Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3](/[C:9](=[N:12]\[OH:13])/[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N/C(=N/O)c1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbonitrile (4.5958 g, 23.09 mmol) was dissolved in MeOH (91.92 mL), cooled to 0° C. and treated with hydroxylamine hydrochloride (1.605 g, 23.09 mmol) and triethylamine (2.336 g, 3.218 mL, 23.09 mmol). The reaction was allowed to warm to ambient temperature, stirred for 48 hours and then evaporated to dryness. Methanol (a minimum amount) was added, the mixture sonicated, filtered and washed with MeOH to give the product as a brown solid 5.27 g, 98% Yield). 1H NMR (400.0 MHz, DMSO) d 5.88 (s, 2H), 7.64 (br s, 2H), 8.14 (s, 1H) and 10.38 (s, 1H) ppm; MS (ES+) 233.75
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Product: O=[N+]([O-])c1c(NCCCO)cc(Cl)cc1NCCCO
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
0.22 mole (50 g) of 2,4,6-trichloronitrobenzene is added in portions to 150 ml of 3-amino-1-propanol heated to 80° C., with stirring. Heating is continued for 1 hour 30 minutes after the addition is complete. The reaction medium is poured into 300 g of ice-cold water. An oil which crystallizes on adding concentrated hydrochloric acid is obtained. The precipitate of the expected product is drained, washed with a 2N solution of hydrochloric acid and then with water to neutrality. After drying at 40° C. in the presence of phosphorous pentoxide, it is recrystallized from 96° ethanol. It melts at 127° C.
Reaction SMILES: Br[C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:11]([C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC1OC(=O)C=C1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC1OC(=O)C=C1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A mixture of 4-bromo-5-ethoxy-5H-furan-2-one (2.07 g, 10.0 mmol) and sodium azide (0.66 g, 10.2 mmol) in dimethylformamide (10 mL) was stirred at room temperature under nitrogen for 24 h. The reaction was diluted with ethyl acetate, was washed with 0° C. water and with brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:9 ethyl acetate:hexanes afforded 4-azido-5-ethoxy-5H-furan-2-one (1.04 g, 62% yield) as a pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ 5.83 (s, 1H), 5.63 (s, 1H), 3.99 (m, 1H), 3.88 (m, 1H), 1.35 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1.CCOCC>[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[N:7][CH:6]=1)([CH3:10])[CH3:9]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(O)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
2-(6-Bromopyridin-3-yl)propan-2-ol (1.08 g, 5 mmol) was dissolved in 10 mL of THF and 50 mL of anhydrous ether. After the solution was cooled to −78° C., 4.20 ml n-butyllithium (2.5 M, 11 mmol) was slowly dropped through a syringe in 10 min. After being stirred at −78° C. for 30 minutes, 1,4-cyclohexanedione mono-ethylene ketal (0.80 g, 5 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 5 mL of water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 40-70% EtOAc in hexane, 0.48 g of white crystals were obtained (42% yield), MS: 294.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:11]2=3)[CH2:26][CH2:25]4)=[CH:4][CH:3]=1>CO.[Pt]=O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:14][C:13]=3[C:12]3[CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([C:11]2=3)[CH2:28][CH2:29]4)=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C=C\n2c3c(c4cc(S(C)(=O)=O)ccc42)CN2CCC3CC2)cn1
Agent: O=[Pt]
Solvent: CO
Product: Cc1ccc(CCn2c3c(c4cc(S(C)(=O)=O)ccc42)CN2CCC3CC2)cn1

Procedure:
A solution of 6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (20 mg, 0.049 mmol; Example 181) in methanol was treated with platinum oxide under a hydrogen atmosphere (1 atm) at 40° C. for 16 hours to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.62-1.76 (m, 2H), 1.90-2.05 (m, 2H), 2.40 (s, 3H), 2.91-3.24 (m, 10H), 4.26 (s, 2H), 4.49 (t, J=6 Hz, 2H), 7.11 (d, J=8 Hz, 1H), 7.34 (dd, J=8, 2 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 7.59 (dd, J=9, 2 Hz, 1H), 7.84 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 410 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([Na])[C:4](=[O:6])[CH3:5])#[N:2].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]>CN(C=O)C.[Cl-].[NH4+]>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:3]([C:4](=[O:6])[CH3:5])[C:1]#[N:2]
Reactant: CC(=O)C([Na])C#N
Reactant: Cc1ccccc1CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)C(C#N)Cc1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (525 mg, 5 mmol) in DMF (15 mL) was added 1-(bromomethyl)-2-methylbenzene (648 mg, 3.5 mmol) dropwise over a period of 15 min at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Then this solution was diluted with saturated aq. ammonium chloride solution. This solution was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated under reduced pressure. The residue was purified by a silica gel chromatography (petroleum ether/ethyl acetate=15/1) to give the titled product (181 mg, 28%) as a colorless oil; LC/MS: MS (ES+) m/e 188 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.35 (s, 3H), 2.38 (s, 3H), 3.06 (dd, J=9.6, 14.1 Hz, 1H), 3.28 (dd, J=5.4, 14.1 Hz, 1H), 3.60 (dd, J=5.4, 9.6 Hz, 1H), 7.18-7.22 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[N:7]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1ccncc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1cccc(-c2nc3cnccc3[nH]2)n1
Temperature: 120 °C
Reaction time: 48 h
Yield: 18.2 %

