Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)C(C)=O
Reaction time: 1 h

Procedure:
Pulverized potassium carbonate (160 g.) was added to a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti isomers) (152 g.) in acetone (500 ml.). Dimethyl sulfate (130 g.) was dropwise added thereto with stirring over 1 hour at 45° to 50° C. and the mixture was stirred for 2 hours. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The filtered insoluble material was dissolved in water (500 ml.) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300 ml.). The extract was washed twice with water (200 ml.) and with a saturated sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (145.3 g.), bp 55° to 64° C./0.5 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[CH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:4][CH2:3]1.ClC(OCC)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].Cl>O1CCCC1.C(N(CC)CC)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]=[C:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]1)[CH3:22]
Reactant: O=C(O)CCCC=C1CCC(=O)CC1
Reactant: CCNCC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)CCCC=C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 21 ml of anhydrous tetrahydrofuran were dissolved 1.50 g of 5-(4-oxocyclohexylidene)-valeric acid and 1.17 ml of triethylamine. Then, 4.50 ml of a solution of 0.80 ml of ethyl chloroformate in anhydrous tetrahydrofuran was dropwise added at −20° C., and the resulting mixture was stirred at the same temperature as above for one hour. Then, 4.50 ml of a solution of anhydrous tetrahydrofuran containing 2.00 ml of diethylamine was dropwise added at the same temperature, and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturate aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:1] gave 1.30 g of N,N-diethyl-5-(4-oxocyclohexylidene)-valeramide as a colorless oily product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:28])[CH2:11][C:12]2[CH:17]=[C:16]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])=[CH:5][CH:4]=1.O1CCCC1>[Pd].C(O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:28])[CH2:11][C:12]2[CH:17]=[C:16]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CC2SC(=O)NC2=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 57.1 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-[5-((2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetamide (300 mg, 0.687 mmol), 10% palladium on carbon (300 mg) and a mixed solvent of tetrahydrofuran and ethanol (2:1 v/v, 40 mL) were mixed, and hydrogenation was performed at room temperature and at an initial pressure of 392 kPa. After completion of the reaction, catalyst was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=2:1 v/v) to obtain 172 mg (57%) of the title compound as colorless powder.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[CH3:6][CH:7]([OH:10])[C:8]#[CH:9]>>[Br:1][C:2]1[CH:9]=[C:8]([CH:7]([OH:10])[CH3:6])[O:4][N:3]=1
Reactant: C#CC(C)O
Reactant: ON=C(Br)Br
Product: CC(O)c1cc(Br)no1

