Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 55 %

Procedure:
Prepared as described in general procedure P using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (1.0 g, 3.0 mmol), piperazine-1-carboxylic acid tert-butyl ester (838 mg, 4.5 mmol), acetic acid (40 μL, 0.6 mmol) and sodium triacetoxyborohydride (765 mg, 3.6 mmol) to afford 835 mg (55%) of the desired product after purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: OCc1ccc(S)cc1
Product: N#Cc1ccc(Sc2ccc(CO)cc2)cn1
Yield: 28.4 %

Procedure:
Using the method of Preparation 155 using (4-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) affords the title compound (4.90 g, 28%).): 243 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:12]([O:15][CH3:16])[O:17][CH3:18])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(Br)ccc1C(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-bromo-2-methoxybenzaldehyde (1 g, 4.67 mmol) was dissolved in MeOH (20 ml) and trimethyl orthoformate (562 μl, 5.139 mmol) and p-toluene sulphonic acid monohydrate (89 mg, 0.467 mmol) were added to the resulting solution. The mixture was stirred overnight at room temperature and then the solvent was removed under vacuo. The residue was taken up with Et2O and washed with 5% Na2CO3 and with water. The organic phase was dried over Na2SO4 and evaporated to give 1.22 g of 4-bromo-1-dimethoxymethyl-2-methoxy-benzene as a colorless oil.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:22]([O-])=O)[CH:18]=[N:19]2)=[CH:14][CH:13]=1>O.C(O)C>[NH2:22][C:17]1[CH:18]=[N:19][C:20]2[C:15]([C:16]=1[NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:14][CH:13]=[C:12]([Br:11])[CH:21]=2
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2cc(Br)ccc2c1NCCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A solution of sodium dithionate (27.5 g, 158 mmol) in water (60 mL) was added to a solution of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (10.3 g, 31.6 mmol) in ethanol (175 mL), and the mixture was stirred vigorously for four hours at ambient temperature. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane/chloroform/methanol (500 mL) and saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was separated and extracted with chloroform (5×200 mL), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 7.27 g of 3-[(3-amino-7-bromoquinolin-4-yl)amino]propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2.CS[C:13]1[S:14][CH2:15][CH2:16][N:17]=1.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:13]1[S:14][CH2:15][CH2:16][N:17]=1)[CH2:6]2
Reactant: Clc1cccc2c1CNC2
Reactant: CSC1=NCCS1
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: ClCCl
Product: Clc1cccc2c1CN(C1=NCCS1)C2
Temperature: 150 °C

Procedure:
A mixture of 4-chloroisoindoline (700 mg), 2-methylthio-2-thiazoline (600 mg), and β-naphthylsulfonic acid (35 mg) was heated at 150° C. for 30 minutes. The product was cooled, dissolved in methylene chloride, washed with water, the organic layer dried over anhydrous potassium carbonate, filtered, and solvent removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel packed in methylene chloride/2% methanol/ammonia, eluting with methylene chloride/2% methanol, to give 4-chloro-2-(thiazolin-2-yl)isoindoline, a compound of Formula (IA), m.p. 167°-169° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:25]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38]([OH:40])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(C(C)C)C(C)C.[N+:50]([C:53]1[CH:58]=[C:57]([NH2:59])[CH:56]=[CH:55][C:54]=1[NH2:60])([O-:52])=[O:51]>CN(C=O)C>[NH2:60][C:54]1[CH:55]=[CH:56][C:57]([NH:59][C:38]([C@H:33]2[CH2:34][CH2:35][CH2:36][CH2:37][N:32]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:40])=[CH:58][C:53]=1[N+:50]([O-:52])=[O:51]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 4.96 g, 13.1 mmol) was added to a stirred solution of (R)—N-Boc-2-piperidinecarboxylic acid (3.00 g, 13.1 mmol) and DIPEA (9.0 mL, 51.2 mmol) in anhydrous DMF (50 mL). The mixture was stirred at room temperature for 5 min and then 2-nitro-1,4-phenylenediamine (3.00 g, 13.1 mmol) was added. The mixture was stirred for a further 18 hr, then the DMF was removed by evaporation. The residue was partitioned between water (200 mL) and EA (100 mL) and the phases separated. The aqueous phase was extracted with two further portions of EA (100 mL each) and the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each). The solution was dried over magnesium sulfate and concentrated to give (R)-tert-butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]-piperidine-1-carboxylate as a brown solid (4.80 g).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CO>[C:11]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])=[CH:23][CH:24]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CO
Product: CSC(Nc1ccc(NC(=O)OC(C)(C)C)cc1)=C(C#N)C#N
Temperature: 25 °C

