pyrimidinyl)-4-penten-2-amine. Cleavage of the methyl ethers using 48% HBr then provides (S)-N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.Cl>C1COCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Br:12]
Reactant: OCc1ccccc1Br
Reactant: BrCc1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1COCc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
Solution of 2-bromobenzylalcohol (3.8 g) in THF (10 ml) was delivered by drops over 15 minutes to suspension of sodium hydride (0.88 g; 60% in oil) in THF (30 ml) cooled to −0° C. in argon atmosphere, and the reaction mixture was further stirred for 20 minutes. Solution of 2-bromobenzyl bromide (6.0 g) in THF (10 ml) was added thereto and the reaction solution was stirred for one hour at room temperature. The reaction mixture was poured to water and neutralized with 1N hydrochloric acid and extracted with hexane. The organic layer was dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=1:0 to 100:1 to 10:1) to obtain the title compound (5.77 g) having the following physical data.
Reaction SMILES: FC1C=C(F)C=CC=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=[C:12]([CH3:33])[CH:11]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.CC1C=C(N)C=CC=1C>>[CH3:33][C:12]1[CH:11]=[C:10]([NH:9][C:35]2[CH:40]=[CH:39][C:38]([C:41]([C:43]3[CH:48]=[C:47]([N:49]4[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]4)[CH:46]=[CH:45][C:44]=3[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1ccc(N)cc1C
Product: Cc1ccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(C)c2)cc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3,4-dimethyl-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.0, 148.9, 145.7, 142.7, 142.3, 138.4, 137.1, 135.5, 135.1, 134.4, 132.0, 130.5, 130.2, 125.4, 121.9, 120.7, 120.2, 118.2, 118.0, 117.0, 110.4, 60.2, 29.2, 22.2, 19.5, 18.8, 18.7
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][CH2:18][CH2:19]O)[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[CH2:5][CH2:4][S:3]1.[N+:21]([C:24]1C=[CH:28][C:27](S([O-])(=O)=O)=[CH:26][CH:25]=1)([O-])=O.N1CCCCC1>C1COCC1>[CH3:1][C:2]1([CH2:16][O:17][CH2:18][CH2:19][N:21]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[CH2:5][CH2:4][S:3]1
Reactant: COc1cc2c(cc1OC)C(C)(COCCO)SCC2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(C)(COCCN1CCCCC1)SCC2

Procedure:
A mixture of 2-[[1-methyl-6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-1-yl]methoxy]ethanol-4-nitrobenzenesulfonate and piperidine is stirred at room temperature in THF. The mixture is then partitioned between methylene chloride and aqueous sodium carbonate. The title compound is isolated by chromatography and is crystallized.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([B:23]3[NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:32]5[CH:33]=[CH:34][CH:35]=[C:25]([C:26]=45)[NH:24]3)=[CH:19][CH:18]=2)O1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:24]1[C:25]2=[CH:35][CH:34]=[CH:33][C:32]3=[CH:31][CH:30]=[CH:29][C:27](=[C:26]23)[NH:28][B:23]1[C:20]1[CH:19]=[CH:18][C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(B3Nc4cccc5cccc(c45)N3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(B2Nc3cccc4cccc(c34)N2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (57.7 mg) was added to a suspension of 3-bromopyridin-2-amine (432 mg), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (1016 mg) and sodium carbonate decahydrate (1429 mg) in DME (10 mL) and water (2 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr and at 70° C. overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (397 mg) as a brown solid.
Reaction SMILES: ClCCl.[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[O:17])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][N:20]=[C:21]=[O:22]>O>[CH3:19][NH:20][C:21](=[O:22])[NH:18][C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: NC(=O)N1CCN(c2ccccc2)CC1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: O
Product: CNC(=O)NC(=O)N1CCN(c2ccccc2)CC1
Yield: 51.5 %

