Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:21])[N:3]=1.[CH3:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([N+:29]([O-])=O)[CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:21])[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:24]4[N:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=4[CH3:22])[CH2:33][CH2:34]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-chloro-6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (210 mg), 1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine, and DIEA (185 mg, 1.44 mmol) in DMA at 120° C. for 16 h. Cool to room temperature and partition between EtOAc and 1N NaOH. Wash with water, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc to afford the title compound as a light-yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H, J=6.4 Hz, CH3); 1.69 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 2.28 (s, 3H, Ar—CH3); 3.10 (m, 4H); 3.47 (br, 2H, NH2); 3.68 (m, 4H); 3.77 (m, 4H); 4.34 (m, 1H); 6.25 (s, 1H, Ar—H); 6.88 (d, J=2.0 Hz, 1H); 7.18 (m, 1H); 7.70 (d, 1H, J=3.2 Hz); 7.89 (m, 1H); 8.07 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S>O>[CH2:13]([O:9][C:8](=[O:10])[C@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[NH2:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N[C@@H](CCCCO)C(=O)O
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCCO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Dissolve 6-hydroxynorleucine (14.7 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl bromide (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give O-benzyl-6-hydroxynorleucine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]([CH3:20])[CH3:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][C:3]=1[CH2:21][OH:22]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]([CH3:20])[CH3:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][C:3]=1[CH:21]=[O:22]
Reactant: CC(C)c1cc(-c2ccc(F)c(CO)c2)c2ncccc2c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccc(F)c(C=O)c2)c2ncccc2c1

Procedure:
A solution of [2-fluoro-5-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol from Step 2 (2.23 g, 7.55 mmol) and MnO2 (13 g, 150 mmol) in CH2Cl2 (70 mL) was stirred at 21° C. for 18 h. The mixture was filtered through a pad of celite and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 70:30) provided the 2-fluoro-5-(6-isopropylquinolin-8-yl)-benzaldehyde compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([NH:27][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Yield: 86.7 %

Procedure:
A solution of 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene (2 mmol; preparation described in Example 5) in THF (5 mL) is treated with benzylamine (2.4 mmol) at rt. After completion of the reaction, the reaction mixture is concentrated in vacuo. The residue is redissolved in EtOAc (10 mL), washed with saturated sodium bicarbonate solution, water, and brine. The organic phase is then dried over sodium sulfate and the solvent is removed in vacuo to afford the product, 2-(benzylamino)-4-(3-diethylamino-1-propoxy)nitrobenzene (620 mg) which was used for further transformation without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].N1C=CC=CC=1.[Cl:35][C:36]([Cl:43])([Cl:42])[CH2:37][O:38][C:39](Cl)=[O:40].FC(F)(F)C(O)=O>C(OCC)(=O)C.C1(OC)C=CC=CC=1>[Cl:35][C:36]([Cl:43])([Cl:42])[CH2:37][O:38][C:39]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:40]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O=C(CCCCCCCCCCCO)OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: O=C(O)CCCCCCCCCCCOC(=O)OCC(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
The whole of this benzhydryl 12-hydroxydodecanoate was dissolved in 400 ml of anhydrous ethyl acetate, and 13.7 ml of pyridine were added to the resulting solution, whilst ice-cooling, after which 3.48 g of trichloroethoxycarbonyl chloride dissolved in 10 ml of ethyl acetate were added dropwise over about 15 minutes. Insoluble salts were precipitated, after which the temperature of the mixture was allowed to return to room temperature, and the mixture was then stirred for a further 2 hours. The reaction mixture was then washed with 200 ml of 0.5N aqueous hydrochloric acid, after which it was washed with 100 ml each of a saturated aqueous solution of sodium chloride and of a 5% w/v aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous magnesium sulfate, after which the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using cyclohexane containing 20% by volume ethyl acetate as eluent, to afford a colorless and transparent viscous oil. The whole of this oil was dissolved in 5 ml of anisole, and 20 ml of trifluoroacetic acid was added to the resulting solution, whilst ice-cooling. The mixture was then left to stand for 1 hour. At the end of this time, the solvent was removed by evaporation under reduced pressure. This evaporating operation was repeated three times by adding 30 ml of toluene and