Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:26]([C:48]([OH:50])=O)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:47])[NH:32][S:33]([C:36]1[C:45]([CH3:46])=[C:43]([CH3:44])[C:40]([O:41][CH3:42])=[CH:39][C:37]=1[CH3:38])(=[O:35])=[O:34].[NH:58]1[CH2:67][CH2:66][CH2:65][C@H:59]1[C:60]([NH:62][CH2:63][CH3:64])=[O:61].Cl.C(N(CC)CC)C>CC(N(C)C)=O>[NH:25]([C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[C@H:26]([C:48]([N:58]1[CH2:67][CH2:66][CH2:65][C@H:59]1[C:60]([NH:62][CH2:63][CH3:64])=[O:61])=[O:50])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:47])[NH:32][S:33]([C:36]1[C:45]([CH3:46])=[C:43]([CH3:44])[C:40]([O:41][CH3:42])=[CH:39][C:37]=1[CH3:38])(=[O:34])=[O:35]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reactant: CCNC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)NC(=O)OC(C)(C)C
Yield: 131.6 %

Procedure:
According to the general procedure for HBTU promoted coupling solutions of 31.5 g Boc-Arg(Mtr)-OH in DMAC, 24.79 g HBTU in DMAC, 11.56 g H-Pro-NHEt.HCl in DMAC and 19.60 g triethylamine in DMAC were premixed and fed into the reactor at 50° C. using a residence time of 1.1 min to yield 52 g crude material which was used in the next step without purification. The calculated yield from HPLC analysis was 99%.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][CH2:43]2)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29]([N:39]3[CH2:40][CH2:41][N:36]([CH:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][CH2:43]4)[CH2:37][CH2:38]3)=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1
Product: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 8 from 500 mg (1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h) and 385 mg (1.20 mmol) ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butanoate.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[O:19]1CCC[CH2:21][CH:20]1OC1CCCCO1.C(Cl)(=O)C>C(O)(=O)C>[C:20]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:19])[CH3:21]
Reactant: CCCCC/C=C\CCCCCCCCCCO
Reactant: C1CCC(OC2CCCCO2)OC1
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CCCCC/C=C\CCCCCCCCCCOC(C)=O
Yield: 62 %

Procedure:
4 g (0.012 moles) of 1-(1-ethoxyethoxy)-11(Z)-heptadecene (Formula III, R=CH3, Y=CHCH3OCH2CH3) are added to a mixture of 8 ml. of acetic acid and 2.5 ml. of acetyl chloride, and the mixture is boiled on an oil bath of about 80° C. for 3 hours. The mixture is cooled, poured onto 20 g. of ice and extracted with 100 ml. of hexane. The extract is washed with water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled in fine vacuo. 2.2 g. (62%) of (Z)-11-heptadecenyl acetate are obtained; b.p.: 120°-126° C./0.05 mmHg. This product is identical with the compound obtained in step (A) above.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:51][N:44]([CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:28]2[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[O:7][C:8]5[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:52][C:26]=3[CH:27]=2)=[O:35])=[CH:38][CH:39]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CCCOc1ccc2cc(OB([O-])[O-])oc2c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOc1ccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc2c1
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 6-propoxy-benzofuran-2-yl borate (165 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 10 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (40 ml) to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(6-propoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 141) (192 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C@@H:12]([OH:23])[CH2:13][C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(B(O)O)C=CC=CC=1.O.[N+](C1C=CC([O:43][C:44]([O:46][CH2:47][C:48]2[S:52][CH:51]=[N:50][CH:49]=2)=O)=CC=1)([O-])=O>C1(C)C=CC=CC=1.CN(C=O)C.Cl>[NH2:22][C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][C@H:12]([OH:23])[C@@H:4]([NH:3][C:44]([O:46][CH2:47][C:48]1[S:52][CH:51]=[N:50][CH:49]=1)=[O:43])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: -60 °C
