Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1>CCO>[Cl:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: Nc1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
p-Aminoaniline (0.48 g, 4.4 mmol) and triethylamine (1.3 ml, 9.2 mmol) were added to 8-bromo-6-chloroimidazo[1,2-b]pyridazine HCl (1.0 g, 4.2 mmol) from Example I(1), step 1b in EtOH (20 mL). The mixture was heated to 90° C. and stirred for 1 hr. The solution was then concentrated in vacuo to give crude N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine. Cold ethanol was then added and the crude solid rinsed 3×. Following filtration, collected 0.45 g of the desired material.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[H-].[Li+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>COCCOC>[N:28]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Yield: 42.5 %

Procedure:
To a mixture of 3.63 grams (9.84 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) and 84.75 milligrams (10.7 millimoles) of lithium hydride in 10 milliliters of 1,2-dimethoxyethane was added 1.0 milliliter (10.0 millimoles) of piperidine in 10 milliliters of 1,2-dimethoxyethane. The mixture was heated under reflux for 22 hours, and the resulting heterogeneous mixture filtered to obtain a clear yellow filtrate. The filtrate was concentrated to an orange oil which after evaporative distillation (bath 120° C.; 0.05 torr.) produced 1.18 grams (42.5 percent yield) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine base having infrared and nuclear magnetic resonance spectral characteristics appropriate for said compound. A 286.23 milligram (1.02 millimoles) sample of the free base, 4-(6-piperidinohexyl)-3,5-dioxomorpholine, was dissolved in 1.0 milliliter of 1 N sodium hydroxide (1.0 millimole) and the mixture concentrated to produce 289.63 grams (90 percent yield) of sodium [2-(6-piperidinohexyl)amino-2-oxoethoxy]acetate product with the following spectral characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[CH:17][C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[O:29])=[CH:24][N:23]=1.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[C:17]([CH:28]([C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[CH:27][CH:26]=3)[OH:29])[C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CCCCNc1nc(=O)cc[nH]1
Reactant: Cc1ccc(C=O)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cccnc1CCCCNc1nc(=O)c(C(O)c2ccc(C)nc2)c[nH]1
Yield: 31.9 %

Procedure:
2-[[4-(3-Methoxy-2-pyridyl)butyl]amino]-4-(1H)-pyrimidinone (1.42 g, 0.005 mol) was dissolved in concentrated hydrochloric acid (10 ml) and 2-methyl-5-formylpyridine (1.35 g, 0.012 mol) was added. The solution was stirred at reflux temperature for 24 hours, cooled, basified with 10N sodium hydroxide to pH 8.5 and the product left to separate as an oil. The aqueous mother liquor was decanted and the oil subjected to medium pressure liquid chromatography (Kieselgel 60, 230-400 mesh) with methanolic ammonia: dichloromethane (10:90) as eluent. The relevant fractions were combined and evaporated under reduced pressure to afford the title compound (0.63 g). Crystallisation from aqueous methanol afforded the title product as a white crystalline solid, m.p. 82° C.; δ(CDCl3) 1.6 (4H, m), 2.5 (3H, s) 2.75 (2H, m), 3.3 (2H, m), 3.8 (3H, s), 5.7 (1H, s), 7.1 (3H, m), 7.4 (1H, s), 7.65 (1H dd), 7.9 (1H, dd), 8.5 (1H, m) ppm.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[N:9]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (2-bromoethyl)benzene (0.23 mL) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.066 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.58 g, 87%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:31][CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[CH:33]=O)=[CH:21][CH:20]=1.CC[O:37][CH2:38][CH3:39]>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:31][CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[CH:33]=[CH:39][CH:38]=[O:37])=[CH:23][CH:24]=1
