Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[C:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[C:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:32]=2)=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCOc1cc(C(C)(C)C)ccc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.60 g), 4-t-butyl-2-ethoxybenzonitrile (1.00 g), anhydrous aluminum chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.20 g of desired compound (melting point: 108.0°-111.0° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[C:16]1[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:30])[C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:31][C:32]#[N:33].[K+].BrBr.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[C:16]1[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:23][C:24]3[C:29]1=[CH:28][CH:27]=[C:26]1[S:31][C:32]([NH2:33])=[N:30][C:25]1=3)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c3c(ccc2s1)C(=C1CC2CCC(C1)N2Cc1ccccc1)c1ccccc1O3
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 9-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine in glacial acetic acid (0.1 to 1 M solution) may be added potassium thiocyanate (2 equiv). A solution of bromine (1 equiv) in glacial acetic acid (0.5 to 2 M solution) may be added slowly, and the resulting mixture may be stirred at rt for 1 to 4 hr. The solution may be basified with a sodium hydroxide solution (5 to 20%), and extracted with a suitable organic solvent such as ethyl acetate. The organic layer may be separated, dried over sodium sulfate, filtered, and evaporated. The residue may be purified via column chromatography to yield Compound 1h.
Reaction SMILES: C(NCC1C=CC=CC=1)C.C([O:13][C:14](=[O:49])[C:15]([CH2:37][CH2:38][N:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:40][CH3:41])([NH:29]C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][B:20]1[O:24]C(C)(C)C(C)(C)[O:21]1)C.[ClH:50]>O>[ClH:50].[ClH:50].[NH2:29][C:15]([CH2:37][CH2:38][N:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:40][CH3:41])([CH2:16][CH2:17][CH2:18][CH2:19][B:20]([OH:21])[OH:24])[C:14]([OH:49])=[O:13]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN(CC)Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCNCc1ccccc1
Agent: Cl
Solvent: O
Product: CCN(CCC(N)(CCCCB(O)O)C(=O)O)Cc1ccccc1
Temperature: 25 °C

Procedure:
2-Amino-2-[2-(benzyl-ethyl-amino)-ethyl]-6-borono-hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 16, except ethylbenzylamine is used as the amine in step 6. The final step is as follows: a solution of (R/S)-2-[2-(benzyl-ethyl-amino)-ethyl]-2-tert-butoxycarbonylamino-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (104 mg) in 6 N hydrochloric acid (6 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give the title compound as a colorless foam (41 mg); 1H NMR (D2O, 300 MHz) δ 7.36 (s, 5H), 4.31 (m, 1H), 4.11 (m, 1H), 2.96-3.29 (m, 4H), 2.10 (m, 2H), 1.68 (m, 1H), 1.43 (t, J=8 Hz, 1H), 1.21 (t, J=6.5 Hz, 3H), 0.89-1.20 (m, 4H),) and 0.59 (m, 2H); MS (+CI): m/z for C17H29BN2O4: expected 336.2. found 337.2 (M+H)+, 319 (M+H−H2O)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:39]C(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:36])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([CH3:39])[C:18]2[N:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:28][CH:29]=3)=[CH:22][N:23]=2)[N:14]=1)[CH3:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(-c2ccc(OC(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
2-Methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (620 mg) synthesized in Example 162-2 and methyl iodide (325 mg) were dissolved in N,N-dimethylformamide (6.0 mL), potassium tertiary butoxide (154 mg) was added, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (215 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC(C)([O-])C.[K+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: BrCc1cccc(Br)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1cccc(Cn2nnc3ccccc32)c1
Reaction time: 4 h

