Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:33]([CH3:35])[C:31]([CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:32]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (41 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-amino-N,N-dimethyl-acetamide (0.33 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 494. 1H NMR (DMSO-d6, 400 MHz): δ 8.42 (t, 1H), 8.09 (s, 1H), 7.90 (m, 1H), 7.78 (br, 1H), 7.72 (br, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.34 (m, 1H), 4.11 (d, 2H), 3.63 (s, 3H), and 3.00 (d, 6H).
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[NH:9][C:10]3[C:11](=[CH:12][C:13]4[NH:14][C:15]5[C:20]([C:21]=4[CH:22]=3)=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:4]=12.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CS(C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CO>[CH2:24]([N:14]1[C:13]2[C:21](=[CH:22][C:10]3[N:9]([CH2:7][CH2:8][CH2:3][CH2:4][CH2:11][CH2:10][CH2:22][CH3:21])[C:5]4[C:4]([C:11]=3[CH:12]=2)=[CH:3][CH:8]=[CH:7][CH:6]=4)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1cc3c(cc12)[nH]c1ccccc13
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCCCCCCCn1c2ccccc2c2cc3c(cc21)c1ccccc1n3CCCCCCCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 180.4 %

Procedure:
A freshly prepared 50% aqueous NaOH solution (4 mL) was added to a well-stirred mixture of 5,11-dihydridoindolo[3,2-b]carbazole, (0.513 g, 2 mmol), benzyltriethylammonium chloride (0.09 g, 0.4 mmol), 1-bromooctane (1.55 g, 8 mmol), and DMSO (20 mL) in a 100-mL flask under an argon atmosphere. The mixture was stirred at room temperature for 2.5 h and then heated to 65° C. and maintained at this temperature for 4 h. Subsequently the reaction mixture was cooled down to room temperature and poured into 200 mL methanol with stirring. The precipitated yellow solid was filtered off and washed with water, and 3 times each with N,N-dimethylformamide, methanol, and acetone. The yellow solid was purified by column chromatography on silica gel using hexane as eluent. Recrystallization from hexane yielded 0.867 g (90.1%) of 5,11-dioctylindolo[3,2-b]carbazole, (1), which was subject to train sublimation to obtain electrically pure material for OTFT fabrication. DSC showed two endotherms at 84° C. and 101° C. on heating. 1H NMR (CDCl3): δ8.21 (d, J=7.6 Hz, 2H), 8.01 (s, 2H), 7.47 (dd, J1=7.0 Hz, J2=0.9 Hz, 2H), 7.41 (d, J=7.6 Hz, 2H), 7.21 (dd, J1=7.0 Hz, J2=0.9 Hz, 2H), 4.40 (t, J=7.3 Hz, 4H), 1.95 (pent, J=7.3 Hz, 4H), 1.25-1.50 (m, 20H), 0.86 (m, 6H); IR (NaCl): 3050, 2952, 2921, 2852, 1510, 1469, 1482, 1326, 737 cm−1.
