Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13](I)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32]B(O)O.C([O-])([O-])=O.[K+].[K+].ClCCl>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([CH3:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(Cc2ccc3c(I)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccc3c(C)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A flask charged with compound methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-iodonaphthalen-2-yl)methyl)azetidine-3-carboxylate (300 mg, 0.56 mmol), methylboronic acid (66 mg, 1.1 mmol, 2.0 eq), 2 M aq K2CO3 (5 mL, 3.0 equiv) and [1,1-bis(diphenylphosphino) ferroene]dichloropalladium (II) complex with dichloromethane (1:1) (45 mg, 0.05 mmol, 0.1 equiv) was flushed with nitrogen. 1,4-Dioxane (20 mL) was added and the reaction was stirred at 90° C. for 5 h. The solution was cooled to room temperature. The solvent was removed and the residue was purified by column chromatography (PE/EA=1:1) to give compound the title compound as a white solid (80 mg, 33%). ESI-MS (M+H+): 424.3. 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, 1H), 7.64-7.61 (m, 2H), 7.40 (dd, 1H), 7.23 (d, 1H), 4.10-4.08 (m, 1H), 3.79 (s, 2H), 3.74 (s, 3H), 3.59-3.56 (m, 2H), 3.39-3.36 (m, 3H), 2.53 (s, 3H), 2.20-2.17 (m, 2H), 1.86-1.83 (m, 2H), 1.48-1.43 (m, 2H), 1.10-1.26 (m, 3H), 0.86 (s, 9H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I-:10].[K+].[OH-].[Na+]>CO.O>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: [I-]
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Ic1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500 mL 3-necked round bottom flask, was placed a solution of 1H-indole (10 g, 85.40 mmol) in MeOH/H2O (150/30 mL). To this was added potassium iodide (15.6 g, 93.98 mmol). To the mixture was added sodium hydroxide (3.76 g, 94.00 mmol). To the above was added 12 (23.88 g, 94.02 mmol) in several batches. The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:10). The reaction mixture was then quenched by the adding 100 mL of H2O. A filtration was performed. The filter cake was washed 3 times with 200 mL of water. This resulted in 18 g (84%) of 3-iodo-1H-indole as a light yellow solid.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:3]([OH:5])=[O:4].[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][SH:18]>>[C:9]([CH2:8][CH2:7][CH2:6][CH:2]([S:18][CH2:17][CH2:16][C:15]([O:14][CH3:13])=[O:19])[C:3]([OH:5])=[O:4])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCS
Reactant: COC(=O)CCCC(Br)C(=O)O
Product: COC(=O)CCCC(SCCC(=O)OC)C(=O)O

Procedure:
5-Carbomethoxypentanoic acid (12), wherein alk is methyl, was reacted with thionyl chloride and then N-bromosuccinimide (NBS) followed by base hydrolysis to give 2-bromo-5-carbomethoxypentanoic acid (13). Compound (13) was reacted with methyl-3-mercaptopropionate (m=1, R1 '=H and R2 '=OCH3) to yield 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanoic acid (14). Compound (14) reacted first with diborane and then with dimethylsulfoxide and trifluoroacetic anhydride to afford 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanal (15). Compound (15) was reacted under Wittig conditions with tridecyltriphenylphosphonium ylid to yield methyl-5-[(2-carbomethoxyethyl)thio]-6(Z)-nonadecenoate (16) which was saponified to afford a compound of the formula (IV) wherein m is 1, R1 is hydrogen, and R2 is hydroxyl.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:19]=O.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:19][N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 5.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of methanol was added 15 ml of 37% formaldehyde. After refluxing for 1 hour, the solution was cooled to ice bath temperature, treated (portionwise), with 2.5 g of sodium borohydride, and then stirred at ambient temperature for one hour. Evaporation of the volatiles yielded a residue which was taken up in ethyl acetate, washed with water followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Concentration afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% methanol/dichloromethane) to yield 4.2 g of 1-methyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil which was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate 2.34 g (39%) of the corresponding hydrochloride salt, m.p. 151°-153° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[F:16][C:17]1([F:33])[C@H:21]([CH3:22])[N:20](C(=O)[C@H](CC(C)C)N)[C@H:19]([C:31]#[N:32])[CH2:18]1>>[F:16][C:17]1([F:33])[C@H:21]([CH3:22])[N:20]([C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH2:8])[C@H:19]([C:31]#[N:32])[CH2:18]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N1[C@H](C#N)CC(F)(F)[C@@H]1C
Product: CC(C)[C@H](N)C(=O)N1[C@H](C#N)CC(F)(F)[C@@H]1C