Procedure:
Into 70 ml of dichloromethane, were dissolved 4.1 g of 4-phenylpiperazine-1-carboxamide and 1.2 g of methyl isocyanate. To the solution, while being stirred and cooled in ice, was added dropwise 5.2 g of stannic chloride. After 15 hours of reaction at room temperature, water was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate and freed from the solvent by distillation. The residue was recrystallized from ethanol to obtain 2.7 g (51% yield) of 1-(4-methylallophanoyl)-4-phenylpiperazine having a melting point of 198°-200° C.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH2:16][CH:17]4[CH2:19][CH2:18]4)[N:14]=[N:15][C:11]=3[C:10]=2[Cl:22])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30].O>O1CCCC1>[Cl:22][C:10]1[C:11]2[N:15]=[N:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:12]=2[CH:20]=[CH:21][C:9]=1[O:8][C:3]1[C:2]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Clc1c(Oc2ncccc2Br)ccc2c1nnn2CC1CC1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
5-[(3-Bromopyridin-2-yl)oxy]-4-chloro-1-(cyclopropylmethyl)-1H-benzotriazole (395, 33 mg, 0.09 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (2 mL), cooled to −70° C. and treated dropwise with n-butyllithium (2.5 M in tetrahydrofuran, 0.038 mL, 0.10 mmol, 1.1 equiv.). After 5 minutes, the mixture was treated with acetone (7.57 mg, 0.13 mmol, 1.5 equiv.). After an additional ten minutes at −70° C., the mixture was treated with water. The mixture was poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC (80:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (saturated aqueous, 20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound 396 as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.10 (dd, 1H, J=7.6, 1.9 Hz), 7.97 (d, 1H, J=8.9 Hz), 7.88 (dd, 1H, J=4.8, 1.8 Hz), 7.44 (d, 1H, J=9.2 Hz), 7.14 (dd, 1H, J=7.4, 4.6 Hz), 4.66 (d, 2H, J=7.5 Hz), 1.68 (s, 6H), 1.45-1.38 (m, 1H), 0.60-0.57 (m, 2H), 0.52-0.49 (m, 2H) ppm. High resolution mass spectrometry (ES+) m/z 359.1277 [(M+H)+; calculated for C18H20ClN4O2: 359.1269].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:48][CH2:49][C:50]([OH:52])=[O:51]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([S:48][CH2:49][C:50]([OH:52])=[O:51])=[O:9])=[CH:5][C:4]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1OS(C)(=O)=O
Reactant: O=C(O)CS
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)SCC(=O)O)cc1OS(C)(=O)=O
Temperature: 50 °C
Yield: 32.3 %

Procedure:
To a solution of 4-methoxy-3-(methylsulfonyloxy)benzoic acid (prepared in an analogous manner to that described in Scheme 23, Step 2 and 3) (0.362 g, 1.470 mmol) in dry DMF (10.7 ml), HATU (0.559 g, 1.470 mmol) and N-methylmorpholine (0.162 ml, 1.470 mmol) were added. The resulting mixture was stirred at 50° C. under nitrogen until complete conversion of the starting acid into the activated specie (detected by UPLC-MS). Then the solution was allowed to warm to RT and 2-mercaptoacetic acid (0.102 ml, 1.470 mmol) was added drop wise; the resulting mixture was stirred overnight at RT. The solvent was removed under vacuum and the residue was partitioned between EtOAc and HCl 1N; the organic phase was dried over Na2SO4 and the solvent was removed. The crude was purified by preparative HPLC to afford 2-(4-methoxy-3-(methylsulfonyloxy)-benzoylthio)acetic acid (0.152 g, 0.474 mmol, 32.3% yield, MS/ESI+ 342.9 [MNa]+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]([C:26]2[CH:27]=[C:22]([Cl:21])[N:23]=[CH:24][N:25]=2)[C:2]1=[O:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (130 mg, 0.52 mmol, described in Intermediate 7) in DMF (0.7 mL) was added sodium hydride (15 mg of a 60% dispersion in mineral oil, 0.38 mmol). The mixture was stirred for 5 min, then 4,6-dichloropyrimidine (234 mg, 1.57 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 140° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl3 (10 mL) and saturated aqueous NaHCO3 (5 mL). The aqueous phase was extracted further with CHCd3 (10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 75:25, to give the title compound. MS: m/z=361 (M+1).