Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=[O:21])[C:15](=[CH:19][CH:20]=2)[C:16](O)=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].O1CCCC1.C[Si]([Cl:31])(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=[O:21])[C:15](=[CH:19][CH:20]=2)[CH2:16][Cl:31])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: CNS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1

Procedure:
From 5.0 g. of 6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 250 ml. of tetrahydrofuran, 2.26 ml. of triethylamine, 2.05 ml. of trimethylsilyl chloride and 2.33 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(O)Cc1ccsc1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccsc1

Procedure:
Following General Procedure BI above, and using 3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:14](O)=O)(O)[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[CH3:17].O[C:19]1[CH:20]=[C:21]([CH:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:22]=[CH:23]C=1>C(O)(=O)C>[O:34]=[C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:35])[C:25]1=[C:21]1[CH:22]=[CH:23][C:14]2=[C:9]([C:5]3[CH:4]=[C:3]([CH3:17])[C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=3)[C:10](=[O:11])[O:12][C:19]2=[CH:20]1
Reactant: O=C1c2ccccc2C(=O)C1c1cccc(O)c1
Reactant: Cc1cc(C(O)(C(=O)O)C(=O)O)cc(C)c1N
Solvent: CC(=O)O
Product: Cc1cc(C2=c3ccc(=C4C(=O)c5ccccc5C4=O)cc3OC2=O)cc(C)c1N
Temperature: 20 °C
Yield: 38 %

Procedure:
4-Amino-3,5-dimethylphenyltartronic acid (2.1 parts), 2-(3-hydroxyphenyl)-1,3-indandione (1.3 parts) and glacial acetic acid (125 parts) were stirred under reflux for 2 hours. The reaction mixture was cooled to 20° C. and the precipitated solid was recovered by filtration, washed with methanol and dried to give 6-(1,3-dioxoindan-2-ylidene)-2-oxo-3-(4-amino-3,5-dimethylphenyl)-2,6-dihydrobenzofuran (0.9 parts, 38%), m.pt. >250° C. λmax (CH2Cl2)=656 nm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12](OC)=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[AlH4-].[Li+].O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][OH:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1Cc2ccc(Br)cc2CN1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1Cc2ccc(Br)cc2CN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 7-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.0 g, 3.7 mmol) in tetrahydrofuran (20 mL) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (7.40 mL, 7.40 mmol, Aldrich Cat. No. 212776) dropwise at 0° C. The solution was stirred at 0° C. for 2 h. Water (0.3 mL), 15% NaOH aqueous solution (0.3 mL) and water (1.0 mL) were added dropwise in sequence to the reaction solution. The suspension was filtered through a pad of celite, and washed with ether. The filtrate was concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=242.2.
Reaction SMILES: [CH3:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3].[NH2:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][N:9]=1>O1CCCC1>[CH3:1][CH:2]([NH:4][C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][N:9]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h

Procedure:
7.5 g of 1-methylethyl isocyanate was added to a stirred mixture of 6.2 g of 1A and 75 ml of tetrahydrofuran at room temperature, then the mixture was stirred at reflux temperature for 24 hours, when an additional 7.5 g of 1-methylethyl isocyanate was added and the mixture was stirred at reflux temperature for 24 hours. The mixture was concentrated to dryness to give a syrup. On standing overnight at room temperature, a solid formed. The solid was recrystallized from ether/hexane to give 1-(1-methylethyl)-3-(5-(1,1-dimethylethyl)-isoxazol-3-yl)urea (4A), as an off-white solid, m.p.: 135°-138° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([CH2:12][CH:13]=O)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:15].[CH3:16][NH:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:23]=2[CH:24]=1)=[O:19].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH3:16][NH:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][N:32]([CH2:13][CH2:12][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]5[C:6]=4[CH2:5][CH2:4][C:3](=[O:15])[N:2]5[CH3:1])[CH2:31][CH2:30]3)[C:23]=2[CH:24]=1)=[O:19]
