Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O[C:39]([NH:41][C@@H:42]([CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=1)C(O)=O)=[O:40])(C)(C)C.[O:59]([C:66]1[CH:67]=[C:68]([CH2:72]C(O)=O)[CH:69]=[CH:70][CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:10][CH:9]([CH3:11])[C@H:8]([NH:7][C:6](=[O:33])[C@@H:42]([NH:41][C:39](=[O:40])[CH2:72][C:68]1[CH:69]=[CH:70][CH:71]=[C:66]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:67]=1)[CH2:46][C:47]1[CH:48]=[C:49]([O:57][CH3:58])[C:50]([O:55][CH3:56])=[C:51]([O:53][CH3:54])[CH:52]=1)[C:12]([NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:29])[CH3:30])[O:20]1)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:32]
Reactant: COc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Product: COc1cc(C[C@H](NC(=O)Cc2cccc(Oc3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc(OC)c1OC

Procedure:
The title compound is prepared from {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester by reiteration of the 2-step (deprotection/coupling) procedure described in example 1 but using (S)-2-tert-Butoxycarbonylamino-3-(3,4,5-trimethoxy-phenyl)-propionic acid and (3-Phenoxy-phenyl)-acetic acid (Trans World Chemicals, Inc.; Rockville, Md., USA) as the partners in each coupling reaction (step B, example 1), respectively. The title compound is obtained as a yellow foam; ES-MS: 812.4 [M+H]+; HPLC: single peak at tR=11.36 min (System 1); Rf=0.53 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].I[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[N:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: Ic1cnc2ccccn12
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cnc3ccccn23)cc1OC(C)c1ccccc1Cl

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.0 Eq.), 3-Iodo-imidazo[1,2-a]pyridine (108 mg, 0.44 mmol, 1.2 Eq.) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.55 mL, 1.10 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% EtOAc/petroleum Ether) to give the sub-title compound as am off-white solid (61 mg, 0.15 mmol, 40%); 1H NMR (400 MHz, CDCl3) δ 1.77 (3H, d), 3.96 (3H, s), 5.86 (1H, q), 6.89 (1H, s), 7.28-7.43 (4H, m), 7.67 (1H, dd), 7.72-7.78 (1H, m), 7.83 (1H, s), 8.32 (2H, d).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]=2[CH3:34])=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O1CCCC1.CO>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]=2[CH3:34])=[CH:35][CH:36]=1)=[O:12]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(2-naphthamido)benzyl]-2-methyl-1H-indol-1-yl]acetate (530 mg, 1.11 mmol), lithium hydroxide monohydrate (140 mg, 3.34 mmol), 5 mL tetrahydrofuran, 5 mL methanol, 10 mL water were added successively, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. A solid precipitated, and was washed with ethyl acetate, dichloromethane, acetonitrile to obtain the product 100 mg as a white solid, at a yield of 20.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([CH3:21])=[C:18]([C:22]([OH:24])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:38]1[CH2:42][CH2:41][N:40]=[C:39]1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][CH3:52])=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[NH:40]1[CH2:41][CH2:42][N:38]=[C:39]1[C:43]1[CH:44]=[CH:45][C:46]([CH2:49][CH2:50][N:51]([CH3:52])[C:22]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:5]([CH3:25])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][C:19]=2[CH3:21])=[O:24])=[CH:47][CH:48]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)c(C)o2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)c(C)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-2-methylfuran-3-carboxylic acid (82 mg, 0.22 mmol) was dissolved in DCE (1 mL) and CDI (72 mg, 0.33 mmol) was added. The reaction was stirred at ambient temperature for 2 h and 0.5 mL of this solution was added to a flask containing 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine 0.3 HCl (34 mg, 0.11 mmol) and DIPEA (0.076 mL, 0.44 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 3 days, then heated in a microwave at 120° C., 250 psi, 200 W for 2×20 min. The reaction was concentrated and diluted with DCM, then washed with water and saturated brine, and dried over MgSO4. The filtrate was shaken with Ambersep and PL-MIA resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21].CN([CH:25]=[O:26])C>C1COCC1.O>[Br:13][C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cl)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=Cc1c(F)ccc(Cl)c1Br
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
To a solution of diisopropylamine (5 mL, 35.4 mmol) in THF (30 mL) at 0° C. under argon was added n-butyl lithium (16.5 mL of 1.6 M solution in hexane, 26.4 mmol) slowly over 20 minutes. The mixture was cooled to −75° C. and 2-bromo-1-chloro-4-fluorobenzene (5 g, 23.9 mmol) in THF (20 mL) was added dropwise over 15 mins whilst maintaining the temperature <−70° C. The solution was then stirred at −75° C. for 45 mins and then DMF (2.2 mL, 28.6 mmol) was added over 5 mins. The mixture was stirred at −78° C. for 2 hrs and then allowed to reach room temperature. Water was added and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine and the solvent evaporated. Chromatography (silica gel, ethyl acetate/hexane) gave the title compound (D21) as a yellow solid (3.344 g)
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[NH:5])C.[CH3:13][N:14]([C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15]>C(OCC)C>[CH3:13][N:14]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])=[N:15]1
Reactant: CCOC(=N)c1ccccc1C
Reactant: CN(N)C(=O)c1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)n(C)n1
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1.14 g. of o-toluimidic acid ethyl ester, 1.14 g. of 1-methyl-1-benzoylhydrazine and 0.1 g. of o-toluimidic acid ester hydrochloride, as a catalyst, is heated at about 100° C. for three hours under reduced pressure (about 200 mm Hg) and then at about 120° C. for five hours. The raw material is taken up with diethyl ether and the organic solution is washed with aqueous sodium bicarbonate and then dried over Na2SO4. After evaporation of the solvent, the product is distilled at 170° C./0.1 mm Hg. Yield 32%.
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[C:8]([CH2:11][OH:12])=[CH:9][CH2:10][C@@H:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][O:3]1.FB(F)F.[CH2:21](OCC)C.C(=O)(O)[O-].[Na+].CCCCCC.C(OC(=O)C)C>CO>[OH:12][CH2:11][C:8]1[C@H:7]2[C@H:2]([O:1][CH3:21])[O:3][CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C@H:6]2[CH2:10][CH:9]=1
Reactant: COC(=O)C1=COC(O)[C@@H]2C(CO)=CC[C@H]12
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO)=CC[C@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
5 g (22.1 mmol) of methyl (4aS,7aS)-1-hydroxy-7-hydroxymethyl-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate was dissolved in 25 ml of methanol and catalytic amount of trifluoroboron diethylether was added thereto. The reaction mixture was stirred at room temperature for 20 hours and then the reaction was stopped by the addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and distilled under vacuum. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1, v/v) to obtain 5.26 g (Yield 100%) of methyl (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:21].[K+].O>O.C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:21])=[CH:16][C:3]1=2
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Yield: 73.7 %

