Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.CN(CCN(C)C)C.[C:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CI>CCCCCC.O>[C:14]([NH:21][C:22]1[C:23]([CH3:1])=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: [Li]CCCC
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Solvent: O
Solvent: CI
Product: COc1cc(C)c(NC(=O)OC(C)(C)C)cn1
Reaction time: 4 h

Procedure:
41.7 ml of 1.6M n-butyllithium in hexane and 7.7 g of TMEDA are added, under nitrogen, to 5 g of 5-(N-Boc-amino)-2-methoxypyridine, at −60° C. The medium turns yellow. The mixture is left stirring for 4 hours, allowing the temperature to return to −10° C., and a pale yellow. precipitate forms. The mixture is recooled to −40° C. and 4.7 g of methyl iodide are then added. The medium is allowed to return to RT and is then poured into water and extracted with EtOAc, and the extracts are dried and evaporated. The residue is chromatographed on silica, eluting with cyclohexane/EtOAc (85/15; v/v).
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:41]([N:60]1[CH:64]=[C:63]([C:65]2[CH:66]=[C:67]([CH:69]=[CH:70][CH:71]=2)[NH2:68])[N:62]=[CH:61]1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:68][C:67]4[CH:69]=[CH:70][CH:71]=[C:65]([C:63]5[N:62]=[CH:61][N:60]([C:41]([C:54]6[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=6)([C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=6)[C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:64]=5)[CH:66]=4)=[O:18])=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Reactant: Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2nc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 59 mg, 0.15 mmol) and TBTU (52 mg, 0.16 mmol) in DMF (2 mL) is stirred for 20 min at room temperature. 3-(1-Tritylimidazol-4-yl)-aniline (Intermediate O, 36 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) are added and the solution stirred at room temperature for 4 h. DMAP (5 mg, 0.04 mmol) is added and the solution is heated at 60° C. overnight. The reaction is cooled to room temperature and H2O was added. The resulting precipitate is filtered off and purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol, containing 1% NH4OH to afford the title compound as an oil (67 mg, 73%).
Reaction SMILES: [Na].[C:2]([O:6][CH2:7][CH2:8][N:9]([CH2:13][OH:14])[C:10]([NH2:12])=[O:11])(=[O:5])[CH:3]=[CH2:4].[C:15]([O:19][CH2:20][CH2:21][OH:22])(=[O:18])[CH:16]=[CH2:17]>CC(=O)OCC>[C:2]([O:6][CH2:7][CH2:8][N:9]([CH2:13][OH:14])[C:10]([NH2:12])=[O:11])(=[O:5])[CH:3]=[CH2:4].[CH3:17][C:16]([C:15]([O:19][CH2:20][CH2:21][OH:22])=[O:18])=[CH2:2]
Reactant: C=CC(=O)OCCO
Agent: C=CC(=O)OCCN(CO)C(N)=O
Agent: [Na]
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCO
Yield: 5.3 %

Procedure:
The procedure of (1) above is repeated replacing the SVS with 660 parts of the sodium salt of acryloxyethyl acid 3,5-disulfophthalate (AEDSP), the methylolated acrylamide with 260 parts of N-methylol-β-ureidoethyl acrylate (MUA), and the EA with a mixture of 7600 parts of EA and 480 parts of β-hydroxyethyl acrylate (HEMA), resulting in an aqueous dispersion of a copolymer of about 7.3% AEDSP, 2.9% MUA, 5.3% HEMA, and 84.5% EA.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])([CH3:17])[CH2:9][S:10][C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])[CH:7]=1.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@@:8]2([CH3:17])[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[S:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CSC(C)(C)C(=O)O)c2cc(Br)ccc2F)c(OC)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)C(C)(C)SC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)-2-methylpropanoic acid (2.6 g, 5.2 mmol, Eq: 1.00) and diisopropylethylamine (2.01 g, 2.72 ml, 15.6 mmol, Eq: 3.0) in ethyl acetate (104 ml) was added at 23° C. 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (4.96 g, 4.63 ml, 7.79 mmol, Eq: 1.5). The colourless reaction solution was stirred at 23° C. for 2 hours. The reaction mixture was washed with sat NaHCO3-sol., water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the crude and nearly pure (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-2,2,5-trimethylthiomorpholin-3-one (2.45 g, 5.08 mmol, 97.7% yield) as a colourless oil which crystallized in the fridge. MS (ISP): m/z=482.0 [M+H]+ and 484.3 [M+2+H]+.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.COC(OC)OC.[CH2:20](O)[CH2:21][OH:22]>>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:11])[O:22][CH2:21][CH2:20][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: N#N
