Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)[O:16][C@@:7]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH2:8][O:9]2)[C@H:6]1[O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2].BrN1C(=[O:49])CCC1=O.O.ClCCl>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[OH:49])[CH:18]=3)[O:16][C@@:7]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH2:8][O:9]2)[C@H:6]1[O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOc1ccc(C(O)c2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (Example 2; 344 mg, 0.569 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (159 mg, 0.893 mmol) followed by the addition of 2,2′-azobisisobutyronitrile (AIBN, 8 mg, 0.05 mmol) and the reaction mixture was heated at reflux under nitrogen. After 16 hours, the reaction mixture was cooled to room temperature, water (50 mL) and dichloromethane (25 mL) were added and the resulting mixture was stirred for 24 hours at room temperature. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane (25 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered through a pad of celite, and concentrated under reduced pressure. The crude material was chromatographed with the Biotage SP4 automated chromatography unit (SNAP 25 g silica gel column) eluting with a gradient of 0-80% ethyl acetate in heptane to produce 316 mg (89% yield) of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-{4-chloro-3-[(4-ethoxy-phenyl)-hydroxy-methyl]-phenyl}6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester as a mixture of diastereoisomers at the bis-benzylic position.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][C@H:3]([C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8])[NH:2]2.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:2]2[C@@H:3]([C:7]([NH:9][C@H:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[CH3:11])=[O:8])[CH2:4][CH:5]3[CH:1]2[CH2:6]3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compounds (D150) (72 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((3R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (D107) (48 mg) and 4-(trifluoromethyl)-benzylbromide (0.031 ml) (Na2CO3: 3 eq; Reaction time: 18 hrs; 68° C.)
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([CH:18]4[CH2:20][CH2:19]4)[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Br.[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28]Br)[CH3:24]>>[CH3:2][C:3]1([CH3:21])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])[CH:5]=[N:4]1
Reactant: CC1(C)N=CC2=C3N=C(C4CC4)N=C3C(=O)CC2C1=O
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: Cl
Product: CCN(CC)CCCC1C(=O)C2=NC(C3CC3)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogous to Example 23 from 2.45 gm of 7,7-dimethyl-2-cyclopropyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione hydrochloride and 2.3 gm of 3-diethylamino-propyl bromide hydrobromide. The crude product was purified by chromatography on a silicagel column (eluant: chloroform with increasing content of acetone).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([O:14]CC)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN1C(=O)CCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:20]([O:25][CH3:26])[CH:19]=1
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Reactant: COc1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-chloroquinoxaline-2-carboxylate (300 mg, 1.27 mmol), 4-fluoro-2-methoxy-phenol (289.0 μL, 2.54 mmol) and Cs2CO3 (826.3 mg, 2.54 mmol) in NMP (3.0 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, the pH was adjusted to pH 6 with 1N HCl and the mixture was extracted with ethyl acetate (3×). The organics were combined, washed with brine, dried with Na2SO4, filtered and evaporated to dryness. Purification by column chromatography using a gradient of 0-10% MeOH in dichloromethane gave 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (360 mg, 90%) as a red oil. ESI-MS m/z calc. 314.07, found 315.1 (M+1)+; Retention time: 1.35 minutes (3 minutes run).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH3:19])[C:8]([C:11]2[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=2)=[N:9][CH:10]=1)([OH:3])=O.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:18][C:13]1[CH:12]=[C:11]([C:8]2[C:7]([CH3:19])=[CH:6][C:5]([CH2:4][C:1](=[O:3])[NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][N:20]=4)=[CH:31][N:30]=3)=[CH:10][N:9]=2)[CH:16]=[CH:15][N+:14]=1[O-:17]
Reactant: Cc1cc(CC(=O)O)cnc1-c1cc[n+]([O-])c(C)c1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cnccn3)cn2)cnc1-c1cc[n+]([O-])c(C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4-(5-(carboxymethyl)-3-methylpyridin-2-yl)-2-methylpyridine 1-oxide 156-6 from Step 4 (0.41 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (141 mg, 0.82 mmol), 1,3-dicyclohexylcarbodiimide (188 mg, 0.90 mmol) and 4-(dimethylamino)pyridine (16 mg, 0.16 mmol) in DMF (2 mL) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble and the filtrate was purified by reverse phase HPLC to give 2-methyl-4-(3-methyl-5-(2-oxo-2-(5-(pyrazin-2-yl)pyridin-2-ylamino)ethyl)pyridin-2-yl)pyridine 1-oxide 156 as white solid. MS m/z 413.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.12 (s, 1H), 9.31 (d, 1H), 9.11 (d, 1H), 8.72 (m, 1H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.48 (d, 1H), 8.31 (d, 1H), 8.21 (d, 1H), 7.73 (m, 2H), 7.52 (dd, 1H), 3.86 (s, 2H), 2.41 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=1>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18](=[O:17])[CH2:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][C:21]=1[CH3:26]
