Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][CH:13]2[OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[N:20]=[C:21]([N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][O:37][CH2:38]3)[C:22]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][S:25][C:23]=2[N:24]=1.CO>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][CH:13]2[O:17][C:19]1[N:20]=[C:21]([N:34]2[CH:35]3[CH2:41][CH2:40][CH:39]2[CH2:38][O:37][CH2:36]3)[C:22]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][S:25][C:23]=2[N:24]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CC2O
Reactant: Clc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC1CC2Oc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Reaction time: 0.17 h
Yield: 162.2 %

Procedure:
Sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added to a solution of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) in dry THF (2 mL). The mixture was stirred for 10 min and then a solution of 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.111 g, 0.3101 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at room temperature. A second batch of sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added and the mixture was stirred overnight. Further batches of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) and sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) were added and the mixture was stirred for 3 nights. It was poured into methanol to quench the reaction, and then the solvent was evaporated. The residue was dissolved in EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL), filtered through a hydrophobic frit and evaporated to give tert-butyl-5-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate as a brown solid (269 mg) which was used in the next step without further purification. LCMS RT=4.23 min. M+1=535.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: O=C(O)c1ccncc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccncc1Br
Temperature: 25 °C

Procedure:
3-bromoisonicotinic acid (3.0 g, 14.9 mmol) in ethanol (100 mL) was treated with concentrated sulfuric acid (5 mL). The mixture was brought to reflux at which time everything went into solution. After 12 hours at reflux, LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator to a third of its original volume. The mixture was then diluted with 250 mL of ethyl acetate and washed twice with saturated aqueous sodium bicarbonate. Concentration on a rotary evaporator yielded 3.25 g of ethyl 3-bromoisonicotinate as a yellowish oil which was sufficiently pure enough for subsequent chemical transformations. LCMS (ESI) 216.2 (M+1)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([N:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][C:30]=5[Cl:33])[C:25]4=[O:34])[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([N:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][C:30]=5[Cl:33])[C:25]4=[O:34])[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:10][CH2:11]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(N4Cc5c(Cl)cccc5C4=O)nc23)C2CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
To a solution of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (40 mg, 0.065 mmol) in dichloromethane (1 mL) at r.t. was added trifluoroacetic acid (0.30 mL, 3.87 mmol). The solution was stirred for 3 h at room temperature then concentrated under vacuum. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.43 mL, 6.45 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated under vacuum. The crude residue was suspended in water:EtOAc (2 mL: 5 mL) and the resultant solid was collected by filtration, washing with EtOAc, to afford 23 mg (73%) of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=512.
Reaction SMILES: C=C[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH:10]=[CH2:11])[CH:4]=1.[CH3:12]CCCCCCCCCCCOC(CCSCCC(OCCCCCCCCCCCC)=O)=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.S(=O)(=O)(O)O.[OH2:74]>>[O-:74][OH:9].[C:5]1([CH:10]([CH3:11])[CH3:12])[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: O
Reactant: C=Cc1ccc(O)c(C=C)c1
Reactant: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=S(=O)(O)O
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CC(C)c1ccccc1
Product: [O-]O
Temperature: 85 °C

