Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Br:10][C:11]([OH:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:14][C:11]([Br:10])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(O)Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinic acid chloride (2.56 g, 20 mmol) and 30 mg of DMAP were added to a mixture of 2-bromo-2-propanol (2.8 g, 20 mmol), triethylamine (5.6 mL, 20 mmol) in dichloromethane at 0° C. The resulting mixture was stirred at room temperature overnight. The product was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, and concentrated to yield 1-Bromoisopropyl nicotinate, which was used in the next reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:19]=2[NH:27][C:28](=[O:42])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:30]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.CC1C=C(C)C(C)=C(C)C=1C>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:19]=2[NH:27][C:28](=[O:42])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH:30]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1sc2c(c1C(=O)Nc1ccc(OCc3ccccc3)cc1)CCCC2)c1cccc(CN2CCOCC2)c1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1sc2c(c1C(=O)Nc1ccc(O)cc1)CCCC2)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 200 mg of N-[4-(benzyloxy)phenyl]-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 6.0 mL of TFA was added 255 mg of 1,2,3,4,5-pentamethylbenzene, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by extraction using ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol/chloroform), thereby obtaining 169 mg of N-(4-hydroxyphenyl)-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [C:1]1([C@H:7]([NH:38][C:39]([O:41][C@@H:42]2[CH:47]3[CH2:48][CH2:49][N:44]([CH2:45][CH2:46]3)[CH2:43]2)=[O:40])[C:8]2[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=2)[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27](OC)[O:28]C)=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(=O)([O-])O.[Na+]>[C:1]1([C@H:7]([NH:38][C:39]([O:41][C@@H:42]2[CH:47]3[CH2:48][CH2:49][N:44]([CH2:45][CH2:46]3)[CH2:43]2)=[O:40])[C:8]2[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=2)[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]=[O:28])=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(Cc1ccc(COC(=O)c2cccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)c2)cc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=CCc1ccc(COC(=O)c2cccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(2,2-dimethoxyethyl)benzyl 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.100 g, 0.15 mmol) in acetone (5 mL) was added para-toluenesulfonic acid monohydrate (0.086 g, 0.45 mmol) and the mixture stirred at RT for 1 hour. The reaction mixture was diluted with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used in the next step with no further purification.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1)[C:4]([F:7])([F:6])[F:5].C(N(C(C)C)CC)(C)C.[CH2:32]([C@@:34]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]1)[CH3:33]>ClCCl>[CH2:32]([C@:34]1([CH2:41][S:42]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:3]([F:2])([F:22])[C:4]([F:7])([F:6])[F:5])=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)(=[O:43])=[O:44])[NH:35][C:36](=[O:40])[NH:37][C:38]1=[O:39])[CH3:33]
Reactant: CC[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)(F)C(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OC(F)(F)C(F)(F)F)cc3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[4-(pentafluoroethoxy)phenoxy]piperidine hydrochloride (0.17 g) and diisopropylethylamine (0.19 mL) in dichloromethane (100 mL) was added [(4S)-4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.13 g). The reaction was stirred at ambient temperature for 18 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:12]([C:11]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2cc(Cl)ccc2o1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 5-chloro-2-hydroxybenzaldehyde (2 g) and phenacyl bromide (1.85 g) in ethanol (10 ml) potassium carbonate (3.53 g) was added. The mixture was stirred at 80° C. for 1 h. Then the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4), and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 12:1) to give 2-benzoyl-5-chlorobenzofuran (1.85 g) as colourless solid.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].[O:31]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-]>C1COCC1>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][N:21]([CH2:36][CH:33]4[CH2:34][CH2:35][O:31][CH2:32]4)[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: O=CC1CCOC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC2CCOC2)C3)cc1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
