Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=O)[O:25]C(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:32]3[CH2:35][CH2:34][CH2:33]3)=[O:25])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: C1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC3)c2)cn1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
A mixture of Example C2 (0.265 g, 0.641 mmol), azetidine hydrochloride (0.120 g, 1.282 mmol) and N-methylpyrrolidine (0.065 g, 0.769 mmol) in dioxane (6 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA); the organics were removed under reduced pressure and the aqueous residue was treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide (70 mg, 25%). 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 10.43 (s, 1H), 9.09 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11-8.06 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H), 3.92 (t, J=7.5 Hz, 4H), 2.12-2.10 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 413.2 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:36])[N:22]=1>CN(C=O)C>[Cl:36][C:23]1[N:22]=[C:21]([S:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]([C:27]([NH:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:28])=[CH:25][CH:24]=1
Reactant: SCCc1ccccc1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1SCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84.9 %

Procedure:
To a solution of 2-phenylethanethiol (295 μl, 2.2 mmol) in DMF (3 ml) was added NaHMDS (2.2 ml, 2.2 mmol). The reaction was stirred at ambient temperature for 2 minutes then added to a solution of 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide (Intermediate 1, 600 mg, 2.2 mmol) in DMF (2 ml). The reaction was stirred at ambient temperature for one hour. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between citric acid (20 ml) and EtOAc (40 ml). The layers were separated and the organic layer was washed with sat NaHCO3 (20 ml), water (20 ml) and brine (10 ml), then dried (MgSO4), filtered and evaporated to a solid. This solid was triturated with EtOAc/IH (1:9) to yield the product as a white solid (700 mg, 85%).
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:30][CH2:31]OS(C)(=O)=O)O[N:10]=[C:9]([C:12]2[C:13]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]3[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:15]3=[N:16][CH:17]=2)[CH2:8]1)(=O)=O.[S-2:37].[Na+].[Na+].[OH2:40]>CN(C)C=O>[CH:24]1([NH:23][C:13]2[C:14]3[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:15]=3[N:16]=[CH:17][C:12]=2[C:9]2[CH2:8][C:7]3([CH2:30][CH2:31][S:37][CH2:6]3)[O:40][N:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CCOS(C)(=O)=O)(COS(C)(=O)=O)C3)cnc21
Reactant: [S-2]
Reactant: O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCSC4)C3)cnc21
Temperature: 95 °C

Procedure:
(3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-{2-[(methylsulfonyl)oxy]ethyl}-4,5-dihydroisoxazol-5-yl)methyl methanesulfonate (280 mg, 0.00051 mole) (example 12) was taken in dimethylformamide (5 ml). Sodium sulphide nanohydrate (372 mg, 0.0015 mole) was added. The reaction mixture was refluxed at 90-100° C. overnight. Water was added, extraction was done with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuum. Purification was done by preparative thin layer chromatography by using ethyl acetate (40%) in hexane solvent.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27](S(C)=O)=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1>C1COCC1>[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: CSCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSCCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
To a solution of 2-(methylthio)ethanol (1.060 g, 11.50 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.203 g, 55%). Mass (m/z): 372.1 (M++1), 370.1 (M+−1).
Reaction SMILES: O=O.[CH2:3]([S:10][C@H:11]1[N:14](C(=C(C)C)C(OCC2C=CC(OC)=CC=2)=O)[C:13](=[O:31])[C@@H:12]1[Br:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].CSC>ClCCl.CO>[CH2:3]([S:10][C@H:11]1[NH:14][C:13](=[O:31])[C@@H:12]1[Br:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2SCc2ccccc2)cc1
Agent: C[O-]
Agent: O=O
Agent: [Na+]
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: O=C1N[C@H](SCc2ccccc2)[C@H]1Br
Reaction time: 16 h
Yield: 64.3 %

