Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].Br[C:59]1[C:64]([F:65])=[CH:63][C:62]([C:66]([F:69])([F:68])[F:67])=[CH:61][N:60]=1>>[F:65][C:64]1[C:59]([NH:35][CH2:36][C@@H:37]2[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]2[C:44]([C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)=[O:45])=[N:60][CH:61]=[C:62]([C:66]([F:68])([F:67])[F:69])[CH:63]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cc2F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Br[C:14]1[S:18][CH:17]=[N:16][C:15]=1[C:19]([NH:21][CH3:22])=[O:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:14]2[S:18][CH:17]=[N:16][C:15]=2[C:19]([NH:21][CH3:22])=[O:20])[C:5]([C:9]([F:10])([F:11])[F:12])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ncsc1Br
Reactant: Nc1cc(Cl)ncc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ncsc1Nc1cc(Cl)ncc1C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)pyridin-4-amine (41 mg, 0.21 mmol) and 5-bromo-N-methylthiazole-4-carboxamide (54 mg, 0.24 mmol; synthesized from the corresponding ethyl-ester), Pd2(dba)3 (19 mg, 0.021 mmol), xantphos (37 mg, 0.064 mmol) and cesium carbonate (138 mg, 0.42 mmol) in dioxane (3.5 ml) were heated in a Biotage Initiator microwave synthesizer at 140° C. for 2 h. The solvent was removed and the residue was purified by silica gel chromatography (DCM/MeOH gradient) to give the title compound as a pale yellow solid in 27% isolated yield.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1)([O-])=O>C(O)C.CO.[C].[Pd]>[S:10]1(=[O:11])(=[O:12])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:14]=[CH:13][C:7]=2[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)S(=O)(=O)CC2
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a suspension of 6-nitro-1-benzothiophene 1,1-dioxide (2.02 g) in ethanol (200 mL) and methanol (60 mL) was added 10% palladium carbon (50% containing water, 265 mg), and the mixture was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a white solid (yield 1.31 g, 75%).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10][C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([C:8]1[C:13](=[O:14])[C:12]([I:17])=[C:11]([CH3:15])[NH:10][C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: II
Reactant: CCCCCCCc1c(C)[nH]c(C)cc1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a solution of 3 (100 mg, 0.45 mmol) in acetonitrile (2.5 mL) was added ceric ammonium nitrate (25 mg, 0.045 mmol) followed by iodine (126 mg, 0.495 mmol). The reaction mixture was stirred at 70° C. under nitrogen for 7 h. After completion of the reaction, the mixture was cooled to room temperature and treated with an ice-cold aqueous solution of sodium thiosulfate with stirring. The mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was purified by chromatography on a silica gel column. Elution with hexane/ethyl acetate gave 3-heptyl-5-iodo-2,6-dimethylpyridin-4(1H)-one (5) as a light yellow solid: yield 119 mg (74%); silica gel TLC Rf 0.45 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.88-0.91 (m, 3H), 1.29-1.35 (m, 10H), 2.33 (s, 3H) and 2.54-2.56 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:23])([F:24])[F:22])[N:9]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.414 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.22 g, 40%). MS (ISN) 550.2 [(M−H)−]; mp 197.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10](=O)(ON1C(=O)CCC1=O)[O:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:10](=[O:11])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Br)cnc2[nH]1

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (0.94 g, 5 mmol, Aldrich) and disuccinimido carbonate (1.28 g, 5 mmol, Aldrich) in chloroform (50 mL) was heated at reflux for 12 h. The solvent was removed in vacuo and the residue was purified by recrystallization from 40% EtOAc/hexane to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 214 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][C:22]([NH:24][C:25]3([C:33]([O:35]C)=O)[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:23])[CH:15]=2)=[CH:10][C:9]=1[F:37].Cl>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:22](=[O:23])[NH:24][C:25]4([CH2:30][CH2:29][C:28]([F:31])([F:32])[CH2:27][CH2:26]4)[C:33]=3[OH:35])[CH:15]=2)=[CH:10][C:9]=1[F:37]
