Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:32])[NH:6][C@@H:7]1[CH2:31][C:10]2[N:11]([CH2:20][C:21]3[C:26]([O:27]CC=C)=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O1CCOCC1.C(N(CC)CC)C.C(O)=O>CN1C(=O)CCC1.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.O>[CH:1]([O:4][C:5](=[O:32])[NH:6][C@@H:7]1[CH2:31][C:10]2[N:11]([CH2:20][C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: C=CCOc1cccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ncccc3O)c3ccc(C#N)cc23)C1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
[(S)-4-(3-Allyloxy-pyridin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (40 g, 87.3 mmol) and 1,4-dioxane (400 mL) are combined and the mixture degassed by bubbling in nitrogen for one hour. Then triethylamine (24.4 mL, 174.7 mmol) and formic acid (6.60 mL, 174.7) are added and the mixture heated under nitrogen at 80° C. Tetrakis(triphenylphosphine)palladium (1.02 g, 0.87 mmol) is added while maintaining the nitrogen atmosphere. The reaction is heated at 80° C. for 3 h and then cooled to room temperature. The reaction is filtered through a pad of diatomaceous earth. The filtrate is evaporated and the crude material dried under vacuum to afford a brown solid. The solid is dissolved in NMP (100 mL) and then added to water (1.2 L). A pale cream solid is collected by filtration and dried overnight under vacuum to afford 41 g of crude material. The material is purified by recrystallization from acetonitrile and then dried under vacuum to constant weight to afford the title compound (29.5 g, 86%). LC-ES/MS m/z: 391.1 [M+H]+.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O[C@@H](CCN4C=C(B5OC(C)(C)C(C)(C)O5)C=N4)C)OCC)=CC=3OC)N=2)=CC=1.[Br:57][C:58]1[N:63]=[C:62]([C:64](=[O:67])[NH:65][CH3:66])[C:61]([NH:68][C:69]2[C:74]([C:75]([F:78])([F:77])[F:76])=[CH:73][N:72]=[C:71]([NH:79][C:80]3[CH:91]=[CH:90][C:83]([CH2:84][CH2:85][CH2:86][PH:87](=[O:89])[OH:88])=[CH:82][C:81]=3[O:92][CH3:93])[N:70]=2)=[CH:60][CH:59]=1.[CH3:94][C:95]1([CH3:113])[C:99]([CH3:101])([CH3:100])[O:98][B:97]([C:102]2[CH:103]=[N:104][N:105]([CH2:107][C:108]3([CH2:111]O)[CH2:110][CH2:109]3)[CH:106]=2)[O:96]1>>[Br:57][C:58]1[N:63]=[C:62]([C:64](=[O:67])[NH:65][CH3:66])[C:61]([NH:68][C:69]2[C:74]([C:75]([F:78])([F:76])[F:77])=[CH:73][N:72]=[C:71]([NH:79][C:80]3[CH:91]=[CH:90][C:83]([CH2:84][CH2:85][CH2:86][PH:87](=[O:88])[O:89][CH2:111][C:108]4([CH2:107][N:105]5[CH:106]=[C:102]([B:97]6[O:96][C:95]([CH3:113])([CH3:94])[C:99]([CH3:101])([CH3:100])[O:98]6)[CH:103]=[N:104]5)[CH2:110][CH2:109]4)=[CH:82][C:81]=3[O:92][CH3:93])[N:70]=2)=[CH:60][CH:59]=1
Reactant: CC1(C)OB(c2cnn(CC3(CO)CC3)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)O[C@H](C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)OCC3(Cn4cc(B5OC(C)(C)C(C)(C)O5)cn4)CC3)cc2OC)ncc1C(F)(F)F
Yield: 43.8 %

Procedure:
Racemic Compound 71A was prepared analogously to Compound 69A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinic acid (Compound 67B, 206 mg, 0.341 mmol) and (1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropyl)methanol (Compound 63B, 400 mg, 2 mmol) to afford 129 mg of the title compound (48%). MS (ESI): m/z=879.92/881.81 [M+H]+. UPLC: tR=1.61 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:39]1([O:45]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl.C(#N)C>[F:30][C:28]([F:31])([F:29])[C:25]1[CH:26]=[CH:27][C:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]4[NH:32][C:39](=[O:45])[O:1][N:2]=4)=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:14][CH2:15]3)=[CH:23][CH:24]=1
Reactant: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)cc2)no1
Temperature: 25 °C