Procedure:
6-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol), 3,4-diaminopyridine (1.52 g, 14.0 mmol) and DIPEA (2.43 mL, 14.0 mmol) were dissolved in DMF (20 mL) and HBTU (5.29 g, 14.0 mmol) was added. The reaction mixture was stirred for 48 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 (2×100 mL), water (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, dissolved in AcOH and heated at 120° C. for 50 min. The solvent was removed in vacuo and the residue was suspended in 1 M aq Na2CO3 (50 mL) and extracted with EtOAc (5×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography and recrystallisation from MeOH to give the title compound (534 mg, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].S(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH2:8][Cl:13])=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(CCl)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6-chloro-5-methylpyridin-3-yl)methanol 74-1 (1.57 g, 10 mmol) in dichloromethane (15 mL) was added dropwise thionyl chloride (3.6 mL, 50 mmol) at 0° C. slowly. The mixture was stirred for 2 hours at room temperature, diluted with dichloromethane (100 mL) and water (100 mL), neutralized with powder sodium carbonate to pH 8. The aqueous layer was further extracted with dichloromethane (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation to afford 2-chloro-5-(chloromethyl)-3-methylpyridine 74-2 as pale yellow solid, which was used for next step directly. MS m/z 176.1 (M+1)
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CO>[CH2:18]([NH:2][C@@H:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 10 g (S)-2-amino-4-methoxy-4-oxobutanoic acid hydrochloride in 400 ml methanol was added 15 g sodium carbonate, and the mixture was stirred at 25° C. Twenty (20) g benzyl chloride was then added dropwise at this temperature. After completion of the reaction, the mixture was maintained at this temperature for 12 h. The reaction solution was neutralized with a diluted aqueous hydrochloride acid solution to produce a neutralized solution. Methanol was evaporated, and the residue was partitioned and extracted with ethyl acetate. The organic layer was concentrated and then washed with water 2˜3 times to afford 16 g crude (S)-2-(benzylamino)-4-methoxy-4-oxobutanoic acid, with a yield of 91.3%.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]([F:38])([F:37])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>O1CCCC1.O>[OH:3][NH:2][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:20]2[CH2:21][CH2:22][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:38])([F:37])[F:9])[CH:12]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.40 g, 4.8 mmol) in water (6 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in tetrahydrofuran (5 mL) and the mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), the precipitate was filtered, washed with water, ether, and dried to give the title compound (0.23 g, 73%). M.p. 178-179° C. 1H NMR (DMSO-d6, HMDSO), δ: 2.95-3.10 (4H, m); 3.23-3.40 (4H, m, overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz); 7.09 (1H, d, 3=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40 (1H, t, 3=7.7 Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz); 7.83 (2K, d, J=8.4 Hz); 9.35 (1H, br s); 10.72 (1H, br s). HPLC analysis on Omnispher 5 C18 column: impurities 3.5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M acetate buffer (pH 5.0), 50:50; sample concentration 1 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd for C20H20F3N3O4S, %: C, 52.74; H, 4.43; N, 9.23; S, 7.04. Found, %: C, 52.04; H, 4.29, N, 8.86; S, 7.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Br:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>C1COCC1>[Br:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:26])=[CH:57][CH:56]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Br)cc3)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 13.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.080 g, 0.204 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.130 g, 0.400 mmol), TEA (1.5 mL), DMF (1.5 mL), THF (7.0 mL) and 4-bromo aniline (0.070 g, 0.400 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.30-1.45 (m, 3H), 1.46-1.56 (m, 3H), 3.08 (s, 2H), 7.39 (m, 2H), 7.53 (d, J=8.7 Hz, 4H), 7.68 (d, J=8.7 Hz, 2H), 9.78 (s, 1H), 11.50-12.00 (s, 2H); MS [M+H]+: 547.16.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].O=S(Cl)Cl.[CH3:26][NH2:27].[OH-].[Na+]>C(Cl)Cl>[CH3:26][NH:27][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: CN
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1OC
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CH2Cl2 (12 mL) was added SOCl2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2Cl2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH2Cl2 (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.C(=O)([O-])O.[Na+:35]>O>[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([O-:26])=[O:25])=[C:16]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[Na+:35]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1