Reaction time: 8 h

Procedure:
The product of Example 66F (9.5 g, 33.4 mmol) and phenylboronic acid (4.1 g, 33.6 mmol) were combined in toluene (150 mL) and refluxed for 2.5 hours with azeotropic water removal (Dean-Stark trap). Toluene (100 mL) was distilled out at atmospheric pressure, then the remaining toluene was removed under vacuum, to provide a yellow syrup which was dissolved in DMF (50 mL) and cooled to -60° C. A solution of 5-(p-nitrophenyloxycarbonyloxy-methyl)thiazole (9.5 g, 33.5 mmol) in DMF (50 mL) was added over 45 minutes. The resulting mixture was stirred for 8 hours at -55°±5° C., then 14 hours at -25° C., then was allowed to warm to room temperature. The reaction mixture was diluted with 1N HCl (250 mL) and washed with CH2Cl2 (2×80 mL). The combined organic layers were back-extracted with 1N HCl (60 mL). The combined aqueous HCl layers were cooled in an ice-bath to 2° C., and conc. (37%) HCL (30 mL) was added over 5 minutes. The desired product (bis HCl salt) began to precipitate within 30 minutes. The slurry was stirred 3 hours at 2°-5° C., then the product (bis HCl salt) was collected by filtration and dried in a vacuum oven at 55°-60° C. Yield 11.4 g (68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[SH:24][CH2:25][CH2:26][OH:27]>C(Cl)Cl>[OH:27][CH2:26][CH2:25][S:24][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: OCCS
Reactant: CCOC(=O)C(C)(C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)C(=O)SCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 3-ethoxy-2,2-dimethyl-3-oxopropionic acid (30.78 mmol) in anhydrous CH2Cl2 (20 mL) was added portionwise CDI (40.02 mmol). The reaction mixture was stirred at room temperature during 30 minutes. This solution was added dropwise at −40° C.<T<−30° C. to a solution of 2-mercaptoethanol (41.21 mmol) in anhydrous CH2Cl2 (60 mL). The mixture was stirred at −40° C.<T<−30° C. during 2 hours. The reaction mixture was washed with ice-cold water (×3), dried through a phase separator and evaporated in vacuo while keeping the crude mixture below 25° C. The crude was purified by chromatography on a silica gel column (eluent: petroleum ether/EtOAc 95/5 to 50/50) to give the expected compound as a colorless oil in 30% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.15 (t, J=7.05 Hz, 3H), 1.38 (s, 6H), 2.94 (t, J=6.59 Hz, 2H), 3.43-3.48 (m, 2H), 4.10 (q, J=7.04 Hz, 2H), 4.96 (t, J=5.44 Hz, 1H); MS (ESI) m/z=243 (MNa+).
Reaction SMILES: C([C@H]([C@@H](C(OC(C)C)=O)O)O)(OC(C)C)=[O:2].[CH2:17]([OH:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OO)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(CC(C)(C)C)(C)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)C>[C:20]1([C@H:19]2[O:2][C@@H:18]2[CH2:17][OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C
Reactant: OCC=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: CC(C)CC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: OC[C@H]1O[C@@H]1c1ccccc1
Temperature: -20 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to -15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.[C:12](=[O:14])=[O:13]>C(OCC)C>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:12]([OH:14])=[O:13]
Reactant: O=C=O
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: CCOCC
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