Procedure:
To 50 mg of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide was added 0.4 g of potassium hydroxide in 4 ml of water/ethanol (1:1), and the mixture was refluxed for 3 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and then a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was recrystallized from acetone to give 37 mg (yield: 72%) of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 181°-184° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH2:15]([Sn](CCCC)(CCCC)/C=C/C)[CH2:16][CH2:17]C>ClC(Cl)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:15]=[CH:16]\[CH3:17]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: C/C=C/[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C/C=C\c1c(C(=O)OC)nc(Cl)c(F)c1N

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (0.4 g, 1.210 mmol), (E)-tributyl(prop-1-en-1-yl)stannane (0.481 g, 1.452 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.085 g, 0.121 mmol) in dichloroethane (2.42 mL) were irradiated at 120° C. for 30 min in a microwave reactor. Celite was then added to the reaction mixture and the solvent was removed under vacuum. The crude product was first purified by flash column chromatography (SiO2, hexane/EtOAc gradient) then by reverse phase HPLC to afford the title compound as an orange oil: 1H NMR (400 MHz, CDCl3) δ 6.39 (dq, J=11.1, 1.7 Hz, 1H), 6.07 (dq, J=11.2, 6.9 Hz, 1H), 4.64 (s, 2H), 3.89 (s, 3H), 1.55 (dd, J=6.9, 1.7 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −139.48; EIMS m/z 245 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:13]([F:22])([F:12])[F:21])[CH:19]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccnc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-(trifluoromethyl)pyridine-4-ol.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:25][C:19]2=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]2[C:17]=1[OH:26])=O)C>>[CH3:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]2[O:25][CH2:16][C:17](=[O:26])[C:18]=12
Reactant: CCOC(=O)c1oc2nccc(C)c2c1O
Agent: O=C1COc2cnccc21
Product: Cc1ccnc2c1C(=O)CO2

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-4-methylfuro[2,3-b]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.O=[C:9]([CH2:14][C:15](OC)=[O:16])[C:10]([O:12][CH3:13])=[O:11]>C(O)(=O)C>[OH:16][C:15]1[N:3]2[N:4]=[C:5]([CH3:7])[N:6]=[C:2]2[N:1]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=1
Reactant: COC(=O)CC(=O)C(=O)OC
Reactant: Cc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)n2nc(C)nc2n1
Yield: 30.7 %

Procedure:
3-Amino-5-methyl-1H-s-triazole (112 mg) and 320 mg of dimethyl 2-oxo-succinate are dissolved in 5 ml of glacial acetic acid. After boiling under reflux for 22 hours the solvent is distilled off in a vacuum. The residue is suspended in warm methanol. After cooling the product is filtered off and washed several times with methanol. After drying in a high vacuum there are obtained 73 mg of methyl 7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate as a beige powder, m.p.>220° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.COC1C=C([CH2:18][CH2:19][NH2:20])C=CC=1.N1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C[O-].[Na+]>>[N:9]1([CH2:1][CH:2]2[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:18][CH2:19][NH:20]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: NCCc1ccccc1
Reactant: C1COCCN1
Reactant: COc1cccc(CCN)c1
Agent: C[O-]
Agent: [Na+]
Product: c1ccc2c(c1)CCNC2CN1CCOCC1

