Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:33].CO>C(Cl)Cl>[NH2:33][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CC1
Solvent: ClCCl
Solvent: CO
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)C3CC3)c2F)n1
Temperature: 80 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide (125 mg, 0.252 mmol) and 7M ammonia in MeOH (7 mL, 0.49 mmol) was heated in a sealed tube to 80° C. for 2 days. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were concentrated to yield the crude product as a yellow solid (62 mg). The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA in both). The combined clean fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound was obtained as a yellow solid (26 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 7.86 (d, J=5.4 Hz, 1H), 7.49 (td, J=7.4, 2.2 Hz, 1H), 7.11-7.38 (m, 2H), 6.53 (s, 2H), 5.84 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.43 (t, J=4.7 Hz, 4H), 2.53-2.68 (m, 1H), 0.74-0.92 (m, 4H). MS (ESI): 477.0 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.[C:28]1(=[O:34])[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[O:34]=[C:28]1[CH2:29][CH2:30][C:31](=[O:33])[N:32]1[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1
Reactant: O=C1CCC(=O)N1
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CCN4C(=O)CCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
A solution (10 mL) of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg), succinimide (29 mg) and triphenylphosphine (93 mg) in tetrahydrofuran was added a 40% toluene solution (0.155 mL) of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hr. A 40% toluene solution (0.155 mL) of diethyl azodicarboxylate was added again to the reaction solution, and the mixture was further stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (36 mg, yield: 30%) as colorless prism crystals. MS: 503 (MH+). melting point 189-191° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=C[C:44]4[O:45]COC=4C=3)C2=O)CC1>>[CH:13]1([CH2:12][CH2:11][N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[C:4]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[O:21][CH2:22][O:23][C:19]=4[CH:18]=3)([CH2:44][OH:45])[C:5]2=[O:16])[CH2:14][CH2:15]1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCC1CC1
Product: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1E, making variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (53%): Rf=0.28 (EtOAc/Hexanes, 1/1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17].N#N>CCN(CC)CC.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.[Cu]I>[C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Temperature: 70 °C
Yield: 15.7 %

Procedure:
To a solution of (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 2.2 mmol) in Et3N (10 mL) was added Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) successively under N2 protection. The reaction mixture was heated at 70° C. overnight. The solvent was removed under vacuum and the residue washed with EtOAc (10 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to afford tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (100 mg, 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.20 (d, J=2.4, Hz, 1H), 8.04 (dd, J=2.4, 9.2 Hz, 1H), 6.79 (d, J=9.6 Hz, 1H), 5.62 (brs, 1H), 1.41 (s, 9H), 0.28 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:58])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:44][C:45]1[N:46]([CH2:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[CH:48][N:49]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:27][C:28](=[O:43])[NH:29][C@H:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32][C:33](O)=[O:34])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([S:68]([NH2:71])(=[O:70])=[O:69])=[CH:64][CH:63]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:53]([O:52][C:51](=[O:57])[CH2:50][N:46]1[CH:47]=[CH:48][N:49]=[C:45]1[CH2:44][N:14]([CH2:13][C:9]1[N:8]([CH2:7][C:6](=[O:58])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:27][C:28]([NH:29][C@@H:30]([CH2:31][CH2:32][C:33](=[O:34])[NH:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]([S:68](=[O:69])(=[O:70])[NH2:71])=[CH:66][CH:67]=1)[C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:43])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:54])([CH3:55])[CH3:56]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](NC(=O)N[C@@H](CCC(=O)NCCc1ccc(S(N)(=O)=O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C
Yield: 101.8 %

Procedure:
A solution of (S)-4-(3-((S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (80 mg, 0.098 mmol), 4-(2-aminoethyl)benzenesulfonamide (30 mg, 0.15 mmol), 2-(1-H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU, 50 mg, 0.17 mmol), and DIPEA (0.50 mL) in DMF (5 mL) was stirred at 40° C. overnight. The solvents were evaporated under reduced pressure to give a residue, which was purified by Biotage SP4 using a gradient of 0-20% MeOH in DCM to give (S)-tert-butyl 6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-tert-butoxy-1,5-dioxo-5-(4-sulfamoylphenethylamino)pentan-2-yl)ureido)hexanoate (100 mg, 100%). ESMS m/z: 501.9 (M/2+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(C(F)(F)F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (85 mg, 82%), MS (ISP) m/z=413.4 [(M+H)+], mp 268° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[N:5][S:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([CH3:33])[C:21]=1[CH3:34]>>[CH:8]1([C:7]2[S:6][N:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)[C:3]=2[CH2:2][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([CH3:33])[C:21]=2[CH3:34])[CH2:10][CH2:9]1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2nsc(C3CC3)c2CCl)cc1
Product: CCc1ccc(-c2nsc(C3CC3)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 122 following Steps 5 and 7 by coupling of 4-(chloromethyl)-5-cyclopropyl-3-(4-ethylphenyl)-1,2-thiazole with ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as a yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.06 (s, 2H), 2.92 (t, J=8.0 Hz, 2H), 2.70 (q, J=7.6, 15.6 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.25-2.27 (m, 4H), 2.11 (s, 3H), 1.20-1.28 (m, 5H), 0.88-0.87 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C26H29NO3S, 436.2 (M+H). found 436.2.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:20]([O:29][CH3:30])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([CH3:26])([CH3:27])[CH3:28])[N:21]=[C:20]([O:29][CH3:30])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Reactant: COc1nc(N)nc(NC(C)(C)C)n1
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(NC(C)(C)C)n1

Procedure:
A mixture of 5.0 g of 2-difluoromethoxyphenyl-sulfonylisocyanate and 4.0 g of 2-amino-4-tert-butylamino-6-methoxy-1,3,5-triazine is stirred in 60 ml of absolute dioxane for 3 hours at 70°-80° C. After filtration of the hot reaction mixture through active charcoal, 6.9 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-tert-butylamino-6-methoxy-1,3,5-triazin-2-yl)-urea, m.p. 213°-214° C., crystallise out on cooling of the solution.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:35]2([CH3:36])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:30])[CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][C@@H:7]([O:38][C:39](=[O:41])[CH3:40])[CH2:6]1)(=[O:3])[CH3:2].[I-:42].[Na+]>C1(C)C=CC=CC=1.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[C:1]([O:4][C@@H:5]1[C@@:35]2([CH3:36])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:30])[CH2:18][I:42])[CH2:8][C@@H:7]([O:38][C:39](=[O:41])[CH3:40])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CI)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 97.5 %

Procedure:
Second process. A solution of 23.4 g of (20S)-1α,3β-diacetoxy-20-methyl-21-p-toluenesulphonyloxy-pregn-5-ene in 260 ml of toluene is treated with 1.04 g of hexadecyl-tri-n-butyl-phosphonium bromide and a solution of 132 g of sodium iodide in 260 ml of water and the mixture is heated under reflux for 5 hours. After cooling, the organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated at 30°/11 Torr. Chromatography of the residue on 270 g of silica gel with hexane/ether (19:1 and 9:1) gives 21.1 g of product of melting point 135°-136°. After recrystallization from concentrated pentane solution, there are obtained 16.0 g of product of melting point 136°; [α]D20 =-11.0° (c=1.0 in CHCl3).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C@@H:19]([CH2:20][CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1[CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
Sodium borohydride (2 mg, 0.053 mmol), followed by MeOH (0.15 mL), was added to a solution of {(Z)-4-[(R)-2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-but-2-enyloxy}-acetic acid methyl ester (11.5 mg, 0.030 mmol) in CH2Cl2 (0.5 mL) at 0° C. The mixture was allowed to warm to rt. After 30 min at rt, the reaction was quenched with aqueous HCl (0.5 M) and extracted with EtOAc (3×7 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 10.1 mg (87%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[S:17][CH:16]=[N:15][C:14]=2/[C:13](=C/C(OC)=O)/[CH2:12][CH2:11][C@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:32]=[O+][O-]>C(Cl)Cl>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[C@@H:10]1[CH2:11][CH2:12][C:13](=[O:32])[C:14]2[N:15]=[CH:16][S:17][C:18]=2[C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[O+][O-]
Reactant: COC(=O)/C=C1\CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2scnc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2scnc2C(=O)CC[C@H]1c1cccc(F)c1F
Yield: 58 %

Procedure:
A solution of (E)-methyl 2-((7S,8S)-8-(tert-butoxycarbonylamino)-7-(2,3-difluorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-4-ylidene)acetate (68 mg, 0.15 mmol) in methylene chloride (5 mL) was treated with ozone under −78° C. for 2 min. The reaction mixture was purged with nitrogen and quenched with dimethyl sulfide. The solvent was removed under vacuum and the product was purified by flash chromatography, eluting with ethyl acetate in hexane from 0 to 100% to afford the desired product (34.5 mg, 58%): 1H NMR (400 MHz, CHLOROFORM-d) δ 8.73 (s, 1H), 7.16-7.09 (m, 3H), 5.62-5.53 (m, 1H), 5.13-5.05 (m, 1H), 3.64-3.53 (m, 1H), 3.13-3.02 (m, 1H), 3.01-2.92 (m, 1H), 2.38-2.24 (m, 2H), 1.36-1.29 (m, 9H); 19F NMR (400 MHz, CHLOROFORM-d) δ −137.33, −141.96.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([CH:45]([OH:47])[CH3:46])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[OH:47][CH:45]([C:37]1[CH:36]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH:20]2[NH:2][N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[C:18](=[O:17])[NH:19]2)[CH:40]=[C:39]([O:41][CH3:42])[C:38]=1[O:43][CH3:44])[CH3:46]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(C(C)O)c1
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C2NC(=O)N(c3ncccn3)N2)cc(C(C)O)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
After adding 22 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 112 mg of {2-[3-(1-hydroxyethyl)-4,5-dimethoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{[3-(1-hydroxyethyl)-4,5-dimethoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-one (93 mg) as a light brown solid.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C@H:5]([CH2:6][O:7][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[C:24]([O:28][C:29]([N:31]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:32]1[CH:33]=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:32]1[CH:33]([OH:34])[CH:3]1[C:2](=[O:1])[N:9]2[C@H:5]([CH2:6][O:7][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
To a solution of (2R, 5S)-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane (50 g, 246 mmol, J. Org. Chem., 51, 3140 (1986)) in tetrahydrofuran (1500 ml), lithium diisopropylamide (2M tetrahydrofuran-heptane solution, 147.6 ml, 295.2 mmol) was dropwise added at -78° C., and the reaction solution was stirred at the same temperature for 30 minutes. A solution of (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (61.0 g, 245.9 mmol) in tetrahydrofuran (400 ml) was dropwise added thereto, and the reaction solution was stirred at the same temperature for 30 minutes. Acetic acid (17.6 ml, 307.5 mmol) was dropwise added to the reaction solution. Then, the dry ice bath was removed and the reaction mixture solution was stirred for 30 minutes. To the reaction solution, ethyl acetate and 5% sodium hydrogen carbonate aqueous solution were added and the solution mixture was subjected to liquid separation and the aqueous layer was extracted with ethyl acetate. The organic layers were put together and washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue and the precipitated crystal was collected by filtration to obtain (2R, 5S)-7-[[(2S, 4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidin-2-yl](hydroxy)methyl]-8-oxo-2-phenyl-3-oxa-1azabicyclo[3.3.01octane diastereomer A (14.0 g, yield: 11.3%). The filtrate was concentrated to obtain an oily diastereomer mixture (114.7 g, yield: 87.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24](OC)=[O:25].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][CH2:24][OH:25]
Reactant: COC(=O)CC1=C(C)/C(=C/c2ccc(S(C)(=O)=O)cc2)c2ccc(F)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=C(CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 1 (2.7 g, 7 mmol) in THF (20 mL) at 0° C. there was added diisobutyl aluminum hydride (1M) in toluene (17 mL, 17 mmol) and the mixture was stirred at 0° C. for 1 hour, then quenched with methanol (10 mL). Ethyl acetate and 1N aqueous HCl were added and after collection of the organic phase the aqueous phase was extracted once more with ethyl acetate. The combined organic extracts, after washing with water three times and drying over Na2SO4, afforded on evaporation a yellow residue which was triturated with ether to afford the title compound as a yellow solid, mp: 102°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C)C=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-hydroxy-benzoic acid methyl ester (4.2 g, 25.4 mmol) in dimethylformamide (85 mL) was treated with K2CO3 (14.2 g, 102.9 mmol, 4 equiv.) and 1,2-dibromoethane (19.3 g, 102.9 mmol, 4 equiv.). The mixture was stirred at 70° C. overnight, then filtered to remove the solids. The filtrate was removed under vacuo, and the residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, 3.65 g (73%) as a light yellow solid, MS (ISP): m/e=235.1 (M+CH3CN+); δH (300 MHz; CDCl3) 7.36 (1H, dd, J=8.5, 2.0), 7.30 (1H, d, J=2.0), 6.78 (1H, d, J=8.5), 4.30 (2H, m); 3.85 (3H, s), 3.43 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(O)[C:8]=2[CH:7]=1.C([Br:40])(=O)C>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([Br:40])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[CH:7]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(O)(c1ccccc1)c1ccccc1-2
Reactant: CC(=O)Br
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(Br)(c1ccccc1)c1ccccc1-2
Reaction time: 6 h
Yield: 62.2 %

Procedure:
The aforementioned 2-(3′,7′,11′-trimethyldodecyloxy)-9-phenylfluoren-9-ol (181 mg, 0.37 mmol) was dissolved in chloroform (2 ml), acetyl bromide (55 μl, 0.74 mmol) was added dropwise and the mixture was stirred for 6 hr. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in heptane, and washed three times with acetonitrile. The solvent of the heptane layer was evaporated to give 2-(3′,7′,11′-trimethyldodecyloxy)-9-bromo-9-phenylfluorene (126 mg, 0.23 mmol, yield 62%).