Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[C:9](=[O:20])[NH:10][C@@H:11]([CH2:12][C:13]([O:15][C:16](C)(C)C)=[O:14])[C:5]=2[O:4][N:3]=1.Cl>CO>[CH3:1][C:2]1[C:6]2[C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[C:9](=[O:20])[NH:10][C@@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2c1-c1ccccc1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)C[C@@H]1NC(=O)c2ccccc2-c2c(C)noc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a re-sealable vial containing a solution of tert-butyl 2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (1.04 g, 3.17 mmol) in MeOH (10 mL) was added hydrochloric acid (0.792 mL, 3.17 mmol, 4 M in 1,4-dioxane). After complete addition of reagents the reaction mixture was allowed to age until complete consumption of the carboxylic acid was detected by LC-MS. After ˜24 h, the reaction mixture was cooled to room temperature and concentrated in vacuo to give yellow solids. The solids were purified on Biotage system (gradient elution 5% EtOAc:1% i-PrOH:94% Hexanes to 80% EtOAc:1% i-PrOH:19% Hexanes) to give the titled product methyl 2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.500 g, 1.747 mmol, 55.1% yield) as white crystalline solids. LC/MS m/z 287 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[O:11][C:12](=O)[C:13]([Cl:16])([F:15])[F:14]>C(OC)(C)(C)C.C([Li])CCC.[Cl-].[NH4+]>[Cl:16][C:13]([F:15])([F:14])[C:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)=[O:11]
Reactant: COC(=O)C(F)(F)Cl
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)Cl
Yield: 96.8 %

Procedure:
In a solution of 5.0 g of 3,5-dichloro-1-iodobenzene in 50 ml of t-butylmethylether, 12.2 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at −78° C. with stirring, after the completion of the addition dropwise, stirred at the same temperature for 30 minutes. 6.6 g of chlorodifluoroacetic acid methyl ester was added dropwise at −78° C. with stirring in the reaction mixture, after the completion of the addition dropwise, continued to stir at 0° C. for further 30 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 4.6 g of crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[N:48]=[C:49]([CH2:55][CH3:56])[NH:50][C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[N:48]=[C:49]([CH2:55][CH3:56])[NH:50][C:51]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cccc4ccccc34)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (0.035 g, 0.199 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.026 g, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28-8.39 (m, 1H), 8.09-8.22 (m, 1H), 7.98 (dd, 1H), 7.57-7.69 (m, 3H), 7.51 (dd, 1H), 7.27-7.40 (m, 2H), 6.52 (d, 1H), 4.52 (d, 2H), 2.59 (q, 2H), 1.16 (t, 3H). ES MS: m/z 458 (M+1).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH:24][C@@H:25]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26](O)=[O:27]>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:26](=[O:27])[CH:25]([OH:24])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.2, 25.9, 26.4, 35.2, 35.3, 52.8, 55.5, 59.1, 67.5, 68.9, 80.0, 105.2, 131.3, 137.2, 169.1, 173.3; MS m/z 438.2 (M+1).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[C@H:17]([NH2:28])[C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([O-:12])([O-:11])=[O:10])([O-:7])=[O:6])(=[O:3])[O-:2].[CH2:30]([NH+:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:31].[CH2:37]([NH+:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38].[CH2:44]([NH+:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH3:45].[CH2:51]([NH+:53]([CH2:56][CH3:57])[CH2:54][CH3:55])[CH3:52].[I:58]I>C([O-])(=O)C.[Na+].C(O)C>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([I:58])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[C@H:17]([NH2:28])[C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([O-:11])([O-:12])=[O:10])([O-:7])=[O:6])(=[O:2])[O-:3].[CH2:30]([NH+:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:31].[CH2:37]([NH+:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38].[CH2:44]([NH+:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH3:45].[CH2:51]([NH+:53]([CH2:56][CH3:57])[CH2:54][CH3:55])[CH3:52]
Reactant: II
Reactant: N[C@@H]1[C@H](O)[C@@H](COP(=O)([O-])OP(=O)([O-])OP(=O)([O-])[O-])O[C@H]1n1ccc(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: CC[NH+](CC)CC
Agent: [Na+]
Solvent: CCO
Product: N[C@@H]1[C@H](O)[C@@H](COP(=O)([O-])OP(=O)([O-])OP(=O)([O-])[O-])O[C@H]1n1cc(I)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of tetrakis(triethylammonium)-2'-amino,2'-deoxyuridine 5'-triphosphate (35.2 mg, 0.02 mmoles, 0.02M) in sodium acetate (0.1M, 2 ml, pH 6.0) was added a solution of mercuric acetate (63.74 mg in 0.1M sodium acetate, 0.01M). The mixture was heated at 50° C. for 3 h. After cooling to room temperature, a solution of iodine in ethanol (25.38 mg I2 in 80 μl ethanol) was added. The mixture was stirred at room temperature in the dark for 1 h. The product was purified by DEAE Sephadex-A25 (Pharmacia) chromatography (0-1M triethyl ammonium bicarbonate buffer). To remove excess buffer salt the product was repeatedly concentrated from methanol to yield 6 mg (30%) tetrakis(triethylammonium)-5-iodo,2'-amino,2'-deoxyuridine 5'-triphosphate. UV: λmax 273 nm.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12]
Reactant: Oc1ccccc1
Reactant: O=C1C=CC(=O)O1
Product: O=C(O)/C=C\C(=O)Oc1ccccc1