Procedure:
To a solution of 1H-benzotriazole (0.52 g, 4.4 mmol) in THF (25 mL) was added potassium tert-butoxide (4.6 mL, 4.6 mmol, 1M in THF) followed by the addition of 1-bromo-3-(bromomethyl)benzene (1.0 g, 4.0 mmol). The solution was allowed to stir for 4 hours before the reaction was quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer was separated and washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/hexanes) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:30]([CH2:35][CH2:36][O:37][CH3:38])[CH:31]([CH3:34])[C:32]#[CH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:35][CH2:36][O:37][CH3:38])[CH:31]([CH3:34])[C:32]#[C:33][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH3:29]
Reactant: C#CC(C)N(CC)CCOC
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: CCN(CCOC)C(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and Ethyl-(2-methoxy-ethyl)-(1-methyl-prop-2-ynyl)-amine were converted to yield Ethyl-(2-methoxy-ethyl)-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as brown oil, MS: 433 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O-:26])=[O:25])=[C:18]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][C:3]([CH3:4])([CH3:14])[CH3:1])=[O:25])=[C:18]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:17]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)COc1cc(N)ccc1OCC(=O)[O-]
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1OCC(=O)OC(C)(C)C
Yield: 169.2 %

Procedure:
In the manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and t-butyl [(4-amino-o-phenylene)dioxy]diacetate (415 mg, 1.17 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1-1/1) to give 473 mg of di-t-butyl [[4-[(5-cyano-2-benzofuranyl)carbonylamino]-o-phenylene]dioxy]diacetate as a colorless solid (84%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([S:26]([CH2:29]C)(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:31])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:31])[CH2:10][CH2:9]1
Reactant: CCS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl(1-{2-[6-(ethylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate (Intermediate 104) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:7][N:6]1[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=[C:5]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(Br)n1C
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
The product from step 152a is added to a solution of tetrakis(triphenylphosphine)palladium(O) (0.530 g, 0.459 mmol) in 90 mL of ethylene glycol dimethyl ether. The resulting solution is stirred under nitrogen for 5 min and then phenylboronic acid (1.34 g, 11.0 mmol) is added followed by a solution of Na2CO3 (19.5 g, 183 mmol) in 90 mL of H2O. The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool to rt, 100 mL of CH2Cl2 is added, and the layers are separated. The aqueous layer is extracted with CH2Cl2 (3×50 mL) and combined organic layers are dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash column chromatography (5% EtOAc in hexane) to give 1.89 g of methyl 1-methyl-5-phenyl-1H-pyrrole-2-carboxylate as a yellow oil (96% yield). MS for Cl3H13NO2 (ESI) (M+H)+ m/z 216.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:54])([F:53])[C:46]1[CH:47]=[C:48]([NH2:52])[CH:49]=[N:50][CH:51]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:48]3[CH:49]=[N:50][CH:51]=[C:46]([C:45]([F:54])([F:44])[F:53])[CH:47]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1cncc(C(F)(F)F)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cncc(C(F)(F)F)c3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-trifluoromethyl-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=424.2 [M+H]+
Reaction SMILES: IC.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13]
Reactant: O=C1OCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1COC2=O
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Iodomethane (1.313 mL, 20.78 mmol) was added to 4-hydroxyisobenzofuran-1(3H)-one (3.12 g, 20.78 mmol) and potassium carbonate (5.74 g, 41.56 mmol) in DMF (50 mL) at 21° C. under air. The resulting solution was stirred overnight. The solvent was removed to give a yellow solid which was then quenched with potassium carbonate (70 ml). The mixture was extracted ethyl acetate (3×75 ml). The combined extracts were evaporated to give the desired material as a yellow solid (3.18 g, 93% yield), which was used without further purification; 1H NMR (400.132 MHz, CDCl3) δ 3.30 (2H, s), 5.37 (2H, s), 7.31-7.42 (2H, m), 7.51-7.61 (1H, m).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15](O)=[O:16])=[O:12].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:16])=[O:12]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1CCc2ccccc2C1
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C([C@@H]1CCCN1C(=O)C1CCc2ccccc2C1)N1CCCC1
Yield: 52 %

Procedure:
A colorless oil of 1-[1-(1,2,3,4-tetrahydronaphthalene-2-ylcarbonyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(1,2,3,4-tetrahydronaphthalen-2ylcarbonyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
Reaction SMILES: CN1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)CC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([CH:5]2[CH2:6][CH:7]=[CH:8][CH2:9][N:10]2[CH3:11])=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Product: CN1CC=CCC1c1cn(C(=O)c2ccccc2)c2ncccc12