dissolving the residue in 100 ml of a mixture of ethyl acetate and water. After this, 100 ml of a saturated aqueous solution of sodium bicarbonate was added to the organic layer, which emulsified the resulting mixture. and then the pH of the mixture was adjusted to a value of about 1 by the addition of concentrated hydrochloric acid. After the organic layer had been separated, it was washed with 100 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, to afford an oily residue. The residue was purified by silica gel column chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as eluent and then recrystallized from hexane to afford 3.96 g of the title compound as white plate-like crystals, melting at 44.6° to 46.4° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[N:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:4]=2[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[NH2:48][C:49]1[CH:50]=[C:51]([CH:58]=[CH:59][C:60]=1[CH3:61])[C:52]([NH:54][CH:55]1[CH2:57][CH2:56]1)=[O:53].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:55]1([NH:54][C:52](=[O:53])[C:51]2[CH:58]=[CH:59][C:60]([CH3:61])=[C:49]([NH:48][C:2]3[C:3]4[CH:12]=[N:11][N:10]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=5)[C:4]=4[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=3)[CH:50]=2)[CH2:56][CH2:57]1
Reactant: Cn1c(=O)cc(Cl)c2cnn(-c3cccc(F)c3)c21
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1cc(=O)n(C)c2c1cnn2-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a glass tube, a mixture of 4-chloro-1-(3-fluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (76 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (0) (12 mg), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (Dave-Phos, 12 mg), 3-amino-N-cyclopropyl-4-methylbenzamide (78 mg, 0.41 mmol) in THF (2 mL) was de-gassed slightly under reduced pressure or a vacuum. LiHMDS (0.82 mL of 1.0 M in THF solution, 821 mmol) was added slowly. The glass tube was sealed and placed in an oil bath at 60° C. for 1 h. The mixture was cooled to RT and treated with saturated ammonium chloride solution, then extracted twice with EtOAc. The combined EtOAc layers were washed with brine, dried and concentrated. The resulting crude material was purified by silica gel chromatography (80-100% EtOAc in hexanes) to provide the title compound as a tan crystalline solid. MS (ESI, pos.ion) m/z: 432.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1>>[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 125 °C
Yield: 24 %

Procedure:
A mixture of anhydrous piperazine (2.75 g, 32 mmol) and 3-chloro-benzo[d]isothiazole (1.00 g, 5.80 mmol) were heated in a sealed tube in an oil bath at 125° C. for 24 hours. The orange melt was then quenched with ice water and 50% NaOH was added in one portion. The mixture was extracted with dichloromethane to get the crude product which was purified by recrystallization to afford the title compound as a pale yellow solid in 24% yield (0.260 g). MS (ES+) m/z 220 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15]C)[CH:8]=[CH:9][C:10]=2[O:13]C)[CH2:5][O:4]1)[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C>[O:13]=[C:10]1[CH:9]=[CH:8][C:7](=[O:15])[C:6]2[CH2:5][O:4][CH:3]([CH2:1][CH3:2])[CH2:12][C:11]1=2
Reactant: CCC1Cc2c(OC)ccc(OC)c2CO1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: CCC1CC2=C(CO1)C(=O)C=CC2=O

Procedure:
To a solution of 3-ethyl-5,8-dimethoxy-isochroman (300 mg; 1.35 mmol) in acetonitrile (10 ml) at room temperature was added dropwise a solution of CAN (prepared by dissolving ceric ammonium nitrate (2.22 g; 4.0 mmol) in water (5 ml)). The resulting mixture was quenched with saturated bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2SO4 affording the crude title compound (251 mg; 97%) which was used as such for subsequent steps.
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[C:5]([O:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][C:20]=2[OH:24])[N:15]=[CH:14]1)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[C:5]([O:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][C:20]=2[O:24][CH:1]([CH3:3])[CH3:2])[N:15]=[CH:14]1)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)cc(O)c2c1=O
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Isopropanol (1.5 ml, 18.7 mmol) was added to a solution of [7-(benzyloxy)-5-hydroxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate (see WO01/094341, 6.5 g, 17.0 mmol) and triphenylphosphine (6.2 g, 23.8 mmol) in dichloromethane (300 ml). The reaction mixture was cooled to 0° C. and then a solution of di-tert-butylazodicarboxylate (4.7 g, 20.4 mmol) in dichloromethane (25 ml) was added dropwise over 30 minutes. The mixture was allowed to warm to room temperature and then stirred for 2 hours. The mixture was evaporated under reduced pressure to afford crude [7-(benzyloxy)-5-isopropoxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate which was used in the next stage without further purification.
Reaction SMILES: [Br-:1].[CH3:2][C:3]([CH3:41])([CH2:30][CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[C:4](=[O:29])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(OCC)C.N>C(Cl)Cl.CO>[Br-:1].[CH3:2][C:3]([CH3:41])([CH2:30][CH2:31][NH:32][CH3:33])[C:4]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][P+:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:29]
Reactant: CN(CCC(C)(C)C(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CNCCC(C)(C)C(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
8,8,11,14,14-pentamethyl-7,12-dioxo-1,1,1-triphenyl-13-oxa-6,11-diaza-1-phosphoniapentadecane bromide (205 mg, 0.32 mmol) was dissolved in methylene chloride (1.0 mL) and methanol (0.10 mL). The solution at room temperature was treated with 2.0 M hydrogen chloride in diethyl ether (0.36 mL, 0.71 mmol). The reaction was stirred overnight at room temperature, cooled with an ice bath, and treated with 7N ammonia in methanol (0.13 mL, 0.93 mmol). After 30 minutes, the slurry that resulted was filtered, and the solids were washed with methylene chloride. The filtrate was concentrated to give the title compound (170 mg, 98%) as a white foam. The product of step 2 was used crude in next step.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[CH2:18][N:17]([CH2:21][C@H:22]([NH:32]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C@@H:23]2[CH2:27][C@@H:26]([CH:28]([CH3:30])[CH3:29])[C:25](=[O:31])[O:24]2)[C:16]([CH3:46])([CH3:45])[CH2:15]1.C1(S)C=CC=CC=1.C(N(CC)CC)C.[C:61](OC(OC(C)(C)C)=O)([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62].N[C@H]([C@@H]1C[C@@H](C(C)C)C(=O)O1)CN1C(C)(C)CN(C2C=CC=CC=2Cl)C(=O)C1>CN(C)C=O.[Cl-].[Na+].O.C(Cl)Cl>[C:64]([O:63][C:61](=[O:62])[NH:32][C@H:22]([C@@H:23]1[CH2:27][C@@H:26]([CH:28]([CH3:29])[CH3:30])[C:25](=[O:31])[O:24]1)[CH2:21][N:17]1[CH2:18][C:19](=[O:20])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])[CH2:15][C:16]1([CH3:46])[CH3:45])([CH3:67])([CH3:66])[CH3:65]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC(C)[C@@H]1C[C@@H]([C@@H](N)CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)OC1=O
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 1 h
Yield: 80.7 %

Procedure:
197 mg of cesium carbonate (0.61 mmol) was added to a solution of 299 mg of N-{(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (1l) (0.50 mmol) and 0.11 ml of thiophenol (content: 95%) (1.00 mmol) in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for one hour. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 0.21 ml of triethylamine (1.51 mmol) and 132 mg of di-t-butyl dicarbonate (0.61 mmol) were added to a solution of the resulting 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=2/1) to obtain 205 mg of the title compound (yield: 80%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH:14]2[CH2:19][CH:18]([NH:20][C:21]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:27]=[C:26]4[C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[O:22])[CH2:17][N:16](C(OCCCC)=O)[CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C([SiH](CC)CC)C>[C:8]1([CH:14]2[CH2:15][NH:16][CH2:17][CH:18]([NH:20][C:21]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][N:27]=[C:26]4[C:51]3[CH:52]=[CH:53][N:54]=[CH:55][CH:56]=3)=[O:22])[CH2:19]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCOC(=O)N1CC(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CNCC(c2ccccc2)C1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (1 mL) was added to tort-butyl 3-phenyl-5-(3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamido)piperidine-1-carboxylate (0.104 mmol). The reaction was stirred at room temperature for 30 minutes. Triethylsilane (1 drop) was added to the reaction and stirred for an additional 5 minutes. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:20]=[C:19]([F:21])[C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([NH2:22])=[CH:14][CH:15]=4)[C@@:10]4([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[CH3:29][O:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[NH2:28][C:24]1[O:25][CH2:26][CH2:27][C@@:10]2([N:23]=1)[C:9]1[CH:8]=[C:7]([C:4]3[CH2:3][CH2:2][O:1][CH2:6][CH:5]=3)[CH:20]=[C:19]([F:21])[C:18]=1[O:17][C:16]1[C:11]2=[CH:12][C:13]([NH:22][C:37]([C:34]2[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=2)=[O:38])=[CH:14][CH:15]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Reactant: COc1cnc(C(=O)O)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCOC(N)=N2)c2cc(C4=CCOCC4)cc(F)c2O3)cn1
Reaction time: 2 h
Yield: 53.2 %

Procedure:
The (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (0.048 g, 0.126 mmol) was suspended in MeOH (2.5 mL). The 5-methoxypyrazine-2-carboxylic acid (0.019 g, 0.126 mmol) was added, followed by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.035 g, 0.126 mmol). After 30 min another 1 mg of the acid (0.05 equiv) and 1.75 mg of the coupling agent (0.05 equiv) were added. After 2 h, the reaction was quenched with 15 mL of half-saturated NaHCO3. The material was extracted with 5% MeOH-dcm (3×25 mL). The organics were combined, washed with dilute brine (8 mL), dried over MgSO4 and concentrated. The material was purified through silica gel (35 mL) using 10% to 20% EtOH in 2:1 hexane-EtOAc, affording (S)—N-(2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-7′-yl)-5-methoxypyrazine-2-carboxamide (35 mg, 0.067 mmol). MS m/z=518 [M+H]−1. 1H NMR in CDCl3 δ: 9.52 (s, 1H), 9.03 (s, 1H), 8.16 (s, 1H), 7.76 (dd, 1H, J=8.7, 2.4), 7.66 (d, 1H, J=2.5), 7.01 (s, 1H), 6.96 (dd, 1H, J=11.3, 1.8), 4.20-4.40 (m, 6H), 4.07 (s, 3H), 3.53 (m, 2H), 2.80 (m, 1H), 1.75-1.90 (m, 4H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[C:13]3[C@H:20]([NH:21]C(=O)OCC4C=CC=CC=4)[C@@:19]4([CH3:35])[C:32]([CH3:34])([CH3:33])[C@H:16]([CH2:17][CH2:18]4)[CH2:15][N:14]3[C:36](=[O:39])[C:37]=2[OH:38])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].N(C)C>C(Cl)Cl.CO>[F:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[C:13]3[C@H:20]([NH:21][S:52]([CH3:51])(=[O:54])=[O:53])[C@@:19]4([CH3:35])[C:32]([CH3:34])([CH3:33])[C@H:16]([CH2:17][CH2:18]4)[CH2:15][N:14]3[C:36](=[O:39])[C:37]=2[OH:38])=[O:10])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](NC(=O)OCc1ccccc1)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Agent: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](NS(C)(=O)=O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a stirred solution of benzyl ((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.025 g, 0.055 mmol) and diisopropyl-ethylamine (0.175 mL, 1 mmol) in CH2Cl2 (3 mL) was added methanesulfonyl chloride (0.039 mL, 0.5 mmol) at room temperature. After 4 h, 2M Me2NH in methanol (1 mL) was added and stirring continued at room temperature. After 16 h, the reaction mixture was concentrated and purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0186 g, 0.038 mmol, 68% yield) as a purple solid after crystallization from methanol/water. 1H NMR (500 MHz, CDCl3) δ: 12.39 (1 H, s), 8.60 (1 H, brs), 7.34 (2 H, dd, J=8.5, 5.2 Hz), 7.01 (2 H, t, J=8.7 Hz), 6.07 (1 H, d, J=9.5 Hz), 5.19 (1 H, dd, J=15.6, 8.5 Hz), 4.79 (1 H, d, J=9.8 Hz), 4.52-4.65 (2 H, m), 3.63 (1 H, d, J=15.6 Hz), 2.76 (3 H, s), 2.10 (1 H, t, J=8.1 Hz), 1.80-1.89 (1 H, m), 1.43-1.51 (1 H, m), 1.30-1.35 (1 H, m), 1.29 (3H, s), 1.04 (3 H, s), 1.01 (3 H, s), 0.96-1.01 (1 H, m). LCMS (M+H) calcd for C23H30FN4O5S: 493.19; found: 493.24. Purity: >98%.