Reactant: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)c(F)c3)ccc2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen 2.23 g (19.9 mmol) of potassium tert-butoxide were added to 8.19 g (18.0 mmol) of the compound from Example 5A in 80 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was then added to ice-water, 1N aqueous hydrogen chloride solution was added dropwise until a pH of 1-2 had been reached, the mixture was stirred for 30 minutes and filtered off with suction, the filter cake was washed with water and the precipitate was dried. For further purification, the product was dissolved in 1N aqueous sodium hydroxide solution, precipitated by acidification with aqueous 1 N hydrochloric acid, stirred for 30 minutes, washed with water, filtered off and dried. This gave 7.50 g (97% of theory) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[C:20]1([C:17]2[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[O:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccccc4)no3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(-c2nc(-c3ccccc3)no2)cc1
Yield: 10.9 %

Procedure:
A suspension of 5-(4-(benzyloxy)phenyl)-3-phenyl-1,2,4-oxadiazole (90 mg, 0.27 mmol) and 10% Pd/C (2 mg, 7 μmol) in methanol (3.0 mL) and THF (3.0 mL) was stirred in a single necked round bottom flask fitted with a condenser under an atmosphere of hydrogen at 55° C. for 72 hours. The solution was filtered through Celite and the solvent was removed under reduced pressure and then purified by column chromatography (EtOAc/Hex 1:2) to give the product (7 mg, 11%) as a white solid. 1H NMR (500 MHz, CDCL3) δ(ppm): 6.86 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=9.2 Hz), 8.01 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=9.2 Hz).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:15]([CH:18]=O)=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.[C:63]([Cl:67])(Cl)(Cl)[Cl:64]>CN(C)C(=O)C.[Zn]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:21])[C:15]([CH:18]=[C:63]([Cl:67])[Cl:64])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Cl)Cl)=CS[C@H]12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Zinc powder (78.4 g) was added to a solution of benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4-carboxylate (102.4 g) and triphenylphosphine (367.2 g) in a mixture of carbon tetrachloride (800 ml) and N,N-dimethylacetamide (200 ml) at ambient temperature and the mixture was stirred at 60° C. for 30 minutes. After being cooled, the mixture was added to ethyl acetate (20 l) and the resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give benzhydryl 7-phenylacetamido-3-(2,2-dichlorovinyl)-2-cephem-4-carboxylate (15.26 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16](Cl)=[O:17].CCN(C(C)C)C(C)C.[N:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[S:30][C:29]=1[C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH2:39]>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([NH:39][C:38]1[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=1[C:29]1[S:30][C:31]2[C:36]([N:28]=1)=[CH:35][CH:34]=[CH:33][N:32]=2)=[O:17]
Reactant: Nc1ccccc1-c1nc2cccnc2s1
Reactant: O=C(Cl)c1nc(-c2ccccc2)sc1CCCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCCl
Reaction time: 16 h
Yield: 26 %

Procedure:
A suspension of 5-(3-chloropropyl)-2-phenylthiazole-4-carbonyl chloride (906 mg, 3.2 mmol), DIPEA (1.1 mL, 6.4 mmol), and 2-(thiazolo[5,4-b]pyridin-2-yl)aniline b (585 mg, 2.6 mmol) in CH3CN (12 mL) was stirred for 16 h. The resulting ppt was collected by filtration, rinsed with CH3CN and dried. The crude product was purified by MPLC eluting with DCM/MeOH (0-5% gradient) to give 5-(3-chloropropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (316 mg, 26% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][CH:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:13][C@H:11]1[CH2:12][N:8]([CH3:6])[CH:9]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CC1COc1ccccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H](O)CC1COc1ccccc1CCc1ccccc1