Procedure:
550 mg N-hydroxy-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine were dissolved in 10 ml dichloromethane. 0.17 ml pyridine and 0018 ml phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 20 ml acetonitrile and 0.89 ml 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 330 mg 3-{4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:6][C:7]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:8]([C:10]2[N:11]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[C:12]([NH:15][C:16]3[CH:21]=CC=CC=3)=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].CN(C)C=[O:51].C(C1NC=CN=1)(=O)C>C(OCC)(=O)C>[CH2:33]([O:32][C:7]1[CH:6]=[C:5]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][C:8]=1[C:10]1[N:11]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[CH:26]=[CH:25]3)[C:12]([NH:15][C:16](=[O:51])[CH3:21])=[N:13][N:14]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)c1cc(-c2nnc(Nc3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nnc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)n1-c1ccc2c(ccn2C)c1
Temperature: 75 °C

Procedure:
A flask was charged with [5-(5-Isopropyl-2,4-dibenzyloxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (0.25 mmol, 136 mg.), dimethylformamide (2 mL), and acetylimidazole (2 eq., 90 mg.), and the reaction was heated at 75° C. for 16 hours. The solution was diluted with ethyl acetate (20 mL) and washed with water (3×10 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide.
Reaction SMILES: [CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].CS(O)(=O)=O.[Cl-].[Cl-].[Zn+2:47]>N[C@H](C(O)=O)CC1N=CNC=1>[Zn:47].[CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3]
Reactant: [Zn+2]
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Agent: CS(=O)(=O)O
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: [Zn]

Procedure:
10 mM solution of Desferal (Ciba-Geigy, Basle) is mixed with an equal volume of 12.5 mM of ZnCl2 (A. R. Aldrich Chemical Co., Inc.) solution, with 10 ml of 5.5 mM Histidine, titrated to pH 7.4. The mixture is heated for 30 min. to 45° C., and cooled and the complex Zn/Desferrioxamine B is formed, the ratio Zn:Desferal is 1.25:1.0
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](Cl)=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26].CC(C)([O-])C.[Na+].C(OCC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:24]=3[F:23])=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: Cc1c(Cl)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc([N+](=O)[O-])cc2F)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Yield: 42.4 %

Procedure:
3-Benzyl-5-chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (7 g, 22.2 mmol, 1 eq), 2-fluoro-4-nitroaniline (53.8 mg, 24.4 mmol, 1.1 eq), tris(dibenzylideneacetone)dipalladium(0) (407 mg, 0.44 mmol, 0.02 eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (257 mg, 0.44 mmol, 0.02 eq) and sodium tert-butoxide (3.2 g, 0.33 mmol, 1.5 eq) were mixed in degassed anhydrous dioxane (50 mL) and subjected to microwave irradiation at 115° C. for 40 minutes. Upon cooling diethyl ether (50 mL) was added. A precipitate formed which was filtered and washed with ether to give 4.1 g of the title compound (42%). [M+H] calc'd for C22H18FN5O4, 436; found, 436.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.CC(C)(C)[C:27](OC(=O)C(C)(C)C)=[O:28]>C(Cl)(Cl)Cl>[CH:27]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([OH:15])[C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)=[O:28]
Reactant: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(O)c32)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C=O)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a suspension of 6,7-dimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (2.26 g, 6.86 mmole) in chloroform (60 ml) was added formic trimethylacetic anhydride (1.16 g, 8.91 mmole) at 0° C. The mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give intermediate 1 (2.23 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=O)=[O:11])[S:8][C:4]=2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1COCC1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:18])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CCCNC(=O)Nc1nc2ccc(Br)cc2s1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)CCCNC(=O)Nc2nc3ccc(Br)cc3s2)CC1
Yield: 58.7 %

Procedure:
Ethyl 4-([(6-bromo-1,3-benzothiazol-2-yl)amino]carbonylamino)butanoate (100 mg, 0.259 mmol) was heated neat at about 80° C. in N-methyl-piperazine (259 mg, 2.59 mmol) for about 8 hrs. To the crude reaction mixture was added THF (2 mL), the ppt was filtered off and washed with THF (1 mL). The product was dried in vacuo and gave 67 mg (53%) pure product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH:21](=[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])O1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.C1C=CC=CC=1.CCOC(C)=O.O>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30](=[O:31])[C:21]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: O=C1OC(=Cc2ccccc2)c2ccccc21
Reactant: CSc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)c3ccccc32)cc1
Reaction time: 0.33 h

