Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cccc(O)c1C
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(OCCCC(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,3-Dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. Seventy five (75) ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol) was added to the solution. The mixture solution was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added to the solution. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered of. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 hours, and monitored with HPLC. The mixture was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. The precipitate was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after being kept in water at room temperature overnight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH:16]1[CH2:18][O:17]1)[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH2:21].CCO>>[OH:17][C@H:16]([CH2:18][NH:21][CH3:20])[C@@H:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)NC(CC1CCOCC1)C1CO1
Solvent: CCO
Product: CNC[C@@H](O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with [1-oxiranyl-2-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid tert-butyl ester (150 mg, 0.55 mmol) dissolved in MeNH2/EtOH solution and stirred overnight at 30-40° C. Then the mixture was concentrated and used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:17][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH2:16]
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnccc2Oc2cc(F)c(N)cc2F)cn1
Temperature: 90 °C
Yield: 64.5 %

Procedure:
In a sealed tube, 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 1.395 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.363 g, 1.744 mmol), potassium carbonate (0.578 g, 4.18 mmol), and tetrakistriphenylphosphine palladium (0) (0.081 g, 0.070 mmol) were suspended in dioxane (8 mL) and water (1.333 mL). The mixture was degassed with Ar and heated at 90° C. overnight. The reaction mixture was cooled and partitioned between EtOAc and saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried, evaporated and purified by silica gel chromatography (hexanes/EtOAc) to yield 2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (272 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H) 8.22-8.20 (m, 2H), 8.00 (s, 1H), 7.24-7.19 (tri, 1H), 6.76-6.71 (m, 1H), 6.62 (d, 1H), 5.50 (br s, 2H), 3.78 (s, 3H); MS (ESI) m/z: 301.0 (M+H+).
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16](Br)[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCCC1.O>[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16]([C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Reactant: CCOC(=O)C(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Temperature: -20 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Under nitrogen, isopropyl magnesium chloride 2M in tetrahydrofuran (0.30 mL, 0.59 mmol) was added dropwise to a solution of 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol) in anhydrous tetrahydrofuran (1.0 mL), previously cooled to −20° C. After 2 hour stirring at the same temperature, ethyl chlorooxoacetate (87 μL, 0.78 mmol) was dropwise added. The mixture was stirred at −20° C. for 60 minutes before being poured in water (2 mL). The mixture was extracted with ethyl acetate (2×3 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired keto-ester (49e) (80 mg, 0.17 mmol, 38%)
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH2:31]Cl)=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C(N(C(C)C)CC)(C)C>C(#N)C>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([CH2:31][C:30]3[N:26]([CH2:25][C:24]4[CH:33]=[CH:34][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:27]=[N:28][CH:29]=3)[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CN2CCC3(CC2)C(=O)NCN3c2ccccc2)cc1

Procedure:
A solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (230 mg, 1 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (265 mg, 1 mmol), and diisopropylethylamine (0.52 mL, 3 mmol) in anhydrous acetonitrile (5 mL) was stirred at room temp. for 2 days. The resulting mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 5% methanol in ethyl acetate. The appropriate fractions were collected and concentrated. The residue was triturated with diethyl ether, and the white solid precipitated was collected by filtration to provide the title compound.
Reaction SMILES: C(OCOC([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[B:18]1[O:22]C(C)(C)[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C)C.Cl.O>C1COCC1>[OH:22][B:18]1[C:10]2[CH:11]=[C:12]([C:15](=[O:17])[CH3:16])[CH:13]=[CH:14][C:9]=2[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: CCOCOC(C)(C)c1ccc(C(C)=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 1-(4-(2-(ethoxymethoxy)propan-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl)phenyl)ethanone (684 mg, 1.89 mmol) in THF (15 mL) was added 6N HCl (10 mL). The reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with EA. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (5:1) to give 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethanone (324 mg; yield 50% over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (b, 1H), 8.29 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 2.61 (s, 3H), 1.44 (s, 6H) ppm; MS: m/z=205.1 (M+1, ESI+).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=O)=[CH:8][C:7]=1[C:16]1[N:17]=[N:18][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:20][CH:21]=1.[NH2:34][C:35]([NH2:37])=[S:36].II>CO>[CH3:4][O:5][C:6]1[C:7]([C:16]2[N:17]=[N:18][C:19]([N:22]([CH3:33])[CH:23]3[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)=[CH:20][CH:21]=2)=[CH:8][C:9]2[CH2:10][C:11]3[S:36][C:35]([NH2:37])=[N:34][C:12]=3[C:13]=2[CH:14]=1
Reactant: NC(N)=S
Reactant: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)CCC2=O
Agent: II
Solvent: CCO
Solvent: CO
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)Cc1sc(N)nc1-2
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a microwave vial containing ethanol (1.2 mL) was added 6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (Intermediate 7-1, 100 mg, 0.25 mmol), thiourea (55.9 mL, 0.73 mmol), and iodine (124 mg, 0.49 mmol). The reaction mixture was stirred at 100° C. for 3 hours. The mixture was diluted with MeOH and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 5-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-2-amine (114 mg) MS [M+H+]=465.0.
Reaction SMILES: [C:1]([C:5]1[N:10]=[N:9][C:8]2[C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:12]=3[S:13][C:7]=2[C:6]=1[OH:19])([O:3]C)=[O:2].C>[OH-].[Na+].O>[C:1]([C:5]1[N:10]=[N:9][C:8]2[C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:12]=3[S:13][C:7]=2[C:6]=1[OH:19])([OH:3])=[O:2]
Reactant: COC(=O)c1nnc2c(sc3nc(C)ccc32)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(n1)sc1c(O)c(C(=O)O)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 4 g (0.015 mol) of 3-carbomethoxy-4-hydroxy-7-methylpyrido[3',2':4,5]thieno[3,2-C]pyridazine in 60 ml of 3% NaOH solution was stirred at room temperature for 2 hours. It was then diluted with water, treated with charcoal and filtered. It was acidified with acetic acid and filtered. Crystallization of the crude product from 3% NaOH/HOAC gave 2 g (53%) of 3-carboxy-4-hydroxy-7-methylpyrido[3',2':4,5]thieno[3,2-C]pyridazine, m.p.>300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-])=O.[H][H]>C(O)C.[Pd]>[NH:1]1[C:4]2=[CH:5][N:6]=[CH:7][CH:8]=[C:9]2[CH:10]=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2ccncc2[nH]1
Yield: 83.5 %

