Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:14]([S:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1)([CH3:16])[CH3:15].[OH-].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][S:17][CH:14]([CH3:16])[CH3:15])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC(C)SCCOc1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)SCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 1.2 g of p-(2-isopropylthioethoxy)benzyl alcohol, and then 0.31 g of powdery potassium hydroxide was added thereto. The resulting mixture was stirred overnight at room temperature, poured into water, extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate and then freed of the diethyl ether by distillation under reduced pressure. The resulting solid was recrystallized from n-hexane to obtain 1.2 g of the aimed compound, m.p. 82.0°~84.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.[CH:36](=O)[CH2:37][CH2:38][CH2:39][CH:40]=O>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[NH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[O:14])=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: O=CCCCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(-c2[nH]c(-c3ccc(N4CCCCC4)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (2.0 g) obtained in Example 48, sodium borohydride (0.8 g), 3N sulfuric acid (4 ml) and 25% glutaraldehyde (4 ml) were treated in the same manner as in Example 62 to give 5-(4-methoxyphenyl)-2-(4-piperidinophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.53 g). This was converted to hydrochloride to give 5-(4-methoxyphenyl)-2-(4-piperidinophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride (0.25 g), melting point 250° C. or above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(CCc2cccc(F)c2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 18c), the reaction of 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a light brown solid; MS: m/e=326 (M−H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)NC(=O)O[C:2]2=[O:3].P(=O)(O)(O)O>>[CH:8]1[C:7]2[C:2](=[O:3])[C:1]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:2][C:1]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=P(O)(O)O
Product: O=C1c2ccccc2Cc2ccccc21

Procedure:
A sample of dextrin was converted by known means to dextrin anthranilate by reaction with isatoic anhydride. The amino group of the anthranilyl radical was diazotized and the diazonium salt was coupled with a keratin hydrolyzate prepared by the partial hydrolysis of hog hair with phosphoric acid. The derivative product, an anthranilyl dextrin keratin polypeptide, was recovered by dialysis to remove salts, followed by lyophilization. Samples of wool, treated with 8% ammonium thioglycolate solution containing the dextrin derivative as a solute, for 15 to 30 minutes, followed by oxidation with 1.5% sodium bromate solution, washing with water and drying with acetone, showed no visual differences, but a portion thus treated gave a distinct carbohydrate test with anthrone reagent, while a control sample prepared by adsorption of the dextrin derivative from an aqueous 9.2 pH buffer solution showed a negative test. Thus, the carbohydrate definitely was coupled to the wool by the described procedure.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=2[CH:20]2[CH:29]3[CH2:30][C:31]4[C:36]([CH:28]3[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:37](=[NH:39])[NH2:38])[CH:26]=3)[NH:21]2)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:6][CH:5]=1.O.[OH-].[Li+]>CO.O>[C:37]([C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:12]1[CH:13]=[C:14]([O:18][CH3:19])[C:15]([OH:17])=[CH:16][C:11]=1[O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=1)[CH:29]1[CH2:30][C:31]3[C:36]([CH:28]21)=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[NH:38])[NH2:39]