Reactant: O=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Reactant: CCOCC
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Solvent: O
Product: O=CC=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 0°-5° C. solution of LDA (26.5 mmoles) in 25 ml anhydrous ether was added ethylidenecyclohexylamine (Org. Syn. 50 66) (3.32 g, 26.5 mmoles) in 25 ml anhydrous ether. The solution was stirred for 10 minutes, cooled to -70° C. and 3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-ene-2-carboxaldehyde (5.55 g, 24.1 mmoles) in 25 ml ether was added. The solution was stirred for 60 minutes, warmed to 0°-5° C., stirred for 90 minutes and diluted with water. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 3% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product rich fractions provided 2.53 g of the product as an orange oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36]/[N:37]=[C:38](\[CH3:46])/[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:26]([NH:28][CH3:29])=O.O>C1(C)C=CC=CC=1>[CH3:23][O:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36]/[N:37]=[C:38](\[CH3:46])/[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:26]([NH:28][CH3:29])=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 137.8 %

Procedure:
Lawesson's reagent (40 mg, 0.1 mmol) was added to a solution of (E)-α-methoxy-N-methyl-2-(α-methyl-4-chloro-benzylideneaminooxy)phenylacetamide (73 mg, 0.2 mmol) in toluene (3 ml), and the mixture was heated at 80° C. for 1.5 hours with stirring. The mixture was cooled to room temperature. Water was added, and the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylthioacetamide (50 mg, 66%) as an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1)=[O:4].Cl[C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[F:26][C:2]([F:1])([F:25])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:16])=[O:17])[CH:13]=2)[N:8]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:7]=1)=[O:4]
Reactant: O=C(Nc1n[nH]c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,2,2-Trifluoro-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-acetamide, (17.93 g, 46.33 mmol) in dry dichloromethane (300 mL) was treated with chlorotriphenylmethane (14.22 g, 50.96 mmol) and triethylamine (14.2 mL, 102 mmol). After stirring at room temperature for two days, the reaction was washed with a solution of NH4Cl, dried and evaporated. The crude was used as such in the next step without any further purification.
Reaction SMILES: C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=O)=[CH:15][CH:14]=2)[N:8]=1)CCCCC.[CH2:22](Cl)[CH2:23]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:9]([C:12]1[CH:11]=[N:10][C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:19])=[CH:20][CH:21]=2)=[N:8][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:22][CH3:23]
Reactant: CCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
15.58 g. of 4-(4-n-hexylpyrimid-2-yl)benzoic acid amide are left in a mixture of 350 ml. of ethylene chloride and 5.58 ml. of phosphorus oxychloride for 90 minutes under reflux, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 14.6 g. of 5-n-hexyl-2-(4-cyanophenyl)pyrimidine result, which are distilled in high vacuum, m.p. 53.5° - 54.5°; cl.p. 35.5° - 36.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([CH:32](O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[SiH](CC)(CC)CC.CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([CH2:32][CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(CC)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-(1-hydroxyethyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.08 g) in CH3CN (3 mL) at 0° C. was added Et3SiH (0.075 mL) followed by BE3.Et2O (0.0197 mL). The mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with CH3OH/H2O and the mixture was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1/2) to give 39 mg of N-(2,6-dichlorobenzoyl)-3-ethyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 500 (MH+).