Procedure:
1-Morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was synthesized by a similar fashion as shown in Example 3-76a, except that in Step 1, phenethylamine was used to replace 2-(3-methoxy-phenyl)-ethylamine, and that in the first part of Step 3, morpholin was used to replace sodium methoxide as the nucleophile. The crude product was used directly in the next coupling step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:27][C:28]1[S:29][C:30]([C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1>O1CCCC1>[CH2:37]([NH:36][C:34]([C:30]1[S:29][C:28]([NH:27][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:32][C:31]=1[CH3:33])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: COc1cc(C(=O)O)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (0.25 g, 1.01 mmol) in anhydrous tetrahydrofuran (10 mL) was added 4-methyl morpholine (0.15 g, 1.45 mmol), followed by the dropwise addition of isobutylchloroformate (0.19 g, 1.36 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours. Then a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide in tetrahydrofuran (10 mL) was added to it. The reaction mixture was stirred at ambient temperature for another 6 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with diluted hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane to yield the title compound as a colorless solid in 83% yield (0.32 g); m.p. 188-190° C.; 1H NMR (CDCl3, 300 MHz) δ 8.32 (d, J=5.3 Hz, 1H), 7.37-7.25 (m, 7H), 7.17 (s, 1H), 5.99 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 3.96 (s, 3H), 2.55 (s, 3H); 1H NMR (CDCl3, 75 MHz) δ 164.9, 163.7, 161.9, 157.1, 151.3, 148.4, 141.5, 137.6, 128.8, 127.8, 127.8, 119.4, 113.8, 109.4, 54.0, 44.2, 16.7; MS (ES+) m/z 383.5 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN(C)C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
A stirred solution of 2-[(2-dimethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (281 mg, 1 mmol) in anhydrous tetrahydrofuran (2 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (3 ml, 3 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred for 1 hour and heated to reflux for another 5 hours. The mixture was added with cold water (5 ml) and 1N hydrochloric acid (2 ml) and stirred for 5 minutes. The resulting solution was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[2-(2-dimethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (300 mg) as a brown oil which was used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18](Cl)(=[O:20])=[O:19].[NH4+:22]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:22])(=[O:20])=[O:19]
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.45 g, 1.0 mmol) in methylene chloride is added aqueous ammonium solution (1 mL). The reaction mixture is stirred for 10 min at room temperature. The solvent is removed and the residue is redissolved in ethyl acetate and extracted with water. The organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. The residue is recrystallized with methylene chloride-hexane to give 100 mg (32% yield) of the title compound as pale yellow solid. 1H NMR (CDCl3): δ 8.40 (m, 1H), 8.05 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.32 (t, 1H), 7.00 (d, J=8 Hz, 2H), 5.15 (s, 1H), 3.90 (s, 3H). Analytics calculated for C14H12FNO4S: C, 54.36; H, 3.91; N, 4.53. Found: C, 53.89; H, 3.50; N, 4.50.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.COCCOC.[Cl:23][C:24]1[S:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[Cl:23][C:24]1[S:28][C:27]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: OB(O)c1ccc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1nc2ccc(-c3ccc(Cl)s3)cc2s1
Temperature: 25 °C
Yield: 16 %

Procedure:
A 40 ml pressure tube was charged with about 100 mg N-(6-bromo-1,3-benzothiazol-2-yl)-N′-ethylurea, and about 2 ml ethylene glycol dimethyl ether. The slurry was stirred via magnetic stirbar followed by evacuation then release to nitrogen atmosphere (3 times). Next about 6 mol percent Pd(PPh3)4 was added, followed by about 1.1 eq of 5-chlorothiophene-2-boronic acid. Following addition of about 3 equivalents sodium carbonate in about 0.5 ml water, the suspension was evacuated and released to nitrogen atmosphere 3 times. The pressure tube was then sealed tightly and heated to about 85–90° C. for about 12–20 hours. The reaction was cooled to room temperature then purified by preparative HPLC to yield 16% of N-[6-(5-chloro-2-thienyl)-1,3-benzothiazol-2-yl]-N′-ethylurea. 1H NMR 1.1 (t, 3H), 3.2 (m, 2H), 6.75 (m, 1H), 7.18 (d, 1H), 7.38 (m, 1H), 7.6 (m, 2H), 8.19 (d, 1H), 10.75 (br s, 1H); LC/MS 3.86 min, 338 (M+1), 336 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:26][C:27]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34](O)=[O:35])[O:29][N:28]=1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:34](=[O:35])[CH2:33][CH2:32][C:30]4[O:29][N:28]=[C:27]([OH:26])[CH:31]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)CCc1cc(O)no1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(C(=O)CCc4cc(O)no4)CC3)cc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-4-{1-[3-(3-hydroxy-isoxazol-5-yl)-propionyl]-piperidin-4-yl}-benzamide was prepared by the ECDI coupling of N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 3-(3-hydroxy-isoxazol-5-yl)-propionic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclonexanecarboxylic acid methyl ester, above. LCMS calcd for C28H33N3O4 (m/e) 475, obsd 476 (M+H).