Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](=O)([O:21]C1C=CC([N+]([O-])=O)=CC=1)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[O:21])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: ClCCCl
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 65 °C

Procedure:
1.17 g (4.85 mmol) of 1-(4-bromophenyl)piperazine are added to a solution of 1.47 g (4 mmol) of 2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate, obtained in step 2.1, in 18 ml of 1,2-dichloroethane. This reaction mixture is heated at 65° C. for 2.25 hours. The mixture is allowed to cool to room temperature and it is then concentrated under reduced pressure. The oily yellow residue is taken up in dichloromethane and washed successively with sodium hydroxide (1N), water, aqueous 5% citric acid solution, water and then brine. This organic phase is dried over sodium sulfate and is concentrated under reduced pressure. After washing with diisopropyl ether, 1.3 g of product are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].O.[NH2:28][NH2:29].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:28][NH2:29])[CH3:25]
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Reactant: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NN)c2cc1OC
Yield: 69.2 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (50 mg) was dissolved in ethanol (1.5 ml) to prepare a solution. Hydrazine monohydrate (20 mg) and triethylamine (45 mg) were added to the solution, and the mixture was stirred under reflux for 3 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (36 mg, yield 67%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethyl acetal (Tet. Lett., 22, 5027 (1981)) (52.2 g) in THF (600 mL), cooled to -78° C., was added dropwise a solution of n-BuLi (78 ml, 2.1 M) in hexane. After 15 min. CuBr·SMe2 (32 g) was added in 3 portions. The reaction mixture was stirred at -78° C. until CuBr·SMe2 was dissolved (approx. 1 hr.), then benzoyl chloride (20 mL) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature over night and was quenched with a saturated NH4Cl solution. The organic phage was diluted with Et2O, washed with H2O (3×), brine, dried (MgSO4) and evaporated to afford the title compound which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Na].Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:13]=1>O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: OCc1ccc(Cl)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(OCc2ccc(Cl)cc2)n1
Yield: 19.8 %

Procedure:
To a solution of 4-chlorobenzyl alcohol (45 mg, 0.32 mmol) in 10 ml of tetrahydrofuran was added metallic sodium (7 mg, 0.30 mmol). The mixture was stirred until the sodium dissolved. (4-Chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (100 mg, 0.29 mmol) was added and the mixture refluxed for 4 hours, diluted with water and extracted with ethyl acetate. The product was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as a solvent to give the title compound (26 mg, 20%) as a colorless solid.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.Cl.[NH2:13][OH:14].N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=[N:13][OH:14])[CH2:2]1)[CH2:8]2
Reactant: NO
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C2CC3CC1CN(C3)C2

Procedure:
A solution of 1-aza-adamantan-4-one (1.1 g), hydroxylamine hydrochloride (0.7 g) and pyridine (0.5 ml) in ethanol (30 ml) was heated under reflux for 1 h. The solution was then treated with saturated K2CO3 solution (30 ml), evaporated to half its volume and extracted with CH2Cl2 (4×50 ml). The combined extracts were dried (K2CO3) and evaporated in vacuo to give D.1 (1.2 g).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](CC(C)C)[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=CC=1)CCC.C[N:34](C=O)C.S(Cl)(Cl)=O.CN1C=CCN1CSC1C=CC(N)=CC=1>O1CCCC1.O.C(N(CC)CC)C>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:32][C:19]=2[CH:20]=[C:21]([C:29]([NH2:34])=[O:30])[CH2:22][CH2:23]1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CN(C)C=O
Agent: CN1C=CCN1CSc1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: NC(=O)C1=Cc2ccccc2NCC1