Solvent: COC(OC)OC
Product: CC1(c2cccc(Br)c2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3′-bromoacetophenone (4.67 mL, 33.89 mmol) in ethylene glycol (36.4 mL) was treated with trimethylorthoformate (7.58 mL, 69.14 mmol) followed by LiBF4 (648 mg, 6.78 mmol). The reaction mixture was heated at 95° C. for 3.5 h. The reaction mixture was cooled to rt and partitioned between ether (100 mL) and sat. aq. Na2CO3 (25 mL). The layers were separated and the aq. layer extracted twice with ether (50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a dark yellow oil. TLC: rf (9:1 hept-EA)=0.44. LC-MS-conditions 02: tR=1.00 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([O:39][CH2:40][CH3:41])[CH:31]=1>CC(N(C)C)=O>[CH2:40]([O:39][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][CH2:37][CH3:38])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)[CH3:41]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: CCOc1ccc(CCl)cc1OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1OCC
Temperature: 60 °C
Yield: 71.2 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.150 g, 0.522 mmol), cesium carbonate (0.255 g, 0.783 mmol) and 4-(chloromethyl)-1,2-diethoxybenzene (0.168 g, 0.783 mmol) were taken up in DMA (2 mL) and heated to 60° C. for 16 h in a 20 mL sealed scintillation vial. The mixture was cooled down to room temperature and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (173.1 mg).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[NH:23][C:22]2=O)=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].P(Cl)(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]=[C:22]2[Cl:35])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
23.3 g of pyridine are added at room temperature while stirring and cooling to a suspension of 38.8 g of isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate in 45.2 g of phosphorus oxychloride and 40 ml of toluene. A solution forms rapidly. The temperature is maintained between 30° to 35° C. and, after 15 minutes, a colourless precipitate begins to separate. The reaction mixture is stirred at 30°-35° C. for 45 minutes and is then poured onto 300 g of ice. The mixture is subsequently extracted with 200 ml of ethyl acetate and the organic phase is washed three times with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 72°-75° C.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:22])([F:21])[CH2:11][O:12][CH2:13][C:14]([F:20])([F:19])[C:15]([O:17]C)=O)[N:8]=1)([O-:3])=[O:2].[CH2:23]([CH2:25][NH2:26])[OH:24]>O1CCOCC1>[OH:24][CH2:23][CH2:25][NH:26][C:15](=[O:17])[C:14]([F:20])([F:19])[CH2:13][O:12][CH2:11][C:10]([F:22])([F:21])[CH2:9][C:7]1[N:8]=[C:4]([N+:1]([O-:3])=[O:2])[NH:5][CH:6]=1
Reactant: NCCO
Reactant: COC(=O)C(F)(F)COCC(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Solvent: C1COCCO1
Product: O=C(NCCO)C(F)(F)COCC(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Yield: 51.2 %

Procedure:
To a solution of methyl 3-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropoxy]-2,2-difluoropropionate (1.0 g, 3.0 mmol) in dioxane (10 ml), ethanolamine (370 mg, 6.0 mmol) was added and reacted for 5 hours at a room temperature with stirring. The reaction solution was concentrated and partitioned between ethyl acetate and water. The ethyl acetate phase was dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain 3-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropoxy]-2,2-difluoropropionic acid hydroxyethylamide (550 mg). m.p. 67°-68° C. 1H-NMR (DMSO-d6): δ=3.24-3.76 (5H, m), 4.14 (2H, t, --CF2CH2 --, J=13 Hz), 4.22 (2H, t, --OCH2, J=14 Hz), 4.88 (1H, brt, --OH), 5.24 (2H, t, CH2CF2, J= 15 Hz), 7.42 (1H, d, H5 "), 7.98 (1H, d, H4 "), 8.93 (1H, brt, NH)
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNS(=O)(=O)c1ccccc1