Procedure:
A thermosetting resin was prepared as in Example 1. Phenyl hydrogen maleate was prepared by reacting excess phenol with maleic anhydride and was added to the above resin.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH3:35][C:36]([CH2:38][C:39]([C:41]1[O:45][CH:44]=[CH:43][CH:42]=1)=[O:40])=O>>[O:45]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:39](=[O:40])/[CH:38]=[C:36](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:35]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccco1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 630 mg (1.31 mmol) of Intermediate 45 (as the TFA salt) and 200 mg (1.31 mmol) of 1-(2-furyl)-1,3-butadione (purchased from Acros Organics) to yield 230 mg (35% yield) of Example 29 as a light brown solid: TLC (DCM/MeOH (4:1): Rf=0.62; 1H NMR (DMSO-d6, 300 MHz) δ11.07 (d, 1H, J=8.7), 7.88 (m, 2H), 7.69 (d, 1H, J=1.0), 7.48 (m, 3H), 7.09 (d, 2H, J=8.5), 6.86 (m, 3H), 6.52 (d, 1H, J=1.5), 5.33 (s, 1H), 4.13 (t, 2H, J=6.6), 4.03 (m, 1H), 3.14 (m, 1H), 2.87 (t, 2H, J=6.6), 2.70 (dd, 1H, J=13.6, 9.0), 2.34 (s, 3H), 1.62 (s, 3H); low resolution MS (ES+)m/e 501.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3c(F)cccc3F)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4c(F)cccc4F)cc3)cc21

Procedure:
Analogously to Method D, 0.540 g of tert-butyl 4-{4-[3-(2,6-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.350 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.18 (1:1 EtOAc-heptane); Rt=5.94.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CCO>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Clc1ncccn1
Reactant: C1CNCCNC1
Solvent: CCO
Product: c1cnc(N2CCCNCC2)nc1
Reaction time: 0.5 h