Procedure:
To a solution of p-bromothioanisole (2.04 g, 10 mmol) in THF (40 mL) cooled to −78° C. was added a solution of n-butyl lithium in hexane (4.0 mL of 2.5 M, 10 mmol). The resulting suspension was stirred at this temperature for 20 min. Then a solution of benzalphthalide (2.11 g, 9.5 mmol) in benzene (20 mL) was added and the reaction was allowed to proceed at r.t. for 2 hrs. The reaction turned deep-red. The reaction was completed by addition of conc. H2SO4 (0.63 mL, 20 mmol) and stirred at r.t. for another 30 min. The reaction was then diluted with EtOAc and a 1:1 mixture of H2O and saturated aqueous NaHCO3 and extracted. The aqueous layer was extracted one more time with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography eluted with 10-15% EtOAc in hexane to give the title compound as an orange-red gum.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:22])[C:11]([C:13](=[S:21])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CCOCC>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([C:11]1[C:10]([OH:22])=[CH:9][C:8]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:12]=1)=[S:21]
Reactant: COC(=O)C1=Cc2cc(C(=S)c3ccccc3C)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccccc1C(=S)c1cc2c(cc1O)C(C(=O)O)=C2
Reaction time: 1 h

Procedure:
5.71 g of 4-(o-methylthiobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 70 ml of ether; 45 ml of 2N sodium hydroxide solution are added and stirring is carried out for 1 hour at room temperature. The aqueous phase is separated off and the ether phase is extracted by shaking twice with 25 ml of water each time. The aqueous phases are combined, acidified with 2N hydrochloric acid and extracted three times with 50 ml of dichloromethane each time. The extracts are combined, washed with water, dried over magnesium sulphate and concentrated by evaporation. After recrystallisation of the residue from dichloromethane/hexane, 4-(o-methylthiobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 177°-178°.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:27]3([OH:30])[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
0.69 ml of n-Butyl lithium (2.5M solution in hexane) was added dropwise to a stirred solution of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (429 mg; 1.44 mmol) in anhydrous THF (10 ml) at −78° C. under an atmosphere of nitrogen. The reaction was stirred for 50 minutes then 1-methyl-4-piperidone (212 μl; 1.2 equiv.) was added and stirred at −78° C. for a further 60 minutes then warmed to room temperature. The reaction was quenched with saturated ammonium chloride solution then extracted with EtOAc. The EtOAc layer washed with saturated NaHCO3, brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on SiO2, gradient elution from 0% to 10% 2M methanolic ammonia/DCM gave 111 mg of 5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:21]([O:22][CH2:23][CH:24]=[CH2:25])[C@@H:20]([O:26]C(=O)C)[C@@H:19]([CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[O:18][C@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.C(O)(=O)C>CO>[CH2:23]([O:22][C@H:21]1[C@@H:20]([OH:26])[C@@H:19]([CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[O:18][C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]1[OH:7])[CH:24]=[CH2:25]
Reactant: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OCC=C)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](O)[C@@H](OCC=C)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
Sodium methoxide (134 mg, 2.5 mmol) was added to a solution of Compound 10 (10.84 g, 24.9 mmol) in methanol (30 ml), and the mixture was stirred at room temperature under nitrogen gas atmosphere for 48 hours. The reaction mixture was neutralized with acetic acid, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 11 (6.8 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7]([OH:9])=O.[CH3:17][N:18]([CH3:34])[C:19](=[O:33])[C@H:20]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:21][C:22]([O:24]C)=[O:23].[N:35]#[S:36][Cl:37].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.CO>[N:35]#[S:36][Cl:37].[CH3:34][N:18]([CH3:17])[C:19](=[O:33])[C@H:20]([C:26]1[CH:27]=[CH:28][C:29]([O:9][CH2:7][C:6]2[S:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:3][C:2]=2[CH3:1])=[CH:30][CH:31]=1)[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)C[C@H](C(=O)N(C)C)c1ccc(O)cc1
Reactant: Cc1ccc(-c2nc(C)c(C(=O)O)s2)cc1
Agent: N#SCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(C)c(COc3ccc([C@H](CC(=O)O)C(=O)N(C)C)cc3)s2)cc1
Reaction time: 14 h