Reactant: CNC(=O)c1cc2c(N3CCNCC3)cccc2o1
Reactant: CN1C(=O)CCc2c(CC=O)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc2c(N3CCN(CCc4cccc5c4CCC(=O)N5C)CC3)cccc2o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(1-Methyl-2-oxo-3,4-dihydroquinolin-5-yl)acetaldehyde (Example 1j, 0.50 g, 2.5 mmol) dissolved in dichloromethane (12 mL) was added to neat N-methyl-4-piperazin-1-yl-benzofuran-2-carboxamide (Example 1e, 0.542 g, 2.09 mmol). Methanol (2 mL) was added and the mixture was stirred at ambient temp for 20 min. Sodium triacetoxyborohydride (0.782 g, 3.69 mmol) was added and the mixture was stirred over the weekend. The mixture was diluted with dichloromethane and water. The organic phase was separated, dried over MgSO4, filtered, concentrated and purified by ISCO (0 to 8% 7 N ammonia/methanol in dichloromethane) to give of the title compound as a solid. Yield: 0.77 g, 70% 1H NMR (500 MHz, CDCl3) δ ppm 2.58-2.71 (m, 4H) 2.78 (br. s., 4H) 2.87-3.00 (m, 4H) 3.06 (d, 3H) 3.31 (br. s., 4H) 3.38 (s, 3H) 6.63 (d, 1H) 6.72 (d, 1H) 6.91 (d, 1H) 6.98 (d, 1H) 7.10 (d, 1H) 7.23 (t, 1H) 7.32 (t, 1H) 7.53 (s, 1H). MS m/z 447.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](=[N:17]O)([NH2:16])[CH3:15].C(Cl)CCl.C(OCC)(=O)C>O1CCOCC1.CN(C)C=O>[CH3:15][C:14]1[N:17]=[C:11]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[O:13][N:16]=1
Reactant: CC(N)=NO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D-alanine (20 g, 106 mmol), acetamide oxime (17.3 g, 234 mmol) in 120 mL of 1,4-dioxane and 30 mL of N,N-dimethylformamide were added EDC (44.8 g, 234 mmol). The mixture was heated at 60° C. for 4 h then at 100° C. for 16 h. After cooling to ambient temperature, 300 mL of ethyl acetate was added. The mixture was washed with aqueous saturated sodium bicarbonate (2×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) to give pure tert-butyl [(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate (6.0 g). MS 172.1 ((M-t-butyl+H)+1).
Reaction SMILES: C[O:2][C:3](=[O:72])[CH2:4][NH:5][C:6](=[O:71])[C@H:7]([NH:11][C:12](=[O:70])[C@H:13]([NH:35][C:36](=[O:69])[C@H:37]([NH:39][C:40](=[O:68])[CH2:41][C@H:42]([OH:67])/[CH:43]=[CH:44]/[CH2:45][CH2:46][S:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH3:38])[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8]([CH3:10])[CH3:9].[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:67][C@H:42](/[CH:43]=[CH:44]/[CH2:45][CH2:46][S:47][C:48]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:41][C:40]([NH:39][C@H:37]([CH3:38])[C:36]([NH:35][C@H:13]([CH2:14][S:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([NH:11][C@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([NH:5][CH2:4][C:3]([OH:72])=[O:2])=[O:71])=[O:70])=[O:69])=[O:68]
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCC(=O)O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of 6A (700 mg, 0.70 mmol) in THF (15 mL) at 0° C. was added a solution of LiOH (25 mg, 1.05 mmol) in H2O (2.4 mL). After stirring for 1 hour, the reaction mixture was diluted with H2O (30 mL), acidified to pH 3-4 with 1M KHSO4, and extracted with EtOAc (3×30 mL). The organic layer was washed with sat NaCl (15 mL), dried (Na2SO4), filtered, and concentrated to give a white solid which was triturated with ether, to give 7A as a white solid (693 mg, 99%) which was used crude directly in the next step. mp=191-193° C.; [α]22D 18.5 (c 0.50, CHCl3); IR νmax 3413, 1711, 1678, 1630, 1451 cm−1; 1H NMR (400 MHz, 5% CD3OD/CDCl3) δ 7.30 (m, 12H), 7.16 (m, 12H), 7.13 (m, 6H), 5.43 (dt, J=15.5 Hz, 6.0 Hz, 1H), 5.30 (dd, J=15.5 Hz, 6.0 Hz, 1H), 4.27 (m, 2H), 4.21 (m, 1H), 3.99 (m, 1H), 3.75 (s, 2H), 3.77 (m, br, 6H), 2.55 (dd, J=12.5 Hz, 6.5 Hz, 1H), 2.44 (dd, J=12.5 Hz, 7.5 Hz, 1H), 2.21 (m, 2H), 2.12 (m, 3H), 2.02 (m, 2H), 1.23 (d, J=7.0 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H), 0.80 (d, J=7.0 Hz, 3H); 13C NMR (100 MHz, 5% CD3OD/CDCl3) δ 173.0, 172.1, 171.6, 171.5, 170.5, 144.9, 144.3, 132.7, 129.8, 129.6, 129.5, 128.2, 127.9, 127.0, 126.7, 69.5, 67.1, 66.7, 58.7, 52.7, 43.5, 40.9, 33.2, 31.5, 31.3, 30.3, 19.2, 19.1, 17.6; LRMS m/z 1013.2 (100%, [M+Na]+).