Reaction SMILES: [OH:1]C1C2C(=CC=CC=2)C(=O)N1CC1SC=CC=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([S:28][CH2:29][C:30]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:31])[N:20]1[CH2:38][C:39]1S[CH:41]=[CH:42][CH:43]=1>>[O:1]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][N:20]1[C:19](=[O:18])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[S:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)=[O:31]
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1nccs1
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Product: O=C(CSC1c2ccccc2C(=O)N1Cc1ccco1)Nc1nccs1

Procedure:
Compound 32 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 14 and illustrated in Scheme 1b. 1H NMR (300 MHz, DMSO): δ 11.96 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.59 (m, 4H), 7.48 (m, 2H), 7.42 (d, J=4 Hz, 1H), 7.19 (d, J=4 Hz, 1H), 5.76 (s, 1H), 4.97 (d, J=16 Hz, 1H), 4.44 (d, J=16 Hz, 1H), 3.09 (d, J=15 Hz, 1H), 2.95 (d, J=15 Hz, 1H). MS: m/z (MH+) 386.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([OH:22])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3ccccc3F)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 86A in analogy to the synthesis of the compound of Example 1. 34 mg (88% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[O:15]CC3C=CC=CC=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29](=[O:36])[NH:30][CH2:31][CH:32]([OH:35])[CH2:33]Cl)([CH3:27])([CH3:26])[CH3:25].CC(C)([O-])C.[Li+].[NH4+].[Cl-]>CN(C=O)C.C1COCC1.O>[S:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:33][C@H:32]([CH2:31][NH:30][C:29](=[O:36])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[O:35][C:14]3=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC(O)CCl
Reactant: O=C(Nc1ccc(N2CCSCC2)cc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3CCSCC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the product of Step 2 (7.0 g, 21.3 mmol) in DMF (14 mL) is cooled at. 0° C. and treated with (3-chloro-2-hydroxy-propyl)carbamic acid tert-butyl ester (5.6 g, 27 mmol) and then lithium tert-butoxide (51 mL of a 1.0 M solution in THF) dropwise over 15 min. The reaction mixture is stirred for 20 h at room temperature and then treated with 40 mL of satd. NH4Cl and 100 mL of H2O. The solution is extracted with two portions of dichloromethane and the combined organic phases washed with H2O, brine and dried (MgSO4), filtered and concentrated. The crude product is purified by column chromatography (0-50% ethyl acetate-hexanes) to provide the title compound as a foam.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])=[S:20])=[C:14]([OH:30])[C:13]=1[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].N1C=CN=C1>>[CH3:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:31]([N:34]([CH3:35])[CH3:36])(=[O:32])=[O:33])[C:14]=1[O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(F)cccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: Cc1c(F)cccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Yield: 49 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-methyl-3-fluorophenyl)thiourea (530 mg, 1.27 mmol), tert-butyldimethylsilyl chloride (951 mg, 6.35 mmol) and imidazole (173 mg, 2.54 mmol) were reacted to form the desired product (331 mg, 49%). EI-MS m/z 532.2 (M+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][CH2:15]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11](=[O:20])(=[O:19])[NH:12][CH2:13][CH:14]2[O:18][CH2:17][CH2:16][CH2:15]2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)NCC2CCCO2)c1
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)NCC2CCCO2)CC1

Procedure:
The reaction was carried out in a manner analogous to that of Example 31, using 32 g of 4-chloro-3-tetrahydrofurfurylsulfamoyl-benzoic acid and 30 g of N-methylpiperazine. The crude product was purified by recrystallization from ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.FC1C=CC(CN2C3C=CC=CC=3N=C2NC2CCN(CC[N:35]=[C:36]=[S:37])CC2)=CC=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:36](=[S:37])[NH2:35])[CH:2]=1
Reactant: NCc1cccnc1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: NC(=S)NCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 part of 3-pyridinemethanamine, 3.9 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 45 parts of tetrahydrofuran was stirred for 4 hours at room temperature. The reaction mixture was evaporated in vacuo. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 3.4 parts (65.7%) of N-[2-[4-[[1-(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]-N'-(3-pyridinylmethyl)thiourea; mp. 147.2° C. (compound 102).