Procedure:
A mixture of 13.89 g (81.58 mmol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 17 g (81.63 mmol) of N-BOC-1,4-phenylenediamine (Fluka) and 200 ml of methanol is heated under reflux for 5 hours. Cooling to room temperature, filtering and washing the filter residue with methanol yield the title compound; m.p. 190° C. Concentration of the filtrate by evaporation and recrystallization of the residue from 50 ml of methanol yield a further batch of the title compound; m.p. 190-191° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18])([O-:7])=[O:6].C(Cl)(Cl)Cl>N1C(C)=CC=CC=1C>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17]([O:4][CH2:3][CH2:2][F:1])(=[O:19])=[O:18])([O-:7])=[O:6]
Reactant: OCCF
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCF)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoroethanol (1.28 g, 20 mmol) in 2,6-lutidine (20 mL) at −10° C. was added 2,4-dinitrobenzene-1-sulfonyl chloride LVI (4.91 g, 18.7 mmol) in portions. A precipitate formed so CHCl3 (50 mL) was added to the reaction mixture in order to ensure efficient stirring. After 10 min, the mixture was washed with cold 10% aqueous HCl (150 mL) and water (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1:2 EtOAc:hexane) to afford 2-fluoroethyl 2,4-dinitrobenzenesulfonate LVII (1.44 g, 4.90 mmol, 24%).
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.Cl[C:6]1[N:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([O:4][C:6]2[N:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CC2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.3 %

Procedure:
Cyclopropanol (542 μL, 8.69 mmol) is added to a suspension of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dimethylformamide (11.6 mL). The reaction mixture is stirred for 15 hours at room temperature then for 24 hours at 50° C. The reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate (3 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65) to give the title compound (610 mg, 54%). ES/MS (m/e): 195.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O-])=O.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]3[NH:20][C:19]4[CH:18]=[CH:17][C:6]([NH:7][C:8](=[O:16])[C:9]5[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(O)cc1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccc(O)cc1

Procedure:
Compound 426 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-hydroxybenzoyl) aniline and 4-morpholinobenzaldehyde. [M+H]+ calcd for C24H22N4O3: 415.18; found: 415.17.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: 0 °C
Yield: 90.4 %

Procedure:
While stirring, D-leucine (76.6 g, 584 mmol, 1.0 eq) was dissolved into 920 mL of aq. 3.0 M HBr (2.8 mol, 4.7 eq) and cooled to 0° C. A solution of NaNO2 (64.5 g, 934 mmol, 1.6 eq) in 200 mL water was slowly added over 20 minutes and the mixture was stirred at 0° C. for 3 hours. The mixture was extracted 2× with 500 mL EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure, to yield (R)-2-bromo-4-methylpentanoic acid as a yellow oil (103 g). 1H-NMR (DMSO) δ (ppm): 0.9 (m, 6H), 1.6-1.7 (m, 1H), 1.7-1.9 (m, 2H), 4.3 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(F)cc1
Solvent: c1ccccc1
Product: NC(=S)c1ccc(F)cc1
Temperature: 25 °C
Yield: 146.8 %