Procedure:
Then, 58 g of styrenated phenol, 44 g of dilaurylthiodipropionate, and 58 g of triphenyl phosphite were added to the obtained polymer latex. The mixture was coagulated at 50° C. with an aqueous 0.25% sulfuric acid so that the latex/water ratio was 1/2, and the mixture was maintained at 85° C. for 5 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(CO)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 6.3 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(hydroxymethyl)phenylboronic acid (15 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-6-(3-(hydroxymethyl)phenyl)-1′-methyl-2-phenylspi-ro[chroman-4,4′-imidazol]-5′(1′H)-one (1.3 mg, 5%). 1H-NMR (MeOD): 2.05 (t, 1H), 2.21 (t, 1H), 3.07 (s, 3H), 4.50 (s, 1H), 5.81 (d, 1H), 6.94 (d, 1H), 7.11 (s, 1H), 7.19 (d, 1H), 7.30 (m, 4H), 7.41 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C)n1
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
A mixture of 2-methoxy-6-methylpyridine (49.15 g, 0.292 mol) and nitric acid (76.0 mL, 0.292 mol) was added dropwise sulfuric acid (177.0 mL, 0.876 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was poured into ice-water. The precipitate was collected by filtration and washed with water to give the title compound as a pale yellow solid (53.37 g, 0.317 mol, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:28](O)[CH3:29]>>[CH2:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:28][CH3:29])=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCO
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 3-amino-5-nitro-4-phenylbenzoic acid (4.0 g), benzylbromide (4.0 ml), and ethanol (40 ml) is refluxed for 40 hours. After 16 and 24 hours additional amounts of benzylbromide (each portion 2.0 ml) are added. After cooling, the mixture is evaporated in vacuo and the obtained crude ethyl 3-benzylamino-5-nitro-4-phenylbenzoate is saponified by heating with a mixture of 2 N sodium hydroxide (25 ml) and ethanol (25 ml) for about 1 hour. The cooled mixture is acidified with acetic acid (5 ml) and diluted with water (15 ml). After cooling at about 5° C for 48 hours, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3-benzylamino-5-nitro-4-phenylbenzoic acid is obtained with a melting point of 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)cs1)c1cc(Cl)ccc1O
Yield: 31 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-[3-(trifluoromethyl)phenyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K].O>CN(C)C=O>[O:10]=[C:8]1[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:15])[N:9]1[CH2:2][C:3]#[N:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CCBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of bromoacetonitrile (22 g) in N,N-dimethylformamide (200 mL) was added potassium phthalimide (34 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 27 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][O:33][CH3:34])[CH2:10][NH:11][C:12]1[CH:21]=[C:20]([C:22]#[N:23])[C:15]([C:16]([O:18]C)=O)=[C:14]([NH:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH3:34][O:33][CH2:32][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][NH:11][C:12]1[N:13]=[C:14]([NH:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[C:15]2[C:16](=[O:18])[NH:23][CH2:22][C:20]=2[CH:21]=1
Reactant: COC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(Nc2cccc(C)c2)n1)NC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottomed flask was added (R)-methyl 6-(2-(tert-butoxycarbonylamino)-3-methoxypropylamino)-4-cyano-2-(m-tolylamino)nicotinate (84.5 mg, 0.180 mmol) in acetic acid (3 mL) and DCM (10 mL). To the resulting yellow solution was added platinum(IV) oxide (4.09 mg, 0.018 mmol). The flask was evacuated and back filled with hydrogen (3×1 atm). The reaction mixture was stirred vigorously at RT for 16 h, subsequently diluted with DCM (10 mL), and filtered through Celite. The filtrate was concentrated to an oil, which was diluted with DCM (10 mL). Potassium carbonate (24.87 mg, 0.180 mmol) was added and the reaction mixture was stirred at RT for 12 h. The crude reaction was diluted with DCM (10 mL), filtered through Celite, and concentrated to give the title compound as a thick yellow oil, which was used without further purification (26.5 mg, 33.4%). [M+H] calc'd for C23H31N5O4, 442; found, 442.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.CCN(CC)CC.[C:50](Cl)(=[O:54])[CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[C:50]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])(=[O:54])[CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (80 mg, 0.14 mmol) in DCM (1 mL) and Et3N (0.057 mL, 0.41 mmol) was added dropwise isobutyryl chloride (0.036 mL, 0.34 mmol) at 0° C. under nitrogen. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give 2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-7-yloxy)ethyl isobutyrate (75 mg, 84%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CCCC)CCCC)CCC.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:2]1(/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: C(=C/c1ccccc1)\c1ccccc1
Yield: 87 %

Procedure:
Table 1, Entry 3. In the reaction tube were mixed iodobenzene (0.204 g, 1.0 mmol), styrene (0.130 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), tri-n-butylamine (0.185 g, 1.0 mmol) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 2.50 min with an effect of 90 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane as the eluent. The yield was 87% (white crystals, terminal/internal arylation 19/1).
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[C:14](Cl)(=[O:23])[C:15]1[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH3:13]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOC(OCC)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)c1ccccc1OC
Reaction time: 0.5 h
Yield: 75 %