20 mL of 2-mesitylmagnesium bromide (1.0 M in diethyl ether, 20 mmol) was added to a flask containing 60 mL of dry diethyl ether and solid carbon dioxide (dry ice). Additional dry ice was added throughout the course of the reaction as needed. After 30 min, the mixture was allowed to warm to room temperature and the solid was separated by filtration. The solid was dissolved in a 1 M KOH(aq) solution followed by neutralization to pH 1 using HCl. This resulted in the precipitation of a white powder that was collected by filtration and dried under vacuum at 80° C. (2.52 g, 77% yield).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH3:27].C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC(CC)=CC=2)(=O)=O)N)=CC=CC=1)=O)CC1C=CC=CC=1>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Agent: CCc1ccc(S(=O)(=O)C(N)c2ccccc2-c2ccccc2C(=O)NCCc2ccccc2)cc1
Product: CCc1ccc(S(=O)(=O)NCc2ccccc2-c2ccccc2C(=O)NCCc2ccccc2)cc1

Procedure:
From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid -phenethylamide (precursor 5a) and 4-ethylphenylsulfonyl chloride, according to the general working procedure 250 mg of 2′-(4-ethylphenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Li+].[OH-].CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoate (504 mg, 1.32 mmol) was dissolved in a mixture of 1 M aq LiOH (2 mL), MeOH (2 mL), and THF (6 mL) and left to stir overnight. The mixture was concentrated in vacuo to remove MeOH and THF. The residue was diluted with dichloromethane (50 mL), washed with saturated aqueous citric acid (2×5 mL) and water (2×5 mL), dried over sodium sulfate, filtered, and concentrated to give the desired product as a yellow solid (417 mg, 1.13 mmol, 86%).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].O1CCCC1.C(OC(=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:28]([NH:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[N:27]=2)[CH2:21][CH2:20]1)(C)(C)C.Cl>O1CCOCC1>[CH3:1][NH:2][S:3]([N:44]1[CH2:45][CH2:46][CH:41]([NH:40][C:28]2[N:27]=[C:26]([NH:25][CH:22]3[CH2:23][CH2:24][CH:19]([NH2:18])[CH2:20][CH2:21]3)[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:42][CH2:43]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4CCCC4)c3n2)CC1
Reactant: CNS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNS(=O)(=O)N1CCC(Nc2nc(NC3CCC(N)CC3)nc3c2ncn3C2CCCC2)CC1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Treat a stirred, cooled (0° C.) solution of N-methyl sulfamoyl chloride (0.2 mmol) and anhydrous tetrahydrofuran (275 mL) with a solution of trans-{4-[9-cyclopentyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9a, 0.2 mmol) triethylamine (9a 0.2 mmol) and tetrahydrofuran (4 mL) overnight at room temperature. Warm to 55° C., cool to room temperature and add 1.0 ml of 4N HCl in dioxane. Allow to stand for 3 hours, concentrate and dissolve the residue in DCM using a small amount of methanol as co-solvent if necessary. Purify the product by chromatography on a 2 g silica gel SPE cartridge pre-equilibrated with heptane. Elute the column in three fractions; first fraction 5 ml DCM; fractions 2 and 3 with 10-15 ml of DCM/methanol (4:1). Concentrate the desired fractions, dissolve the residue in ethanol and adjust to pH 2.0 with 10% HCl. Concentrate to dryness to give 4-[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purin-6-ylamino]-piperidine-1-sulfonic acid methylamide. Using N,N-dimethyl sulfamoyl chloride under similar conditions provides the corresponding trans-4-[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purin-6-ylamino]-piperidine-1-sulfonic acid dimethylamide. The corresponding 9-isopropyl and 9-cyclopent-2-enyl compound I sulfonic acid amides are prepared in a similar manner from 9b and 9c.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]1[N:30]=[CH:31][N:32](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]1[NH:30][CH:31]=[N:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCN(Cc3cnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