Procedure:
Thiazyl chloride 4.8 was prepared according to the method described in Example 2 starting from commercially available 4-methyl-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid. The phenol 3.5 (276 mg, 1.10 mmol) was dissolved in 5 mL of DMF and thiazyl chloride 4.8 (317 mg, 1.16 mmol) was added followed by cesium carbonate (715 mg, 2.20 mmol). The reaction was stirred for 14 hours and diluted with 250 mL of EtOAc. The organic layer was washed with 1N HCl (aq) (50 mL), saturated NaHCO3 (aq) (50 mL), and brine (2×50 mL). The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 15 mL THF and 0.111 N NaOH (aq) (15 mL, 1.65 mmol) was added. MeOH (10 mL) was added and the mixture became homogeneous. The solution was stirred for 8 hours and concentrated to remove the organic solvent. The slurry was diluted with water (50 mL) and DCM (300 mL). The mixture was adjusted with 2N HCl (aq) to a pH of 2. The material was extracted with DCM (3×75 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was flashed through silica with 5% MeOH in DCM to afford dimethylamide 4 (346 mg, 0.79 mmol) as a white solid. 1H NMR (400 MHz) (CDCl3) δ 7.83 (d, J=8.0, 2H); 7.20-7.28 (m, 4H); 6.96 (d, J=8.5, 2H); 5.17 (s, 2H); 4.22 (dd, J=3.8, 8.9 Hz, 1H); 3.13 (dd, J=8.9, 15.8 Hz, 1H); 3.02 (s, 3H); 2.93 (s, 3H); 2.80 (dd, J=3.8, 15.8 Hz, 1H); 2.51 (s, 3H); 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([OH:10])[C:6]([OH:9])=[CH:7][CH:8]=1.[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[Br:13][C:7]1[CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=[C:5]([OH:10])[C:6]=1[OH:9]
Reactant: Oc1ccc(C(F)(F)F)cc1O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1cc(C(F)(F)F)cc(Br)c1O
Temperature: 60 °C
Reaction time: 10 h

Procedure:
To a solution of 4-trifluoromethyl-benzene-1,2-diol (870 mg, 4.8 mmol) in 20 mL CCl4, Br2 (770 mg, 4.8 mmol, 1 eq.) was added and the mixture was stirred at 60° C. for 10 h. The sol-vent was then removed in vacuo and the crude product was purified by flash chromatography (silica gel, hexane/EtOAc 4:1→3:2) to yield the desired product as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[CH:4][C:5](I)=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.C(N(CC)CC)C.[CH2:22]([S:24][CH2:25][C:26]([CH3:30])([OH:29])[C:27]#[CH:28])[CH3:23]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:28]=[C:27]([C:26]([OH:29])([CH3:30])[CH2:25][S:24][CH2:22][CH3:23])[N:8]2[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:14]
Reactant: CS(=O)(=O)Nc1cc(Cl)c(F)cc1I
Reactant: C#CC(C)(O)CSCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2n1S(C)(=O)=O

Procedure:
To a 50 mL round-bottom flask were added N-(5-chloro-4-fluoro-2-iodo-phenyl)-methanesulfonamide (0.30 g, 1.0 mmol), bis(triphenylphosphine) palladium(II) chloride (35 mg, 0.05 mmol) and copper (I) iodide (19 mg, 0.1 mmol). The flask was fitted with a septum and stirred under argon. Tetrahydrofuran (5 mL) and triethylamine (0.28 mL, 2.0 mmol) were then added via syringe. 1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.14 g, 1.0 mmol) in tetrahydrofuran (1 mL) was added via syringe and the reaction maintained with stirring at 50-60° C. for four hours. The solution was evaporated and the residue purified by column chromatography using dichloromethane as solvent to yield the title compound as a brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>CN(C=O)C.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: OCCCCS
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCCCO)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-hydroxybutanethiol (5.0 g, 47 mmol) in DMF (100 mL) was added NaH (60% dispersion in mineral oil 2.1 g). After the effervescence had ceased, p-chloroacetophenone (4.3 mL, 33 mmol) was added. The solution was then stirred at 110° C. for 3 h. The mixture was cooled to RT and then diluted with ether (200 mL). The ethereal suspension was washed with 5% HCl (aq, 2×100 mL), water (100 mL), and then brine (50 mL). The ether extract was dried (MgSO4), filtered and concentrated to afford crude 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone, which was used without purification. 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12 h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate 3-Dimethylamino-1-[4-(4-hydroxybutylsulfanyl)phenyl]propenone. The mixture was filtered, washed with hexanes (50 mL), and dried to afford 3-Dimethylamino-1-[4-(4-hydroxy-butylsulfanyl)phenyl]propenone (6.4 g, 23 mmol): HPLC Retention Time; 5.58 min. (Method B) M+1; 279.8.