Procedure:
4-Fluorobenzamide (5.0 g, 35.9 mmol) in benzene (100 ml) is added Lawesson's reagent (7,27 g, 18.0 mmol) and the resulting solution is heated to reflux for 1 hour. The solution is cooled to room temperature, concentrated and water (150 ml) added. The mixture is heated to reflux for 3 hours, and cooled to room temperature. The precipitate is filtered and dried under vacuum to yield 4-fluorothiobenzamide as a yellow solid (4.1 g, 71%). 1H NMR (CDCl3): δ 7.09 (t, 2H), 7.90(dd, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[N:16]=[C:17]([C:24]#[N:25])[C:18]([C:22]#[N:23])=[N:19][C:20]=1Cl>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:20]2[C:15]([Cl:14])=[N:16][C:17]([C:24]#[N:25])=[C:18]([C:22]#[N:23])[N:19]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2Cl)CC1
Temperature: -45 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a solution of 1-Boc-piperazine (8 mmol, 1.5 g) and anhydrous tetrahydrofuran cooled at −45° C. was added 5,6-dichloro-2,3-dicyanopyrazine (4 mmol, 800 mg). The mixture was stirred at −45° C. for 1.5 hours. Reaction mixture was concentrated and stirred in EtOAc, filtered and concentrated. The crude material was purified on silica column using 30% EtOAc/hexanes to yield 3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (640 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10](=[O:15])[CH:9]=[CH:8]2.C(O[CH2:20][C:21](=[CH2:27])[CH2:22][Si](C)(C)C)(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C:10](=[O:15])[CH:9]3[CH2:22][C:21](=[CH2:20])[CH2:27][CH:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc2oc(=O)ccc2c1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C=C1CC2C(=O)Oc3ccc(OCOC)cc3C2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxymethoxy coumarin 17a (21 g, 0.102 mol) and Pd(OAc)2 (2.75 g, 0.012 mol) in 500 mL THF add 2-(acetoxymethyl)allyl-trimethylsilane (26 mL, 0.122 mol) followed by triisopropyl phosphite (18.1 mL, 0.073 mol). After stirring at 60° C. overnight, cool the solution to RT, concentrate under reduced pressure, and dilute with EtOAc. Wash the solution with saturated aqueous sodium bicarbonate and brine. Dry over Na2SO4, and then concentrate to an oil. Purify the material by silica gel chromatography (Biotage 40M+65M columns, 10 to 30% EtOAc/Hex over 60 min at 50 mL/min followed by 30 to 50% EtOAc/Hex over 60 min at 50 mL/min) to give 18.3 g (0.070 mol, 69%) of cyclopentanoid 18 and 3.8 g (18.3 mmol, 18%) of recovered starting material. HRMS (ES+) calc for C15H17O4: 261.1127, found: 261.1122 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[C@@H:6]([CH3:16])[CH2:5]1)[CH:2]=[CH2:3].[OH-].[K+].C(=O)=O.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([N:4]1[CH2:5][C@@H:6]([CH3:16])[NH:7][CH2:8][C@@H:9]1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CCN1C[C@@H](C)NC[C@@H]1C
Temperature: 100 °C
Yield: 69 %