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([B:13]([OH:15])[OH:14])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+].[F:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1.C(OC(C)C)(=O)C>C1COCC1>[F:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([N:5]2[CH2:6][C:7]3[CH:12]=[C:11]([B:13]([OH:15])[OH:14])[CH:10]=[CH:9][C:8]=3[O:2][CH2:3][CH2:4]2)=[O:30])[CH2:25][CH2:24]1
Reactant: OB(O)c1ccc2c(c1)CNCCO2
Reactant: O=C(Cl)N1CCC(CF)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: O=C(N1CCC(CF)CC1)N1CCOc2ccc(B(O)O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (188 mg, 0.82 mmol) was taken into 50% aqueous THF (2 mL) followed by addition of solid sodium bicarbonate (360 mg, 4.3 mmol) then 4-(fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (218 mg, 1.21 mmol) in a minimum of THF. The mixture was stirred at room temperature over 1 h then partitioned with 0.5M aqueous hydrochloric acid and ethyl acetate. The organic solution was then brine washed, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was taken into isopropyl acetate and extracted once with 1M aqueous sodium hydroxide. The aqueous solution was then acidified to pH 2 using concentrated hydrochloric acid and extracted once with ethyl acetate then brine washed, dried over anhydrous sodium sulfate, filtered and concentrated to provide (4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (143 mg, 52% yield) as an amorphous residue. MS (EI) for C16H22BrFN2O4: 337 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(=NC3CCCCC3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 3.347 g (17.69 mmol) of 1-benzyl-4-piperidinone and 1.75 g (17.7 mmol) of cyclohexylamine in 150 ml of toluene was refluxed under dehydrating conditions for 2.5 hours in a Dean-Stark trap. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure to yield N-(1-benzyl-4-piperidylidene)cyclohexylamine. This product was used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>CCOCC.CCCCCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([B:23]([OH:24])[OH:22])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccccc1-c1ccccc1
Temperature: -67 °C
Yield: 64.6 %

Procedure:
Under an atmosphere of argon, 2-bromobiphenyl (20 g, 86 mmole) was dissolved into anhydrous ether (200 ml) and the resultant solution was cooled at −35° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 63 ml, 95 mmole) was added dropwise and the resultant mixture was stirred at −20° C. for 1 hour. After the reaction mixture was cooled at −67° C., a solution (50 ml) of triisopropoxyborane (50 ml, 0.22 mole, 2.5 eq) in anhydrous ether was added and the resultant mixture was stirred at −65° C. for 1 hour and at the room temperature for 2 hours and left standing for one night. To the obtained reaction mixture, a 10% hydrochloric acid (200 ml) was added. After the resultant mixture was stirred at the room temperature for 1 hour, the formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. The solid obtained after removing the solvent by distillation was washed with hexane and a white solid (11 g, 62%) was obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[NH4+].C(O)(=O)CC(O)=O>C(O)C>[C:9]([OH:12])(=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1
Agent: O=C(O)CC(=O)O
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)C=Cc1ccccc1

Procedure:
β-substituted-β-amino-acids were prepared by refluxing the corresponding benzaldehyde derivatives with excess ammonium acetate (˜2 equiv.), and malonic acid (1 equiv.) in absolute ethanol until the reaction has completed (determined by TLC and NMR). Cinnamic acid derivative was produced as a side product. The reaction mixtures were then workup with standard procedures, e.g., as described in FIG. 4.
Reaction SMILES: C[Si](N)(C)C.[K].[N:7]12[CH2:15][CH:11]([CH2:12][CH2:13][CH2:14]1)[CH:10]([OH:16])[CH2:9][CH2:8]2.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([O:16][CH:10]2[CH:11]3[CH2:15][N:7]([CH2:14][CH2:13][CH2:12]3)[CH2:8][CH2:9]2)=[CH:22][CH:23]=1
Reactant: OC1CCN2CCCC1C2
Reactant: Clc1ccc(Cl)nn1
Agent: C[Si](C)(C)N
Agent: [K]