To a suspension of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (ca) (174 mg, 0.4 mmol) and tetrahydrofuran-3-carbaldehyde (55 μL, 0.6 mmol) in THF (3 mL) was added Na(OAc)3BH in portions. After 2 hrs, more aldehyde (18 μL) and borohydride (71 mg) were added, and the resultant mixture was stirred for 1 h. The reaction mixture was quenched by addition of MeOH and few drops of AcOH, and concentrated in vacuo. The crude solid was redissolved in H2O, extracted with EtOAc (4×10 mL). The combined EtOAc were dried over Magnesium sulfate, filtered, and purified by RP-HPLC to afford 110 mg (57%) of compound ng as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.15 (d, J=8.8, 2H), 7.47 (d, J=8.8, 2H), 6.16 (t, J=5.5, 1H), 4.13 (d, J=6.6, 1H), 3.87 (d, J=11.3, 1H), 3.80-3.39 (m, 12H), 3.16-3.07 (m, 2H), 2.75-2.64 (m, 3H), 2.55 (d, J=8.6, 1H), 2.46 (d, J=7.4, 2H), 1.98 (td, J=12.7, 7.7, 1H), 1.57 (td, J=13.5, 7.1, 1H), 1.24 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC-MS: m/z=+481 (M+H)+.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][C:3]1([C:7]([O:9][CH3:10])=[O:8])[O:4][CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(COCC[Si](C)(C)C)CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Yield: 79.5 %

Procedure:
E1 (5.0 g 20.39 mmol) was dissolved in THF (45 mL) and cooled to −78° C. LHMDS (1 M in hexane/ethylbenzene) (40.8 mL, 40.8 mmol) was added in 30 minutes and the solution was stirred for 35 min at −78° C. (2-(Chloromethoxy)ethyl)trimethylsilane (10.02 mL, 56.5 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated NH4Cl and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (heptane:EtOAc=100:0 to 70:30) yielding the title compound (6.09 g, 80%). 1H NMR (400 MHz, CDCl3, 300K): δ 0.00 (3H, s), 0.92 (2H, t, J=7.5 Hz), 1.47 (9H, s), 3.02 (2H, d, J=13.3 Hz), 3.55 (4H, m), 3.78 (3H, s), 3.83 (3H, m), 4.34 (1H, d, J=13.3 Hz). MS (ES) C17H33NO6Si requires: 375. found: 398.2 [M+Na]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1)[CH2:8][CH2:9][NH:10][CH:11]([C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[N:14]=1)[CH3:12])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([CH2:25][NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)[N:14]=3)[CH3:12])=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: Cc1cc(C(C)NCCN(Cc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)NCCNCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Yield: 90.4 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-{2-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethylamino]-ethyl}-carbamic acid tert-butyl ester (155 mg, 0.320 mmol) in DCM/TFA (50%, 5 mL) was stirred for 0.5 h. The solvent was evaporated and sat. aqueous K2CO3 solution was added. The mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave 110 mg (90%) of N-benzo[1,3]dioxol-5-ylmethyl-N′-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethyl]-ethane-1,2-diamine as a red oil. [M+H]+ 380.96; 1H-NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.87 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 6.79 (s, 1H), 6.71 (s, 2H), 5.90 (s, 2H), 3.74 (q, 1H), 3.66 (s, 2H), 2.70-2.50 (m, 6H), 2.2 (br s, 2H), 1.37 (d, 3H); 13C-NMR (100 MHz, CDCl3) δ 175.6, 170.0, 154.6, 147.9, 146.8, 136.4, 134.2, 130.5, 121.4, 116.8, 115.6, 108.8, 108.3, 101.1, 58.8, 53.8, 48.9, 47.4, 24.4, 22.4.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.C(N(CC)CC)C.Cl.[NH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:5]=2)[CH:26]=1
Reactant: CCOC(=O)CN
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 15.3 %

Procedure:
A mixture of N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)-phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.39 mmol), triethylamine (394 mg, 3.89 mmol), ethyl 2-aminoacetate hydrochloride (271 mg, 1.94 mmol) in ethanol (20 mL) was stirred at 80° C. for 24 hours then concentrated under reduced pressure. The crude product was purified by high pH Prep-HPLC to afford the title compound as an off-white solid (31.9 mg, 15%). LCMS (Method 14) [M+H]+=534.2, RT=1.13 min. 1H NMR (300 MHz, CD3OD-d4) δ: (ppm) 9.11 (dd, J=1.5, 7.0 Hz, 1H), 8.66-6.65 (m, 2H), 8.36 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.58 (dd, J=2.7, 8.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.39 (dd, J=4.5, 7.2 Hz, 1H), 6.55 (t, J=73.5 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.41 (s, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:24]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNCC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl 4-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)piperidine-1-carboxylate (1.631 g) [see Preparation 31] in dichloromethane (10 ml) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 2 hours, after which time the solvent was removed under reduced pressure and the residue was dissolved in water. Sodium hydrogen carbonate was added until the solution reached a pH of 8 and the product was then extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-(4-piperidinyl)-2-piperidinecarboxamide (1.48 g) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[S:34]1[C:38](B(O)O)=[CH:37][C:36]2[CH:42]=[CH:43][CH:44]=[CH:45][C:35]1=2.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:33])[CH:7]=[C:8]([C:38]1[S:34][C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[CH:37]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1
Temperature: 95 °C

Procedure:
To a stirred solution of 9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoic acid tert-butyl ester 29-6 (100 mg, 0.20 mmol) in toluene (2.5 mL) was added palladium(tetrakis)-triphenylphosphine (23 mg, 0.020 mmol), benzo[b]thiophene-2-boronic acid (50 mg, 0.41 mmol) and potassium carbonate (56 mg, 0.41 mmol). The resulting suspension was heated at 90-100° C. for 2 hours, and then was allowed to cool to ambient temperature. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 4:1 ethyl acetate/hexanes to give 29-7b as a colorless oil.
Reaction SMILES: C([C:5]1([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)(OC)=O.[I-].[Li+].O.Cl>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1
Reactant: COCCC1(C(=O)OC)CSCCC1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCC1CSCCC1=O
Yield: 50.1 %

Procedure:
To a solution of 2.4 g (10.3 mmol) of product from Step A in 50 ml DMF was added 6 g (44.8 mmol) lithium iodide. The resulting solution was refluxed under N2 for 2 hours. The reaction mixture was poured into 500 ml H2O/HCl and extracted with ethyl acetate. THe organic solution was washed with water; saturated NaCl, dried over MgSO4 and concentrated in vacuo to give 1.7 g crude product which was chromatographed through a pressure column eluting with 10% ethyl acetate/n-hexane to give 0.9 g of title compound.
Reaction SMILES: C([CH:3]([C:37]([OH:39])=[O:38])[N:4]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:25]([C:35]#[N:36])[CH:24]=1)[C:5]([C:7]1[C:8]([CH3:22])=[N:9][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:11]=1)=[O:6])C.[OH-].[Na+]>C(O)C>[C:35]([C:25]1[CH:24]=[C:23]([N:4]([C:5]([C:7]2[C:8]([CH3:22])=[N:9][N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[CH:11]=2)=[O:6])[CH2:3][C:37]([OH:39])=[O:38])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])#[N:36]
Reactant: CCC(C(=O)O)N(C(=O)c1cn(-c2cccc(C(F)(F)F)c2)nc1C)c1ccc(OCC(C)(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)cc1C(=O)N(CC(=O)O)c1ccc(OCC(C)(C)C)c(C#N)c1
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