Reaction time: 1 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[[(1-methylpyrazol-2-yl)methyl]sulfanyl]aniline (456 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[[(1-methylpyrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (827 mg) (Compound 320) as yellow amorphous.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[Na+].O=[CH:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O>[C:27]([O:26][C:25]([NH:24][CH2:23][CH2:22][NH:3][C@@H:4]([CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)cn1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1cn(C)cn1)NCCNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Methyl (2S)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoate dihydrochloride (1.06 g, 4 mmol), sodium acetate (1.3 g, 16 mmol) and 4 Å molecular sieves (500 mg) were added to a solution of tert-butyl N-(2-oxoethyl)carbamate (637 mg, 4 mmol) in methanol (10 ml), and the solution stirred for 10 minutes. Sodium cyanoborohydride (1.3 g, 16 mmol) was then added, and the reaction stirred at room temperature for 72 hours. 2M Hydrochloric acid (2 ml) and water (50 ml) were added, and the solution then basified using saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (5×100 ml), the combined organic extracts dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:methanol:diethylamine (100:0:0 to 96:2:2) to afford the title compound as a colorless oil, 220 mg, 17% yield.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:29](=[O:67])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:66])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[C:46](=[O:47])[CH:45]([CH2:48][CH2:49][CH:50]([OH:57])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[CH:44]4[C:58]4[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=4)=[CH:39][CH:38]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.OC(C1C=CC=CC=1)CCC1C(=O)N(C2C=CC(NC(=O)CCCCN)=CC=2)C1C1C=CC(OC)=CC=1>CN(C)C=O>[OH:57][CH:50]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:49][CH2:48][CH:45]1[C:46](=[O:47])[N:43]([C:40]2[CH:39]=[CH:38][C:37]([NH:36][C:35](=[O:66])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29](=[O:67])[CH:18]([NH2:17])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=3)=[CH:42][CH:41]=2)[CH:44]1[C:58]1[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(Cc3ccc(N=[N+]=[N-])cc3)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Agent: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(N)Cc3ccc(N=[N+]=[N-])cc3)cc2)cc1
Yield: 18.5 %

Procedure:
300 mg (0.33 mmol) of product 11 and 0.8 ml of diethylamine are solved in 4 ml DMF (dimethylformamide) and reacted according to production of compound 9. 42 mg (19%) of compound 12 is obtained in form of an amorphic solid compound: C39H43N7O5 (689.82) MS (ESI+) 690.3 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:29])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([F:28])[CH:19]=3)=[O:16])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:29])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:28])[CH:19]=3)=[O:16])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1F
Agent: [Li+]
Agent: [OH-]
Product: CC(C(=O)Nc1ccc(C(=O)O)c(F)c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
82 mg (0.17 mmol) of methyl 4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluorobenzoate (racemate) (Example 2.4A) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 8 mg (purity 93%, 10% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[NH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]>CCOC(C)=O>[NH2:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=1
Reactant: CC(=O)NCCN
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CCOC(C)=O
Product: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of chloroarene 4 (20.57 g; 0.100 mol) in N-(2-aminoethyl)-acetamide (71.05 g; 0.696 mol) was heated from 60 to 120° C. over 20 min then kept at 120° C. for 4.0 h. After cooling to rt, the reaction was diluted with EtOAc (500 mL) then washed with water (1×150 mL). The aq phase was extracted with EtOAc (3×25 mL) and the combined organic portions were washed with water (2×25 mL) and saturated NaCl (2×50 mL). The solution was dried (MgSO4), filtered then concentrated in vacuo to 21.34 g of an off-white hard foam. The product was purified in two batches on silica gel (1.7 L total) using 15-8:1 DCM:MeOH yielding a hard white foam (15.36 g; 57%). LC (method B) tR=5.5 min; 1H NMR (200 MHz, CDCl3) δ 8.29 (m, 2H), 7.43 (m, 3H), 6.71 (brs, 1H), 5.41 (s, 1H), 5.12 (brt, J=5.4 Hz, 1H), 4.68 (brs, 2H), 3.53 (m, 1H), 3.45 (m, 1H), 1.83 (s, 3H); ESIMS 272.03 (100) [MH+].