Procedure:
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105° C., while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 100° C. and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5° C. and maintained at 5° C. for 30 minutes. The solution was filtered, washing the filter cake with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans-1-allyl-2,5-dimethylpiperazine as a dark liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[C:37]([C:39]([O:41]C)=[O:40])[CH:38]=1)[CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][S:16]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:39]([C:37]1[CH:36]=[C:7]([CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][SH:16])[C:10]([OH:12])=[O:11])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:38]=1)([OH:41])=[O:40]
Reactant: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cc(C(C)(C)C)c1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC(CCCS)C(=O)O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-5-[(triphenylmethyl)thio]pentanoic acid XII (5.5 g, 9.7 mmol) in dichloromethane (30 mL) were added triisopropylsilane (2.4 mL, 11.6 mmol) and trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (1% AcOH in Hexanes/EtOAc, 4:1) to afford 3-carboxy-5-(1,1-dimethylethyl)-alpha-(3-mercaptopropyl)-benzenepropanoic acid 49 (1.7 g, 5.3 mmol, 55%) as a white solid: 1H NMR (CD3OD) δ 1.3 (s, 9H), 1.5-1.8 (m, 4H), 2.4 (m, 2H), 2.6-2.7 (m, 1H), 2.8-2.9 (m, 1H), 2.9-3.0 (m, 1H), 7.5 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H); 13C NMR (CD3OD) δ 24.8, 31.7 (3C), 31.9, 32.9, 35.6, 39.5, 48.6, 125.7, 128.5, 131.6, 132.0, 140.9, 152.8, 170.3, 179.0. Anal. Calcd for C17H24O4S: C, 62.93; H, 7.46; S, 9.88. Found: C, 63.02; H, 7.36; S, 9.82.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Yield: 46.5 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (100 g, 373 mmol) in DMF (190 mL) and water (10 mL) was added sodium cyanide (22 g, 448 mmol). The reaction was heated to 70 degrees Celsius for 3 hours, concentrated to a volume of 100 mL, and then the solution was diluted with 100 mL of ethyl acetate. After the solids were removed by filtration, water (250 mL) was added and the layers were separated. The organic layer was further washed with 3×100 mL of water. The organic layer was dried over MgSO4, filtered to remove solids, and then concentrated. Purification by distillation gave the desired product (37.124 g, 46%). B.P.=72-75 degrees Celsius.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][N:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[Si:18]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)[OH:12])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COc1ncc([C@@H](O)CO)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COc1ncc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-1-(2-methoxypyrimidin-5-yl)ethane-1,2-diol (3.46 g, 20.3 mmol) and imidazole (3.08 g, 44.7 mmol) was dissolved in methylene chloride (40 mL). The mixture was cooled to 0° C. and tert-butyldimethylsilyl chloride (3.48 g, 22.4 mmol) dissolved in methylene chloride (40 mL) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at room temperature overnight. The mixture was treated with water (200 mL) and extracted with methylene chloride (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].Br[CH:16]=[C:17]1[C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:18]1=2>>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:18]2[C:17](=[CH:16][C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]=2[CH:30]=1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=CBr
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=Cc1cccc(NS(C)(=O)=O)c1
Yield: 39 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-methanesulfonamidophenyl boronic acid (473 mg, 2.2 mmol) with 5-bromomethylene-2,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (690 mg, 2 mmol) to give 1.3 g crude product. Purify the crude product using column chromatography eluting with 10% EtOAc/hexane to 30% EtOAc/hexane to give 340 mg (39%) product as a pale yellow solid, mp 109.6° C. MS (ES) 436 (M+1), 434 (M−1). HPLC shows 91% purity at t=3.11 min.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1(/[CH:22]=[CH:23]/[C:24](Cl)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH:16]1(/[CH:22]=[CH:23]/[C:24]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=3[N:15]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][C:14](=[O:16])[CH3:15])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][C:14](=[O:16])[CH3:15])=[O:9])[CH2:6][S:7][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](CSC(C)=O)C(=O)NCCSC(C)=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution comprising 83 mg (0.31 mmol) of I-152 in 1 ml of pyridine is stirred at 0° C. and 90 μm (0.95 mmol) of acetic anhydride are added. The reaction mixture is maintained at 0° C. for 15 min, then it is allowed to return to ambient temperature and stirring is continued for 12 h. The solution is subsequently evaporated to dryness under vacuum and the residue formed is taken up in 30 ml of CH2Cl2. The organic phase is washed with water (3×20 ml), dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residual gum is crystallized from AcOEt and provides 73 mg (Yd=75%) of the expected compound in the form of colorless platelets. Rf (CH2Cl2/MeOH, 9.5/0.5): 0.46. M.p.=153-154° C. [α]D20=−33.7° (c 0.8, CHCl3).