Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[O:48]1[C:52]([CH2:53][NH2:54])=[CH:51][N:50]=[CH:49]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:54][CH2:53][C:52]3[O:48][CH:49]=[N:50][CH:51]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NCc1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCc1cnco1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 25 mL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.250 g, 1.0 eq.) was dissolved in dichloromethane (5.0 mL, 20 V). The reaction mixture was cooled to 0° C. and then added HOBT (0.119 g, 1.1 eq.) followed by EDC HCl (0.150 g, 1.1 eq.) and oxazol-5-ylmethanamine HCl (0.143 g, 1.1 eq.). DIPEA (0.101 g, 1.1 eq) was added to this reaction mixture dropwise at the same temperature. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC analysis on silica gel with 5% methanol in dichloromethane as mobile phase and visualization with UV.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22].[OH-:23].[Na+]>O1CCOCC1>[C:16]1([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:22])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [OH-]
Reactant: C[C@H]1[C@@H](CCCc2ccccc2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-phenyl-1-propyl)-4-methylazetidin-2-one (20.5 g, 67.6 mmol) in dioxane (220 mL) is added 1 M aqueous sodium hydroxide (102 mL). The solution is stirred at 23° C. for 20 h, then extracted with hexanes (200 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 300 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (21.5 g, 99% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[C:6]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:5]=1>CO.[OH-].[Na+]>[CH2:22]([O:21][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1)[C:3]([OH:32])=[O:2])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)O)c1
Yield: 96.5 %

Procedure:
A solution of 6.0 g (0.013 mol) of 3,5-bis(decyloxy)benzoic acid methyl ester in 300 ml of methanol and 40 ml of 1N sodium hydroxide was stirred at reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 6N HCl. The product was extracted with ethyl acetate and the dried extract was concentrated under reduced pressure to a yellow solid. Recrystallization from methanol-water gave 5.45 g (95% yield, mp 56°-58°) of 3,5-bis(decyloxy)benzoic acid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCCI
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
In step b, the 4-iodo functionality of the appropriate ethyl 4-iodobutyrate of structure (52) is displaced with dibenzylamine to give the corresponding 4-dibenzylaminobutyric acid, ethyl ester of structure (53).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[O:43]=[C:44]1[NH:48][CH:47]([C:49](O)=[O:50])[CH2:46][CH2:45]1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([CH:47]3[CH2:46][CH2:45][C:44](=[O:43])[NH:48]3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)C2CCC(=O)N2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and 5-oxopyrrolidine-2-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.02 minutes; C30H35ClN6O4 (579.10); mass spectrum: (M−H)−=578.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]1[C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([CH:35]=[O:36])=[CH:28][CH:27]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 29.8 %

Procedure:
n-Butyllithium (1.56M in hexane, 14 ml, 21.8 mmol) was added to a solution of (2S)-1,4-dibenzyl-2-(4-bromophenyl)piperazine (6.1 g, 14.5 mmol) in tetrahydrofuran (60 ml) at −78° C. After one hour stirring, dimethylformamide (1.6 g, 21.9 mmol) was added and the solution was stirred for one hour. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzaldehyde (1.6 g, 41%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]2[CH:45]=[CH:46][C:36]([F:35])=[CH:37][CH:38]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(/C=C/c2ccc(F)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-fluorostyrylboronic acid (49.9 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and was extracted into EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) for 1.5 hours to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a tan solid (58 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.92 (m, 8H), 3.74 (br s, 1H), 4.40 (d, J=2.53 Hz, 2H), 4.51 (br s, 1H), 6.86 (d, J=6.57 Hz, 1H), 7.27 (t, J=8.84 Hz, 1H), 7.56-7.73 (m, 3H), 7.82 (br s, 3H), 8.14 (d, J=15.92 Hz, 1H), 8.49 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22F2N4O, 385. found, 385.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[CH2:9]Cl.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[CH2:9][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cnc(CCl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2ncn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 246.2 %

Procedure:
A mixture of 5-chloro-4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (463 mg, 2.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (213 mg, 1.5 mmol), and potassium carbonate (1.1 g, 8.0 mmol) in acetone (15 mL) was stirred at room temperature overnight. The solid material was removed by filtration and washed with 50% acetone/MeOH (2×15 mL). The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/DCM and 0-6% MeOH/DCM), affording 2-{[(5-chloro-1-methyl-1H-imidazol-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.0 g, 93% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 3.53 (s, 3H), 4.25 (s, 2H), 5.97 (s, 1H), 7.70 (s, 1H); M+271. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([OH:20])[CH:19]=1)[C:15]#[N:16]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(O)cc(F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1cc(F)cc(Oc2ccc(C=O)cc2F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-fluoro-5-hydroxybenzonitrile.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=3)=[CH:8][C:7]=2[CH:20]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=3)=[CH:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2oc(-c3ccc(C(N)=O)cn3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc(-c2cc3cc(O)ccc3o2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(5-Methoxy-benzofuran-2-yl)-nicotinamide (0.25 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2) (1.0 mL) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.). The resulting mixture was filtered, and the obtained precipitate was washed with H2O and EtOAc. The solid was dried at 40° C. for 15 h under vacuum (12 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[I:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[I:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: COCCNS(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from [2-(methyloxy)ethyl]amine and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Description 30.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:35][C:36](=[O:38])[CH3:37])=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]>C(O)=O>[CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:35][C:36](=[O:38])[CH3:37])=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Solvent: O=CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)O)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.4 %