Procedure:
Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2-[(3S, 4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (2 g, 4 mmol) in dichloromethane (40 ml) at -78° C. and the reaction monitored by infra-red spectroscopy. When the band at 1780 cm-1 had disappeared, methanol (4 ml) together with a trace of sodium methoxide and dimethyl sulfide (1 ml) was added and stirring continued at room temperature for 16 h. The reaction was evaporated and the residue purified by flash chromatography using 1:1 ether:pentane as the eluting solvent. Evaporation of the appropriate fractions gave the product as a colourless oil (0.7 g, 64%). 1H NMR δ (CDCl3) 3.87 (2H, s, SCH2), 4.52 (1H, m, H4), 4.69 (1H, d, H3) 5.85 (1H, bs, NH), 7.18-7.39 (5H, m, Ph--H).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2].[CH2:9](N(CC)CC)C.[N+:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])([O-:18])=[O:17]>C(OCC)C>[N+:16]([O:19][CH:20]([CH3:9])[CH2:21][CH2:22][CH2:23][C:24]([O:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])=[O:25])([O-:18])=[O:17]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCCCO[N+](=O)[O-]
Reactant: O=[N+]([O-])OCCCO
Solvent: CCOCC
Product: CC(CCCC(=O)OCCCO[N+](=O)[O-])O[N+](=O)[O-]

Procedure:
20 mmol 3-Nitrooxypropanol dissolved in 10 ml Diethylether and 20 mmol Triethylamine were cooled to 0° C. 18.2 mmol 5-nitrooxypentoylchlorid were dropped over a period of 5 min at 0 to 5° C. After stirring over night without cooling, the reaction mixture was extracted with 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:41][C:42]1[CH:43]=[N:44][NH:45][CH:46]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([N:44]4[CH:43]=[C:42]([CH3:41])[CH:46]=[N:45]4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Cc1cn[nH]c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-n4cc(C)cn4)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 28 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) with 4-methyl-1H-pyrazole yielded the title compound (28% yield) as a white foam. MS (ISP): m/z=609.2 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27][O:28][CH2:29][CH2:30]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[NH3:10].[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH2:30][CH2:29][O:28][CH3:27])[CH2:23][CH2:22]3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCCN1CCNCC1)N1CCN(c2ccccc2)CC1
Reactant: COCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Product: N
Temperature: 170 °C
Yield: 88.4 %

Procedure:
2-(piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (None HCl salt of Example 30; 311 mg, 0.98 mmol) was dissolved in DMF (2 mL). 2-bromoethyl methyl ether (92 μl, 0.98 mmol) and DIPEA (0.3 mL, 1.72 mmol) were added and the reaction mixture was heated at 170° C. for 15 minutes in a Biotage Initiator microwave at high absorption. The reaction mixture was concentrated in vacuo, dissolved in 1 M aq Na2CO3 solution (25 mL) and extracted with DCM (3×25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 200:8:1 mixture of DCM:EtOH:NH3) to give 2-(4-(2-methoxyethyl)-piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (163 mg, 44%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23]([NH2:24])=[N:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23]([NH2:24])=[N:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a stirred solution of 19 (601 mg; 1.18 mmol) in anhydrous THF (28 mL), 1 M TBAF in THF solution (1.31 mL; 1.31 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. After evaporation, the residue was dissolved in ethyl acetate (100 mL). The solution was then washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. After evaporation, the residue was purified by flash column chromatography using CH3OH—CH2Cl2 (1:10) as the eluent to afford 20 as white crystals (329 mg; 71% yield): 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H, 6-H), 6.15 (dd, J=6.2, 6.7 Hz, 1H, 1′-H), 5.87-5.98 (m, 1H, CH2CH═CH2), 5.26-5.33 (dm, J=17.2 Hz, 1H, one of CH2CH═CH2), 5.14-5.19 (dm, J=10.5 Hz, 1H, one of CH2CH═CH2), 4.18 (m, 1H, 3′-H), 4.08 (m, 1H, 4′-H), 3.98-4.10 (m, 2H, CH2CH═CH2), 3.82 (dd, J=3.2, 13.0 Hz, 1H, one of 5′-H), 3.72 (dd, J=3.3, 13.0 Hz, 1H, one of 5′-H), 2.44-2.51 (ddd, J=3.2, 6.0, 13.6 Hz, 1H, one of 2′-H), 2.07-2.15 (m, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 165.4, 156.9, 148.8, 135.6, 117.0, 87.9, 86.9, 79.6, 71.2, 62.7, 57.2, 39.7; HRMS (FAB+) calcd for C32H37O4N3I (M+H+): 394.0264, found: 394.0274.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[NH:9].[CH2:11]([O:13][C:14](=[O:23])[C:15](=[CH:19]N(C)C)[C:16](=O)[CH3:17])[CH3:12]>CCO>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[N:10][CH:19]=1)=[O:23])[CH3:12]
Reactant: N=C(N)c1ccccn1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccn2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Na0 (31.7 mmol) is added to anhydrous EtOH (100 mL) and stirred at rt for 15 min. Pyridine-2-carboxamidine hydrochloride (31.7 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (31.7 mmol) is added and the reaction mixture is heated at reflux under N2 for 1 h. The reaction is cooled to rt and concentrated in vacuo. The residue is dissolved in EtOAc (200 mL), washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid ethyl ester (6.77 g, 88%). MS: 261 (M+H); 1H 1H NMR (300 MHz, CDCl3): δ 1.44 (t, 3H), 2.97 (s, 3H), 4.44 (q, 2H), 7.44 (m, 1H), 7.91 (m, 1H), 8.60 (m, 1H), 8.90 (m, 1H), 9.31 (s, 1H).
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[N:8]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:8]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reaction time: 8 h