Procedure:
This compound was prepared from 51 mg (0.23 mmol) of (S)-N-tert-butoxycarbonylvaline and 50 mg (0.23 mmol) of (2,5-cis) 4,4difluoro-5-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (Example 95G) according to the same five step sequence as for (2S,5S) 4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile (example 95H through example 95L) to give the titled compound as a colorless foam. 1H NMR (500 MHz, DMSO-d6) (mixture of rotamers, major rotamer only) δ ppm 0.99 (m, 6 H) 1.37 (m, 3 H) 2.11 (m, 1 H) 2.96 (m, 1 H) 3.09 (m, 1 H) 4.09 (bs, 1 H) 4.65 (m, 1H) 5.06 (t, J=8.6 Hz, 1 H) 8.31 (bs, 3 H) MS (ESI) m/z=246 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[CH3:24][C:25]1([CH3:32])[NH:30][CH2:29][CH2:28][NH:27][C:26]1=[O:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:24][C:25]1([CH3:32])[N:30]([C:21](=[O:23])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:29][CH2:28][NH:27][C:26]1=[O:31]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC1(C)NCCNC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C(=O)NCCN1C(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.15 g, 0.485 mmol) and 3,3-dimethylpiperazin-2-one (CAS 22476-74-0) (0.062 g, 0.485 mmol) in dichloromethane (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.184, 0.485 mmol) and diisopropylethylamine (0.53 mL, 2.91 mmol). The reaction mixture was stirred at ambient temperature overnight and then concentrated followed by chromatographic purification on an Analogix silica gel column eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.05-8.11 (m, 1H), 7.16-7.32 (m, 10H), 4.20 (s, 2H), 3.46-3.52 (m, 2H), 3.33-3.41 (m, 2H), 3.16-3.22 (m, 2H), 2.51-2.57 (m, 2H), 1.63-1.75 (m, 2H), 1.60 (s, 6H); MS (DCI+) m/z 420 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:26]([OH:28])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:52][C:53]([F:64])([F:63])[O:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C@@H:10]([C:26](=[O:28])[NH:60][CH2:59][C:58]2[CH:61]=[CH:62][C:55]([O:54][C:53]([F:52])([F:63])[F:64])=[CH:56][CH:57]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)cc2)C1
Yield: 55.3 %

Procedure:
To a solution of the compound (168 mg) obtained in Step 2 in N,N-dimethylformamide (1.7 ml) were successively added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole hydrate (75 mg) and 4-trifluoromethoxybenzylamine (85 mg). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (132 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccoc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccoc1
Yield: 77.2 %

Procedure:
8.3 g of N-(4-chlorobenzoyl)-(3-furylcarbonyl)methylamine, 1.5 g of 61% sodium hydride and 5.8 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 8.5 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-furylcarbonyl)propionate are thereby obtained. Yield: 77.3%
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][S:11][CH3:12])[CH:7]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][S:11][CH3:12])[CH:7]=1
Reactant: CSC[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N[C@@H](CSC)C(=O)O)c1

Procedure:
27 g of N-(5-fluoro-2-nitrophenyl)-S-methyl-L-cysteine (0.1 mol) from Example 1 are dissolved in 150 ml of absolute methanol in a four-necked flask, and 14.4 g of 95% sodium methoxide (0.25 mmol) are added in portions, within the space of 20 minutes and under argon, to this solution while stirring well and while cooling by means of an ice bath. The mixture is then heated to reflux for 2 hours while stirring. TLC monitoring then indicates that the reaction is complete.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](/[CH:13]=C/COC)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[O:18]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:18])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[O+][O-]
Reactant: COC/C=C/c1cc(C(=O)OC)cc(Br)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C)c(C=O)c1
Temperature: 25 °C