Reactant: COC(=O)c1ccc(F)c(C)c1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(=O)c2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17.3 g KOtBu was dissolved in 500 mL THF and 9 mL acetophenone was added. After 15 min at RT 25.9 g 4-fluoro-3-methyl-benzoic acid methyl ester was added and stirred for 3 h at RT. The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2) to yielded 19.3 g of the desired compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](O)=[O:30]>>[CH2:13]([C@H:3]([NH:2][C:29]([C:21]1[NH:20][C:28]2[C:23]([CH:22]=1)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:30])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2ccccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperdin-1-yl)-3-phenyl-propan-1-one hydrochloride (3.4 mmol) and 1H-indole-2-carboxylic acid (3.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hour reaction time). The product was purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes, followed by trituration with 1:1 ether-hexanes. Yield 1.14 g, 88%; HPLC (60/40) 3.52 minutes (98%); PBMS 392 (MH+, 100%);
Reaction SMILES: C(#N)C1C=CC=CC=1.OO.[C:11](=[O:14])(O)[O-].[K+].[CH2:16]([O:19][C:20]1[C:29]2[O:28][NH:27][C:26](=[O:30])[CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH:17]=C>CO>[O:14]1[CH2:11][CH:17]1[CH2:16][O:19][C:20]1[C:29]2[O:28][NH:27][C:26](=[O:30])[CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C([O-])O
Reactant: C=CCOc1cccc2c1ONC(=O)C2
Agent: OO
Agent: [K+]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: O=C1Cc2cccc(OCC3CO3)c2ON1
Reaction time: 72 h

Procedure:
5.2 g of benzonitrile, 18 ml of a 30 percent strength aqueous solution of hydrogen peroxide and 1.0 g of potassium bicarbonate are added to a suspension of 10.1 g of 8-allyloxy-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one in 400 ml of methanol and the mixture is then stirred for 3 days at 20°. The reaction mixture is then concentrated to a volume of 40 ml under reduced pressure. After leaving to stand at 0°, 8-(2,3-epoxy-propoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one is obtained in the form of colourless crystals, which are filtered off and washed with a little cold methanol; melting point 158°-160°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][N:10](CC2C=CC=CC=2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[H][H]>CO.Cl.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][NH:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][C:3]=1[C:23]([F:24])([F:25])[F:26]
Reactant: [H][H]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(N)c(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(N)c(C(F)(F)F)c1

Procedure:
0.45 gm of 1-(4'-amino-3'-trifluoromethyl-phenyl)-2-(N-benzyl-N-tert.butylamino)-ethanol were dissolved in 10 ml of methanol and 1.4 ml of 1N hydrochloric acid, and the solution was hydrogenated in a hydrogenation vessel in the presence of 50 mgm of palladium/coal-catalyst (10%) until 1 mol of hydrogen had been absorbed. The catalyst was removed by filtration, the filtrate was evaporated in vacuo, and the residue was distributed between ethyl acetate and 2N ammonia. The organic layer was washed with water, dried and again evaporated in vacuo. The residue was crystallized from ethanol/water. M.p. 145°-147° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[O:15][N:14]=[C:13]([C:16](O)=O)[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:37]=[C:38]([NH2:43])[C:39]([NH2:42])=[CH:40][CH:41]=1>C1COCC1.O>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:41]=[CH:40][C:39]2[N:42]=[C:16]([C:13]3[CH:12]=[C:11]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[O:15][N:14]=3)[NH:43][C:38]=2[CH:37]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cc(C(=O)O)no1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-isoxazole-3-carboxylic acid (55 g, 0.215 mol) and Et3N (36 mL, 0.26 mol) in THF (2 L) was added dropwise isobutyl chloroformate (33 mL, 0.26 mol) at −20° C. The reaction mixture was stirred for 1 hr, and a solution of 4-(trifluoromethyl)benzene-1,2-diamine (45.4 g, 0.26 mol) in THF was added. After stifling for 2 h at −20° C., the mixture was allowed to warm up to RT and stirred for another 2 hr. Water was added to quench the reaction and the reaction mixture was evaporated under reduced pressure to remove THF. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was re-dissolved in acetic acid (250 mL) and stirred for 2 hr at 90° C. The solution was concentrated under vacuum and partitioned with ethyl acetate and water. The organic layer was separated, washed with water, Na2CO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to afford compound N.7, (R)-tert-butyl 1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethylcarbamate (75.7 g, 88.8%). 1H NMR (DMSO-d6) δ7.8 (m, 4H), 6.9 (s, 1H), 4.91 (m, 1H), 1.46 (d, 3H), 1.39 (s, 9H).