Procedure:
tert-Butyl N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-aminobenzoate (0.250 g, 0.455 mmol) was dissolved in formic acid (3.0 ml) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was concentrated and the obtained residue was recrystallized from methanol to obtain the titled compound (0.129 g, 0.261 mmol, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:9]=2[CH:10]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-1H-indazol-4-amine (5 g) was dissolved in DMF (20 ml) and cooled in an ice bath. 60% Sodium hydride in mineral oil (0.94 g) was added portionwise and the reaction was left under an ice bath for 30 min. Benzenesulfonyl chloride (3 ml) in DMF (5 ml) was added slowly over 15 minutes and the reaction was left to warm up to room temperature overnight. Water (100 ml) was added and the reaction stirred for 20 minutes. Ethyl acetate (120 ml) was added and the water was separated, washed with ethyl acetate (50 ml×2) and the combined organics were washed with 7.5% lithium chloride (aq) (50 ml×2) then water (50 ml) before being separated and passed through a hydrophobic frit. The ethyl acetate was evaporated and the residue passed through a silica cartridge, eluting with DCM (ca. 300 ml) followed by diethyl ether (ca. 400 ml). Product containing pure fractions were combined and evaporated to dryness to give title compound, 5.9 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][C:39]([NH:42][CH2:43][CH2:44][CH2:45][NH2:46])([CH3:41])[CH3:40]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH2:45][CH2:44][CH2:43][NH:42][C:39]([CH3:41])([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: CC(C)(C)NCCCN
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCCNC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1,1-dimethylethyl)-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) 1.09 (m, 9 H), 1.70 (m, 2 H), 2.33 (m, 3 H), 2.47 (m, 1 H), 2.66 (m, 1 H), 3.13 (m, 1 H), 3.47 (m, 1 H), 6.36 (d, J=8.8 Hz, 1 H), 7.10 (m, 1 H), 7.23 (m, 2 H), 7.47 (m, 2 H), 7.58 (m, 2 H), 8.04 (m, 1 H), 8.13 (d, J=7.6 Hz, 1 H).
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](C)[C:33](=O)C(F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:31][CH:30]([NH:32][CH3:33])[CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2)N(C)C(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 800 mg of bovine serum albumin (BSA) in 8 mL of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution was added 12 mL of DMSO dropwise, and the reaction mixture was maintained below room temperature. To the protein solution was added a solution of 15 mg of MDMA derivative (1L) in 1 mL of anhydrous DMF dropwise. The reaction mixture was allowed to stir at room temperature 48 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each for at least 6 hours). The protein concentration was determined to be 6.8 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 38 mL of the conjugate was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:25])[CH:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:6][CH2:5]1.[F:26][C:27]1[CH:28]=[C:29]2[C@:36]3([C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37]3)[CH2:35][C@@H:34]([C:43](Cl)=[O:44])[O:33][C:30]2=[CH:31][CH:32]=1>>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22])[CH:12]=[CH:11][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:43]([C@@H:34]2[CH2:35][C@@:36]3([C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37]3)[C:29]3[C:30](=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)[O:33]2)=[O:44])[CH2:5][CH2:6]1)=[O:25]
Reactant: COc1cc(C=CC(=O)N2CCN(CCN)CC2)cc(OC)c1OC
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Product: COc1cc(C=CC(=O)N2CCN(CCNC(=O)[C@@H]3C[C@]4(NC(=O)NC4=O)c4cc(F)ccc4O3)CC2)cc(OC)c1OC
Yield: 72 %

Procedure:
The procedure similar to that described in Example 8 was carried out with the use of the compound of 4-(2-aminoethyl)-1-(3,4,5-trimethoxycinnamoyl)piperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) to give the desired compound with yield of 72.0%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[SH:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][S:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccnc1S
Reactant: CS(=O)(=O)OCc1ccnc(N)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1nccc(CSc2ncccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 70 %

Procedure:
2-Amino-4-methanesulfonyloxymethylpyrimidine (580 mg, 2.9 mmol, Reference Compound No. 8-1) was suspended in N,N-dimethylformamide (15 mL), and 2-mercaptonicotinic acid (400 mg, 2.6 mmol) and triethylamine (1.2 mL, 8.6 mmol) were added thereto under ice-cooling, and the mixture was stirred for 21 hours at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), and extracted with water (50 mL) and saturated aqueous sodium hydrogencarbonate solution (30 mL). 2M hydrochloric acid was added to the aqueous layer until bubbles were no longer formed, and the precipitated solid was filtered off. The solid was dried at 55° C. under reduced pressure, to give 470 mg of the title Reference Compound as a white solid (Yield: 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=CC=CC=1C1NC2C=C(F)C(F)=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: Fc1cc2nc(-c3ccccc3Br)[nH]c2cc1F
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: Fc1cc2nc(-c3ccccc3Br)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-phenyl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-cyclohexane (2550-36-9). Yellow sticky solid (94%). MS (Turbo Spray): m/z=406.1 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C1C=CC=CC=1>[Br:31][CH2:2][C:3]1[CH:4]=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: CSc1ncc(CO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CSc1ncc(CBr)cn1
Yield: 59.9 %

Procedure:
5-hydroxymethyl-2-methylthiopyrimidine (0.1 g, 0.61 mmol), triphenylphosphine (0.45 g, 1.7 mmol) and carbon tetrabromide (0.28 g, 0.85 mmol) are stirred in benzene (5 mL) for 24 h. The mixture is evaporated and the residue is purified by flash chromatography (silica gel, 4:1 hexanes/ethyl acetate) to provide the intermediate title compound as a white solid (0.08 g, 61%). MS (ES), 219/221 [M+H]+ (Br).