Procedure:
An ice bath is used to cool a solution of 3 g of 2-chloropyrimidine in 20 ml of EtOH which is then admixed dropwise with a solution of 13 g of 1,4-diazepane in 50 ml of EtOH, left with stirring in the cold for 30 minutes and then at AT for 24 hours. It is concentrated under vacuum, the residue is taken up with 100 ml of AcOEt and 100 ml of saturated K2CO3 solution, the system is decanted, the organic phase is diluted by adding 100 ml of AcOEt, the organic phase is washed with saturated K2CO3 solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives the expected product, which is used as it is.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1)=[O:7]
Reactant: NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (0.1 g, 0.37 mmol) in CH2Cl2 (4 mL) was added DIPEA (0.3 mL, 1.8 mmol), N-(2-(4-(aminomethyl) piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide dihydrochloride salt (0.1 g, 0.3 mmol) and HATU (0.17 g, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic layer was washed with sat. NaHCO3 aq. (8 mL), dried over Na2SO4, and concentrated to give crude product as gummy solid. Purification of the crude material was done using High Throughput Purification System (HiTOPs).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([OH:13])=[S:12])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.P(Cl)(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:13][C:11]([C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[C:3]=2[CH:10]=1)=[S:12])[CH3:20]
Reactant: CCO
Reactant: Cc1csc2ccc(C(O)=S)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=S)c1ccc2scc(C)c2c1

Procedure:
A mixture of 3-methylthiobenzo[b]thiophene-5-carboxylic acid (5.62 g) and phosphorous oxychloride (2 ml) in ethanol (200 ml) was heated under reflux for 18 hours and then evaporated. The residue was dissolved in ether and the solution was washed with sodium bicarbonate solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from ethanol to give 3-methylthiobenzo[b]thiophene-5-carboxylic acid ethyl ester (5.84g), m.p. 67°-69°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5](Cl)=[CH:6][C:7]=1[Cl:8].[CH2:14]([O:16]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:15].[F-].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([C:14](=[O:16])[CH3:15])=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C(C)=O)cc(Cl)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A solution of methyl 3,4,6-trichloropyridine-2-carboxylate (2.00 g, 8.31 mmol), ethoxyvinyltributyltin (3.09 mL, 9.15 mmol) and cesium fluoride (2.78 g, 18.30 mmol) in dioxane (50 mL) was sparged with nitrogen for 15 minutes. Dichlorobis(triphenylphosphine) palladium(II) (292 mg, 0.42 mmol) was then added and the mixture heated at 100° C. for 3 hours. After cooling, the mixture was concentrated, taken up into ethyl acetate and was filtered through a silica gel plug. The solvent was removed and the crude ethoxyvinyl intermediate was then dissolved in a solution of tetrahydrofuran (50 mL) and 1N HCl acid (20 mL). After stirring the mixture at room temperature overnight, the tetrahydrofuran was removed in vacuo and the remaining aqueous phase extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), and concentrated. Purification by column chromatography (10% ethyl acetate in hexane) provided methyl 3,4-dichloro-6-acetylpyridine-2-carboxylate (0.98 g, 3.95 mmol) as a white solid; 1H NMR (CDCl3): δ 8.20 (s, 1H), 4.05 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1[C:19](=[O:20])[CH2:18]CC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[O-]CC.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)C>[CH2:19]([O:20][CH:12]1[C:13]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][CH2:10][O:11]1)[CH3:18]
Reactant: O=[N+]([O-])c1cccc2c1COCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1OCOc2cccc([N+](=O)[O-])c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred solution of 5-nitro4H-1,3-benzodioxine (10.0 g, 55.203 mmol) in carbon tetrachloride (70 mL) were added N-bromosuccinimide (10.808 g, 60.723 mmol) and 2,2′-azobisisobutyronitrile (0.906 g, 5.520 mmol). The mixture was stirred at 100° C. for 2 hrs. After cooled to room temperature, a solution of sodium ethoxide (4.884 g, 71.764 mmol) in ethanol (70 mL) was added to the mixture, and the stirring was continued at room temperature for 3 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 4-ethoxy-5-nitro-4H-1,3-benzodioxine as a pale yellow oil (10.8 g, yield; 87%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:23]([CH2:24][OH:25])=[CH:22][C:12]3[C:13]([C:16]4[N:17]=[C:18]([CH3:21])[O:19][CH:20]=4)=[N:14][O:15][C:11]=3[C:10]=2[F:26])[CH2:3]1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:23]([CH:24]=[O:25])=[CH:22][C:12]3[C:13]([C:16]4[N:17]=[C:18]([CH3:21])[O:19][CH:20]=4)=[N:14][O:15][C:11]=3[C:10]=2[F:26])[CH2:3]1
Reactant: Cc1nc(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO)cc23)co1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(C=O)cc23)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
MnO2 (227 mg, 2.8 mmol) was added at 0° C. to a solution of {6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-(2-methyl-1,3-oxazol-4-yl)-1,2-benzoxazol-5-yl}methanol Intermediate 311, 50 mg, 0.13 mmol) in anhydrous DCM (5 mL), and the mixture was allowed to stir for 1 h at room temperature. The reaction mixture was filtered and the solvents were removed under vacuum and the residue was purified by silica gel chromatography using ethyl acetate-pet. ether gradient to give product as a solid. Yield: 37 mg, (75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(CBr)cc1