Procedure:
To a dichloromethane (0.16 M) solution of methyl 3-bromo-5-[(1E)-3-methoxy-1-propen-1-yl]-4-methylbenzoate (1 eq., Amine 88, Step 1) was bubbled at −78° C. with freshly generated ozone until a persistent blue color was observed. The reaction vessel was then thoroughly purged with nitrogen before triphenylphosphine (1.1 eq.) was added. The resulting mixture was slowly warmed to RT over 6 h. The volatiles were then removed in vacuo and the resulting residue was suspended in a 1:1 (v/v) mixture of hexanes and ether. The insolubles were removed via filtration through a pad of silica gel. Concentration of the filtrate thus obtained in vacuo afforded a white solid. Further purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH2:21]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][C:30]([C:35](O)=[O:36])=[CH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:35]([C:30]3[CH:31]=[CH:32][C:33](=[O:34])[N:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=3)=[O:36])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc(=O)n(Cc2ccccc2)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(=O)n(Cc2ccccc2)c1

Procedure:
Benzyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-benzyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid. MS calcd. for C29H23ClN3O3 [(M+H)+] 496.1, obsd. 496.1.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C1(S(O[C@H:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:27])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CC(CC)=O>O>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][C@@H:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCC[C@H](C)OS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCC[C@@H](C)Oc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Yield: 91.4 %

Procedure:
A mixture of 4 g of ethyl 4-hydroxy-3-nitrobenzoate, 5.4 g of (S)-2-octyl benzenesulphonate 6.9 g of potassium carbonate and 110 ml of ethyl methyl ketone was heated to reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue on silica gel with dichloromethane gave 5.6 g of ethyl 3-nitro-4-[(R)-2-octyloxy)benzoate as of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])[C:5](Cl)=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>O1CCOCC1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:5]2[C:4]([C:9]3[N:10]=[N:11][S:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[Cl:21])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:26][CH:25]=1
Reactant: Clc1cccc(-c2snnc2-c2cc(Br)cnc2Cl)c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncc(Br)cc2-c2nnsc2-c2cccc(Cl)c2Cl)cc1
Temperature: 120 °C
Yield: 90.3 %

Procedure:
To a solution of 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)-1,2,3-thiadiazol-4-yl)pyridine (0.37 g, 0.88 mmol) in dioxane (2 mL) was added 4-methoxybenzylamine (4 eq, 460 μL, 3.5 mmol). The solution was heated in a sealed tube at 120° C. for 18 h. After cooling, the mixture was filtered and the filtrate was reduced in vacuo. The resulting oil was purified by silica gel chromatography (5 to 70% EtOAc/hexanes) to provide N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)-1,2,3-thiadiazol-4-yl)pyridin-2-amine as a yellow sticky solid (415 mg, 90% yield)
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[C:1]([C:5]1[C:6]([NH:14][C:25](=[O:26])[CH2:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]([CH3:16])[CH3:17])=[CH:19][CH:20]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)c1ccc(CC(=O)Nc2nn3cccnc3c2C(C)(C)C)cc1

Procedure:
The product from Example 105B and 4-isopropylphenylacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.7 Hz, 3H), 1.39 (s, 9H), 2.82-2.91 (m, 1H), 3.58 (s, 2H), 6.99 (dd, J=7.1, 4.0 Hz, 1H), 7.18-7.23 (m, 4H), 8.48 (dd, J=4.0, 2.0 Hz, 1H), 8.91 (dd, J=7.0, 2.0 Hz, 1H), 9.91 (s, 1H); MS (DCI) m/z 351 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:8](=[O:16])[O:7][CH:6]2[OH:17])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CN(C=O)C.Cl>[CH2:1]([C:3]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[C:9]([C:8]([O:7][CH2:25][CH3:26])=[O:16])=[C:5]([CH:6]=[O:17])[CH:4]=1)[CH3:2]
Reactant: CCI
Reactant: CCc1cc2c(c(C(F)(F)F)c1)C(=O)OC2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)cc(CC)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of (±)-5-ethyl-3-hydroxy-7-(trifluoromethyl)isobenzofuran-1 (3H)-one (1.97 g, 8.0 mmol) in 20 mL of DMF was added potassium carbonate (4.42 g, 32.0 mmol) followed by iodoethane (1.92 mL, 24.0 mmol). The resulting mixture was allowed to stir at ambient temperature for 1 h. The reaction was diluted with 1N HCl to pH ˜4 and extracted with EtOAc. The organics were washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (elution with 10% EtOAc/hexane) to afford 1.8 g (83%) of the title compound. 1H NMR (CDCl3): δ 10.05 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 4.47 (q, 2H), 2.80 (q, 2H), 1.38 (t, 3H), 1.29 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:27]=[CH:26][C:14]4[N:15]=[C:16]([NH:18][C@@H:19]5[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]5[OH:25])[S:17][C:13]=4[CH:12]=3)[C:6]=2[CH:28]=1.BrC1C=CC2N(CC3C=CC4N=C(N[C@@H:46]5CCCC[C@H:47]5[OH:52])SC=4C=3)C=NC=2C=1>>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([CH2:10][N:7]3[C:6]4[CH:28]=[C:2]([C:47](=[O:52])[CH3:46])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH:27]=[CH:26][C:14]=2[N:15]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)cc43)cc2s1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Product: CC(=O)c1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2c1