Procedure:
Reaction of dibromoformaldoxime with 3-butyn-2-ol gives 3-bromo-5-(1-hydroxyethyl)-isoxazole which is converted by oxidation into 3-bromo-5-acetylisoxazole, an intermediate for the preparation of 1-(3-bromoisoxazol-5-yl)-2-tert.butylamine-ethanol, a compound having broncodilating activity (European Patent No. 16255) known as Broxaterol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([NH:17][C@H:18]2[C@@H:21]([CH2:22][N:23]3[CH2:27][CH2:26][O:25][C:24]3=[O:28])[N:20]([S:29]([OH:32])(=[O:31])=[O:30])[C:19]2=[O:33])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][O:36][C@H:37]([C:62]([O:64][CH:65]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:63])[CH2:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](=[NH:59])[NH:45][CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1.CC(O)=O>C(Cl)(Cl)Cl.CCO>[CH:65]([O:64][C:62](=[O:63])[C@@H:37]([O:36]/[N:35]=[C:14](/[C:12]1[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[S:10][CH:11]=1)\[C:15]([NH:17][C@H:18]1[C@@H:21]([CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[N:20]([S:29]([OH:32])(=[O:30])=[O:31])[C:19]1=[O:33])=[O:16])[CH2:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](=[NH:59])[NH:45][CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=N)c2ccc(OC[C@H](ON)C(=O)OC(c3ccccc3)c3ccccc3)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a soln of (3S,4R)-3-(2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (170 mg, 0.328 mmol) in CHCl3 (2 mL, ratio: 1) and EtOH (6 mL, ratio: 3) was added (S)-tert-butyl 4-(4-(2-(aminooxy)-3-(benzhydryloxy)-3-oxopropoxy)benzimidamido)piperidine-1-carboxylate (prepared according to WO2013110643, 193 mg, 0.328 mmol). After stirring for 2 h, AcOH (19 μL, 0.328 mmol) was added. After 12 h, more solution of (3S,4R)-3-(2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (170 mg, 0.328 mmol) in 3:1 CHCl3:EtOH was added. After stirring for 45 h, it was concentrated in vacuo, and the crude residue was purified with HP21 resin (10-100% ACN-water), affording the title compound (117 mg, 33%) as an off white solid. LCMS: Rt=0.96 min, m/z=1091.1 (M+1) Method 2m_acidic.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2cc(-c3ccccc3)ccc2C1
Yield: 90.8 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), a solution of phenylboronic acid (111 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml) and tetrakis(triphenylphosphine)palladium(0) (84.2 mg, 0.0729 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (180 mg, 90.9%) as an oil.
Reaction SMILES: [S-2:1].[K+].[K+].CN(C=O)C.Cl[C:10]1[CH:29]=[CH:28][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.Cl>CC1C=CC=CC=1>[C:22]1([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[C:13]3[CH:28]=[CH:29][C:10]([SH:1])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Reactant: [S-2]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(S)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
15 g anhydrous potassium sulfide and 100 ml DMF are added into a 250 ml three-neck flask. The solution is heated to 50° C. under stirring, and then 8 g 4-chloro-4′-phenyl benzophenone is added into the solution; the solution is heated to reflux (about 110° C.), and is cooled after 7 h; adding 100 ml methylbenzene, regulating the pH value to 5-6 with diluted hydrochloric acid, and separating the solution; the organic phase is extracted twice with 50 ml NaOH solution having a content of 5%, and the aqueous phases are mixed; the obtained aqueous phase is put into a 250 ml three-neck flask, and nitrogen is supplied to blow for 30 min, then 15% hydrochloric acid is dropped into the aqueous solution while agitating to regulate the pH value to 5-6, and light yellow solid precipitate; filtering to obtain a light yellow solid, and the weight after drying at a reduced pressure is 5.0 g, the purity is 99.11%, the yield is 63%, the melting point is 173˜176.7° C., and 1H-NMR data (solvent CDCl3): δ3.654 ppm, s, 1H; δ7.432, 7.370 ppm, d, 2H; δ7.413, 7.436 ppm, d, 1H; δ7.466, 7.491, 7.515 ppm, t, 2H; δ7.641, 7.665 ppm, d, 2H; δ7.695, 7.719 ppm, 7.743, t, 4H; δ7.850, 7.874 ppm, d, 2H.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C>CO>[CH3:14][O:15][CH:16]([O:20][CH3:21])[N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH2:9][CH2:10]1
Reactant: C1CNC(CCC2CCNCC2)=N1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(OC)N1CCC(CCC2=NCCN2)CC1
Temperature: 90 °C

Procedure:
A mixture containing 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]piperidine (1 g, 0.0055M), methanol (10 ml) and dimethylformamide dimethylacetal (10 ml) was heated at 90° C. for 8 hours. The excess of dimethylformamide was removed in vacuo to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.01 g, 0.0045M) and diisopropylethylamine (0.54 ml) in dried chloroform (30 ml) was added the chloroform solution (20 ml) of the above piperidinecarboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hour and at room temperature for 3 hours. After the reaction, the solvent was removed and the residue dissolved in water (20 ml). The aqueous solution, washed with ethylacetate was acidified to pH3 with dil. HCl and purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6 beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid hydrochloride (1.11 g, 45% yield).
Reaction SMILES: [CH2:1]1[CH2:37][O:36][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=5)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:2]1.I([O-])(=O)(=O)=[O:39].[Na+]>O1CCCC1.CO.O>[CH2:37]1[CH2:1][O:2][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][C:30]([S:33]([CH3:34])=[O:39])=[CH:31][CH:32]=5)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:36]1
Reactant: CSc1ccc(-c2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CC=C5CC6(CC[C@@H]5[C@H]43)OCCO6)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1ccc(-c2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CC=C5CC6(CC[C@@H]5[C@H]43)OCCO6)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
494 mg of 3,3-(ethylenedioxy)-11β-[4'-(methylthio)[1,1'-biphenyl]-4-yl]-5-estren-17-one is dissolved in a mixture of 6 ml of tetrahydrofuran, 6 ml of methanol and 2 ml of water and mixed with 924 mg of sodium periodate. The reaction mixture is stirred at room temperature overnight, then filtered on Celite and the filtrate is diluted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate, 346 mg of the title compound is obtained as white foam.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.N1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=3)[N:23]=2)CCNCC1>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([F:28])([F:30])[F:29])=[N:25][N:26]=4)[N:23]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: C1CC(OCC2CC2)CCN1
Product: FC(F)(F)c1nnc2ccc(N3CCC(OCC4CC4)CC3)nn12
Yield: 69 %