Reaction SMILES: Br[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Mg].Cl[C:9]1[C:14]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:13][CH:12]=[C:11]([O:24][CH3:25])[N:10]=1.[Cl-].[NH4+]>C(OCC)C.CC(C1C=CC=C(C(C)C)C=1N1[C-]=[N+](C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1COCC1>[F:23][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[C:14]1[C:9]([CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=1
Reactant: COc1ccc(F)c(-c2ccc(OC)nc2Cl)c1
Reactant: CC(C)(C)CBr
Agent: CC(C)c1cccc(C(C)C)c1N1[C-]=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OC)nc2CC(C)(C)C)c1

Procedure:
Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (9.82 mL) in diethyl ether (100 mL) was added dropwise to magnesium (1.72 g) at a slow refluxing rate, and the reaction mixture was heated under reflux further for 1 hr. Under an argon atmosphere, the obtained solution was added dropwise to a solution of 2-chloro-3-(2-fluoro-5-methoxyphenyl)-6-methoxypyridine (3.79 g) and a PEPPSI™-SIPr catalyst (trade name) (970 mg) in THF (70 mL) at room temperature, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium 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 (3.97 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>C1COCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture of 2-bromo-1-[4-(methyloxy)phenyl]ethanone (3.5 g, 15.28 mmol) and sodium azide (1.490 g, 22.92 mmol) in THF (40 mL) and water (13.33 mL) was stirred at 25° C. for 2 hours. The mixture was diluted with water (150 mL), and extracted with Et2O (3×100 mL), dried (Na2SO4), filtered, concentrated to afford the title compound (3.0 g) as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 3.87 (s, 3H), 4.83 (s, 2H), 7.07 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:42])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:30]4C(=O)C5=CC=CC=C5C4=O)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:43]=1.O.NN.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:42])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][NH2:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:43]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Yield: 56.3 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-phthalimidoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in ethanol (5 ml) is added hydrazine monohydrate (0.03 ml), and the mixture is refluxed for one hour, and cooled. To the mixture is added water, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. The aqueous layer is made basic with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-aminoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (110 mg) as white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11]([C:32]4[S:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(O)c1ncc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2cnc(C(C)(C)O)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 15.1 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (167.0 mg, 0.405 mmol), 2-(5-bromothiazol-2-yl)propan-2-ol (90.0 mg, 0.405 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.55 mL, 0.55 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (10.6 mg, 0.009 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give brown solids, 26.1 mg (yield 15.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.60-7.53 (broad s, 1H), 5.97 (s, 1H), 5.52-5.36 (m, 1H), 3.73-3.64 (m, 1H), 3.46-3.35 (m, 1H), 3.24-3.15 (m, 1H), 2.94-2.75 (m, 1H), 2.36-2.28 (m, 2H), 1.52 (d, J=1.2 Hz, 6H), 1.41 (d, J=6.2 Hz, 3H), 1.17-1.10 (m, 2H), 1.10-0.99 (m, 2H) ppm; MS (ESI+) m/z 428.06 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.CCN(CC)CC.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[N:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of NEt3 (triethylamine) and 230 mg of 4-methyl-benzenesulphonic acid chloride are mixed together then the reaction medium is agitated at ambient temperature for approximately 30 minutes. Then 2 ml of water is added, followed by extracting with 2×5 ml of methylene chloride, washing with 5 ml of water, drying, evaporating, impasting in ether, separating and drying. In this way 345 mg of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(I)cc1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1sc2c(c1C(=O)c1ccc(I)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-iodobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue purified by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 89-90 ° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([NH:19][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a solution of 6.0 g (22.5 mmoles) of ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate in 80 ml of tetrahydrofuran was added 2.3 g (24.8 mmoles) of aniline in 60 ml of tetrahydrofuran. The solution was briefly warmed and after standing for 10 minutes, a yellow solid began to precipitate. The mixture was kept at room temperature for 18 hours. The solvent was rotary evaporated. The residue dissolved in 200 ml of methanol and the pH made slightly basic (pH 8) with sodium bicarbonate. Water (700 ml) was added and an oil formed which solidified and after standing, additional solid crystallized. The solid was filtered and air-dried to give 6.9 g (95%) of crude material. The solid was dissolved in 300 ml of hot isooctane and the solution was charcoaled and filtered. The volume of the filtrate was reduced to 150 ml. Upon cooling, pale yellow needles separated; 6.5 g (89%); m.p. 120°-121° C.
