Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:40][S:37]([F:38])([F:39])([F:41])([F:42])[C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was filtered, dried and purified by chromatography on silica (ethyl acetate/methanol 8:1) to give 133 mg (47%) amorphous material.
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][C:13](=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]([N:26]=[N+:27]=[N-:28])[C:9]1=[O:29])(C(C)(C)C)(C)C.Cl>CO.O>[N:26]([CH:10]1[CH:11]([CH2:12][C:13](=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[NH:8][C:9]1=[O:29])=[N+:27]=[N-:28]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC(=O)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NC1C(=O)NC1CC(=O)CC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of N-(t-butyldimethylsilyl)-3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (1.0 g) in methanol (10 ml) is treated with conc. hydrochloric acid (0.1 ml) and left at room temperature for 2 hr. The solution is diluted with water and extracted with ethyl acetate. The extracts are washed with 5% sodium bicarbonate solution and brine, dried, and evaporated under vacuum. The residue is chromatographed on silica gel to give 3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][NH:8][C:9]([NH2:11])=[S:10]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[NH:7][N:8]=[C:9]([SH:10])[N:11]=1
Reactant: NNC(N)=S
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCc1nc(S)n[nH]1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
Methoxyacetyl chloride (2.82 g; 0.023 mol) was added to a solution (15 ml) of 2.09 g (0.0230 mol) of thiosemicarbazide in pyridine followed by stirring for a whole day and night at room temperature. The reaction solution was concentrated and 10 ml of methanol and 8 ml of a 25 wt % methanolic solution of sodium methoxide ere added thereto followed by heating to reflux for a whole day and night. After cooling to room temperature, the solvent was evaporated and concentrated hydrochloric acid was added thereto to acidify. The solid separated out therefrom was filtered, washed with distilled water and dried to give 1.0 g (yield: 33%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)C1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)n3nccc3n2)C1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate (3.40 g, 10.5 mmol) in a solution of ammonia in MeOH (7N, 20 mL) was heated in sealed vessel at 80° C. for 5 h. The reaction mixture was cooled down and concentrated in vacuo. The residue was dried in high vacuum and used for the next step without further purification. LC/MS RT=1.30 min (5 min method). Mass calculated for, M+H 303.17, observed 318.19.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH2:16][CH2:17][CH3:18].[Li+].[OH-]>C1COCC1.O>[CH2:16]([C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:19])=[O:2])[CH2:17][CH3:18]
Reactant: CCCc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a suspension of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (220 mg, 0.81 mmol) in THF (3 mL) was added a solution of 1N-LiOH (6 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with H2O, which was washed three times with EtOAc, acidified with 1N HCl to pH 1-2. The resulting solution was extracted three times with methylene chloride and then dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound (155 mg, 74%).
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.Cl.[NH:49]1[CH2:54][CH2:53][CH:52]([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:65]=[C:56]1[C:55]([CH:52]2[CH2:53][CH2:54][N:49]([C:1]([O:2][C@H:3]([CH2:18][C:19]3[CH:27]=[C:26]([CH3:28])[C:25]4[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[N:24]=4)[CH:20]=3)[C:4](=[O:17])[N:5]3[CH2:10][CH2:9][CH:8]([N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]4)[CH2:7][CH2:6]3)=[O:37])[CH2:50][CH2:51]2)=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[NH:57]1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (89.5 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (0.16 mL, 0.90 mmol), and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 102 mg (60%) as a colorless film. Mass spec.: 755.53 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][OH:12])[C:9]#[N:10].[C:13](OCC)(=[O:15])[CH3:14]>CCCCCC>[C:13]([O:12][CH2:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]#[N:10])(=[O:15])[CH3:14]
Reactant: N#CC(CO)c1ccccc1Cl
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)OCC(C#N)c1ccccc1Cl

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2-chlorophenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-(2-chlorophenyl)-3-hydroxypropanenitrile is described in Example 13. The recovered ester product was a colorless oil (70% yield), Rf 0.3 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:10]=[C:9]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:10]=[C:9]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:6][CH:7]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc(N)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-n2c(-c3ccccc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