Reactant: COC(=O)c1ccc(Oc2cc(O)c(OC)cc2C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(Oc2ccc(C(=O)O)cc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 4-[2-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5-hydroxy-4-methoxy-phenoxy]-benzoic acid methyl ester (54 mg, 0.1 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol) in 2.5 mL of MeOH and 1.5 mL of H2O was stirred at room temperature overnight. The desired product 4-[2-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5-hydroxy-4-methoxy-phenoxy]-benzoic acid was purified using reverse phase HPLC. Mass spectrum 521 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[NH:17][C:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=3[CH:10]=2)O1.[C:20]([NH:24][C:25]1[N:30]=[C:29]2[C:31](Cl)=[N:32][CH:33]=[CH:34][C:28]2=[N:27][C:26]=1[CH3:36])([CH3:23])([CH3:22])[CH3:21].O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([NH:24][C:25]1[N:30]=[C:29]2[C:31]([C:9]3[NH:17][C:16]4[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=4[CH:10]=3)=[N:32][CH:33]=[CH:34][C:28]2=[N:27][C:26]=1[CH3:36])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: Cc1nc2ccnc(Cl)c2nc1NC(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2ccnc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 23.3 %

Procedure:
A glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (31 mg, 0.12 mmol) and N-(tert-butyl)-5-chloro-2-methylpyrido[3,4-b]pyrazin-3-amine (15 mg, 0.06 mmol) in 1,4-Dioxane (0.8 mL)/Water (0.2 mL) followed by Xphos (2.8 mg, 6.0 μmol) (Sigma Aldich), Pd2dba3 (2.7 mg, 3.0 μmol) (Strem) and K2PO4 (38 mg, 0.18 mmol) (Sigma Aldich). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with CHCl3/iPrOH (4:1, 30 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified with prep-TLC (eluted with 8% MeOH in DCM) to give 2-(3-(tert-butylamino)-2-methylpyrido[3,4-b]pyrazin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (5.0 mg, 0.014 mmol, 24% yield) as a light brown solid. MS (ESI, pos. ion) m/z: 351.1 (M+1); 1H NMR (400 MHz, MEOH-D4-d4) δ ppm 8.33 (1H, d, J=5.5 Hz), 7.79 (1H, s), 7.45 (1H, d, J=5.5 Hz), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.62 (3H, s), 1.70 (9H, s).
Reaction SMILES: C(OC([N:8]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]1[CH2:22][CH2:23][CH2:24][OH:25])=O)(C)(C)C.C[O-].[Na+]>CO>[CH:13]([C:12]1[NH:8][C:9]([CH2:22][CH2:23][CH2:24][OH:25])=[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(-c2ccccc2)c(CCCO)n1C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(-c2ccccc2)c(CCCO)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
In a 100 ml flask containing compound 15 (0.197 g, 0.57 mmol), 3.7 ml (8.7 mmol) of a 2.33 M solution of anhydrous sodium methanolate in methanol are added. The solution is left stirring at ambient temperature for 72 h. The solvent is then evaporated with a rotary evaporator. 5 ml of an aqueous solution saturated with ammonium chloride are added to the residue obtained. The solution thus obtained is extracted with ether. After separation of the phases, the organic phase is washed with brine then dried on MgSO4. After separation of the magnesium salts by filtration, the ether is evaporated. The residue obtained is purified by chromatography on a silica gel column (AcOEt/heptane 1/2 in volume, Rf 0.1). Compound 18 is isolated with a yield of 86.4% (0.121 g) in the form of a brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(OCCN4CCCCC4)cc3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.01-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=7.8 Hz), 7.05-7.01 (m, 2H), 6.21 (d, 1H, J=7.8 Hz), 6.04 (d, 1H, J=8.7 Hz), 4.30-4.20 (m, 3H), 3.70-3.64 (m, 1H), 3.53-3.45 (m, 1H), 2.84 (t, 2H, J=6.2 Hz), 2.56 (brs, 4 h), 2.20-2.03 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.27 (d, 3H, J=6.3 Hz). LC/MS: 498 [M+H]+, tR=1.13 min. HPLC: 99.24% at 214 nm, 99.34% at 254 nm, tR=5.70 min.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([N+:10]([O-])=O)[C:6]=1[N+:7]([O-])=O.[Sn].[ClH:15]>>[ClH:15].[ClH:15].[NH2:7][C:6]1[C:5]([NH2:10])=[CH:4][S:3][CH:2]=1
Reactant: O=[N+]([O-])c1c(Br)sc(Br)c1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Product: Nc1cscc1N

Procedure:
Concentrated HCl (230 mL) and 2,5-dibromo-3,4-dinitrothiophene (11, 12.8 g, 38.0 mmol) were added into a flask, cooled in an ice bath, and mixed together. A metal tin was slowly added for 1 hour while maintaining a temperature of 25 to 30. After the addition was complete, the reactant was stirred until tin was consumed, and stored in a fridge for one night. A solid precipitate was vacuum filtered, collected and washed with diethylether and acetonitrile. The product 2H+ salt 12 is significantly stable; however, a free-amino product is significantly sensitive to oxidation. Due to the above reason, this precursor was generally stored as the product 2H+ salt. In the case of conversion to free-diaminothiophene, the product 2H+ salts was dissolved into water of 600 mL and cooled in an ice bath. This solution was basified with 4N Na2CO3, extracted with diethylether, dried with anhydrous sodium sulfate, followed by concentration in a rotary evaporator, thereby obtaining 3,4-diaminothiophene as white crystalline product (2.6 g, 61%). 1H NMR (CDCl3, 400 MHz, d/ppm): 6.16 (s, 2H, 2×CRS), d 3.36 (s, br, 4H, 2×NH2). 13C NMR (CDCl3, 100 MHz, d/ppm): 137.2, 101.7. C4H6N2S (114.17): Theoretical value C, 42.08; H, 5.30; N, 24.54; S, 28.09; Experimental value C, 42.18; H, 5.50; N, 24.66; S, 27.92.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:49]([O:53][C:54]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][NH-:63])=[O:55])([CH3:52])([CH3:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:49]([O:53][C:54]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][NH-:63])=[O:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CCCCCCC[NH-]
Agent: On1nnc2ccccc21
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In manner analogous to that described in Example 1, using as starting materials 153 mg of Z-Phe-His-OH, 150 mg of H-Leu-Val-7-tert.-butoxycarbonylheptyl amide (Example 5a), 54 mg of HOBt and 94 mg of DCCI, the title compound is obtained after flash chromatography (100 g of silica gel 60, 40-63 μm, system B3), Rf (N8)=0.40, Rf (B4)=0.55.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=[O:4].[O-]CC.[Na+]>C(O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:11]2[C@H:6]3[C@H:5]([CH2:10][CH2:9][CH2:8][CH2:7]3)[C:3]([OH:4])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@H]3CCCC[C@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Yield: 35.2 %

Procedure:
The crude (1S,2R)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester (4.97 mmol) was dissolved in ethanol (50 mL) at 25° C. and a 21% w/w solution of sodium ethoxide in ethanol (2.86 mL) was added. The reaction mixture was heated to 60° C. for 8 h, then was cooled to 25° C. and partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 150 g; 0-6% methanol in dichloromethane) to afford the desired product, (4aS,8aR)-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-octahydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.96 g, 1.75 mmol, 40% over 4 steps), as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.10-1.26 (3H, m), 1.36-1.48 (3H, m), 1.61-1.64 (1H, m), 1.77-1.80 (1H, m), 2.27-2.31 (1H, m), 3.06 (3H, s), 3.59 (1H, bs), 4.32 (1H, bs), 4.45 (1H, s), 4.99 (1H, d, J=15.3 Hz), 7.07-7.11 (1H, m), 7.12-7.17 (2H, m), 7.29-7.33 (1H, m), 7.39-7.42 (1H, m), 7.51 (1H, dd, J1=2.3 Hz, J2=8.5 Hz), 7.57 (1H, s), 7.58-7.59 (1H, m), 10.17 (1H, s), 13.80 (1H, s). LC-MS (ESI) calcd for C24H25FN4O6S2 548.12, found 549.4 [M+H+]. >99.5% e.e. as determined by chiral HPLC analysis: column: Chiralpak AS-RH 4.6×250 mm ID 5 um, solvent: acetonitrile+0.05% trifluoroacetic acid (mobile phase B); water+0.05% trifluoroacetic acid (mobile phase A), gradient: 50% to 90% mobile phase B over 15 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Br:13]Br.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: c1ccc(Nc2nccs2)nc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cnc(Nc2ccccn2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of N-(pyridin-2-yl)thiazol-2-amine (9.76 g, 55.07 mmol) in degassed chloroform (180 mL) was added bromine (3.11 mL, 60.6 mmol, 1.1 eq) at 23° C. The reaction was stirred for 15 minutes and followed by LC/MS. Bromine (2×0.3 mL) was added until reaction completed. The mixture was cooled down to 0° C. and 10% aq. NaHSO3 (150 mL) was added. The suspension changed color and the solid was filtered, washed with water and vacuum dried overnight. The title compound was obtained as a solid (10.79 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94-6.99 (1H, m), 7.04 (1H, d, J=8.34 Hz) 7.45 (1H, s), 7.74 (1H, td, J=7.83, 1.77 Hz), 8.31 (1H, d, J=5.31 Hz), 11.54 (1H, s). LC/MS (M+H)+: 256, 258; (M−H)−: 254, 256.