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCN3CCCC2C3)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Potassium trimethylsilylamine (5.25 mmol) is added to a solution of (rac.)-1-Aza-bicyclo[3.3.1]nonan-4-ol (5.0 mmol) in THF (20 ml) at room temperature and the solution is stirred for 30 min. The resulting potassium alcoholate is slowly added to a precooled solution of 3,6-dichloropyridazine (7.5 mmol) in THF (50 ml) and the resulting mixture is stirred for another 20 minutes. The solution is allowed to warm to 0° C. is quenched with brine and extracted with diethylether. The organic layer is dried over magnesium sulfate and evaporated. The brown oil is purified by silica gel column chromatography (CH2Cl2:MeOH:NH3, 9:1:0.1) to afford (rac.)-4-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane (320 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[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]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)(=[O:18])=[O:17])[CH3:34])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of (R)-{[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (example 1-5, prepared by the method analogous to the one described for example 1-1, 48.6 mg, 0.100 mmol) in acetonitrile (3 mL) was added potassium carbonate (27.6 mg, 0.200 mmol) and methyl iodide (9.5 μL, 0.150 mmol). After being heated at 70° C. under an argon atmosphere for 6 hours, the reaction mixture was cooled to room temperature, filtered through a glass funnel and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloro-methane) to afford {(R)-4-[(3,5-bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (42.6 mg, 83%) as a white solid. MS cald. (calculated) for C20H21F6N3O4S 513, obsd. (observed) (ESI+) [(M+H)+] 514.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[C:18]2[S:17](=[O:20])(=[O:19])[N:16]=[C:15]([C:21]3[C:22](=[O:37])[N:23]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:24]4[C:29]([C:30]=3[OH:31])=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:14][C:13]=2[S:12][CH:11]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[CH:34]1([CH2:33][NH:32][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]([OH:31])=[C:21]([C:15]3[NH:14][C:13]4[S:12][CH:11]=[C:10]([CH2:9][NH:8][S:39]([CH3:38])(=[O:41])=[O:40])[C:18]=4[S:17](=[O:19])(=[O:20])[N:16]=3)[C:22]2=[O:37])[CH2:35][CH2:36]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
To the suspension of the triethylamine salt of 3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (85.26 mg, 0.16 mmol) in N,N-dimethylformamide (1.6 mL) was added triethylamine (48 □L, 0.34 mmol) and then methanesulfonyl chloride (13.3 □L, 0.17 mmol) at room temperature. The solution was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue purified by reverse phase chromatography, eluting with 20% to 95% acetonitrile/0.1% trifluoroacetic acid in water to give N-[(3-{1-[(cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl}-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide (compound II) (39.86 mg, 49%). MS (ESI+) m/z 524 (M+H)+. NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 2.99 (s, 3 H) 4.29 (d, J=6.25 Hz, 2 H) 6.37 (br s, 1 H) 7.41 (m, 2 H) 7.75 (t, J=6.25 Hz, 1 H) 7.87 (m, 1 H) 8.08 (d, J=8.09 Hz, 1 H) 8.16 (m, 1 H) 14.46 (m, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10](=[S:12])[NH:9][N:8]=2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[CH:16].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH2:16]([S:12][C:10]1[NH:11][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][N:9]=1)[C:15]#[CH:14]
Reactant: S=c1[nH]nc(-c2ccncc2)[nH]1
Reactant: C#CCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCSc1nnc(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
A mixture of 3-(pyridin-4-yl)-1H-1,2,4-triazole-5(4H)-thione (2 g, 11.2 mmol), 3-bromoprop-1-yne (1.47 g, 12.3 mmol) and sodium acetate (5.34 g, 65.1 mmol) in DMF (20 mL) was stirred for 6 h at room temperature. The reaction mixture was then poured into water (50 mL) and extracted with DCM. The combined organic layers were washed with water three times, dried with Na2SO4, filtered and concentrated to obtain the title compound (1.5 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]=[CH2:14])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:14][O:23]1)[CH3:2]
Reactant: C=Cc1ccc2c(c1CC)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1c(C2CO2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-ethyl-5-vinyl-2-benzofuran-1(3H)-one (1.1 g, 5.85 mmol) in 50 mL of DCM was slowly added mCPBA (3.60 g, 85% purity, 17.6 mmol) in 50 mL of DCM at 0° C. Warmed to room temperature, the mixture was stirred for 3 days. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were combined, washed with brine and concentrated. The residue was purified by column chromatography to give product 4-ethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=8.6 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 5.30 (s, 2H), 4.11-4.13 (m, 1H), 3.23-3.25 (m, 1H), 2.75-2.82 (m, 2H), 2.70-2.72 (m, 1H), 1.27 (t, J=7.4 Hz, 3H).