Reaction SMILES: [C:1](Cl)(=O)[CH:2]=[CH2:3].C(N([CH2:11][CH3:12])CC)C>C1COCC1>[CH3:3][CH2:2][CH2:1][CH2:3][CH2:2][CH2:1][CH2:11][CH2:12][CH2:11][CH3:12]
Reactant: CCN(CC)CC
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of 1 mmol of α,α-dimethyl-2-endotricyclo[5.2.1.02,6]decanemethanol obtained according to Example 9, 1.5 mmol of acrylic chloride, 1.5 mmol of triethylamine, and 3 ml of THF was stirred at 60° C. for 3 hours. The resulting reaction mixture was subjected to column chromatography on a silica gel to yield 4a-(1-acryloyloxy-1-methylethyl)-endotricyclo[5.2.1.02,6]decane represented by the following formula (yield: 52%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[C:13]2[C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].ClN1C(=O)CCC1=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][C:8]1[C:13]2[C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@@H]4CCC[C@H]4O)c23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OC4CCCC4=O)c23)CC1
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 4-{[(4-{[trans-2-hydroxycyclopentyl]oxy}-1,2-benzisoxazole-3-yl)oxy]-methyl}piperidine-1-carboxylate (158 mg, 0.365 mmol, EXAMPLE 32, step 1), 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2.4 mg, 0.015 mmol), sodium bicarbonate (98.3 mg, 1.17 mmol), and tetra-n-butylammonium bromide (8.2 mg, 0.025 mmol) in dichloromethane (2 mL) and water (0.4 mL) was added N-chlorosuccinimide (60.3 mg, 0.453 mmol) at ambient temperature. After being stirred for 4 h, the mixture was quenched with aq. sodium thiosulfate. The mixture was extracted with ethyl acetate (20 mL) and washed with aq. potassium carbonate and brine. The extract was dried over magnesium sulfate and concentrated in vacuo to give 167 mg (crude mixture) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].Cl>C1COCC1.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]([OH:26])=[O:25])=[CH:3][CH:4]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C=O
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A −78° C. solution of Example 66A (1.5 g, 4.68 mmol) in THF (50 mL) was treated dropwise with 2.5M n-butyllithium in hexanes (4.7 mL, 11.71 mmol), stirred for 30 minutes at −78° C., then treated with excess dry ice. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature, diluted with water, adjusted to pH 3 with 2N HCl, and filtered. The filter cake was dried to provide 686 mg (51%) of the desired product. MS (CI) m/e 285 (M+); 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H); 8.29 (s, 1H); 8.09 (d, J=8.4 Hz, 2H); 7.53 (d, J=8.4 Hz, 2H); 2.28 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].CCCCCC.C([Li])CCC.[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]I)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][CH2:8][C:7](=[O:9])[CH2:6][C:3](=[O:5])[CH3:4])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)CC(C)=O
Reactant: ICc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)CC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
That is, 0.30 g (60% in oil) (7.5 mmol) of sodium hydride was weighed in a nitrogen atmosphere and 20 ml of THF was added thereto and the mixture was cooled to 0° C. in an ice bath. To the suspension was dripped a mixed solution of 0.75 g (7.5 mmol) of acetylacetone and 0.5 ml of hexamethyl phosphoric triamide to produce colorless precipitate. After stirring the mixture at 0° C. for 10 minutes, 4.6 ml (7.5 mmol) of a hexane solution (1.6 M) of n-butyllithium was dripped therein to dissolve the precipitate and the mixture was further stirred at 0° C. for 20 minutes. To the obtained pale yellow transparent solution was dripped a solution of 2.28 g (7.0 mmol) of 4-benzyloxybenzyl iodide in 10 ml of THF. After stirring the reaction mixture at room temperature for 1 hour, it was cooled again to 0° C. Then, dilute hydrochloric acid was added thereto to neutralize it. After washing the organic layer with a saturated aqueous solution of sodium chloride, the solvent was distilled off by using a rotary evaporator. The residue was passed through a silica gel column (eluent: a mixed solvent of dichloromethane/hexane of 1:1 (by volume ratio)) to separate a main product. Separation of this and concentration to dryness under reduced pressure afforded 1.31 g (4.4 mmol) of the objective 6-(4-benzyloxyphenyl)-2,4-hexanedione as pale yellow solid. Yield: 63%. Identification was performed by elementary analysis of C and H, and 1H-NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:9])[CH3:8].