The intermediate (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1-trityl-1H-imidazol-4-ylmethyl)-piperazine (90 mg, 0.13 mmol) was dissolved in CH2Cl2 (0.5 mL) and was treated with triethylsilane (0.5 mL) followed by trifluoroacetic acid (1.0 mL). The reaction mixture was stirred for 2 h then evaporated to a residue which was triturated with a 10% EtOAc/hexane solution (4×1 mL). The residue was then partitioned between EtOAc (1 mL) and a saturated aqueous K2CO3 solution (0.5 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to afford the title compound as a foam (50 mg, 83%). LC/MS (Method A) 4.50 min, [M+1]+ 447.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:6][OH:7]>[Pd]>[CH3:6][O:7][C:3](=[O:4])[CH2:2][CH:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:1]1
Reactant: CO
Reactant: C1CCOC1
Agent: [Pd]
Product: COC(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 303 (490 mg, 3.1 mmol) in 1:1 THF:MeOH (10 mL) is added 10% palladium-on-carbon (74 mg), and the mixture is stirred at RT under hydrogen for 16 h. The mixture is filtered, and the filtrate is evaporated to give 481 mg of the product 304. 1H NMR (CDCl3) δ 4.0-3.9 (m, 2H), 3.70 (s, 3H), 3.40 (t, 2H), 2.25 (d, 2H), 2.01 (m, 1H), 1.65-1.60 (m, 2H), 1.40-1.25 (m, 2H); MS: m/z 159 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[SH:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:22][C:13]3[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=3[N:11]=2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Solvent: CN(C)C=O
Product: Oc1ccc(-c2nc3cc(C(F)(F)F)ccc3s2)cc1Br
Temperature: 100 °C

Procedure:
In a N,N-dimethylformamide (DMF) solvent, a suspension of 3-bromo-4-hydroxybenzaldehyde (1.0 eq.) and 2-amino-4-(trifluoromethyl)benzenethiol (1.0 eq.) was heated at a temperature of 100° C. After cooling, DMF was removed therefrom under reduced pressure. Methylene chloride was added to the resultant solid, and the produced precipitate was filtered, and washed with methylene chloride to obtain a solid target product.
Reaction SMILES: [OH:1][CH:2]([C:30]1[O:31][C:32]([CH2:35][O:36][CH3:37])=[N:33][N:34]=1)[CH:3]([NH:6][C:7](=[O:29])[C:8]([CH3:28])([S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[CH3:37][O:36][CH2:35][C:32]1[O:31][C:30]([C:2]([CH:3]([NH:6][C:7](=[O:29])[C:8]([CH3:28])([S:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:19])[CH2:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH2:4][CH3:5])=[O:1])=[N:34][N:33]=1
Reactant: CCC(NC(=O)C(C)(CC(=O)N1CCOCC1)S(=O)(=O)Cc1ccccc1)C(O)c1nnc(COC)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(C)(CC(=O)N1CCOCC1)S(=O)(=O)Cc1ccccc1)C(=O)c1nnc(COC)o1
Reaction time: 1 h

Procedure:
This amide then was treated with Dess-Martin periodinane (111 mg, 0.149 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 was added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 13 mgs of N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonyl-methyl-butyramide; H1 NMR(CDCl3): 7.8, 7.5(1H, d,d NH, diastereomeric), 7.4–7.2(5H, m), 5.3–5.1(1H, m), 4.6(2H, s, OCH2), 4.3–4.1(3H, m), 3.8–3.1(13H, m), 3–2.4(2H, m), 2.2–1.5(2H, m), 0.95(3H, t); MS: 535.7(M−1), 537.5(M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 226, step 4) was reacted with 4-cyanophenylboronic acid (CAS RN: [126747-14-6]) in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound containing 10% of the corresponding Z isomer as a white solid, MS (ESI+): m/z=482.16 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)C([N:5]1[CH:12]2[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=O.C(O)(C)C.[OH-].[Na+].O>C1(C)C=CC=CC=1>[CH:6]12[CH2:14][CH:10]3[CH2:9][CH:8]([CH2:13][CH:12]([CH2:11]3)[NH:5]1)[CH2:7]2
Reactant: O=C(N1C2CC3CC(C2)CC1C3)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: C1C2CC3CC1CC(C2)N3
Temperature: 80 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution containing 23.4 g (83 mmol) of N-trichloroacetyl-2-azaadamantane and 70.1 g of isopropanol, was heated to 80° C., and 99.4 g of a 20 wt % NaOH aqueous solution was added, followed by stirring for one hour. 47 g of water and 47 g of toluene were added, followed by liquid separation, to obtain a toluene solution of 2-azaadamantane.