Procedure:
1.8 g of 10% palladium-on-charcoal are charged into an autoclave, the atmosphere of which is then made inert with a stream of argon. A solution of 6 g of ethyl 3-(3-nitro-4-pyridyl)-2-oxopropionate in 72 mL of absolute ethanol is added. The reaction medium is then stirred for 3 hours at 20° C. under a pressure of 2 bar of hydrogen. The mixture is then filtered through Celite®. The filtrate is concentrated under reduced pressure and oven-dried at 40° C. to give 4 g of ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:27])=[N:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].O>C(OCC)(=O)C>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]3[NH:27][C:34](=[O:35])[O:26][N:25]=3)[CH:16]=2)[C:11](=[O:28])[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=1[CH2:8][NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=NO)cc12
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3noc(=O)[nH]3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.78 g, 1.7 mmol) in ethyl acetate (10 ml) tetrahydrofuran (10 ml) was added 1,1′-carbonyldiimidazole (0.83 g, 5.1 mmol) and the mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give tert-butyl [4-butoxy-2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.54 g, 65.9%) as crystals.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C@H:8]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:9]([CH3:20])[O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.Br[C:30]1[S:34][C:33]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(O)C.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>[OH:7][C@H:8]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:9]([CH3:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:30]2[S:34][C:33]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:32][CH:31]=2)=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: C[C@H](Oc1ccc(-c2ccc(S(N)(=O)=O)s2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C

Procedure:
2M Aqueous sodium carbonate (0.75 ml), (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (Example 21a)), 0.19 g), and tetrakis(triphenylphosphine)palladium(0) (0.025 g) were added to a solution of 5-bromothiophene-2-sulfonic acid amide (0.242 g) in ethanol (2 ml). The mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature and the solvents were evaporated under reduced pressure. The reaction mixture was triturated with acetone (10 ml) and filtered through a short silica gel column. The column was eluted with acetone and the resulting filtrate evaporated to give the title compound as a solid (0.064 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.C1COCC1.Cl.[CH3:50][O:51][CH2:52][CH:53]1[CH2:58][NH:57][CH2:56][CH2:55][N:54]1[CH2:59][CH:60]([N:64]1[CH:68]=[C:67]([C:69]2[C:70]3[CH:77]=[CH:76][N:75]([CH2:78][O:79][CH2:80][CH2:81][Si:82]([CH3:85])([CH3:84])[CH3:83])[C:71]=3[N:72]=[CH:73][N:74]=2)[CH:66]=[N:65]1)[CH2:61][C:62]#[N:63]>>[C:62]([CH2:61][CH:60]([N:64]1[CH:68]=[C:67]([C:69]2[C:70]3[CH:77]=[CH:76][N:75]([CH2:78][O:79][CH2:80][CH2:81][Si:82]([CH3:84])([CH3:83])[CH3:85])[C:71]=3[N:72]=[CH:73][N:74]=2)[CH:66]=[N:65]1)[CH2:59][N:54]1[CH2:55][CH2:56][N:57]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:58][CH:53]1[CH2:52][O:51][CH3:50])#[N:63]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: COCC1CNCCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1 h

