Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[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>[Cl:12][C:4]1[CH:3]=[C:2]([CH:13]2[CH2:15][CH2:14]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2CC2)cc1Cl
Temperature: 110 °C
Yield: 63.2 %

Procedure:
Charged methyl 4-bromo-2-chlorobenzoate (1.50 g, 6.01 mmol), cyclopropylboronic acid (931 mg, 10.82 mmol), Pd(PPh3)4 (347 mg, 0.30 mmol), K3PO4 (1.82 g, 18.04 mmol), toluene (15 mL) and water (15 mL) to a flask, the mixture was then purged with nitrogen, and heated to 110° C. overnight. It was then cooled to room temperature and filtered, the filtrate was extracted with ethylacetate twice, concentrated the organic phase and purified by flash column chromatograph to give 800 mg of the title compound (63%). 1H NMR (400 MHz, CDCl3): δ 0.73-0.77 (2H, m), 0.98-1.07 (2H, m), 1.85-1.90 (1H, m), 3.90 (3H, s), 6.96 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.11 (1H, d, J=1.6 Hz), 7.74 (1H, d, J=8.0 Hz).
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1/[CH:14]=[CH:15]/[C:16]([CH3:18])=[O:17]>C1COCC1>[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:12])([CH3:13])[C:7]=1/[CH:14]=[CH:15]/[C:16]([OH:17])([CH:2]=[CH2:3])[CH3:18]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(O)/C=C/C1=C(C)CCCC1(C)C
Temperature: 7.5 °C
Yield: 837.1 %

Procedure:
0.1 mols of magnesium turnings are suspended in 50 ml of THF and treated with some drops of a solution of 0.12 mols of vinyl bromide in 100 ml of THF with stirring and under nitrogen atmosphere. As soon as the Grignard starts to form, the mixture is is cooled to 5-10° C. and added with the remaining solution of vinyl bromide in 30 min. The mixture is then cooled to −60° C. and added with 0.09 mols of beta ionone in 100 ml of THF in 20 min. The mixture is left to warm to room temperature, then heated at 40° C. for 2 hours. After that, the reaction is quenched as above described and vinyl beta-ionol is recovered by double distillation under vacuum, to obtain 166 g of a product, corresponding to an about 84% yield, with purity higher than 90%, determined by NMR.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[Pd]>[NH2:11][C:9]1[C:8]([F:14])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(C(=O)O)cc1F
Reaction time: 8 h
Yield: 93.1 %

Procedure:
2,5-Difluoro-4-nitrobenzoic acid (1 g, 4.9 mmol) was dissolved in ethanol. 10% Palladium on carbon (500 mg) was added and reaction stirred under a hydrogen balloon overnight. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to afford the title compound (0.79 g).
Reaction SMILES: N1C=CC=CC=1.[C:7]([NH:14][CH2:15][CH2:16]O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CCOCC>[C:7]([NH:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Pyridine (1.5 mL, 18.5 mmol) was added to 2-(N-Boc-amino)-ethanol (280 mg, 1.7 mmol) at 0° C. Tosyl chloride (1.65 g, 8.7 mmol) was then added and the reaction was allowed to stir at 0° C. overnight. The resulting cloudy reaction was diluted with Et2O and washed with water, saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The resulting white solid was purified using SiO2 with AcOEt/petroleum ether 20:80 to 30:70. A white solid was obtained (250 mg, 46%). NMR 1H (ppm, CDCl3): 7.77 (d, J3=8.3 Hz, 2H), 7.33 (d, J3=8.0 Hz, 2H), 4.82 (br. s., 1H), 4.05 (t, J3=5.08 Hz, 2H), 3.38-3.33 (m, 2H), 2.43 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].CC(O)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1-c1cccc(C(=O)O)c1
Temperature: 80 °C