Yield: 84 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, benzenesulfonyl chloride (0.201 g, 1.16 mmol) was reacted with 2-azidoethanamine (0.100 g, 1.16 mmol) and triethylamine (0.235 g, 2.32 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)benzenesulfonamide (0.289 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=1.8 Hz, 2H), δ 7.55 (m, 3H), δ 5.47 (s, 1H), δ 3.39 (t, J=5.1 Hz, 2H), δ 3.12 (t, J=5.4 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 139.8, 133.2, 129.5, 127.2, 50.9, 42.6 ppm; HRMS (ESI) calcd for C6H8N4O2S (M+) 226.0524. found 226.0523.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@H:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[O:26][C:20](=[O:21])[NH:19]2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)c2cccc(Br)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-tert-Butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-hydroxy-2-(3-methoxyphenyl)ethylcarbamate (114 mg, 0.135 mmol) was dissolved in trifluoroacetic acid (10% in dichloromethane, 5 mL) and stirred at room temperature for 2 h. The reaction was concentrated under a stream of nitrogen, dissolved in methanol, and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (2 mL), cooled to 0° C., and treated with carbonyldiimidazole (43.7 mg, 0.27 mmol) in a single portion. The resulting suspension was stirred at 0° C. for 5 min. The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was dissolved in a minimum of ethyl acetate and poured into water. The organics were diluted with several volumes of diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%-->50% EtOAc/Hex) gave 25 mg (53%). 1H-NMR (CDCl3, 500 MHz) δ 7.64 (dd, J=7.9, 7.6, 1H), 7.51 (d, J=7.9, 1H), 7.40 (d, J=7.6, 1H), 7.35 (dd, J=8.2, 8.2, 1H), 7.03 (m, 2H), 6.93 (m, 1H), 6.84 (bs, 1H), 5.60 (d, J=5.5, 1H), 4.91 (d, J=5.8, 1H), 3.85 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 159.9, 159.1, 142.6, 139.8, 139.7, 130.2, 128.2, 119.7, 117.8, 114.8, 111.0, 83.4, 64.4, 55.5. Mass spec.: 349.04 (MH)+.
Reaction SMILES: [Zn](C)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@H:20]([OH:21])[CH3:2])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Zn]C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: C[C@@H](O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Using Schlenck glassware and air-free conditions, anhydrous ethyl ether freshly distilled from sodium/benzophenone (2.43 mL) was added to catalyst 14 prepared according to Example 15, protocol 1. Freshly distilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added, and the reaction was cooled to −78° C. Commercial Me2Zn (1.21 mL, 2 M in toluene) was added, and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.300 g, 1.21 mmol) in Et2O (0.3 mL) was added, and the reaction was warmed to −30° C. and stirred overnight. The reaction was then quenched at −30° C. with saturated aqueous NH4Cl. Et2O was added, and the reaction was filtered through Celite wet with Et2O. The reaction was dried with sodium sulfate, filtered, concentrated, and purified using an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 16 (0.167 g, 52%). HLPC analysis of the product is depicted in the Figures. 1H NMR (CDCl3, 300 MHz) 7.42-7.30 (5H, broad s), 5.15 (2H, s), 4.08 (2H, broad d, J=12.8 Hz), 3.67 (1H, dq, J=6.2, 6.2 Hz), 2.81 (1H, td, J=12.4, 3.1 Hz), 3.90-2.60 (1H, broad), 2.40-1.90 (2H, broad), 1.80-1.68 (1H, m), 1.56-1.40 (2H, m), 1.23 (3H, d, J=6.3 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.58, 137.06, 128.61, 128.07, 127.91, 69.38, 67.14, 46.94, 44.81, 43.14, 25.71, 24.95, 21.03 ppm.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[CH:11]=[O:12].[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:13]1([C:11]([C:3]2[S:4][C:5]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:2]=2[CH3:1])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1c(C=O)sc2cccnc12
Reactant: Br[Mg]C1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1c(C(=O)C2CCCCC2)sc2cccnc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution (50 mL) of 3-methylthieno[3,2-b]pyridine-2-carbaldehyde (2.24 g) synthesized above in tetrahydrofuran was added a 1.0M solution (18.9 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred at 0° C. for 1.5 hr under argon atmosphere. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give a pale-yellow oil. To a mixture of the obtained oil, 4-methylmorpholine N-oxide (1.81 g) and acetonitrile (40 mL) was added tetrapropylammonium perruthenate (238 mg), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (1.38 g, 79%) as a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.[C:24]([O-:27])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:4]3[S:3][C:2]([N:10]4[CH2:11][CH2:16][C:24](=[O:27])[CH2:8][CH2:9]4)=[N:6][C:5]=3[CH3:7])=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCC(=O)CC4)nc3C)c(C)nc12
