Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[N:29][C:28]([CH3:31])=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[N:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1nnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 23.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (203 mg, 0.302 mmol), DCM (3.0 mL) and TFA (1.39 mL, 18.1 mmol) for 2 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (37 mg, 24%) as a white powder. LCMS: Rt=0.35 min, m/z=518.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.03 (s, 1H), 5.37 (d, J=5.5 Hz, 1H), 5.08-4.97 (m, 1H), 4.90-4.80 (m, 2H), 2.35 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH3:11]
Reactant: CCN
Reactant: Cc1cncc(C=O)c1
Solvent: C1CCOC1
Product: CCNCc1cncc(C)c1

Procedure:
prepared by reaction of 5-methyl-pyridin-3-carbaldehyde (Kemnitzer W. et al J. Med. Chem. 2004, 47, 25, 6299-6310) with 2M ethylamine in THF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][C:62]=1[F:63])[N:59]=[C:58]([NH:64][CH2:65][CH2:66][NH:67][CH3:68])[CH:57]=[N:56]2>CN(C=O)C>[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][C:62]=1[F:63])[N:59]=[C:58]([NH:64][CH2:65][CH2:66][N:67]([CH3:68])[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16])[CH:57]=[N:56]2
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N(C)CCNc2cnc3cc(F)c(F)cc3n2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (50 mg, 0.21 mmol) in DMF (3 ml) was treated sequentially with N,N-diisopropylethylamine (0.20 ml, excess), HATU (79 mg, 0.21 mmol) then after 15 min. N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol). The reaction mixture was stirred at room temperature, under argon for 72 h then partitioned between diethyl ether and water. The organic phase was washed with water (3×), brine, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with pentane to afford the title compound as a pale yellow powder (38 mg, 40%).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]=1.[CH:9]1[C:14]([C:15]2[O:19][C:18](/[CH:20]=[N:21]/[N:22]3[C:27](=[O:28])[NH:26][C:24](=[O:25])[CH2:23]3)=[CH:17][CH:16]=2)=[CH:13][CH:12]=[C:11]([N+:29]([O-:31])=[O:30])[CH:10]=1>CO>[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]=1.[N+:29]([C:11]1[CH:12]=[CH:13][C:14]([C:15]2[O:19][C:18]([CH:20]=[N:21][N:22]3[CH2:23][C:24](=[O:25])[NH:26][C:27]3=[O:28])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1)([O-:31])=[O:30]
Reactant: O=C1CN(/N=C/c2ccc(-c3ccc([N+](=O)[O-])cc3)o2)C(=O)N1
Agent: Cn1cc[n+](C)c1
Agent: [I-]
Solvent: CO
Product: O=C1CN(N=Cc2ccc(-c3ccc([N+](=O)[O-])cc3)o2)C(=O)N1
Reaction time: 1 h

Procedure:
An ion exchange column of Amberlite® IRA-410 resin (85 ml, 110 meq. on a 2.5 cm × 30 cm column) was activated by elution with 170 ml of 2N NaOH followed by washing with water to neutrality and then with 300 ml of methanol. A solution of 12.3 g (0.055 mole) of 1,3-dimethylimidazolium iodide (Part A) in 100 ml of methanol was placed on the basic anion exchange resin and eluted with methanol until the pH returned to neutral. The methanol solution of the quaternary hydroxide was collected in a flask containing 15.7 g (0.05 mole) of dantrolene suspended in 100 ml of methanol. The mixture was stirred for 60 min., then filtered. The methanol filtrate was concentrated in vacuo to dryness. The residue was triturated with 1000 ml of isopropanol and filtered, hot. The red-orange insoluble quaternary salt was then recrystallized from 100 ml of methanol, with Darco, to yield 12 g (53%), m.p. 172° -175° C.
Reaction SMILES: C[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:12]([CH3:14])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][C:7]=1[CH3:2]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1=C(/C=C/C(C)N)C(C)(C)CC1