1-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H-imidazole-4-carboxamide (Example 45) (51 mg, 0.12 mmol) was dissolved in dry dichloromethane (2 mL) and treated with acetic anhydride (14 μL, 0.15 mmol) dropwise. The solution was stirred at rt for 4 h, and then the solvent was evaporated to give an amber oil. It was purified by HPLC (YMC-packed Pro C18 15×200 mm column, 30-90% CH3CN in H2O/TFA, 20 mL/min.) to afford an off-white solid (13 mg, 15%): LC-MS m/z 452.3 (MH+), retention time 2.31 min (method 1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1.[H][H]>CO.[Pd]>[N:17]1([C:4]2[C:5]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:14])[CH3:15])=[N:6][CH:7]=[CH:2][N:3]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CC(C)NCC(O)COc1ncc(Br)nc1N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC(O)COc1nccnc1N1CCOCC1
Reaction time: 0.17 h

Procedure:
7.5 g of 5-bromo-3-morpholinyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine are dissolved in 80 ml of methanol and hydrogenated in the presence of 0.4 g of palladium on charcoal (5% strength) at 20°-30° C. under normal pressure. After 10 minutes, the reaction is complete and the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is evaporated in a waterpump vacuum. The residue is partitioned between water and ether. The aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. 3-Morpholinyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, melting point 74°-76° C., is thus obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[C:8]([C:12]1[CH:13]=[C:14]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])([CH3:10])[CH3:9].C1(C)C(C)=CC=CC=1>O>[C:19]([C:16]1[CH:15]=[C:14]([CH2:23][CH2:24][C:25]([NH:27][N:28]2[C:1](=[O:7])[CH:2]=[CH:3][C:4]2=[O:6])=[O:26])[CH:13]=[C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:17]=1[OH:18])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1cc(CCC(=O)NN2C(=O)C=CC2=O)cc(C(C)(C)C)c1O
Yield: 86.5 %

Procedure:
A mixture of maleic anhydride (4.9 g, 50.0 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (15.2 g, 50.0 mmol) and 250 ml of xylene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water. The solvent was then removed on a rotary evaporator. The residual mass was extracted with 100 ml of tetrahydrofuran and the extract was added to 500 ml of hexane to precipitate the product. The product was collected by filtration and air dried. 16.1 g of a solid material was obtained having a melting range of 90°-94° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7](I)[S:6][N:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([Sn:19]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18])[S:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1cc(C2CC2)ns1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C2CC2)ns1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a cold (−78° C.) solution of 3-cyclopropyl-5-iodoisothiazole (100 mg, 0.398 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.299 mL, 0.478 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (0.129 mL, 0.478 mmol) in anhydrous THF (2.0 mL) was added to the reaction mixture, which was stirred for 30 minutes −78° C. and subsequently allowed to warm to ambient temperature over a 1 hour period. Saturated aqueous sodium bicarbonate was added to the reaction mixture. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as a colorless oil (142.8 mg, 87%). 1H NMR (500 MHz, CDCl3) δ ppm 0.85-0.93 (m, 9H), 0.95-1.05 (m, 4H), 1.09-1.17 (m, 6H), 1.28-1.38 (m, 6H), 1.47-1.61 (m, 6H), 2.20-2.29 (m, 1H), 6.93 (s, 1H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([O:12][Si:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][Si:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:30][CH:31]=1)=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](OC(=O)c1ccc(O)cc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(=O)c1ccc(OC(=S)Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 40.7 ml of thiophosgene in 300 ml of dry diethyl ether at -78° C. was added dropwise a solution of 20 g of diphenyl-(2-methylprop-2-yl)silyl 4-hydroxybenzoate and 8.5 ml of triethylamine. After having been stirred for a further 30 minutes at -78° C. and 90 minutes at room temperature, the mixture was partitioned between diethyl ether and water. The organic layer was washed with water and brine, was dried over calcium chloride, and then evaporated in vacuo to afford 25.9 g of an orange oil. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded 16.8 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]2[CH2:9][CH2:8]2)=[N:5][N:6]=1.[Cl:10][C:11]1[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=[C:13]([S:32](Cl)(=[O:34])=[O:33])[CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:10][C:11]1[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=[C:13]([S:32](=[O:33])(=[O:34])[NH:1][C:2]2[S:3][C:4]([CH:7]3[CH2:9][CH2:8]3)=[N:5][N:6]=2)[CH:12]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Reactant: Nc1nnc(C2CC2)s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Nc3nnc(C4CC4)s3)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-5-cyclopropyl-1,3,4-thiadiazole (0.236 g, 0.126 mmol) was added to a mixture of Example 49j (0.3 g, 0.68 mmol) and pyridine (8 mL) in ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 15 h, concentrated, treated with water and extracted with n-butanol. The organic extract was washed with water, dried concentrated and purified using flash chromatography (silica gel, 4% methanol/chloroform) to obtain the title compound. Yield: 0.03 g, (8%); 1H NMR (DMSO-d6): δ 0.98 (m, 2H, CH2), 1.12 (d, 2H, CH2), 2.3 (m, 1H, CH), 2.7 (s, 3H, CH3), 5.46 (s, 2H, CH2), 7.95 (d, 1H, Ar,), 8.06 (s, 1H, Ar), 8.14 (s, 1H, Ar), 8.16 (s, 1H, Ar).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@H:10]([OH:13])[C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[S:8][C:7]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:6]1=2.N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:13][C@@H:10]1[C@H:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[S:8][C:7]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])[C:11]1=[O:12])(=[O:39])[CH3:38]
