Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:6]([CH:8]=1)[NH2:7].Cl.[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:6]([NH:7][NH2:15])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1SCCCCl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NNc1cc(Br)ccc1SCCCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-[(3-chloropropyl)sulfanyl]aniline (0.938 g, 3.3 mmol) was dissolved in TFA (4 mL). The reaction flask was cooled to 0° C. and HCl (15 mL) was added. To the resulting suspension, an aqueous solution of NaNO2 (0.25 g, 3.7 mmol, 3 mL H2O) was slowly added. The flask was warmed to rt and stirred for 2 hrs. The flask was re-cooled to 0° C. and was transferred via cannula to an aqueous solution of SnCl2.2H2O (1.49 g, 6.6 mmol, 3 mL of H2O). The solution was stirred for 3 hours. The precipitate was collected by filtration and the residue was air-dired overnight. 1-{5-bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloroide was isolated (0.800 g, 73%) was a light-brown powder. 1H NMR (CD3OD, 300 Mhz) δ7.42 (d, 1H, 8.0 Hz), 7.14-7.21 (m, 2H), 3.66 (t, 2H, 6.2 Hz), 2.97 (t, 2H, 6.9 Hz), 1.90-1.99 (m, 2H) ppm. MS (CI, NH3): 297 (base, M+H).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30].[OH-].[Li+]>O1CCOCC1.O>[CH2:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([CH3:30])[CH:6]=1)([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH3:27])[CH:14]=1)[CH2:28][CH3:29])[CH3:12]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)O)c(C)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To an ambient temperature solution of 4-{1-Ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid methyl ester (2.40 g, 5.73 mmol) in dioxane/water (30/30 ml) is added lithium hydroxide (412 mg, 17.20 mmol) and heated to 60° C. for 1 h. The reaction is concentrated and partitioned between Et2O/EtOAc (150/150 ml) and 1N HCl (50 ml). The aqueous phase is extracted with a second portion of EtOAc (100 ml) and the combined organic phases are washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated to yield the title compound (1.57 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]#[N:21])[N:10](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]#[N:21])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: N#Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cc2nc(Cl)ccc2[nH]1

Procedure:
5-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-2-carbonitrile (0.50 g, 1.6 mmol, from Step 1) in THF (10. mL) was treated with 1.0 M NaOH (10. mL, 10. mmol) until removal of phenylsulfonyl protecting group was complete as determined by LCMS. The reaction mixture was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated until solid product precipitated. The solid was collected via filtration and triturated with EtOAc. Yield: (0.21 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.O>CN(C=O)C.CCOC(C)=O>[Br:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[N:9]([CH3:12])[C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: CN1C(=O)CCc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2cc(Br)c(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To an ice cold solution of 7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (16.0 g, 89.4 mmol) in DMF (200 mL) was added NBS (16.0 g, 89.4 mmol). After the addition, the reaction mixture was warmed up to room temperature and stirred for 3 hr. After LC-MS analysis indicated the completion of reaction, the mixture was diluted with EtOAc (500 mL) and poured into water (500 mL). The aqueous layer was then extracted with EtOAc (200 mL, 3×) and the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give crude title compound as oil (18.0 g, 78% yield). It was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCC3CCCNC3)c2c1C
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c2c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (700 mg), pyridine-3-aldehyde (700 μl) and acetic acid (1 ml) were dissolved in THF (20 ml). The solution was stirred at room temperature for four hours. To the solution was added NaB(OAc)3H (1.4 g) and the resulting suspension was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution and brine. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (777 mg) as a colorless oil. FAB-MS: m/z 409 (MH+); 1H-NMR (CDCl3): δ 1.15-2.30 (7H, m), 1.44 (3H, t, J=7 Hz), 2.58 (3H, s), 2.80 (1H, br d, J=11 Hz), 2.96 (1H, br d, J=8 Hz), 3.48 (1H, d, J=13.5 Hz), 3.57 (1H, d, J=13.5 Hz), 3.89 (1H, dd, J1=9 Hz, J2=8 Hz), 3.96 (1H, dd, J1=9 Hz, J2=5 Hz), 4.43 (2H, q, J=7 Hz), 6.57 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.21 (1H, dd, J1=8 Hz, J2=5 Hz), 7.28 (1H, t, J=8 Hz), 7.67 (1H, br d, J=8 Hz), 8.49 (1H, dd, J1=5 Hz, J2=1.5 Hz), 8.54 (1H, d, J=1.5 Hz).