Procedure:
(6.7 mg, 18%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (25.0 mg, 0.12 mmol) and benzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB+for C20H19N3O: calculated MH+:318.16064; found:318.16191.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:10]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>[Cl:10][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[S:9][CH:8]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1nc2ccsc2s1
Solvent: ClCCl
Product: Cc1nc2c(Cl)csc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 218.1 %

Procedure:
To a solution of 1.18 g (7.2 mmol) of 2-methylthieno[3.2-d]thiazole (from Step 1) in 35 ml of CH2Cl2 was added 670 mg (2.9 mmol) of trichloroisocyanuric acid at 0° C. The reaction was stirred at 0° C. for 30 min., then at r.t. for 2 h.; 60 mg (0.26 mmol) of trichloroisocyanuric acid was again added, and the reaction was stirred at r.t. for another hour. The product was partitioned between CH2Cl2 and aqueous NaHCO3. Chromatographic purification on silica gel using hexane/EtOAc=5:1 afforded 1.2 g (90%) of the title product. 1H NMR (CDCl3) 7.28(s, 1H), 2.82(s, 3H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[O-]CC.[Nb+5:12].[O-]CC.[O-]CC.[O-]CC.[O-]CC>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Nb+5:12].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Nb+5:12]
Reactant: Oc1ccccc1O
Agent: [Nb+5]
Agent: CC[O-]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (8.64 g, 78.5 mmol) and toluene (70 ml) was dehydrated by distilling 10 mL of the solution. Thereafter, 10.0 g (31.4 mmol) of niobium(V) ethoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 110° C. or higher, distilled until the amount of the solution became half. After the distillation, volatile components of the residual mixed solution were vaporized under reduced pressure by a rotary evaporator. The residual solid content was further heated to 100° C. under vacuum using a vacuum dryer so that the remaining volatile components were completely removed. The solid content (catechol-niobium complex) was brown in color. The yield amount was 11.4 g (31.4 mmol), and the yield percentage was 100%. 3.63 g of catechol-niobium complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:18])[NH:12]2.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C)C=O>[C:19]([O:22][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:18])[NH:12]2)(=[O:21])[CH3:20]
Reactant: Cc1ccc(OC/C=C/CCl)c2ccc(=O)[nH]c12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC/C=C/COc1ccc(C)c2[nH]c(=O)ccc12
Temperature: 120 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
5-[(E-4-Chloro-2-butenyl)oxy]-8-methylcarbostyril (16.15 g) was dissolved in dimethylformamide (200 ml), to which sodium acetate (35.0 g) was added and stirred at 120° C. for 6 hours. After the reaction was completed, the reaction mixture was condensed under reduced pressure. Water was added to the condensate and extracted with chloroform. The chloroform phase was dried, and the solvent was removed. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 11.80 g of 5-[(E-4-acetoxy-2butenyl)oxy]-8-methylcarbostyril as colorless powdery crystals (67.1%).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:34])(=[O:33])[N:19]=3)=[C:14]([OH:35])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:36][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:39].[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([N:28]([CH3:40])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:33])(=[O:34])[N:19]=3)=[C:14]([OH:35])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:36][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:39]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(N(C)S(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
N-{3-[(1R,2S,7R,8S)-3-(4-Fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 15, 92 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (44 mg, 0.32 mmol) and iodomethane (0.011 mL, 0.18 mmol) were added sequentially. The reaction was stirred at 25° C. for 18 h. The reaction was quenched via the addition of 1.0 M aqueous hydrochloric acid solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (91 mg, 0.15 mmol, 96%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.18-2.85 (9H, m), 2.90 (3H, s), 2.97 (3H, s), 3.38 (3H, s), 3.45-3.47 (1H, m), 5.17-5.21 (2H, m), 6.96-7.08 (3H, m), 7.72-8.02 (3H, m). LC-MS (ESI) calcd for C27H29FN4O6S2 588.67, found 589.2 [M+H+].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][C:16](=[O:17])[N:18]([CH3:20])[CH3:19])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)CCl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
Amine preparation: a mixture of 1-BOC-piperazine (387 mg), 2-chloro-N,N-dimethylacetamide (0.43 mL) and triethylamine (0.58 mL) in chloroform was stirred at room temperature. After stirring overnight the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-dimethylcarbamoylmethyl-piperazine-1-carboxylic acid tert-butyl ester (558 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.