Procedure:
A solution of β-ionone (10.0 g., 52 mmol), ammonium acetate (40.0 g., 520 mmol) and sodium cyanoborohydride (3.27 g., 52 mmol) in methanol (150 ml) is stirred at room temperature for 3 days. The mixture is then made acidic to a pH less than 2 with concentrated hydrochloric acid, and most of the solvent is evaporated under vacuum. Water (150 ml) is added and the solution is washed with two 50 ml portions of ether. The aqueous solution is then made basic to pH greater than 10 with solid sodium hydroxide. The mixture is extracted with two 50 ml portions of ether, and the combined extracts washed with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated to yield a colorless oil (2.3 g.). The product is isolated by HPLC on a bonded C18 reverse phase column using methanol as the eluent to yield approximately 1 g. of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([OH:15])=O)[CH:9]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:53][N:54]1[C:58]([CH3:59])=[C:57]([C@H:60]([NH2:62])[CH3:61])[CH:56]=[N:55]1>C(Cl)Cl>[CH3:53][N:54]1[C:58]([CH3:59])=[C:57]([C@H:60]([NH:62][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:12]=[CH:11]3)=[O:15])[CH3:61])[CH:56]=[N:55]1
Reactant: Cc1c([C@@H](C)N)cnn1C
Reactant: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c([C@@H](C)NC(=O)c2ccc3nc(C(F)(F)F)ccc3c2)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
2-Trifluoromethylquinoline-6-carboxylic acid (100 mg, 0.415 mmol) was dissolved in DCM (10 mL) and N,N-di-iso-propylethylamine (Hunig's base, 268 μl, 1.54 mmol) was added. HATU (158 mg, 0.415 mmol) was added followed by (1R)-1-[1,5-dimethyl-1H-pyrazol-4-yl]ethanamine dihydrochloride (88 mg, 0.415 mmol) and the solution was stirred at RT overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (65 mL) then partitioned with sat. aq. NaHCO3 (2×20 mL) and then brine (30 mL). The organic layer dried over MgSO4, filtered and solvent removed under reduced pressure to give a golden oil/gum. The product was purified using an ISCO (12 g column), eluting with EtOAc:Heptane (5:95 increasing to 100:0). Fractions containing pure product concentrated under reduced pressure to give a white foamy solid, 150 mg, yield=41%. 1H NMR (400 MHz, CD3OD) δ 8.68 (1H, d), 8.47-8.49 (1H, m), 8.20-8.23 (2H, m), 7.92 (1H, d), 7.48 (1H, s), 5.29 (1H, q) 3.76 (3H, s), 2.33 (3H, s) and 1.61 (3H, d). LCMS (2 min run): UV (1.37 min, 82%); ELSD (1.37 min, 100%). Mass ion: 363=MH+
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:18]
Reactant: Oc1ncccc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncccc1C(F)(F)F
Yield: 2 %

Procedure:
As described for example 320a, 2-hydroxy-3-(trifluoromethyl)-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 40:60) afforded 2 compounds. The title compound was eluted first and was obtained as a colorless liquid (yield: 2%). MS: m/e=250.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:30][CH:31]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)(C)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-tert-butylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-tert-butylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[OH-].[Na+].[CH2:11](I)[CH2:12][CH2:13][CH3:14].C(O)(=O)C>O>[CH2:11]([S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: CCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thioxo-2,3-dihydro-1H-pyrimidin-4-one (12.8 g) was added to a solution of NaOH (8.0 g) in water (70 mL). After complete dissolution of the solids butyl iodide (12.4 mL) was added to the solution and the resulting mixture was stirred at RT overnight. A second aliquot of butyl iodide (1.2 mL) was then added and the reaction mixture was stirred for 24 h. A third aliquot of butyl iodide (1.2 mL) was added and the resulting mixture was stirred for 6 days. Glacial acetic acid (5.5 mL) was added and the reaction mixture was stirred for 30 min, it was then stored at 4° C. overnight. The precipitate formed was collected by filtration and dried under reduced pressure to give 12.3 g of 2-butylsulfanyl-3H-pyrimidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[O:24][N:23]=[C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=2)[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30]([C:28]3[N:29]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:34])([F:18])[F:33])[O:24][N:23]=4)[O:26][CH:27]=3)=[O:31])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1coc(-c2noc(C(F)(F)F)n2)n1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1coc(-c2noc(C(F)(F)F)n2)n1)c1coc(-c2ccc(F)cc2)n1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxylic acid as described in example 8 step 6 (6 mg, yield 13%). 1H NMR (400 MHz, CDCl3) δ 8.88-8.86 (m, 1H), 8.49 (s, 1H), 8.25-8.21 (m, 2H), 7.46 (s, 1H), 7.23-7.19 (t, J=8.8 Hz, 2H), 3.62-3.60 (d, J=6.0 Hz, 2H), 1.39 (s, 6H). MS (ESI) m/z: Calculated for C20H15F4N6O4: 465.11. found: 466.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][CH:4]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1coc(C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1coc(C)n1
Temperature: 25 °C