Reaction SMILES: C(N(CC)CC)C.C(Br)C=C.N[C:13]1[C:18](Cl)=[CH:17][C:16]([C:20](=[O:23])[CH2:21][Br:22])=[CH:15][C:14]=1Cl.O>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[CH2:21]([Br:22])[C:20]([C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:23]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: O=C(CBr)c1ccccc1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Triethylamine (17.0 g, 0.168 mol) is added in one portion to allyl bromide (105.9 g, 0.875 mol) under a nitrogen atmosphere. The resulting white emulsion gives an exotherm to 70° C. and becomes a thick white solid mass within 5 minutes. The solution formed with the addition of ~100 ml of DMF is stirred for 1 hour at 70°-95° C. A solution of 4'-amino-2-bromo-3',5'-dichloroacetophenone (25.0 g, 0.088 mol) in 50 ml of DMF is added in one portion and the resulting brown reaction mixture is maintained at 80°-90° C. for 2 hours. The progress of the reaction is frequently checked by thin layer chromatography SiO2 /CH2Cl2 /hexanes (1/1)) since prolonged heating results in the decomposition of both starting material and products. The reaction mixture is poured into 1.51 of H2O and is stirred for 0.5 hours. After a second aqueous trituration, the residual brown semi-solids are stirred with ~150 ml of CCl4 for 0.5 hours to form a suspension. The yellowish-brown solids are collected by filtration and are air dried to give 14.9 g (59.6%) of recovered phenacyl bromide starting material. The CCl4 filtrate is stirred with MgSO4, filtered and concentrated to yield 9.42 g of a brown syrup. Gradient elution (hexanes/CH2Cl2 (10/0→8/2) flash chromatography on a 9"×2" column of Silica Gel 60 gives two major fractions:
Reaction SMILES: CCCCCCCCCCCCCC(O[C@H]1[C@@]2(OC(C)=O)C(C)(C)[C@H]2[C@@H]2C=C(CO)C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]2(O)[C@@H]1C)=O.C[C@H]1[C@@H](CC2[O:73][C:72]3[CH:74]=[CH:75][C:76](NC)=[C:77](C(O)=O)[C:71]=3N=2)O[C@]2(O[C@H]([C@@H](C(C3NC=CC=3)=O)C)[C@H](C)C[C@H]2C)CC1.[NH2:83][C@H:84]([C:87]([OH:89])=[O:88])[CH2:85]S>>[NH2:83][C@H:84]([C:87]([OH:89])=[O:88])[CH2:85][C:76]1[CH:77]=[CH:71][C:72]([OH:73])=[CH:74][CH:75]=1
Reactant: CNc1ccc2oc(C[C@H]3O[C@@]4(CC[C@H]3C)O[C@H]([C@H](C)C(=O)c3ccc[nH]3)[C@H](C)C[C@H]4C)nc2c1C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Agent: CCCCCCCCCCCCCC(=O)O[C@@H]1[C@@H](C)[C@@]2(O)[C@@H](C=C(CO)C[C@]3(O)C(=O)C(C)=C[C@@H]23)[C@@H]2C(C)(C)[C@]12OC(C)=O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Reagents Phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 were purchased from Sigma. Bromelain (E.C 3.4.22.4; proteolytic activity, 1,541 nmol/min/mg) was obtained from Solvay Inc. (Germany). E-64 (L-transepoxysuccinylleucylamido-(4-guanidino)butane, a selective cysteine protease inhibitor, was from Sigma.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:33])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:33])[C:19]2[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@H](CCO)C1c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H]1OCCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
5.68 g (11 mmol) of the resulting alcohol derivative were dissolved in methylene chloride (60 ml) followed by the addition of 2.3 ml (16.5 mmol) of triethylamine under a nitrogen atmosphere, the addition of 1.02 ml (13.2 mmol) of methanesulfonyl chloride with ice-cooling, and stirring for 30 minutes at room temperature under a nitrogen atmosphere. Water was then added to the reaction solution followed by washing the methylene chloride layer with water and a saturated aqueous solution of sodium chloride and drying with anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/2) to obtain 6.09 g of the desired compound (93%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17](O)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:28][N:29]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17]([NH:29][OH:28])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)SCCCO)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)C(C)(C)SCCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid (500 mg, 1.2 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole (194 mg, 1.