Reactant: COC(=O)c1cccc2c1S[C@@H](c1ccc(OC)cc1)[C@@H](O)C(=O)N2CCN(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c1S[C@@H](c1ccc(OC)cc1)[C@@H](OC(C)=O)C(=O)N2CCN(C)C
Temperature: 22 °C
Reaction time: 3 h

Procedure:
To a solution of 19 mg (0.045 mmol) of (+/−)-(2S,3S)-methyl 5-(2-(dimethylamino)ethyl)-3-hydroxy-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-9-carboxylate in 0.5 mL of DCM was added 22 μL (0.27 mmol) of pyridine and 4 μL (0.06 mmol) of acetyl chloride. The reaction was stirred at 22° C. for 3 hours. The reaction mixture was diluted with DCM, washed sequentially with 1 M Na2CO3 and water, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography on silica gel, eluting with DCM then gradually increasing to 3% methanol/DCM to give 1a. MS found M+H=473. The hydrochloride salt of 1a was recrystallized from ethyl acetate; mp 169-172° C.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:23])[OH:19])=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of tert-butyllithium (1.7 M in pentane, 12 ml, CAUTION-PYROPHORIC) was added dropwise to a stirring solution of 4-bromophenyl tert-butyl ether (2.33 g) in tetrahydrofuran (20 ml) at -70° C. After a further 5 minutes the resulting solution of anion was added dropwise to a solution of triisopropyl borate (6 ml) in tetrahydrofuran (10 ml) at -70 ° C. After the addition was complete the reaction mixture was allowed to warm to room temperature. After 20 minutes a solution of saturated aqueous ammonium chloride (25 ml) and ether (25 ml) was added. The layers were separated and the aqueous phase washed with ether (50 ml). The combined organic extracts were washed with dilute hydrochloric acid (5%, 25 ml) and were then dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under reduced pressure to give a white solid. This was purified by column chromatography over silica eluting with ether then methanol to give the sub-title compound as a white solid (0.69 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:9](=[O:16])[CH2:8][O:7][C:6]=2[CH:17]=1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][N:10]1[C:9](=[O:16])[CH2:8][O:7][C:6]2[CH:17]=[C:2]([NH:1][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])[CH:3]=[CH:4][C:5]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1C(=O)COc2cc(N)ccc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1C(=O)COc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A solution of 7-amino-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.125 g, 0.531 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.3 g, 1.062 mmol) at room temperature and stirred overnight (18 hours). At this time, additional methyl thiophene-2-carbimidothioate hydroiodide (0.3 g, 1.062 mmol) was added, and stirring was continued for another 24 hours. The reaction was diluted with saturated NaHCO3 solution (20 mL), and the product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound 5 (0.16 g, 88%) as a solid. 1H NMR (DMSO-d6) δ 2.19 (s, 6H), 2.43 (t, 2H, J=6.9 Hz), 3.97 (t, 2H, J=6.9 Hz), 4.58 (s, 2H), 6.48-6.58 (m, 4H), 7.06-7.14 (m, 2H), 7.60 (d, 1H, J=5.1 Hz), 7.74 (d, 1H, J=3.3 Hz); ESI-MS (m/z, %): 345 (MH+, 100), 128 (85); ESI-HRMS calculated for C17H21N4O2S (MH+), calculated: 345.1379; observed: 345.1384; HPLC-purity: 93.15% by area.
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.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: N#Cc1ccc(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-formylbenzonitrile was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:20]=3)[C:15]2=[O:31])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:25]([O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[N+:28]([O-:30])=[O:29])[C:15](=[O:31])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:22]2=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCNCC1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-isopropoxy-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester generated in the previous step in 3 mL of DCM is added TFA (3 mL). The reaction mixture is stirred at room temperature for 1 h. After concentration, water (5 mL) is added to the crude reaction mixture, the resulting mixture is neutralized to pH=8 by adding NaHCO3, and the product is extracted with DCM. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give crude 5-isopropoxy-6-nitro-2-piperidin-4-yl-isoindole-1,3-dione, which is directly used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](=[O:26])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2cccs2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cccs2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(thiophen-2-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(thiophen-2-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 69%).