Yield: 63.8 %

Procedure:
Following a procedure similar to that described in Example 38, 300 mg of (4R)-1-t-butoxycarbonyl-4-hydroxy-2-[2-(2-phenylethyl)phenoxymethyl]pyrrolidine [prepared as described in Example 65(b)] were reacted with 85.9 mg of lithium aluminum hydride dispersed in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 150 mg (yield 63%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]([CH3:22])[C:5]2[C:6]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:7]=3[N:8]=[C:9]([CH2:11][C:12](O)=[O:13])[N:10]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C[CH2:34][N:35]=[C:36]=NCCCN(C)C.Cl>C1COCC1.O>[CH:1]1([N:4]([CH3:22])[C:5]2[C:6]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([N:35]([CH3:36])[CH3:34])=[O:13])[N:10]=2)[CH2:2][CH2:3]1
Reactant: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetic acid (100 mg, 0.000315 mol) in anhydrous THF (10 ml) 2M dimethyl amine in THF (0.017 g, 0.000378 mol) and HOBt (0.051 g, 0.000378 mol) were added. This mixture was cooled to 0° C. and then treated with EDC HCl (0.120 g, 0.00063 mol). The reaction mixture was allowed to warm to room temperature and kept stirred for 16 h. After completion, the reaction was diluted with water (50 ml) and extracted with ethyl acetate (25 ml×3). Combined organic extracts were washed with water (50 ml), dried over anhydrous Na2SO4 and concentrated under vacuum to get crude compound. It was then purified by column chromatography by using 100-200 mesh silica gel. Pure compound was eluted in 1-2% MeOH: DCM to afford 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-N,N-dimethylacetamide as a pale yellow oil. Yield—50 mg, (46.29%); 1H-NMR: (400 MHz, CDCl3); δ=3.97 (s, 2H), 3.04 (s, 3H), 3.01 (s, 3H), 2.97 (s, 3H), 2.89-2.80 (m, 5H), 1.92-1.86 (m, 2H), 1.77-1.71 (m, 2H), 0.72-0.67 (m, 2H), 0.45-0.41 (m, 2H); LC-MS [M+H]=345.3; HPLC purity=98.78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.[S:31](N)([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][NH:34][SH:31](=[O:33])=[O:32])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: NS(N)(=O)=O
Reactant: NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: C1COCCO1
Product: O=[SH](=O)NNC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine (36.6 mg, 0.083 mmol, 1 eq.) in 2 mL of dioxane was added sulfamide (40 mg, 0.42 mmol, 5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield 34 mg (79%) of desired compound. 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.51-1.72 (m, 2 H) 2.15 (br. s., 2 H) 3.38-3.52 (m, 2 H) 3.54-3.65 (m, 1 H) 5.18-5.41 (m, 2 H) 7.24-7.50 (m, 7 H) 7.54-7.67 (m, 1 H) 8.23 (s, 1 H), [M+h]+ 518.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[Cl:41][C:42]1[CH:47]=[CH:46][C:45](F)=[CH:44][CH:43]=1>CN(C)C=O>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([O:1][CH2:2][C:3]2[N:4]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:15]3)[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:44][CH:43]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: OCc1cc2ccccc2n1CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2cc3ccccc3n2CCC2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 2-hydroxymethyl-1-[2-(1-tritylpiperidin-4-yl)ethyl]-1H-indole (3.91 g, 7.81 mmol) was dissolved in about 10 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.468 g, 11.71 mmol) was added and the resulting mixture was stirred at room temperature for about 30 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.915 ml, 1.12 g, 8.59 mmol) was added and the resulting mixture was stirred at room temperature for about four days, protected from light.