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (322 mg, 1.68 mmol) followed by N-methylmorpholine (0.198 mL, 1.8 mmol) and the resulting mixture was stirred for 1 h at room temperature. A 50% aqueous solution of hydroxylamine (0.367 mL, 6 mmol) was added and the mixture was stirred for 15 h at room temperature. The solvent was removed and the product was partitioned between ethyl acetate and water. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, brine, and dried over anhydrous sodium sulfate. Removal of the solvent gave (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanamide, which was triturated with hexanes to obtain 130 mg (25%) of the pure product, HRMS (C18H26N2O6S2)(M+H); calcd. 431.1305, found 431.1313.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([F:32])=[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:19])[CH:12]=3)[CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:42]=[C:43]=[O:44])[CH:38]=[C:39]([F:41])[CH:40]=1>O1CCOCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:18]([CH3:19])[C:13]2[N:14]=[CH:15][CH:16]3[CH:11]([CH:12]=2)[N:10]([CH2:29][CH3:30])[C:9](=[O:31])[C:8]([C:6]2[C:5]([F:32])=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:43]([NH:42][C:37]4[CH:38]=[C:39]([F:41])[CH:40]=[C:35]([F:34])[CH:36]=4)=[O:44])[CH:7]=2)=[CH:17]3)=[CH:22][CH:23]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: O=C=Nc1cc(F)cc(F)c1
Solvent: C1COCCO1
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 mL) was treated with 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) and stirred at RT overnight. Additional 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) was added and the mixture stirred for 4 h. The resulting precipitate was collected via filtration and dried to yield 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (112 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.05 (t, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.19-7.14 (m, 4H), 6.86 (d, 2H), 6.80-6.77 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH2:10][C:11]1[N:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=1>C(O)(=O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[N:12]2[N:13]=[C:14]([S:16][CH3:17])[N:15]=[C:11]2[N:10]=1)[CH3:1]
Reactant: CSc1nc(N)n[nH]1
Reactant: CCC(=O)CC(=O)CC
Solvent: CC(=O)O
Product: CCc1cc(CC)n2nc(SC)nc2n1
Temperature: 135 °C
Yield: 87.9 %

Procedure:
A mixture of 3,5-heptanedione (9.85 g, 76.8 mmol), 3-amino-5-methylthio-1H-1,2,4-triazole (10.0 g, 76.8 mmol), and glacial acetic acid (60 mL) was added to a 200 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 135° C. The mixture was heated for 24 hours. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-methylthio-1H-1,2,4-triazole eluted rapidly with retention time of 0.7 min, and the product eluted with retention time of 4.7 min. The mixture was cooled to room temperature, then slowly poured into stirring ice/water (800 mL) to precipitate product and stirred ˜20 minutes. Solids were isolated by filtration, rinsed with water (200 mL), and then dried under reduced pressure to afford the title compound as a powder (15.0 g, 88% yield).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13]O>C(O)(=O)C.O>[CH2:1]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: ClCCCSCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=S(CCCCl)Cc1ccccc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
1.2 g of 1-benzylthio-3-chloro-n-propane, synthesized by ◯1 of Synthesis Example 2 was dissolved in 50 ml of acetic acid, and 8.7 g of 35% aqueous hydrogen peroxide was added thereto dropwise under stirring below 10° C. After that, it was warmed gradually to room temperature again, then stirred further for 4 hours. The reaction mixture was poured in 300 ml of iced water, and extracted 2 times by each 150 ml of methylene chloride. The methylene chloride layer was washed 2 times with 5% aqueous solution of sodium hydroxide, followed by water, and dried over anhydrous magnesium sulfate. A colorless solid residue was obtained by distilling off methylene chloride. It was washed by n-hexane to give 12.6 g (yield: 96.9%) of the object 1-benzylsulfinyl-3-chloro-n-propane as a colorless crystal. m.p. 70° to 71° C.