Procedure:
A mixture of the intermediate from Step B (2.336 g, 13.81 mmol), NBS (2.458 g, 13.81 mmol), and AIBN (0.113 g, 0.690 mmol) in 50 mL of CCl4 was refluxed for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.72 (1H, s), 3.89 (3H, s), 2.50 (3H, s), 2.29 (3H, s).
Reaction SMILES: [C:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl-].[CH2:10]([NH2:12])[CH3:11]>C1C=CC=CC=1>[C:1]1([C:6]([NH:12][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)C1=CCCC1
Reactant: CCN
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCNC(=O)C1=CCCC1
Temperature: 30 °C
Reaction time: 10 h
Yield: 69.8 %

Procedure:
N-Cyclopentenoyl-ethylamine was prepared from cyclopentenoic acid (2 grams, 17.5 mmol) and oxallyl chloride (2.2 grams, 17.5 mmol) after stirring at 25-35° C. for 8-12 hours. To this was added a benzene solution of ethylamine (2.1 grams, 48.7 mmol) at 0° C., and this reaction mixture was stirred for 3 hours at 25-35° C., after which time the solvent was evaporated under vacuum to yield N-cyclopentenoyl-ethylamine (1.7 grams), yield: 68.9%. A solution of N-cyclopentenoyl-ethylamine (1.7 grams, 13.3 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) under a nitrogen atmosphere, and lithium aluminum hydride (LiAlH4; 1.3 grams, 36.1 mmol) was added to the solution. After being stirred for 1 hour at 25-35° C., the reaction mixture was gently refluxed for 8 hours. The reaction mixture was quenched with saturated sodium sulfate solution, filtered, and the precipitate washed with diethyl ether (Et2O). The filtrate was concentrated to afford N-cyclopentylmethyl ethylamine (0.6 g), yield: 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][NH:29][CH2:30][CH:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:28][CH2:27][OH:26])[CH2:30][CH:31]([OH:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCCNCC(O)c1ccccc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(CCO)CC(O)c2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (75 mg, 0.190 mmol), α-2-hydroxyethylaminomethyl-benzyl alcohol (Bulletin of the Chemical Society of Japan, 56(1), 212-18; 1983)(51 mg, 0.28 mmol) and diisopropylethylamine (50 μL, 0.29 mmol) in dry DMF (4.0 mL) was heated to 60° C. for 18 hours. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo at 60° C. to provide the titled compound (92 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (532 mg) in DMF (45 ml) was dripped into a suspension of 60% sodium hydride-oil (144 mg) in DMF (12 ml) on an ice-water bath. The mixture was stirred at room temperature for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.02 g) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-yellow powder (711 mg, yield 58%).
Reaction SMILES: [CH2:1]([C@:8]([OH:24])([CH2:21][CH2:22]O)[C:9]([NH:11][C@H:12]([C:17](=[O:20])[NH:18][CH3:19])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:46])[NH:28][C@H:29]([C:34]([NH:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:25][O:26][C:27](=[O:46])[NH:28][CH:29]([C:34]([NH:36][N:37]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)[CH2:22][CH2:21][C:8]([C:9](=[O:10])[NH:11][CH:12]([C:17](=[O:20])[NH:18][CH3:19])[C:13]([CH3:16])([CH3:14])[CH3:15])([OH:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)N[C@H](C(=O)NNCc1ccc(Br)cc1)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)[C@@](O)(CCO)Cc1ccccc1)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)C(NC(=O)C(O)(CCN(Cc1ccc(Br)cc1)NC(=O)C(NC(=O)OC)C(C)(C)C)Cc1ccccc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
A mixture of (2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydroxy-butyramide (52S) (0.337 g, 1.00 mmol), IBX (0.560 g, 2.0 mmol) and 10 mL 1,2-dichloroethane in a reaction vial sealed with a screw cap was heated at 80° C. for 2 h. The resulting suspension was transferred to a 20 mL syringe and filtered through a syringe filter into a solution of hydrazide (9) (0.372 g, 1.00 mmol) in 15 mL DCE in a flame dried 50 mL round-bottom flask equipped with a septum. To this was added acetic acid (0.12 mL 2.0 mmol), mixture was stirred for 10 min and then sodium triacetoxyborohydride (0.636 g, 3.0 mmol) was added. The septum-sealed flask was flushed with nitrogen and the reaction was stirred at room temperature for 24 h. The reaction was quenched by addition of water and volatiles were evaporated. The residue was dissolved in 50% MeCN/water and purified by preparative RP-LC-MS (repeated 1 mL injections) to give 0.191 g of the title compound (28% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl>[ClH:20].[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([S:17]([N:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)(=[O:19])=[O:18])=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(S(=O)(=O)Cl)cc21
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(S(=O)(=O)N3CCCNCC3)cc21
Product: Cl
Reaction time: 18 h