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14](=[O:16])[CH3:15].C(N(CC)CC)C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[Br:39]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>CCCCCCC.C(OCC)(=O)C.O1CCCC1>[Br:39][CH2:15][C:14]([C:4]1[C:5]([O:12][CH3:13])=[CH:6][C:7]([CH2:9][O:10][CH3:11])=[CH:8][C:3]=1[O:2][CH3:1])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1cc(OC)c(C(C)=O)c(OC)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(OC)c(C(=O)CBr)c(OC)c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a tetrahydrofuran (120 mL) solution of 1-[2,6-dimethoxy-4-(methoxymethyl)phenyl]ethanone (10.0 g, 44.9 mmol) was added triethylamine (18.8 ml, 135 mmol), and tert-butyldimethylsilyl trifluoromethanesulfonate (15.5 ml, 67.4 mmol) was added dropwise while cooling on ice, and the mixture was stirred for 30 minutes. N-bromosuccinimide (12.0 g, 67.4 mmol) was added and the mixture was stirred for 1.5 hours. To the reaction mixture, a saturated aqueous solution sodium hydrogencarbonate was added, and the reaction mixture was extracted with ethyl acetate, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To a tetrahydrofuran (80 mL) solution was added dropwise tetrabutylammonium fluoride (1M, 40.4 ml, 40.4 mmol) while cooling on ice, and the mixture was stirred for 30 minutes. To the mixture was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate 3/1 then 2/1) to obtain the title compound (12.0 g, 39.6 mmol).
Reaction SMILES: [PH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].N([C:13]([CH3:17])([CH3:16])C#N)=NC(C)(C)C#N>>[CH2:17]([P:1]([CH2:4][CH2:5][P:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[CH2:2][CH2:3][P:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[CH2:13][CH3:16]
Reactant: CCPCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCP(CCP(CC)CC)CCP(CC)CC
Yield: 5502.7 %

Procedure:
A mixture of n-PrP(CH=CH2)2 (1.29 g, 10.0 mmol), Et2PH (2.25 g, 25.0 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg) in a closed flask under inert atmosphere was irradiated by a GE Sunlamp (275 W) one foot away for 24 hours. The resulting colorless liquid was stripped of volatiles under vacuum and vacuum distilled to give 3.1 g (97% yield) of product collected at 132°-135° C./0.35 mm Hg. 31P-NMR (toluene): δ--18.5 (2P); δ--22.8 (1P).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[C:3]=1[F:26].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[CH:40][C:39]=3[CH:43]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[C:4]([F:25])[C:3]=3[F:26])=[CH:43][C:39]=2[CH:40]=[CH:41]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)c(F)c2F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)c(F)c2F)C1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To a microwave vial were added 4-(4-bromo-2,3-difluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.117 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (42.8 mg, 0.176 mmol), cesium carbonate (114 mg, 0.351 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (6.0 mg, 0.00735 mmol). The mixture was purged with nitrogen, followed by the addition of 1,4-dioxane (1 mL) and water (0.5 mL). The resulting suspension was heated overnight at 100° C., at which point analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title product as a white solid (37 mg, 68%). MS(ES)+ m/e 465.1 M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:23][C:19]1[S:18][CH:22]=[CH:21][CH:20]=1)[CH3:15]
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1cccs1
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1cccs1
Yield: 40 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and thiophen-2 carbaldehyde in 40% yield as a brown oil.