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:1][N:2]1[CH2:6][CH:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]1([CH3:9])[CH3:8]
Reactant: CN1CCC(=O)C1(C)C
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CN1CC=C(N2CCCC2)C1(C)C
Temperature: 25 °C

Procedure:
1,2,2-Trimethylpyrrolidin-3-one (1.00 g) was dissolved in cyclohexane (5 mL). Pyrrolidine (1.31 mL) and p-toluenesulfonic acid monohydrate (7.48 mg) were sequentially added thereto, and the mixture was heated under reflux for 3 days, and allowed to cool to room temperature. The resultant mixture was concentrated under reduced pressure to thereby give a crude product of 1,2,2-trimethyl-3-(pyrrolidine-1-yl)-2,5-dihydro-1H-pyrrole (972 mg). To the product dissolved in dimethylformamide (10 mL), formamidine disulfide hydrochloride (1.20 g) was added, followed by stirring at room temperature for 4 days. The resultant mixture was concentrated under reduced pressure. Methanol (50 mL) and sodium carbonate anhydrate (20 g) were added to the residue, and the resultant mixture was stirred at room temperature for 1 hour. The insoluble material was removed through filtration, followed by washing with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (methanol methylene chloride=1:99→1:9), to thereby give the title compound (580 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:13]=[C:12]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][S:23][CH:24]=3)[CH:3]=2)[CH:8]=[CH:9][C:10]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:11]1=2
Reactant: CS(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: OB(O)c1ccsc1
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+]
Product: CS(=O)(=O)Nc1ccc2ccc3ncc(-c4ccsc4)cc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (0.100 g, 0.30 mmol), 3-thienylboronic acid (0.077 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.009 mmol) and potassium carbonate (0.124 g, 0.90 mmol) were combined in a dry flask. The flask was purged with argon and 5 mL of dry dioxane was added. Argon was bubbled through the solution for 5 minutes and the solution was stirred and heated to 100° C. After 12 hours, the reaction mixture was poured into 100 mL of ethyl acetate, 100 mL of water, and 25 mL of saturated ammonium chloride. The organic layer was separated, dried with magnesium sulfate, filtered, concentrated, and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, DMSO-D6) δ 10.40 (s, 1H); 9.34 (d, 1H); 8.70 (d, 1H); 8.28 (s, 1H); 8.00 (d, 1H); 7.78 (m, 2H); 7.73 (m, 1H); 7.58 (dd, 1H); 7.38 (d, 1H); 7.26 (d, 1H); 3.08 (s, 3H). LRMS (APCI) calculated for C19H15N2O3S2 [M+H]+, 383.0; found 383.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[CH3:25][O:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1([CH2:23][CH2:22][C@@H:20]2[CH2:19][S:18][C:17]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:21]2)[CH2:33][CH2:32][CH2:31][NH:30]1)=[O:28]
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: COC(=O)[C@@H]1CCCN1
Product: COC(=O)C1(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CCCN1

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and (S)-pyrrolidin-2-yl-carboxylic acid methyl ester were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]1[CH2:15][CH2:14][O:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:15][CH2:14][O:13]2)=[CH:4][C:3]=1[F:9]
Reactant: OCC1CCO1
Reactant: Oc1ccc(Br)c(F)c1
Product: Fc1cc(OCC2CCO2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and rac-2-hydroxymethyl-oxetane in analogy to Example 9c): MS (EI): 260 and 262 M+.