Procedure:
Add the product of step 2 (0.5 g, 1.3 mmol) as a suspension in methylene chloride (10 mL) to hexahydro-2H-1,4-diazepine erazine (0.16 g) in methylene chloride (5 mL) at room temperature over 5 minutes. Stir the reaction mixture for 18 hours. Add aqueous sodium hydroxide (50 mL, 0.1N) to the reaction mixture, separate, and dry the organic layer (MgSO4), filter and concentrate to the title compound free base as a white solid. Chromatograph the solid on a column of silica gel (300 g) eluting with 5:95 methanol:methylene chloride. The solid is dissolved in aqueous hydrochloric acid (50 mL, 1N), concentrated, redissolved in water (25 mL) and lyophilized to give the title compound hydrate (200 mg, 31%) as a white solid. Rf=0.30 (1:9 methanol:methylene chloride). Calculated for C20H26O3N2SCl2Br: C, 49.04; H, 5.35; N, 5.72; S, 6.53. Observed: C, 48.62; H, 4.64; N, 5.70; S, 6.52.
Reaction SMILES: C1(O[C:8]#[N:9])C=CC=CC=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[N:25][CH:24]=[C:23]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:18]=1[C:19]([NH:21][NH2:22])=[O:20]>CS(C)=O>[NH2:9][C:8]1[O:20][C:19]([C:18]2[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])=[CH:26][N:25]=[CH:24][C:23]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[N:21][N:22]=1
Reactant: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Reactant: N#COc1ccccc1
Solvent: CS(C)=O
Product: Nc1nnc(-c2c(Nc3ccc(I)cc3F)cncc2-c2ccccc2F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Phenyl cyanate (6 mg, 0.05 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (22 mg, 0.05 mmol) in DMSO (1 mL), and stirred overnight at room temperature. The reaction solution was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (15 mg, 65%). LC-MS (M+H=492, obsd.=492). 1H NMR: δ 8.78 (s, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.73 (dd, 1H), 7.44 (m, 3H), 7.30 (m, 3H), 7.14 (s, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH2-:13].[Na+].C(OCC)(=O)C.[BrH:21]>C1(C)C(C)=CC=CC=1>[BrH:21].[NH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: [NH2-]
Reactant: COc1ccc2ccncc2c1
Agent: Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Nc1nccc2ccc(O)cc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
5.6 g (35.2 mmol) of 7-methoxyisoquinoline was dissolved in 200 ml of xylene. 26.6 ml (176 mmol) of N,N,N′,N′-tetramethylenediamine and 7.28 g (186 mmol) of sodium amide were added to the obtained solution, and they were stirred at 140° C. for 1 hour. After the treatment with ethyl acetate as the extracting solvent in an ordinary manner, 50 ml of hydrobromic acid was added to the obtained crude product and they were stirred at 140° C. overnight. The solvent was evaporated to obtain the title compound.