Procedure:
Add imidazole (3.01 g, 44.19 mmol) to a solution of the product from Step 1 (5.54 g, 29.46 mmol) and t-butyldimethylsilyl chloride (4.97 g, 32.99 mmol) in CH2Cl2 (60 ml) at RT and stir overnight. Filter the reaction mixture and concentrate the filtrate. Purify the residue by chromatography to give the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[S:15][C:16](I)=[C:17]([CH3:19])[CH:18]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].CCN(CC)CC.[CH2:28]([O:31][CH3:32])[C:29]#[CH:30]>CN(C=O)C.[Cu]I.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>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[S:15][C:16]([C:30]#[C:29][CH2:28][O:31][CH3:32])=[C:17]([CH3:19])[CH:18]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)sc1I
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1sc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
4-hydroxy-3-(5-iodo-4-methylthien-2-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (200 mg, 0.48 mmol, Example 222) was dissolved in DMF (2.4 ml). Et3N 0.133 ml, 0.96 mmol) and methyl propargyl ether (0.202 ml, 2.4 mmol) were added and the mixture was degassed with N2 for 2 min. CuI (9.1 mg, 0.048 mmol) and PdCl2(PPh3)2 (17 mg, 0.024 mmol) were added, the vessel was capped and the reaction was heated at 60° C. with stirring for 2.5 h. The reaction mixture was then cooled and filtered through a plug of silica gel eluting with CH2Cl2→EtOH. The organics were removed by rotary evaporation and the residue was purified by RP-HPLC to give the title compound. MS (ESI) m/z 357.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.49 (s, 1H), 6.92 (s, 1H), 4.38 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](OC)(OC)(OC)C>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: COC(C)(OC)OC
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Product: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-6-nitrobenzoic acid (300.0 g, 1.66 moles, from Acros Organics, Morris Plains, N.J.) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwauke, Wis.) was charged into a 3-L 3-necked flask at about 20-25° C. under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100° C. After 2 hours, the reaction mixture was cooled to 20-25° C. over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5° C. over 0.5-1 hour and kept at 0-5° C. for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35° C. under a vacuum at 100-120 torr. The yield of methyl 2-methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of 2-methyl-6-nitrobenzoic acid. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[CH3:17][NH2:18].O>C(O)C>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([NH:18][CH3:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1cc(C(N)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzamide (6.14 g, 25 mmol) [Goldstein, H.; Stamm, R.; Helv. Chim. Acta, 1952, 35, 1330-1333] and 40% aqueous methylamine (20 mL) in ethanol (80 mL) is heated in a sealed pressure vessel at 100° C. for 2 h. After cooling, dilution with water gives 2,4-dinitro-5-methylaminobenzamide (5.89 g, 98%). 1H NMR (DMSO) δ8.88 (1H, q, J=4.9 Hz), 8.76 (1H, s), 8.07 (1H, brs), 7.77 (1H, brs), 6.98 (1H,s), 3.07 (3H, d, J=5.0 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.[CH2:8]([NH:15][S:16]([CH2:19][C@:20]12[C:26]([CH3:28])([CH3:27])[C@H:23]([CH2:24][CH2:25]1)[CH2:22][C@H:21]2[NH2:29])(=[O:18])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:8]([NH:15][S:16]([CH2:19][C@:20]12[C:26]([CH3:27])([CH3:28])[C@H:23]([CH2:24][CH2:25]1)[CH2:22][C@H:21]2[N:29]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:18])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCOCCBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)[C@H](N)C2
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)[C@H](N1CCOCC1)C2
Temperature: 25 °C