Ethyl N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(3-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine (1.5 g) was added to ethanol (15 ml). 10% Aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure. Dilute hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of chloroform-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous acetic acid to give the title compound (0.9 g), melting point: 110–112° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:6]([C:15]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (3.67 g, 15.6 mmol) and 1-hydroxybenzotriazole (2.53 g, 18.7 mmol) in DCM (50 mL) cooled to 0° C. N-Methylmorpholine (8.50 mL, 77.3 mmol), benzylamine (1.87 mL, 17.2 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.26 g, 17.2 mmol) added sequentially. The reaction was stirred at rt overnight, washed with H2O (50 mL), 6N HCl (30 mL), H2O (50 mL) and dried over MgSO4 to provide the title compound of step C (5.09 g, 15.6 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (d, J=15.2 Hz, 1H), 3.82 (t, J=2.9 Hz, 1H), 3.86-3.97 (m, 2H), 4.07-4.17 (m, 2H), 4.23-4.34 (m, 2H), 5.30 (d, J=15.4 Hz, 1H), 7.17-7.22 (m, 5H), 7.24-7.32 (m, 5H), 8.60 (t, J=5.6 Hz, 1H).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][C:21]3[O:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1>O1CCCC1>[CH3:4][NH:1][C:2]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][C:21]3[O:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:3]
Reactant: CN=C=O
Reactant: Cc1ccc(Cn2c(NC3CCN(CCN)CC3)nc3ccccc32)o1
Solvent: C1CCOC1
Product: CNC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(C)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
A mixture of 0.7 parts of isocyanatomethane, 2.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran was stirred for 3 hours at room temperature. The precipitated product was filtered off and dried, yielding 1.2 parts (41.1%) of N-methyl-N'-[2-[4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]urea; mp. 200.1° C. (compound 40).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[O:15][CH3:16])(=O)=O.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1>>[CH3:16][O:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[CH2:6][N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: COc1ccc(COS(C)(=O)=O)c(OC)c1
Reactant: O=Cc1cccc2[nH]ccc12
Product: COc1ccc(Cn2ccc3c(C=O)cccc32)c(OC)c1
Yield: 24.7 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.03 g of 2,4-dimethoxybenzyl methanesulfonate and 2.00 g of indole-4-carbaldehyde as a starting material to give 602 mg of 1-(2,4-dimethoxybenzyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 15%.
Reaction SMILES: C([O:8][C:9]1[CH:65]=[CH:64][C:12]([C:13]([O:15][C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:34]CC4C=CC=CC=4)=[CH:22][C:23]=3[O:26]CC3C=CC=CC=3)[O:18][C@@H:17]2[C:42]2[CH:47]=[CH:46][C:45]([O:48]CC3C=CC=CC=3)=[C:44]([O:56]CC3C=CC=CC=3)[CH:43]=2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1.CO>[OH-].[OH-].[Pd+2].CO.C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([OH:34])=[CH:22][C:23]=3[OH:26])[O:18][C@@H:17]2[C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([OH:56])[CH:43]=2)=[O:14])=[CH:64][CH:65]=1
Reactant: O=C(O[C@H]1Cc2c(OCc3ccccc3)cc(OCc3ccccc3)cc2O[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(O[C@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1ccc(O)c(O)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
Under an H2 atmosphere, Pd(OH)2/C (20%, 100 mg) was added to a solution of 102 (200 mg, 0.23 mmol) in a solvent mixture of THF/MeOH (1:1 v/v, 20 mL). The resulting reaction mixture was stirred at r.t. under H2 for 6 h, TLC showed that the reaction was completed. The reaction mixture was filtered to remove the catalyst. The filtrate was evaporated, and the residue was rapidly purified by flash chromatograph on silica gel (10% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2) to afford 11 (82 mg, 87% yield): mp 220-222° C. (decomposed); [α]D=+87.2 (c=2.0, EtOH); 1H NMR (acetone-d6, 400 MHz): δ 7.98 (d, J=8.8 Hz, 2H), 7.13 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.99-6.96 (m, 2H), 6.27 (d, J=2.2 Hz, 1H), 6.19 (d, J=2.2 Hz, 1H), 5.62 (dd, J=11.8, 6.3 Hz, 1H), 5.34 (d, J=6.3 Hz), 3.15 (A of ABq, J=16.5, 5.2 Hz, 1H), 3.00 (B of ABq, J=16.5, 6.4 Hz, 1H); 13C NMR (acetone-d6, 400 MHz): δ 163.3, 160.0, 155.2, 154.5, 153.6, 143.1, 129.9, 128.7, 119.6, 116.6, 113.4, 113.3, 111.8, 111.7, 96.7, 93.8, 93.0, 76.2, 67.9, 21.9; HRMS (ESI) calcd for C22H18O8Na (M+Na) 433.0899. found 433.0909.