Procedure:
4-cyano-2-fluorobenzoic acid (24.2 mg, 0.146 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (51.7 mg, 0.136 mmol) and triethylamine (87.4 μL, 0.627 mmol) in THF (1.3 mL, 16 mmol) was stirred at RT for 15 min. Following this, 4-[2-(methoxymethyl)piperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloric acid salt (0.061 g, 0.10 mmol, as a mixture of diastereomers from Step 4) was added. After 1 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and brine, dried over sodium sulfate, decanted and concentrated. The product was purified by preparative HPLC-MS, (C18 eluting with a gradient of H2O/MeCN/0.1% TFA. After removing solvent in vacuo, the residue was dissolved in saturated sodium bicarbonate and DCM. The aqueous phase was extracted with a further portion of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated under high vacuum to afford product as a mixture of diastereomers (55 mg, 80%). The diastereomers were partially separated using chiral HPLC (Phenomenex Lux Cellulose-1, 20×250 mm, 5 micron particle size, 30% ethanol in hexane, 20 mL/min, 8 mg/injection). Retention time of Peak 1: 32.84 min, retention time of peak 2: 37.30 min, retention time of peak 3: 45.74 min (contains two isomers).
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[CH3:20][C:21]1[N:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][CH:22]=1>O>[CH3:27][C:25]1[N:26]=[C:21]([CH2:20][N:13]([C:11]2[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(CBr)n1
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(CN(c2ccccn2)c2ccccn2)n1
Reaction time: 0.75 h

Procedure:
To a flask were added 0.6 g pulverized potassium hydroxide and 15 ml dimethylsulfoxide. After adding 1.4 g of 2,2′-dipyridylamine, the mixture was stirred under nitrogen for 45 minutes, when 1.5 g 6-methyl-2-(bromomethyl)pyridine was added. After stirring for 1 hour, 35 ml of water was added and the product was extracted with 60 ml of 50% ethyl acetate, 50% hexane. The organic layer was washed with 30 ml water and the solvent was removed. The residue was purified by silica gel chromatography using 48% ethyl acetate, 48% hexane, and 4% methanol resulting in 2.0 g of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(Br)cc1
Product: ClCCCOc1ccc(Br)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-bromophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:11]([CH2:12][OH:13])[CH2:10][N:9]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:11]([CH2:12][O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][N:9]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CO)[C@@H](C(=O)NC2CC2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](C(=O)NC2CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
(3R,4S)-N-Cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (7.54 g) was dissolved in N,N-dimethylformamide (180 mL). While this solution was cooled on an ice bath, imidazole (2.67 g) and tert-butylchlorodimethylsilane (4.72 g) were sequentially added. The mixture was stirred at room temperature for 90 min and was subsequently concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (300 mL) and the solution was washed with water (2×100 mL), followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate) to give 7.05 g of (3R,4S)-N-cyclopropyl-4-(tert-butyldimethylsilyl)oxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide as a pale yellow tar-like product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Cl:19])C(=O)C1>O1CCCC1>[Cl:19][C:11]1[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:8][NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cc(C2CCOCC2)n[nH]1
Solvent: C1CCOC1
Product: Clc1c[nH]nc1C1CCOCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.2, 3.5 g, 23.0 mmol) in tetrahydrofuran (20 mL) was added NCS (3.4 g, 25.4 mmol). The reaction mixture was stirred overnight at 40° C. The resulting mixture was concentrated under reduced pressure. This resulted in 4.75 g (crude) of the title compound as a light yellow solid.
Reaction SMILES: Cl.[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[F:29][C:30]([F:41])([F:40])[CH:31]([C:36]([F:39])([F:38])[F:37])[CH2:32][C:33](O)=[O:34]>>[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:33](=[O:34])[CH2:32][CH:31]([C:30]([F:40])([F:41])[F:29])[C:36]([F:37])([F:39])[F:38])[CH2:27][CH2:28]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(O)CC(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(C3CCN(C(=O)CC(C(F)(F)F)C(F)(F)F)CC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 4-{2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}piperidine monohydrochloride and 4,4,4-trifluoro-3-(trifluoromethyl)butyric acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][C:7]=1[Cl:16]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(N)c(Cl)c1
Yield: 8.6 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.2 g), N-chlorosuccinimide (0.135 g) and dimethylformamide (3 ml) was stirred with ice-cooling for an hour. The reaction mixture was poured into water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure and the residue was crystallized from chloroform to give 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.02 g).
Reaction SMILES: [Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:22]NC.C(Cl)Cl.C=O>C(O)(C)(C)C>[Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:22])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C=C1C(C)=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Yield: 5.6 %

Procedure:
A mixture of t-butyl 7α-bromo-3-methyl-3-cephem -4-carboxylate 1,1-dioxide (700 mg, 1.9 mmol), dimethylamine hydrochloride (460 mg, 5.7 mmol), methylene chloride (3 ml) and t-butyl alcohol (50 ml), formaldehyde (0.57 g, 37% w/v) was heated to reflux at 80°-90° C. for 20 hours. t-Butyl alcohol was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 200 mg of crude product which was purified over silica column using methylene chloride as eluant to give 40 mg of pure t-butyl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide.