Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.[NH4+].[OH-].O>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 204 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (466 mg, 315 μL, 4.1 mmol) and the mixture stirred at room temperature for 16 h. The mixture was diluted with 25% aqueous NH4OH, dichloromethane, and water. The organic phase was separated and washed with water (2×), then concentrated in vacuo and purified by chromatography (silica, 3 to 10% methanol in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (39 mg, 100 μmol, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.60 (t, J=9.2 Hz, 1H), 6.88 (dd, J=8.9, 2.9 Hz, 1H), 6.78 (d, J=7.7 Hz, 1H), 3.96 (br. s, 1H), 3.80 (m, 1H), 3.70 (dd, J=11.4, 2.8 Hz, 1H), 3.49 (dd, J=11.4. 1.7 Hz, 1H), 3.37 (m, 2H), 2.96 (s, 1H), 1.80 (m, 1H), 1.69 (m, 2H), 1.29 (d, J=6.8 Hz, 6H); MS (EI/CI) m/z: 390.2 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]4[NH:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[N:30]=4)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)(C)C>[NH:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[C:24]1[CH:23]=[C:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Solvent: CC(=O)Cl
Solvent: CC(C)O
Product: O=C(C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1)N1CCNCC1
Temperature: 40 °C
Yield: 107.2 %

Procedure:
4-{1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-4-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.05 g, 0.11 mmol) was suspended in isopropanol (4 mL). Acetyl chloride (55 μL, 0.77 mmol) was added dropwise and the reaction mixture was heated to 40° C. until no starting material remained. The reaction was concentrated under reduced pressure to afford 0.05 g of the title compound. (100%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[CH:28]([CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:21][CH:20]=1>O1CCCC1>[C:19]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)[CH:28]([CH2:36][CH2:37][OH:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A solution of tetra-n-butylammonium fluoride (1.0 M in THF; 6.2 mL, 6.2 mmol) was added dropwise over 15 min to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-2-(2-{[(1,1-dimethylethyl) (dimethyl)silyl]oxy}ethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (3.39 g, 5.61 mmol) in tetrahydrofuran (20 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. The volatiles were evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (50% to 75% diethyl ether: cyclohexane) to give the title compound (1.6 g, 58%) as a yellow oil which was a mixture of diastereomers. LC/MS: 3.98 min; z/e 491, calcd (M+1) 491. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.45 (4H), 7.30 (5H), 6.90 (2H), 4.50 (2H), 3.80 (3H), 3.65 (2H), 2.80 (2H), 2.65 (1H major), 2.05 (1H minor), 1.85 (3H), 1.60-1.35 (11H).
Reaction SMILES: CO[Na].[CH3:4][O:5][CH:6]([CH:8]1[CH:10]([CH3:11])[O:9]1)[CH3:7].[CH3:12][OH:13].OS(O)(=O)=O>CO>[CH3:12][O:13][CH:10]([CH:8]([OH:9])[CH:6]([O:5][CH3:4])[CH3:7])[CH3:11]
Reactant: COC(C)C1OC1C
Reactant: CO
Agent: CO[Na]
Agent: O=S(=O)(O)O
Product: COC(C)C(O)C(C)OC

Procedure:
3-Pentanone was brominated to get 2,4-dibromo-3-pentanone (1.2.4.11) using conventional methods. The dibromoketone was reduced with BH3 *THF to the corresponding alcohol (1.2.4.15). This compound was reacted with MeONa in methanol to yield 2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) which after reaction with MeOH/H2SO4 gave 2-bromo-3-hydroxy-4-methoxy pentane (1.2.4.38). This intermediate was reacted again with MeONa in methanol and the resulting 2-(1-methoxyethyl)-3-methyl oxirane (1.2.4.22) was reacted again with MeOH/H2SO4 to yield 2,4-dimethoxy-3-hydroxy pentane (1.2.4.39). After oxidation with CrO3 /Py in methylenechloride the resulting ketone was reacted with trimethylsulfoxonium iodide to give the title compound (1.2.4.37). ##STR42## 1.2.5 Phosphite and Alkyl Phosphonate Esters.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[C:14]([N+:19]([O-:21])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N+:19]([C:14]1[C:13]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)c1ccc(S)cc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Sc2cccnc2[N+](=O)[O-])cc1
Yield: 84.2 %

Procedure:
Stirred a mixture of methyl 4-mercaptobenzoate (4.46 g, 26.5 mmol), 3-chloro-2-nitropyridine (4.00 g, 25.2 mmol) and cesium carbonate (9.04 g, 27.8 mmol) in DMSO (60 mL) at ambient temperature for 90 minutes. The solution was diluted with water, extracted with EtOAc, dried, and concentrated. The crude solid was suspended in MeOH (80 mL) and triturated for 0.5 hours. The solid was filtered and dried to provide the title compound (6.16 g, 84.1% yield).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CCNCC1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylic acid was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[N:11](O)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([OH:58])[CH2:36][NH:37]C2C=CNC(=O)C=2C2NC(C3C=CC=CC=3)=C(CC)N=2)[CH:32]=[CH:33][CH:34]=1.Cl.C(O)(=O)C>[Cl-].[Ti+3].[Cl-].[Cl-]>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([OH:58])[CH2:36][NH:37][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CCc1nc(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1-c1ccccc1
Reactant: COc1nccc(I)c1-c1ncc(-c2ccc(N3CCOCC3)cc2)n1O
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)O
Product: O=c1[nH]ccc(NCC(O)c2cccc(Cl)c2)c1-c1ncc(-c2ccc(N3CCOCC3)cc2)[nH]1

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-(4-morpholin-4-yl-phenyl)-imidazol-1-ol (0.049 g, 0.102 mmol) was reacted as described for the synthesis of 4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-ethyl-5-phenyl-1H-imidazol-2-yl)-1H-pyridin-2-one except that the compound was first treated with titanium(III) chloride LCMS (+ESI, M+H+) m/z 463) and then hydrochloric acid/acetic acid. The title material was obtained (0.007 g, 14%) as a yellow solid. HPLC 85% (220 nm), LCMS (+ESI, M+H+) m/z 492; 1H NMR (400 MHz, methanol-d4) δ (ppm): 3.18 (4H, br t), 3.65 (1H, br dd), 3.74 (1H, br dd), 3.87 (4H, m), 5.02 (1H, m), 6.26 (1H, d, J=7.5 Hz), 7.02 (2H, d, J=8.6 Hz), 7.22-7.56 (7H, m), 7.74 (1H, d, J=7.9 Hz).
Reaction SMILES: P(Cl)(Cl)Cl.P(Br)(Br)Br.P(F)(F)F.S(Cl)([Cl:15])=O.[NH2:17][C:18]1[N:22]([CH2:23][CH2:24]O)[N:21]=[C:20]([C:26]2[N:27]([CH3:34])[C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[C:19]=1[C:35]#[N:36]>CN(C)C=O.C1C=CC=CC=1>[NH2:17][C:18]1[N:22]([CH2:23][CH2:24][Cl:15])[N:21]=[C:20]([C:26]2[N:27]([CH3:34])[C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[C:19]=1[C:35]#[N:36]
Reactant: O=S(Cl)Cl
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nn(CCO)c(N)c1C#N
Agent: BrP(Br)Br
Agent: FP(F)F
Solvent: ClP(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cn1c([N+](=O)[O-])cnc1-c1nn(CCCl)c(N)c1C#N

Procedure:
The preparation of a 5-amino-1-(haloalkyl)-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile is accomplished by reacting the corresponding hydroxyalkyl compound with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus trifluoride, thionyl chloride and the like. Thus, 5-amino-1-(β-hydroxyethyl)-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile is allowed to react with thionyl chloride in an inert solvent such as benzene, in the presence of a small amount of dimethylformamide to yield 5-amino-1-(β-chloroethyl)-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[O:17]=[C:16]1[NH:15][CH2:14][CH2:13][N:1]1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C=NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(N2CCNC2=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of methyl 2-aminoisonicotinate (5.00 g, 32.9 mmol) and 2-chloroethyl isocyanate (4.51 g, 42.7 mmol) in anhydrous tetrahydrofuran (85 mL) was stirred at ambient temperature for 17 hours and refluxed for 3 hours, followed by the addition of triethylamine (10 mL) and potassium carbonate (9.60 g, 69.50 mmol). The reaction mixture was refluxed for 23 hours, cooled to ambient temperature and filtered. The solid residue was washed with water (2×20 mL hexanes (2×20 mL) and dried in vacuo to give methyl 2-(2-oxoimidazolidin-1-yl)isonicotinate as a colorless solid (4.22 g, 58%): 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.35-7.33 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 3.85 (s, 3H), 3.41-3.36 (m, 2H); MS (ES+) m/z 222.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:7][C:6]2[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 35.5 %

Procedure:
A mixture of (R)-2-[4-(4-chloro-benzyl)-phenoxymethyl]-pyrrolidine hydrochloride (1.37 g, 4 mmol), methyl 4-bromobutyrate (916 mg, 5 mmol), and potassium carbonate (1.12 g, 8 mmol) in DMF (15 mL) was stirred for 60 h at rt. The solvent was removed in vacuo to obtain the crude mixture. The mixture was diluted with 30 mL of water and extracted with ethylacetate (130 mL). The aqueous layer was re-extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (570 mg, 35%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]2[O:20][CH2:21][C:22](=O)[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:10]([Si:7]([CH3:8])([CH3:9])[O:14][C@@H:15]1[CH2:16][O:17][C@@H:18]2[C:22](=[CH2:1])[CH2:21][O:20][C@H:19]12)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CO[C@@H]2C(=O)CO[C@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 234.7 %

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (1.84 g, 5.16 mmol) and potassium tert-butoxide (578 mg, 5.16 mmol) in tetrahydrofuran (15 mL) was heated at reflux under an atmosphere of argon for 3 hours then allowed to cool to ambient temperature. A solution of ketone (87) (888 mg, 3.44 mmol) in tetrahydrofuran (7.5 mL) was added then heating at reflux continued for 2.25 hours. The mixture was diluted with water (30 mL) then the product extracted into diethyl ether (2×30 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and reduced in vacuo to leave residue (2.07 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 15:85 gave alkene (88) as a colourless oil (799 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCC=C3
Temperature: -20 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-8-hydroxy-4H-azocino [3,2,1-hi]indole-2-carboxylate (0.70 g, 2.27 mmol), triethylamine (0.61 g, 6.00 mmol) and tetrahydrofuran (30 ml) was cooled to -20° C. with stirring, and methanesulfonyl chloride (0.31 g, 2.73 mmol) was added dropwise. After completion of the dropwise addition, the reaction temperature was raised to room temperature and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with an aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetatein-hexane= 2/98) to obtain 0.63 g of ethyl 5,6-dihydro-11-chloro-4H-azocino [3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:12]=[C:13]([F:18])[C:14]=1[N+:15]([O-:17])=[O:16]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[C:13]([F:18])[C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
Trifluoroacetic acid (150 mL) was added dropwise over 20 minutes to a cold (0° C.) solution of tert-butyl (3,5-difluoro-4-nitrophenyl)acetate (83.33 g, 305 mmol) in DCM (300 mL). On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to leave a sticky brown solid. Trituration with heptanes afforded the title compound as a yellow solid (53.29 g, 67% yield over two steps).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]#[N:12])=[CH:7][CH:8]=2)[NH:3]1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[ClH:13].[CH3:32][N:31]([CH3:33])[CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:10]3[C:9]4[C:4](=[CH:5][C:6]([C:11]#[N:12])=[CH:7][CH:8]=4)[NH:3][C:2]=3[OH:1])=[N:19][CH:18]=2)(=[O:21])=[O:22])[CH2:24][CH2:25]1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: CN(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Product: CN(C)CCN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4cc(C#N)ccc34)nc2)CC1
Product: Cl
Yield: 8 %

Procedure:
Starting materials: 2-oxoindoline-6-carbonitrile (added at 5-10° C.) and (2-{4-[(6-chloropyridin-3-yl)sulfonyl]piperazin-1-yl}ethyl)-N,N-dimethylamine. Yield: 8%: 1H NMR (D2O, 400 MHz) δ 8.19 (s, 1H), 7.74 (d, J=9 Hz, 1H), 7.28 (d, J=9 Hz, 1H), 7.20 (s, 1H), 7.03 (s, 1H), 3.43 (t, J=7 Hz, 2H), 3.34 (m, 4H), 3.20 (t, J=7 Hz, 2H), 3.09 (m, 4H), 2.90 (s, 6H); MS (ES) m/z 455 (M++1).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:5]=1[OH:14])C=C.[CH3:15][C:16]([CH3:18])=[O:17].[OH2:19]>C(O)(C)(C)C.C[N+]1([O-])CCOCC1.[Os](=O)(=O)(=O)=O>[Cl:13][C:6]1[C:5]([OH:14])=[C:4]([CH2:15][CH:16]([OH:17])[CH2:18][OH:19])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: C=CCc1cc([N+](=O)[O-])cc(Cl)c1O
Reactant: O
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(CC(O)CO)c1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To a mixture of 2-allyl-6-chloro-4-nitrophenol (30.0 g), acetone (270 mL), and water (30.0 mL) were added a 2.5 wt % osmium (VIII) oxide solution in tert-butanol (10.0 mL) and 4-methylmorpholin-4-oxide (18.1 g), followed by stirring at room temperature for 41 hours. The reaction mixture was concentrated under reduced pressure, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of chloroform and hexane to obtain 3-(3-chloro-2-hydroxy-5-nitrophenyl)propane-1,2-diol (20.8 g).
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].[Cl:17]CCl.S(Cl)(Cl)=O>CN(C)C=O>[Cl:17][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: ClCCl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
14.2 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide was mixed with 100 ml of dichloromethane, 7.2 g of thionyl chloride and 0.1 g of N,N-dimethylformamide and the reaction was effected while stirring under reflux for three hours. The solvent was distilled off to obtain N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide (m.p.: 113°-113.5° C.). Without taking this out, 100 ml of dichloromethane and 3.8 g of iso-propyl mercaptan were added thereto and then 4.0 g of pyridine was also added dropwise. After effecting the reaction at room temperature for one hour, water was added thereto, the dichloromethane layer was separated out, dried and concentrated to obtain 16.2 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH2:45][F:46])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.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.O>[F:46][CH2:45][CH2:44][O:43][C:40]1[N:41]=[CH:42][C:37]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:38][CH:39]=1
Reactant: FCCOc1ccc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(OCCF)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 10.9 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.041 mmol), 5-bromo-2-(2-fluoroethoxy)pyridine (9.2 mg, 0.041 mmol), and 2 N aq Cs2CO3 (0.2 mL, 0.41 mmol) in 1,4-dioxane (2 mL) was added Pd(PPh3)2Cl2 (3 mg, 0.0041 mmol) under N2. The mixture was refluxed for 2 h under N2, treated with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give (S)-3-((S)-1-(4-(6-(2-fluoroethoxy)pyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (2.20 mg, 11%). LC-MS Method 2 tR=1.21 min, m/z=515, 493; 1H NMR (CD3OD): δ 0.95 (s, 3H), 1.26 (s, 3H), 1.54 (d, 3H), 2.15 (s, 2H), 2.21 (m, 1H), 2.46 (m, 2H), 3.02 (m, 1H), 4.50 (t, 1H), 4.57 (t, 1H), 4.66 (t, 1H), 4.79 (t, 1H), 5.57 (q, 1H), 6.88 (d, 1H), 7.02 (d, 2H), 7.31 (m, 7H), 7.85 (dd, 1H), 8.25 (d, 1H).