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=2)[CH:9]=1)(=O)C(C)(C)C.[OH-].[Na+].O.Cl>CO.C1COCC1>[C:28]([C:25]1[S:24][C:23]([C:10]2[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][C:11]=2[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[N:27][N:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2-c2nnc(C(C)(C)C)s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)s2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl pivalate (191 mg) in methanol (2.0 mL) and THF (2.0 mL) was added 1N aqueous sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 40 min. Water and hydrochloric acid were added, and the mixture was extracted with ethyl acetate. 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 (113 mg) as a white amorphous solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C@H:8]([NH2:30])[CH2:9][C@@H:10]1[C@@H:14]([O:15]CC#C)[C@@H:13]([OH:19])[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[NH2:29])[O:11]1)[C:3]([OH:5])=[O:4].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-]=[N+]=[N-].C(#N)C.O.C(O)(C(F)(F)F)=O>O.CN(C=O)C.S([O-])([O-])(=O)=O.[Cu+2].CO.O.CC(O)=O>[CH:23]1[N:24]=[C:25]([NH2:29])[C:26]2[N:27]=[CH:28][N:20]([C@@H:12]3[O:11][C@H:10]([CH2:9][C@@H:8]([NH2:30])[CH2:7][CH2:6][C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[C@@H:14]([OH:15])[C@H:13]3[OH:19])[C:21]=2[N:22]=1
Reactant: C#CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C[C@@H](N)CC[C@H](N)C(=O)O
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C[C@@H](N)CC[C@H](N)C(=O)O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.6 %

Procedure:
To a mixture consisting of Compound 8 (<671 μg, <0.0016 mmol) in water (100 μL) with sodium ascorbate (1 mg, 0.005 mmol) in water (200 μL) was added copper(II) sulfate (500 μg, 0.0031 mmol) in water (100 μL) and CAL Fluor® Red 610 azide (Biosearch Technologies, Inc. Lot #MVR1716, 1.4 mg, 0.0016 mmol) in DMF (400 μL). The reaction mixture was stirred at room temperature overnight. HPLC (Gemini C18, 110 {acute over (Å)}, 5 {acute over (Å)}, 250×4.6 mm, 1 mL/min, 5/95/0.05→90/10/0.05 ACN/H2O/TFA) showed mainly one product (13.1 min, 3%) and starting fluorophore azide (19.4 min, 75%). Prep HPLC (Gemini C18, 110 {acute over (Å)}, 10μ, 250×21.2 mm, 20 mL/min, 15/85/0.05→90/10/0.05 ACN/H2O/TFA) was done to purify the product which eluted from the column at around 8.6 min. The product solution was concentrated to remove the ACN and then lyophilized to afford the title detection analyte compound (12 μg as quantified by UV (MeOH, extinction coefficient 91,000), ˜0.6% yield) as a dark purple solid; LC/MS (Gemini C18, 3μ, 2.0×50 mm, 400 μL/min, A: 90/10/0.01 H2O/MeOH/HOAc, B 90/10/0.01 MeOH/H2O/HOAc 0-6 min 0-100% B, 6-9 hold at 100% B, 9.1-15 min re-equilibrate at 0% B) consistent with that expected for pure title detection analyte compound (5.1 min, ESI+ m/z=1162/2=581).