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:8][CH2:9][CH:10]([N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(OCC)C>C(O)(=O)C.C(O)C.[Pt]=O>[C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:8][CH2:9][CH:10]([NH:12][CH:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CN=C(c1ccccc1)c1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CC(CNC(c1ccccc1)c1ccccc1)NC(c1ccccc1)c1ccccc1

Procedure:
180 g of N,N'-bis-(diphenylmethylene)-1,2-propylenediamine are dissolved in 540 ml of acetic acid. 3 g of platinum oxide are added and the mixture is scavenged thoroughly with argon and then hydrogen is introduced while stirring vigorously until starting material can no longer be detected by thin layer chromatography (silica gel 60, diethyl ether: Rf =0.62) (generally 24 to 48 hours). The reaction solution is diluted with 150 ml of ethanol, the catalyst is filtered off and then the filtrate is concentrated to dryness by evaporation under reduced pressure in a water bath. The oil residue obtained after concentration by evaporation is triturated with 375 ml of 10% sodium hydroxide solution and extracted twice with 375 ml of diethyl ether each time. The ether phases are combined, washed twice with 70 ml of saturated sodium chloride solution each time, dried over magnesium sulphate and then evaporated to dryness on a water bath, first at approximately 20 mbar and then at approximately 0.03 mbar. The residue is dissolved in approximately 300 ml of ethanol, water is added until the solution starts to become cloudy (approximately 20 ml) and then the whole is caused to crystallise in an ice bath. The precipitated crystals are filtered with suction, washed with a little methanol and dried thoroughly at approximately 0.03 mbar. N,N'-bis-(diphenylmethyl)-1,2-propylenediamine having a melting point of 72°-75° C. is obtained which can be further purified by recrystallisation from approximately double the quantity of methanol and by precipitation with water, and then melts at 75°-77° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1(F)CCCNC1
Product: Cc1nc(N2CCCC(F)(F)C2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 6-chloro-2-methyl-3-nitropyridine and 3,3-difluoropiperidine following the method used to prepare Intermediate 51. LCMS (ES+) 258.05 (M+H)+, RT 3.069 minutes (method 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][NH:48][C:49](=[O:54])[C:50]([F:53])([F:52])[F:51])=[CH:43][CH:42]=2)[C:36]([N:55]=[O:56])=[C:35]([NH2:57])[N:34]=1.Cl>C1COCC1>[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][NH:48][C:49](=[O:54])[C:50]([F:52])([F:53])[F:51])=[CH:45][CH:46]=2)[C:36]([N:55]=[O:56])=[C:35]([NH:57][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[N:34]=1
Reactant: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)Nc1nc(N)nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c1N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Under an argon atmosphere 4-(tert-butoxycarbonylamino)-butyric acid (1.58 g, 8 mmol) is dissolved in 20 mL dry THF and cooled to 0° C. Diisopropyl ethylamine (1.18 g, 9 mmol) is added, the mixture cooled to −20° C., and chloroformic acid isobutylester (1.15 g, 8 mmol) added. The mixture is stirred at this temperature for 5 min, and nitroso-pyrimidine 38 (Example 21, 2.64 g, 7 mmol) dissolved in 20 mL dry THF is added via a syringe. The reaction mixture is allowed to warm to room temperature, heated to 55° C. and stirred at this temperature over night. After cooling to room temperature, the mixture is poured into 100 mL of 1 N HCl and the product extracted with ethyl acetate (300 mL). The combined organic phases are washed with water and brine, subsequently dried over MgSO4 and the solvent evaporated. The residue is adsorbed on SiO2 and purified by flash column chromatography (cyclohexane/ethyl acetate 1:2 to 1:10) to yield the title compound as a blue solid (1.96 g, 3.53 mmol, 50.4%). From the crude material, an analytical sample is recrystallized from ethyl acetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A suspension consisting of 1,1′-(4-bromobutylidene)bis[4-fluorobenzene] (25 g, 77 mmol) and potassium phthalimide (17 g, 92 mmol) in 300 mL DMF was stirred at 50° C. for 16 hours, cooled to 25° C., and poured into 900 mL of cold H2O. The mixture was extracted with ethyl acetate (3×300 mL), and the combined extracts were washed with H2O (2×1 L), followed by brine (700 mL), then dried over anhydrous sodium sulfate. Evaporation of solvent in vacuo afforded 28.6 g of a golden oil, which was triturated with 250 mL 2,2,4-trimethylpentane containing 5% 2-propanol, and the solid thus obtained was collected by filtration and dried at 50° C. in vacuo, to give 28.7 g (97%) of titled compound as a white powder; mp 69-70° C. APCI-MS m/z 391.1 (M−).