Procedure:
Bis(2-bromoethyl)ether (18.3 mL, 146 mmol) was added to a solution of (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) (23.5 g, 72.9 mmol) and N,N-Diisopropylethylamine (DIPEA) (55.8 mL, 320 mmol) in N,N-dimethylacetamide (DMAC) (470 mL). The solution was heated at 120° C. until the amine (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) was <2% by HPLC analysis. The mixture was cooled to ambient temperature and diluted with toluene (470 mL) and was extracted with water (470 mL). After layer separation, the toluene layer was washed twice with 10% aq. NaCl (230 mL each) and concentrated to give the crude product as a brown solid. The sulfonamide (1S,2R,4R)—N-benzyl-2-morpholino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (IIa) was crystallized from a mixture of toluene (23 mL) and n-heptane (47 mL) by slowly cooling from 75° C. to 60° C., stirring at 60° C. for an hour and then cooling to ambient temperature, followed by the addition of n-heptane (70 mL) and stirring for an hour. The suspension was filtered and the powder was washed with a mixture of toluene and n-heptane (1:5, 47 mL) to give (1S,2R,4R)—N-benzyl-2-morpholino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (IIa) as an orange to light brown powder (22.2 g; 78%; 98.9% pure as assessed by HPLC).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20].C(N(CC)CC)C>O1CCOCC1.O>[C:1]([NH:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.22 g lauroylchloride dissolved in 46 ml dioxane were slowly added to 6.72 g glutamine and 13.94 g triethylamin in 92 ml water and 92 ml dioxane, the temperature being 0° C. After stirring at room temperature for 1 hour, the dioxane was evaporated and the remaining solution was acidified to pH 1 with HCl. The crystals were filtered off and recrystallized from acetone and then from methanol: 9.9 g white needles.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:11]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:12]=1[C:13]([O:15]C(C)(C)C)=[O:14].Cl.[N+](=C)([O-])[O-]>CS(C)=O.O>[C:13]([C:12]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:11]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([OH:15])=[O:14]
Reactant: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: C=[N+]([O-])[O-]
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 75 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
Sodium hydride (12.42 g of a 60% dispersion in oil, 310 mmol) was washed with petroleum ether (×3) under nitrogen and suspended in dry DMSO (250 mL). A solution of dimethyl malonate (37.3 mL, 330 mmol) in DMSO (50 mL) was added dropwise over 35 min with water-bath cooling. t-Butyl 2-chloro-5-nitrobenzoate (20.0 g, 78 mmol) was added and the mixture stirred at 70-80° C. under nitrogen for 4 h. The red-brown solution was cooled, poured into water (300 mL), and aq. HCl (2 N, 60 mL) added slowly until the red nitronate colour was dispersed. The mixture was extracted with CH2Cl2 (×3), the extracts were dried (Na2SO4) and evaporated. Formic acid (60 mL) was added to the residue and the mixture stirred at 20° C. for 15 h then 50° C. for 7 h (when tlc analysis showed no remaining t-butyl ester). The formic acid was evaporated and the residue taken up in EtOAc and washed with aq. NaCl (×3). The organic layer was extracted with aq. NaHCO3 (×3), the aqueous phase acidified (c.HCl), and extracted with CH2Cl2 (×3). The organic phase was dried (Na2SO4), evaporated, and the residue recrystallised from benzene (two crops) to give dimethyl (2-carboxy-4-nitrophenyl)malonate as cream needles (20.27 g, 88%), mp 163-164° C. 1H NMR (CDCl3) δ8.99 (d, J=2.5 Hz, 1H, H-3), 8.44 (dd, J=8.6, 2.5 Hz, 1H, H-5), 8.4 (v br s, 1H, CO2H), 7.73 (d, J=8.6 Hz, 1H, H-6), 5.94 (s, 1H, ArCH), 3.83 (s, 6H, CO2Me); 13C NMR δ169.6, 167.8 (CO2Me, CO2H), 147.4, 141.4, 132.2, 129.7, 127.6, 126.8 (C-1,2,3,4,5,6), 54.4 (ArCH), 53.3 (OMe). Anal. Calculated for CH11NO8 : C, 48.5; H, 3.7; N, 4.7. Found: C, 48.7; H, 3.7; N, 5.0%.