Temperature: 110 °C
Yield: 225.5 %

Procedure:
100 mg of 3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 mmol), 182 mg of 4-piperidineethylene ketal (1.27 mmol) and 244 mg of Cs2CO3 (0.75 mmol) are put into 4.0 ml vial with 2.0 ml of THF. The vial is capped with a Teflon® lined cap and heated at 110° C. for 3 days. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 116 mg of the title compound. Yield 100%. mass spectrum (m/e): 456 (M+1). 1H NMR (CDCl3): δ 6.69 (s, 1H), 4.05 (s, 4H), 3.70 (t, J=6.2 Hz, 4H), 3.35 (m, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.18 (s, 3H), 1.90-1.78 (m, 8H), 0.90 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([F:20])([F:19])[F:18])[C:9]1=[O:21])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.CO>[N:31]1[CH:32]=[CH:33][N:34]=[CH:35][C:30]=1[NH:29][C:5](=[O:7])[C@@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([F:19])([F:18])[F:20])[C:9]1=[O:21])[CH2:3][CH:2]([CH3:22])[CH3:1]
Reactant: Nc1cnccn1
Reactant: CC(C)C[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
A solution of (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid (95 mg, 0.30 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) at room temperature was treated with a solution of oxalyl chloride (2.0M in methylene chloride, 200 μL, 0.36 mmol) and stirred for 15 min. After this time, the reaction mixture was concentrated in vacuo and then diluted with methylene chloride (5 mL) and added to a flask containing a solution of 2-aminopyrazine (Aldrich, 57 mg, 0.60 mmol), 2,6-lutidine (250 μL) in methylene chloride (2.5 mL) at 0° C. The reaction mixture was then stirred at room temperature for a period of 30 min. After this time, the reaction mixture was treated with methanol and then diluted with methylene chloride. The reaction mixture was then transferred to a reparatory funnel and washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated with silica gel (2 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25%-40% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid pyrazin-2-ylamide (14 mg, 12%): HR-ES(+) m/e calcd for C19H19N4O2F3 [M+H]+ 393.1533, observed 393.1532; 1H NMR (400 MHz, CHLOROFORM-d) δ 9.49 (s, 1H), 9.03 (br. s., 1H), 8.29-8.38 (m, 2H), 8.10 (d, J=7.67 Hz, 1H), 7.84 (d, J=7.88 Hz, 1H), 7.65 (t, J=7.67 Hz, 1H), 5.14 (dd, J=6.93, 8.84 Hz, 1H), 4.69-4.82 (m, 1H), 4.58-4.67 (m, 1H), 1.88-2.15 (m, 2H), 1.62 (td, J=6.87, 13.96 Hz, 1H), 1.01-1.10 (m, 6H).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)CCO
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(COCCC(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of isoamyl alcohol (35 g, 0.4 mol) and acetone (5 g) and stirred at 80° C. for 30 minutes. Sodium carbonate (4.7 g, 44 mmol) is added and the slightly yellow reaction mixture is stirred at 80° C. for 30 minutes. Acetone is removed under vacuum, salts are filtered off and the reaction mixture is evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 7.0 g of 2-(2H-Benzotriazol-2-yl)-6-(3-methyl-butoxymethyl)-4-methyl-phenol.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH3:9].Cl.O>CO>[CH2:6]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: NNC(N)=S
Reactant: CCCCNC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCNC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 68.5 %

Procedure:
Thiosemicarbazide (1.95 g, 21.4 mmol) was added to a solution of N-butyl-4-oxo-4-phenyl-butyramide (5.0 g, 21.4 mmol), prepared in the previous step, in 75 ml of methanol plus 5.8 ml of 1 N HCl plus 5.8 ml of water and the reaction stirred at room temperature for 22 hours. The reaction was concentrated under reduced pressure at which time a solid formed. The solid was collected by filtration and dried to give 4.49 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 3.16 g (48%) of the title compound as a white solid, mp 64-68° C.