Procedure:
To a mixture of 3-iodobenzoic acid (11.9 g, 48 mmol), 4-chloro-2-methylphenylboronic acid (9.8 g, 57.7 mmol) and sodium carbonate (6.1 g, 57.7 mmol) under nitrogen atmosphere, was added i-PrOH-water (1/1, 180 mL) followed by 10% Pd—C (2 g, 19.2 mmol) with caution. The reaction mixture was heated at 80° C. under nitrogen overnight. The catalyst was removed by filtration, and the filtered catalyst was washed with EtOH (60 mL). Most of organic solvent was removed under reduced pressure. The resulting aqueous residue was treated with 2N HCl (aq) to bring the pH <2. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 9.7 was obtained as white solid (12 g), which was used directly in the next step. MS ESI (neg.) m/e: 245 (M−H).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[C:11]([O:10][C:9](=[O:15])[NH:8][C@H:3]([C:2](=[S:26])[NH2:1])[CH2:4][CH:5]([CH3:7])[CH3:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=S
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 140 %

Procedure:
A mixture of (S)-tert-butyl 1-amino-4-methyl-1-oxopentan-2-ylcarbamate (1.8 g, 8 mmol) and Lawesson's reagent (1.58 g, 4 mmol) in toluene (20 mL) was stirred at 90° C. for 2.5 h. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, 30 g, ethyl acetate/MeOH, 20/1) to yield the title compound (1.38 g, 72%) as yellow solid; MS: m/e 269.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:17]([NH2:20])[CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:20][CH2:17][CH2:18][CH3:19])[CH2:5][CH2:4]1
Reactant: CCCN
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCNC1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
10.0 g 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in 160 ml analytical grade tetrahydrofuran, and 2.72 g n-propylamine followed by 5.97 ml glacial acetic acid were added, while stirring in an ice-bath. 13.6 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 85 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 100 ml diethyl ether each time. The combined organic phases were then washed twice with 100 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. 5.00 g of the crude product obtained (9.79 g) were chromatographed over silica gel with diethyl ether, to which one percent by volume of aqueous ammonia solution (25 wt. %) was added, and an addition of methanol increasing from one to forty per cent by volume. 2.79 g of the nonpolar and 1.33 g of the polar diastereoisomer of N,N-dimethyl-1-phenyl-N′-propyl-cyclohexane-1,4-diamine were obtained. From a sample of 356 mg of the nonpolar diastereoisomer, 253 mg of the corresponding hydrochloride were obtained as described for example 1 with water and chlorotrimethylsilane in 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:22]([NH:24][CH:25]([CH:30]([CH3:32])[CH3:31])[C:26]([O:28]C)=[O:27])=[O:23])[S:20][CH:21]=2)=[CH:13][CH:12]=1>C1COCC1.O.[OH-].[Li+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:22]([NH:24][CH:25]([CH:30]([CH3:31])[CH3:32])[C:26]([OH:28])=[O:27])=[O:23])[S:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)cs1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 2-(4-(4-(3-(2-chlorophenyl)ureido)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (Example 23, 120 mg) in THF (2 ml), 1N lithium hydroxide monohydrate (1.2 ml) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated and added water, dilute HCl was added under stirring to pH acidic. The reaction mixture was filtered, and the residue was washed by water, and dried. The residue was dissolved in acetone, pet ether was added, solid was filtered and dried obtain title compound as solid. Yield: 70 mg (60%). 1H NMR (DMSO-d6, 300 MHz): δ 12.98 (bs, 1H), 9.59 (s, 1H), 8.48 (d, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.17 (d, 1H), 8.03 (d, 2H), 7.58 (d, 2H), 7.46 (d, 1H), 7.30 (t, 1H), 7.02 (t, 1H), 4.33 (s, 1H), 2.26 (s, 1H), 0.98 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][N:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[O:12][C:11]2=[O:25])=[C:4]([O:26][CH3:27])[CH:3]=1.N1C=CC=CC=1.[Br:34][CH2:35][C:36](Br)=[O:37].[K+].[Br-]>C1COCC1>[Br:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([O:26][CH3:27])[C:5]([CH2:9][N:10]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[O:12][C:11]2=[O:25])=[CH:6][C:7]=1[Cl:8])=[O:37]
Reactant: COc1cc(N)c(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Reactant: O=C(Br)CBr
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NC(=O)CBr)c(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazol-2(3H)-one (3 g, 7.5 mmol) and pyridine (0.68 ml, 8.41 mmol) were dissolved in THF (35 ml) under N2 and cooled to 0° C. Bromoacetyl bromide (0.72 ml, 8.26 mmol) was added dropwise and the reaction mixture stirred for 18 h at 24° C. before being partitioned between ethyl acetate (400 ml) and 0.1N HCl solution (50 ml). The organic phase was washed with saturated NaHCO3 solution and brine, and dried over MgSO4. Active carbon (500 mg) was added and the solution filtered through a plug of Celite. Concentration gave 3.8 g (98%); mp 140-182° C. (dec); IR(KBr, υ=cm-1) 3348, 2972, 1784, 1672, 1594, 1234, 1168, 1066; 1H NMR (300 MHz, DMSO-d6) δ 3.77 (3H, s), 4.15 (2H, s), 4.90 (2H, s), 7.47-7.48 (2H, m), 7.86 (2H, d, J=8.4 Hz), 7.96 (1H, d, J=8.3 Hz), 9.30 (1H, s); MS(ESl)m/z: 520(MH+)
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([CH:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@@H:29]2[CH2:34][CH2:33][C@H:32]([N:8]3[CH2:12][CH2:11][CH:10]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH2:9]3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN([C@H]2CC[C@@H](c3ccccc3)CC2)C1