Reaction SMILES: [F:1][CH:2]([F:6])[CH2:3][NH:4][CH3:5].Cl.CCN(C(C)C)C(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([NH:35][CH3:36])=[CH:28][C:27]=2F)=[CH:20][C:19]=1[Cl:39]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([NH:35][CH3:36])=[CH:28][C:27]=2[N:4]([CH3:5])[CH2:3][CH:2]([F:6])[F:1])=[CH:20][C:19]=1[Cl:39]
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: CNCC(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N(C)CC(F)F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(2,2-difluoroethyl)-N-methyl-amine×HCl (64 mg, 0.48 mmol), DIPEA (0.64 ml, 3.73 mmol), N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (150 mg, 0.44 mmol) and MeCN (5 mL) is stirred for two weeks at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, dried with Na2SO4 and concentrated and directly used in the next step.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:31][CH3:32])=[C:7]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:8]([C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>CN(C)C=O.O>[CH2:1]([O:4][C:5]1[C:6]([CH2:31][CH3:32])=[C:7]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:8]([C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:42][CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:17]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: BrCCOC1CCCCO1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(OC)c(O)c2)c(CC(=O)OC)c1CC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(OC)c(OCCOC3CCCCO3)c2)c(CC(=O)OC)c1CC
Temperature: 25 °C

Procedure:
Methyl 3,5-diallyloxy-2-ethyl-6-(3-hydroxy-4-methoxybenzoyl)phenylacetate (330 mg, 0.75 mmol) obtained in Example 82, Step 1 was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (550 mg, 4.0 mmol), sodium iodide (100 mg, 0.67 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.6 mL, 4.0 mmol) were added thereto with stirring at room temperature. The reaction mixture was stirred at 80° C. for 3 hours and cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain methyl 3,5-diallyloxy-2-ethyl-6-[4-methoxy-3-(2-tetrahydro-2H-pyran-2-yloxyethoxy)benzoyl]phenylacetate.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45]CC2C=CC=CC=2)[C:35]=1[C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[OH:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:34]([O:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:25](=[O:27])[CH2:24][CH2:23][C:11]2[CH:12]=[CH:13][C:14]([N:15]3[CH2:19][C:18](=[O:20])[NH:17][S:16]3(=[O:21])=[O:22])=[C:9]([OH:8])[CH:10]=2)[C:35]=1[C:36]([N:38]([CH3:39])[CH3:40])=[O:37]
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: CN(C)C(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Product: CN(C)C(=O)c1c(O)cccc1OCCCCNC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared using (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid and 2-(4-aminobutoxy)-6-benzyloxy-N,N-dimethylbenzamide analogous to Example 100 steps C and D: 1H NMR (DMSO-d6) δ 9.78 (s, 1H), 9.54 (s, 1H), 7.83-7.80 (t, J=5.55 Hz, 1H), 7.22-7.20 (d, J=8.08 Hz, 1H), 7.09-7.05 (t, J=8.34 Hz, 1H), 6.73 (d, J=1.76 Hz, 1H), 6.66-6.63 (dd, J=1.77, 8.09 Hz, 1H), 6.46-6.44 (d, J=8.08 Hz, 2H), 4.38 (s, 2H), 3.93-3.86 (m, 2H), 3.08-3.02 (m, 2H), 2.91 (s, 3H), 2.73-2.69 (t, J=6.32 Hz, 2H), 2.71 (s, 3H), 2.33-2.29 (t, J=8.34 Hz, 2H), 1.59-1.53 (m, 2H), 1.48-1.42 (m, 2H); (M−1)−=533.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCSc1cccc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(SCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A solution of 22.0 grams (0.105 mole) of methyl 3-(3-methylphenylthio)propanoate in 200 mL of methanol was stirred, and 40 mL of aqueous 10% potassium hydroxide was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature during an 18 hour period. GC analysis of the reaction mixture indicated that the reaction was not complete. An additional 30 mL of the aqueous 10% potassium hydroxide was added, and the reaction mixture was stirred for an additional three hours. After this time, 100 mL of water was added to the reaction mixture and the methanol was removed under reduced pressure. The residue was washed with three 50 mL portions of diethyl ether. The cooled residue was then acidified with aqueous 10% hydrochloric acid, and extracted with 100 mL of diethyl ether. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily residue. The residue was stirred with hexane and cooled, resulting in a solid material being formed. The solid was collected by filtration and dried, yielding 17.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.