Procedure:
A mixture of 4-(cyclopropylmethoxy)piperidine and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 216 to give 6-[4-(cyclopropylmethoxy)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 69% yield.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:28]1([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)Nc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and phenyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Brc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)cc2c1=O
Yield: 18.6 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 43 mg of the target compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1.[Cl:23][CH2:24][CH2:25][CH2:26][N:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:28]>>[ClH:23].[ClH:23].[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([N:27]([CH2:26][CH2:25][CH2:24][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=4)[C:9]3=[O:22])[CH2:2]2)[CH3:28])=[CH:30][CH:31]=1
Reactant: COc1ccc(N(C)CCCCl)cc1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)CC2
Product: COc1ccc(N(C)CCCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C3=O)C2)cc1
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-dimethoxy- 1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(4-methoxy-N-methyl-phenylamino)-propane analogously to Example 1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](N2C=CN=N2)[CH:6]=[N:7][CH:8]=1.[N:16]1(C2C=NC=CC=2)[CH:20]=[CH:19][N:18]=[N:17]1.ClC1C=C(N2C=CN=N2)C=C(Cl)N=1.ClC1C=C(N2C=CN=N2)C=C(C(F)(F)F)N=1.ClC1C(Cl)=C(N2C=CN=N2)C(Cl)=C(Cl)N=1>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[N:7][CH:8]=1
Reactant: c1cncc(-n2ccnn2)c1
Reactant: FC(F)(F)c1cncc(-n2ccnn2)c1
Agent: Clc1cc(-n2ccnn2)cc(Cl)n1
Agent: Clc1nc(Cl)c(Cl)c(-n2ccnn2)c1Cl
Agent: FC(F)(F)c1cc(-n2ccnn2)cc(Cl)n1
Product: FC(F)(F)c1ccc(-n2ccnn2)nc1

Procedure:
The following were prepared analogously and identified by NMR spectroscopy and elemental (CHN) analysis: 5-(trifluoromethyl)-3-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 129.5°-131° C.; 3-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 80.5°-83° C.; 2,6-dichloro-4-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 80°-83° C.; 2-chloro-6-(trifluoromethyl)-4-(1H-1,2,3-triazol-1-yl)pyridine, and 2,3,5,6-tetrachloro-4-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 161°-162.5° C.
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[C:11]#N.[OH:13]S(O)(=O)=O.N([O-])=O.[Na+].[OH2:22]>>[Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[C:11]([OH:13])=[O:22]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(C(F)(F)F)nsc1Br
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)c1c(C(F)(F)F)nsc1Br
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed 5-bromo-3-(trifluoromethyl)-1,2-thiazole-4-carbonitrile (4.2 g, 16.34 mmol, 1.00 equiv), con. H2SO4 (10 mL). This was followed by the addition of a solution of NaNO2 (1.69 g, 24.49 mmol, 1.50 equiv) in water (5 mL) dropwise with stirring at 0° C. To this was added water (25 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 days at 20° C. The resulting solution was allowed to react, with stirring, for an additional 5 h while the temperature was maintained at 50° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 4.5 g of 5-bromo-3-(trifluoromethyl)-1,2-thiazole-4-carboxylic acid as yellow crude oil. Mass spectrum (ESI, m/z): Calcd. for C5HBrF3NO2S, 273.9 (M−H). found 273.9.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:20](=[O:22])[CH3:21])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC1CCCc2c(Br)cncc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCc2c(Br)cncc21
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-12 [A], 318 mg, 1.4 mmol) and Et3N (3.0 mL) in DCM (10 mL) was added acetyl chloride (0.106 mL, 1.4 mmol) at 0° C. and stirring was continued at 0° C. for 1 hour. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product which was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (346 mg, 92%) as light yellow solid. MS: 269.1 & 271.1 (M+H+).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].[CH3:25][C:26]1([CH3:34])[O:33][C:31](=[O:32])[CH2:30][C:28](=[O:29])[O:27]1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:25][C:26]1([CH3:34])[O:33][C:31](=[O:32])[CH:30]([C:22](=[O:24])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:13])([CH3:14])[CH3:15])[C:28](=[O:29])[O:27]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
EDCI (59.39 g, 310.8 mmol) was added at 0° C. to a stirred solution of 3-(tert-butoxycarbonylamino)propanoic acid (I-59a: 49 g, 258.9 mmol), meldrum's acid (41.05 g, 284.8 mmol) and DMAP (47.4 g, 388.5 mmol) in DCM (490 mL) and the resulting reaction mass was allowed to stir at room temperature overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was washed with 5% KHSO4 solution and separated the layers. The organic layer was dried over Na2SO4 and concentrated to afford 70 g of the product (85.8% yield).
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=3[Cl:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:13]=3[Cl:19])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1cc(N2CCCC2)ccc1OC12CC3CC(CC(C3)C1)C2

Procedure:
1.7 g. (0.00612 Mole) of 4-(1-adamantyloxy)-3-chloroaniline, 1.32 g. (0.00612 mole) of 1,4-dibromobutane and 1.86 g. (0.0135 mole) of potassium carbonate were combined in 50 ml. of absolute ethanol and refluxed for 18 hours.