Procedure:
The title compound, MS: m/e=386.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and 4-phenylcyclohexanone.
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)OC1C=CC=CC=1)(=[O:4])=[O:3].[CH3:21][N:22]([CH2:31][C:32]1[O:36][C:35]([CH2:37][S:38][CH2:39][CH2:40][NH2:41])=[CH:34][CH:33]=1)[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6](=[N:41][CH2:40][CH2:39][S:38][CH2:37][C:35]1[O:36][C:32]([CH2:31][N:22]([CH3:21])[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])=[CH:33][CH:34]=1)[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CN(Cc1ccc(CSCCN)o1)C(=O)OCC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Product: CN(Cc1ccc(CSCCN=C(NS(C)(=O)=O)Oc2ccccc2)o1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 78 %

Procedure:
11.6 g of diphenyl methanesulfonylimidocarbonate was dissolved in 40 ml of methylene chloride. With ice-cooling, thereto was added 15 g of 2-[[5-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl)aminomethyl]-2furyl]methylthio]ethylamine. The mixture was stirred for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: benzene:ethyl acetate=2:1) to obtain 17.8 g (yield: 78%) of oily N-methanesulfonyl-N'-[2-[[5-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl)aminomethyl]-2furyl]methylthio]ethyl]-O-phenylisourea.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1COCC1>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CC(C)c1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-isopropylbenzyl chloride (4{19}, 5 g, 29.6 mmol, 1 equiv.), piperazine (15.3 g, 177.9 mmol, 6 equiv.), THF (64.9 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{19} (5.82 g, 90%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.21 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 4.15 (q, 2H, J=7.0 Hz), 3.43 (s, 2H), 2.89-2.84 (m, 5H), 2.39 (br s, 4H), 2.25 (br s, 1H), 1.22 (d, 6H, J=6.5 Hz). 13C-NMR (125 MHz, CDCl3): δ 147.3, 135.0, 128.9, 125.9, 63.2, 54.1, 45.7, 33.5, 23.8.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:36])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>>[CH3:18][O:17][CH:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:36])[CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)=[C:7]([O:19][CH3:20])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(C(=O)Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 1-(4-Hydroxy-phenyl)-2-phenyl-ethanone following the Standard Procedure J. MS (ES) for C28H30O7 [M+H]+: 479.
Reaction SMILES: [NH2:1][C:2]1[C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:19](OCC)(OCC)(OCC)[CH2:20][CH3:21]>C(O)(=O)C>[CH2:20]([C:21]1[NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:2]=2[N:1]=1)[CH3:19]
Reactant: COc1ccc(COc2cccc(N)c2N)cc1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)O
Product: CCc1nc2c(OCc3ccc(OC)cc3)cccc2[nH]1
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a stirred solution of 2-amino-3-(4-methoxybenzyloxy)-aniline (1.15 g) in acetic acid (12 ml) was added triethyl orthopropionate (994 mg) at ambient temperature, and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (900 mg) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25]>CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH:23]([CH2:22][CH3:21])[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCC(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O
Temperature: 55 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
A mixture of (+) 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (14.25 g, 0.046 mole) potassium carbonate (12.5 g, 0.09 mole) and ethyl 4-bromobutanoate (17.5 g, 0.08 mole) in DMF (150 ml) is stirred at 55° C. for 4 hours then poured into ice water and extracted with ether, washed with water and the ether evaporated at reduced pressure. The residual oil is dissolved in acetic acid (150 ml) and 5% hydrochloric acid (50 ml), heated at 95° C. for 21/2 hours, cooled and treated with ie (50 g) to give 17.65 g of (+)[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-oxy]butanoic acid which melts at 75°-77° C. [α]D25 (C=2, acetone)=+36.8°.