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C(OCC)C>[CH2:35]([O:34][C:32]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH3:23])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:13][CH:14]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(c1ccccc1)c1ccc(OC[C@H]2CCC[C@H]2N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(C(C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of (±) cis-1-amino-2-[4-(1-methyl-1-phenylethyl)phenoxymethyl] cyclopentane (0.35 g, 1.13 mmol) in dry diethyl ether (30 ml) containing triethylamine (0.31 ml, 2.26 mmol) was added a solution of ethyl chloroformate (0.18 g, 1.70 mmol) in diethyl ether (5 ml). The reaction was stirred at room temperature for 2 h and then poured into ice-water. The pH of the aqueous phase was adjusted to approximately 7 by the addition of dilute hydrochloric acid. The aqueous layer was separated and extracted with diethyl ether (2×30 ml). The combined organic layers were washed with water followed by brine, then dried over sodium sulfate and concentrated in vacuo to give an oil (0.41 g) which was used in the next stage without purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:5][CH:4]=1)=O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[N:24]1([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(CN3CCCCC3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 8 (2.0 g), piperidine (0.91 mL), and acetic acid (0.42 mL) in DCM (100 mL) was treated with sodium triacetoxyborohydride (1.95 g) at room temperature. After 16 h, the resulting mixture was treated with 10% aqueous sodium hydroxide (30 mL). The aqueous phase was extracted with DCM (2×300 mL). The combined organic phases were dried (magnesium sulfate) and concentrated under reduced pressure. The residue was diluted in DCM (100 mL) and passed through a pad of silica gel. The pad was washed with DCM (3×200 mL). The combined filtrate was concentrated under reduced pressure, giving the title compound as a brown oil (2.3 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:5]([C:13]2[CH:14]=[CH:15][C:10]([CH3:18])=[CH:11][CH:12]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: O=Cc1cccc(I)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cccc(I)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodobenzaldehyde (10 g) in tetrahydrofuran (50 mL) at 30° C. is added a 0.43M solution of p-tolylmagnesium bromide in tetrahydrofuran. After stirring at 50° C. for 1 hour, the reaction mixture is hydrolyzed with a saturated aqueous solution of ammonium chloride and extracted ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient heptane/ethyl acetate 95/5 to 90/10) to yield (3-iodophenyl)-p-tolylmethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[CH3:15][O:16][C:17](=[O:21])[CH:18](Br)[CH3:19].C(=O)=O>>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:19]
Reactant: Cc1cccc(C)c1N
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Product: COC(=O)C(C)Nc1c(C)cccc1C
Reaction time: 1 h

Procedure:
6 g-moles of 2,6-dimethylaniline, 6.6 g-moles of NaHCO3 and 18.0 g-moles of α-bromopropionic acid methyl ester are placed together and heated slowly, with stirring, for 1 hour upto 120°-125° C. bath temperature. As CO2 is evolved, stirring of the mixture at this temperature is continued for 18 hours. The mixture is subsequently cooled, the inorganic constituents are filtered off, and the filtrate distilled in a water-jet vacuum (ca. 10- 12 Torr). After removal of the excess α-bromopropionic acid methyl ester, the resulting yield is 990.3 g (79.6% of theory) of final product, which boils at 133°-134° (12 Torr).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]=[O:10].C[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:6]([CH3:7])=[C:5]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)[S:4][C:3]=2[CH:9]=[O:10])=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(I)sc(C=O)c1Br
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)cc1
Yield: 109.6 %

Procedure:
Starting from 3-bromo-5-iodo-4-methylthiophene-2-carbaldehyde (3.2 g, 9.7 mmol, Compound III) and 4-methoxyphenylboronic acid (3.2 g, 21 mmol, 2.2 eq), the title compound (3.3 g, 94%, m.p. 223-25° C.) was synthesized in essentially the same manner as described in Example 1, Steps 1 and 4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([O:14]C(OCC)C)[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate (3.80 g, 0.00834 mol) in 67 mL of THF was added 13 mL of water followed by 13 mL of 1 N HCl. The mixture was stirred at rt for 1 h. After diluted with ethyl acetate, the mixture was neutralized with 1N NaOH, washed with brine, dried. The residue after concentration was purified on column, eluting with 0 to 50% EtOAc in hexane, to generate the corresponding alcohol compound (2.90 g, 90.6%). MS (ESI): (M+H)+=384.1.