Procedure:
L-prolinal diethyl acetal hydrochloride is dissolved, together with the o-anisoyl chloride (853 mg, 4.01 mmol), in methylene chloride (12 ml), and triethylamine (1.7 ml, 12.2 mmol) is added dropwise thereto under ice-cooling and agitation. After the dropwise addition, stirring is further continued for 30 minutes under cooling and then for one hour and a half at room temperature. Ether (40 ml) is added to the reaction mixture, and the ethereal layer is separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of edible salt, dried over sodium sulfate and filtrated. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane-ethyl acetate, 2:1) to give 952 mg (75%) of the title compound as a pale yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][C:13]=3[Cl:14])=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[S:10][CH:11]=[CH:12][C:13]=4[Cl:14])=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3sccc3Cl)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4sccc4Cl)nc13)C2
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (67 mg, 0.21 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (5 mL) was stirred at room temperature, then triethylamine (0.15 mL, 1.05 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide (35 mg, 37%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J=6.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.61 (d, J=5.5 Hz, 1H), 7.17 (d, J=5.0 Hz, 1H), 4.63-4.53 (m, 1H), 3.24-3.13 (m, 2H), 2.70-2.55 (m, 5H), 2.12-2.00 (m, 3H), 1.64-1.48 (m, 3H), 1.28-1.12 (m, 2H); MS (ESI+) m/z 450 (M+H); HPLC>99% (AUC), tR=13.32 min.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:17]([O:19][C:20](=[O:23])[CH:21]=O)[CH3:18]>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:23])[CH:21]=[N:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:18]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-1-phenyl-ethylamine (59 g, 0.49 mmol) dissolved in toluene (500 mL) was added sodium sulfate (173 g, 1.22 mmol) followed by oxo-acetic acid ethyl ester (134 g, 0.49 mmol, 50% in toluene) dropwise. The reaction mixture was stirred at RT for 1 h. The solid was filtered and the filtrate was concentrated under vacuum to provide ((R)-1-phenyl-ethylimino)-acetic acid ethyl ester, which was dissolved in DMF (300 mL) at RT. TFA (56 g, 0.49 mmol) was added dropwise at RT, followed after 10 min by cyclopenta-1,3-diene (65 g, 0.98 mmol) and water (0.25 ml). The mixture was stirred at RT overnight, concentrated under vacuum and the residue was poured into a 10% aqueous solution of NaHCO3 (500 mL). The solution was adjusted to pH 8 with solid Na2CO3, and extracted with EtOAc (3×80 mL). The combined organic layers were purified by silica gel chromatography (30:1-15:1 petroleum ether:EtOAc) to provide the title intermediate (35 g, 26% yield), as a colorless oil. (m/z): [M+H]+ calcd for C17H21NO2 272.16 found 272.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a 10 mL round-bottomed flask, 6-(3-(piperazin-1-yl)propoxy)-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one (30 mg, 1.2 eq) obtained in Step 1 of Example 66 and CH2Cl2 (1 mL, 0.05M) were charged. Triethylamine (0.02 mL, 1.5 eq) was added and then the mixture was cooled to 0° C. and treated with a solution of methylsulfonyl chloride (6.2 mg, 0.05 mmol) in CH2Cl2 (1 mL) over 5 min. After being stirred for 3 h, the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=9:1) and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (19.8 mg, 68%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH2:30][CH2:31][CH3:32])=[CH:27][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:25][C:24]=2O)=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][C:28]=2[O:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:22]=1
Reactant: CCCOc1cc(C(=O)OCC)cc(O)c1-c1ccc(F)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCCOc1cc(C(=O)OCC)cc(OS(=O)(=O)C(F)(F)F)c1-c1ccc(F)cc1

Procedure:
Trifluoromethanesulfonic anhydride (20.1 mL) was added at 0° C. to a mixture of ethyl 4′-fluoro-2-hydroxy-6-propoxybiphenyl-4-carboxylate (31.5 g) and pyridine (200 mL), and the resultant mixture was stirred at the same temperature as above for 20 minutes. The reaction mixture was passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (44.6 g).