Reaction SMILES: [Si]([O:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.CCCCCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH2:22]/[CH:21]=[CH:20]/[CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](OC/C=C/CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(C/C=C/CO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
The (E)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene (Isomer 246-B) (465 mg, 0.761 mmol) obtained in Example 246 was dissolved in tetrahydrofuran (10 ml), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 1.5 ml, 1.5 mmol) of tetrabutylammonium fluoride. At room temperature, the mixture was stirred for 1 hour. After addition of water (0.2 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (225 mg, 0.605 mmol, 80%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A mixture of 5-bromoindole-2-carboxylic acid (5 g, 21 mmol), and 1,1′-carbonyldiimidazole (4.39 g, 27 mmol) in tetrahydrofuran (60 mL) was stirred at room temperature overnight. Morpholine (3.63 mL, 42 mmol) was added and the mixture was stirred for an additional 40 min. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with hydrochloric acid (1N) and brine, then dried over sodium sulfate, filtered and evaporated in vacuo, to give 6.74 g (99%) of the desired compound as a yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:41])[C:5]([CH3:40])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:36]C(=O)C)=[C:17]([CH:35]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:41])[C:5]([CH3:40])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH:35]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Yield: 73.4 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(tert-butoxycarbonyl)aminoaniline (0.140 g, 0.248 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ether and hexane (3:1) to obtain the titled compound (0.095 g, 0.182 mmol, 73%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH3:41])[CH:34]=[CH:35][C:36]=1[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:41][Br:1])(=[O:29])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C(C)(C)C

Procedure:
16.4 g of N-bromosuccinimide, 1 g of α,α'-azoisobutyronitrile and 1 g of dibenzoyl peroxide are added in succession to a solution, stirred at 70° C., of 19 g of 3-acetoxy-4-tert-butyltoluene in 900 ml of CCl4. The reaction mixture is stirred under reflux for 31/2 hours under UV irradiation and is filtered, and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of FC (900 g of silica gel, hexane/ethyl acetate=95:5): Rf (hexane/ethyl acetate=95:5)=0.40.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:25]=[CH:24][N:23]([C@@H:26]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:33])[C@@H:27]2C#N)[C:21](=[O:22])[N:20]=1)=[O:17].[C@@H]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)[C@H]1[OH:38].C(OC(=O)CCCCCCCCCCCCCCC)(=O)CCCCCCCCCCCCCCC>CN(C=O)C>[C:16]([NH:18][C:19]1[CH:25]=[CH:24][N:23]([C@@H:26]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:33])[C@H:27]2[OH:38])[C:21](=[O:22])[N:20]=1)(=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2C#N)c(=O)n1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1

Procedure:
The preparation of CYC682 described in EP 536936 (see Scheme 1 below) involves reacting cytidine [1] with palmitic anhydride in DMF to form N4-palmitoylcytidine [2] and subsequently protecting with 1,3-dichloro-1,1,4,4-tetraisopropyldisiloxane (CIPS) to form intermediate [3]. Oxidation of [3] with pyridinium dichromate/acetic anhydride in dichloromethane produces intermediate ketone [4], which is then reacted with sodium cyanide and sodium dihydrogen phosphate dihydrate in ethyl acetate to form the cyanohydrin [5]. Intermediate [5] is then reacted with N,N-dimethylaminopyridine, phenoxythiocarbonyl chloride and triethylamine to form intermediate [6], which is subsequently reacted with AIBN and tributyltin hydride in toluene to give intermediate [7]. Deprotection of [7] with acetic acid and tetrabutylammonium fluoride in THF yields the desired product, CYC682.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[CH2:42](I)[CH3:43]>>[CH2:42]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:7][CH:8]=1)[CH3:43]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Reactant: CCI
Product: CCOCc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
Analogously to Method D, 0.100 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c) and 0.0395 g of ethyl iodide are reacted. The title compound is obtained as a yellow oil. Rf=0.49 (2:1 EtOAc-heptane); Rt=5.60.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:52]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:65]3[CH2:66][CH2:67][N:62]([C:60]([O:59][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[O:61])[CH2:63][CH2:64]3)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole (37 g) was dissolved in N,N-dimethylformamide (180 mL). To the solution were added 1-(benzyloxycarbonyl)piperazine (28.4 g), 1-hydroxybenzo-triazole (10.5 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (14.8 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate twice. The extracts were washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (40.5 g).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].Cl.N([O-])=O.[Na+].[F:23][C:24]1[CH:30]=[CH:29][C:27](N)=[CH:26][C:25]=1[CH3:31]>O1CCOCC1.O.C(O)C>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])=[CH:26][C:25]=1[CH3:31]