Procedure:
1-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanone was synthesized as a white powder (8 mg, 6%) using a procedure analogous to that described in Example 110, substituting (1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Steo 6 of Example 107 for (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol used in Example 110. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.24 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 5.58 (s, 2H), 4.75 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.61 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.10-1.34 (m, 4H); LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(C)=CC=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(Cl)c1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Reaction time: 24 h

Procedure:
3-(m-Chlorophenyl)-3-hydroxy-3H-indol-2-one (25.9 g., U.K. specification No. 1,125,671), xylene (400 ml.), 3-aminopropanol (15 g.) and toluene-p-sulphonic acid (150 mg.) were heated under reflux, with stirring, in an apparatus fitted with a water separator. After 24 hours, 6.9 ml. of water and 3-aminopropanol had been collected. The mixture was cooled and the xylene removed under reduced pressure leaving a yellow crystalline material which was recrystallised from ethyl acetate to give the title compound (14.33 g.), m.p. 164° to 165°C. (Found C, 64.45; H, 5.4; N, 8.85. C17H17Cl2N2O2 requires C, 64.75; H, 5.6; N, 8.7%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34](O)=[O:35])[CH:25]=1>>[OH:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:34]([C:26]3[CH:25]=[N:24][C:33]4[C:28]([CH:27]=3)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:35])[CH2:3][CH2:2]1)[CH2:11]2
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Product: CCCN(CCN1CCN(C(=O)c2cnc3ccccc3c2)CC1)C1CCc2c(O)cccc2C1
Yield: 99.9 %

Procedure:
Compound 40j was prepared following Procedure G using 39b (172 mg, 0.542 mmol) and quinoline-3-carboxylic acid (112 mg, 0.650 mmol) to give 40j (256 mg, 85%) after column chromatography. 1H NMR (400 MHz, CD3OD) 0.93-0.96 (t, 3H, J=7.2 Hz), 1.57-1.59 (m, 3H), 2.18 (m, 2H), 2.55-3.00 (m, 14H), 3.55 (bs, 2H), 3.85 (bs, 2H), 6.53-6.58 (t, 2H, J=8 Hz), 6.88-6.91 (t, 1H, J=11.2 Hz), 7.81-7.72 (t, 1H, J=7.6 Hz), 7.85-7.88 (t, 1H, J=7.6 Hz), 8.03-8.1 (m, 2H), 8.45 (bs, 1H), 8.89 (bs, 1H). The free base of 40j was converted into its HCl salt. m.p. 142-146° C. Anal. [C29H36N4O2.3HCl.2H2O] C, H, N.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:7])\[CH:4]([CH3:6])[CH3:5].[Cl:8][CH2:9][CH2:10][C:11](O)=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[Cl:8][CH2:9][CH2:10][C:11]1[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=1
Reactant: CC(C)/C(N)=N\O
Reactant: O=C(O)CCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)c1noc(CCCl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-N′-hydroxyisobutyrimidamide (510 mg, 5 mmol), 3-chloropropanoic acid (542 mg, 5 mmol) and dicyclohexylcarbodiimide (1.24 g, 6 mmol) in anhydrous dioxane (20 mL) was stirred at 0° C. for 1 h and then at room temperature for an additional 1 h. The reaction was then heated at 80° C. for an additional 18 h. The reaction was filtered and the filtrate was evaporated. The resulting residue was purified by silica chromatography (0-100% EtOAc in hexanes gradient) to give 5-(2-chloroethyl)-3-isopropyl-1,2,4-oxadiazole; 1H NMR (400 MHz, CDCl3) δ 3.85 (t, J=7.2 Hz, 2H), 3.27 (t, J=7.2 Hz, 2H), 3.03 (septet, J=7.2 Hz, 1H), 1.13 (d, J=7.2 Hz, 6H); ESMS m/z 175.1 (M+H+).