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C@@H:32]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][C:34]([NH2:36])=[O:35]>>[C:34]([CH2:33][C@@H:32]([NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:35])[NH2:36]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NC(=O)C[C@@H](N)c1ccccc1
Product: NC(=O)C[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (3R)-3-amino-3-phenylpropanamide instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.22 (1H, s) 8.65 (1H, d, J=8.44 Hz) 8.01 (1H, d, J=5.42 Hz) 7.80 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.52 Hz) 7.33-7.39 (3H, m) 7.26-7.32 (4H, m) 7.17-7.23 (1H, m) 6.86 (1H, br. s.) 6.80 (1H, d, J=5.86 Hz) 6.40 (1H, d, J=3.56 Hz) 5.44 (1H, q, J=7.24 Hz) 2.66-2.75 (1H, m) 2.57-2.65 (1H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.C(Cl)(Cl)Cl>CN(C)C=O>[Cl:23][C:20]1[N:19]=[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cl)ccc1Cl
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccc(Cl)nc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
4-Methoxythiophenol (0.927 ml; 7.55 mmol) and 1.14 g (8.26 mmol) of potassium carbonate were added, at room temperature, to a solution (70 ml) of 1.70 g (6.86 mmol) of the resulting ester compound in N,N-dimethylformamide followed by stirring for 1 hour. Chloroform was added to the reaction solution followed by washing with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution, drying and concentrating in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1) to give 743 mg (yield: 31%) of tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate as a colorless oily substance.
Reaction SMILES: C(OC(N1CCC(C[NH:15][C:16]([C:18]2[S:28][C:27]3[N:29]4[C:20](=[CH:21][N:22]=[C:23]4[CH:24]=[CH:25][CH:26]=3)[CH:19]=2)=[O:17])CC1)=O)(C)(C)C.[ClH:30].[CH2:31](O)[CH3:32]>>[ClH:30].[ClH:30].[NH:22]1[CH2:23][CH2:24][CH:31]([CH2:32][C:21]2[N:22]=[C:23]3[N:29]4[C:27]([S:28][C:18]([C:16]([NH2:15])=[O:17])=[CH:19][C:20]=24)=[CH:26][CH:25]=[CH:24]3)[CH2:20][CH2:21]1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Product: NC(=O)C1=Cc2c(CC3CCNCC3)nc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While 26.48 g (121.3 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 15.4 g (133 mM) of N-hydroxysuccinimide were stirred together in 250 ml of acetonitrile, 25.6 g (133 mM) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 6 hours. To this reaction mixture was added 20.3 ml (146 mM) of triethylamine as well as 27.3 g (127 mM) of 1-(tert-butoxycarbonyl)piperidin-4-ylmethylamine and the mixture was stirred at room temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9:1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide. To this crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added 30 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for one hour. To this reaction mixture was added ethanol, followed by stirring, and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=O)=[CH:16][C:3]1=2.[CH3:21][N:22](C=O)[CH3:23].S(Cl)(Cl)=O.N(C)C>C(#N)C>[CH3:21][N:22]([CH3:23])[C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CN(C)C=O
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CN(C)C(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 2.5 °C
Yield: 60 %

Procedure:
8 g (0.029 moles) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid were dissolved in 30 ml of acetonitrile and 0.15 ml of DMF were added to this solution. 2.3 ml (0.032 moles) of thionyl chloride were added to the resulting solution at 20-25° C. Once the reaction had ended, the reaction mixture is slowly poured over an aqueous solution of 40% Me2NH (14.4 g, 0.32 ml) cooled at 0-5° C. and stirring was maintained at this temperature for 30 minutes. Subsequently, the organic part was distilled under reduced pressure and 80 ml of methylene chloride were added. The phases were decanted, separating the organic phase. The solvent was distilled, obtaining an oil with the product of the title with a yield of 60%.