Procedure:
A solution of 4-methoxybenzyl alcohol (6.2 ml, 50 mmol) in dry ether (120 ml) was treated dropwise with phosphorus tribromide (2.07 ml, 22 mmol). The mixture was heated under reflux for 1 h, cooled, washed twice with water, dried and the solvent was evaporated. The 4-methoxybenzyl bromide thus produced was added to a mixture of 4-bromo-1,2-dihydro-3,6-pyridazinedione (for a preparation see Example 6(a)) (4 g, 21 mmol) and potassium carbonate (8.28 g, 60 mmol) in dry DMF (60 ml) and stirred overnight at rt. The mixture was diluted with ethyl acetate, washed 3 times with water, dried over magnesium sulfate and evaporated to low volume. Some solid was filtered off and washed with ethyl acetate. The filtrate was evaporated to dryness and the residue chromatographed on silica, eluting with 20% ethyl acetate/hexane and then 100% ethyl acetate. This gave the less polar of the two desired products (3.233 g), the more polar of the two desired products (1.626 g) and a mixture of these (1.351 g). Total yield: 6.30 g, 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccc(F)cc3)c1)N2
Yield: 42.1 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) and pyridine (90 mg, 1.14 mmol) in dichloromethane (6 mL) was added 4-fluoro-benzenesulfonyl chloride (120 mg, 0.62 mmol) under nitrogen. The resultant mixture was stirred overnight. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 100 mg of 4-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 42%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[S:9].[CH:11]1(N)[CH2:13][CH2:12]1>O>[CH:11]1([NH:10][C:8](=[S:9])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:13][CH2:12]1
Reactant: NC(=S)Cc1ccccn1
Reactant: NC1CC1
Solvent: O
Product: S=C(Cc1ccccn1)NC1CC1

Procedure:
A solution of 7.6 g. (0.05 mole) of 2-(2-pyridyl)thioacetamide in a 40% aqueous solution of cyclopropylamine is refluxed for 45 minutes. After cooling, approximately 30 ml. of water is added. The reaction mixture is extracted three times with chloroform. The extracts are combined and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is recrystallized twice from ethyl acetate/hexane to give N-cyclopropyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([O:26][C@H:27]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:28][C:29]([O:31]CC(Cl)(Cl)Cl)=[O:30])=[O:25])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([O:26][C@H:27]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCC[C@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC[C@H](CC(=O)O)OC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 104.8 %

Procedure:
To a solution of 2,2,2-trichloroethyl (3R)-3-[N2 -benzyloxycarbonyl-N5 -tert-butoxycarbonyl-L-ornithyl]oxy-hexadecanoate (100 mg) in 90% aqueous acetic acid (3 ml) was added zinc powder (400 mg) at 0° C. and stirred for 1 hour. After the reaction mixture was filtered, the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid. The organic layer was dried over with sodium sulfate and evaporated in vacuo to give (3R)-3-[N2 -benzyloxycarbonyl-N5 -tert-butoxycarbonyl-L-ornithyl]oxy-hexadecanoic acid (86.5 mg).