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Reactant: Cc1cc(N)ccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Cc1cc(NC(=NO)c2nonc2NCCNS(C)(=O)=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
N-Hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (35 mg, 0.13 mmol) was stirred in 1,4-dioxane (2 mL) and 6 N hydrogen chloride solution (4 mL) was added. The solution was cooled to 0° C. and a solution of sodium nitrite (11 mg, 0.16 mmol) in water (3 mL) was slowly added. The mixture was stirred for 1 hour at 0° C. and evaporated. Dry 1,4-dioxane (2 mL) was added and the mixture evaporated two more times. A solution of 4-fluoro-3-methylaniline [Aldrich, product #559415] (25 mg, 0.20 mmol) in ethanol (2 mL) was added and the mixture was stirred for 1 hour. Purification by preparative LCMS (pH 2) gave the desired compound (17 mg, 27%). LCMS calculated for C13H18FN6O4S (M+H)+: m/z=373.1. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.61 (s, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.72 (m, 1H), 6.58 (m, 1H), 6.24 (s, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.89 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH:3]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:23]=2[N:24]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:7]3[C:6]4[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=4[O:4][CH:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]3=[O:1])=[N:24][C:23]=2[CH:25]=1
Reactant: CCOC(=O)CC1Oc2ccccc2NC1=O
Reactant: Clc1ccc2sc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)CC1Oc2ccccc2N(Cc2nc3cc(Cl)ccc3s2)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl 2-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]acetate (150 mg), 2-bromomethyl-5-chlorobenzothiazole (186 mg) and potassium iodide (13 mg) were dissolved in dimethyl sulfoxide (2 ml). Potassium carbonate (133 mg) was added and the mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled away.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)phenyl)propanoate (379 mg) in THF (7.0 mL) and methanol (14 mL) was added 1N aqueous sodium hydroxide solution (7.3 mL), and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, and water and 1N hydrochloric acid were added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (334 mg) as a colorless oil.
Reaction SMILES: [F-].[Cs+].C([Sn](CCCC)(CCCC)[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)CCC.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[C:28](I)[C:27]([OH:31])=[CH:26][CH:25]=1>[Cu]I.C(#N)C>[N:11]1[CH:12]=[CH:13][C:8]([C:26]2[CH:25]=[C:24]([C:23]([F:33])([F:32])[F:22])[CH:29]=[CH:28][C:27]=2[OH:31])=[CH:9][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1ccc(C(F)(F)F)cc1I
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 47.5 °C
Yield: 76.5 %

Procedure:
To a 5 L jacketed vessel was added acetonitrile (9 L) and the solvent was sparged with nitrogen for 2 hours. To the solvent was added cesium fluoride (335.8 g, 2.21 moles), 4-(tributylstannyl)pyridazine (408 g, 1.11 moles), 4-trifluoromethyl-6-iodophenol (318.33 g, 1.11 moles), palladium tetrakis triphenylphosphine (61.31 g, 53.05 mmole) and copper (I) iodide (40 g, 210 mmol) at 20° C. The resulting orange suspension was heated to 45-50° C. for 2 hours. The reaction was cooled and partitioned between ter-tbutylmethylether (2×5 L) and 2N (aq) HCl (2×5 L). The resulting biphasic solution was filtered and the layers separated. The aqueous phases were combined and basified with 4M (aq) sodium hydroxide solution (6 L) to obtain a pH=4-5. The resulting suspension was extracted into ethyl acetate (10 L) and the organic layer concentrated to dryness to afford the title compound (204 g, 60%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1>CO.CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Cl)cc3)nc(O)c12
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A stirred suspension of 6-chloro-2-(4-chloroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0.670 g, 1.79 mM) in methanol (60 mL) and methanesulfonic acid (15 mL) was refluxed for 3 hours and cooled to room temperature. The mixture was filtered (the filtrate was saved for use in Example 17), and the collected yellow solids were washed with methanol and ether to give the title compound (0.156 g, 23%) as a yellow powder, mp >400° C.: MS(CI): 374 (M+H).