Procedure:
In a solution of 0.2 g sodium hydrogen carbonate in 4 ml of water was dissolved of 0.619 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid hydrochloride. The solution was subjected to column chromatography on dextran gel (Sephadex LH-20, Pharmacia), development being carried out with water. The fractions containing the desired product were pooled and lyophilized. By the above procedure there was obtained 0.42 g of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:27]([NH2:26])=[O:28])[CH2:21][CH2:22]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCN(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Yield: 47.2 %

Procedure:
A mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 5.1 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized from ethyl acetate (2×) to yield 2.7 g (47%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 148°-150°.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH3:28])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[CH2:29](N)C>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CCN
Reactant: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Product: CCNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
Compound 19 was prepared in a manner similar to that of compound 16 using ethylamine instead of methylamine, MS 405.35 (M+1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C@H:8]([NH2:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1>>[Br:15][C:16]1[CH:21]=[C:20]([NH:12][C@@H:8]([C:7]([CH3:13])([CH3:14])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]([CH3:10])[CH3:11])[CH:19]=[N:18][CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)[C@@H](N)C(C)(C)O[SiH2]C(C)(C)C
Product: CC(C)[C@@H](Nc1cncc(Br)c1)C(C)(C)O[SiH2]C(C)(C)C

Procedure:
In analogy to the procedures described for the preparation of intermediate A-3 [B] and A-3 [C]: i) (R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-propylamine has been reacted with 3,5-dibromopyridine to give (5-bromo-pyridin-3-yl)-[(R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-propyl]-amine; ii) subsequent condensation with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as light yellow amorphous solid. MS: 454.3 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>C(O)C>[C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(c1ccccc1)O2
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To tert-butyl 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (0.98 g, 2.93 mmol) and NaHCO3 (0.99 g, 11.73 mmol) in ethanol at room temperature was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.82 g, 545 μL, 3.52 mmol) and the reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was cooled, the solid precipitate was removed by filtration and the solvent was removed in vacuo. The residue was taken up in DCM and washed sequentially with 1:1 NaOH(1N):NaHCO3 and then brine. The organics were separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.15 g, 95%). ESI-MS m/z calc. 414.2. found 415.3 (M+1)+; Retention time: 2.46 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.44-7.26 (m, 5H), 4.81 (dd, J=10.5, 2.6 Hz, 1H), 3.73 (s, 2H), 3.31 (s, 1H), 3.09 (s, 1H), 2.98 (m, 3H), 2.74 (dd, J=11.0, 1.5 Hz, 1H), 2.51 (d, J=14.1 Hz, 1H), 2.40-2.29 (m, 2H), 1.58 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]([Mg]Cl)=[CH2:11]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:10]=[CH2:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a cooled solution of 3-chlorobenzaldehyde (22.5 g, 160 mmol) in 100 mL anhydrous THF under inert nitrogen atmosphere was added slowly via syringe a 1.6 M solution of vinyl magnesium chloride in THF (100 mL, 160 mmol) and the solution stirred for three h allowing to warm to room temperature. The reaction was quenched with saturated solution of ammonium chloride and the organic layer was separated, extracted with ethyl acetate (2×200 mL), and organic layers were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by Horizon MPLC with a 40M+ silica gel column using a gradient eluent of 0-40% ethyl acetate in hexane afforded the title compound (22.4 g, 44%). m/z (ES) 168, 170 (M, M+2)+, 190, 192 (MNa, MNa+2)+. 1HNMR (500 MHz, CDCl3) δ: 7.38 (s, 1H), 7.35-7.22 (m, 3H), 5.90 (ddd, J=7.3, 10.0, 17.4 Hz, 1H), 5.38 (d, J=17.5 Hz, 1H), 5.18 (d, J=7.2 Hz, 1H), 5.15 (d, J=10.1 Hz, 1H), 0.96 (s, 9H), 0.18 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[C:23]2=[CH:22][N:21]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4cnn(C)c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS (M+H)+=373.0. 1H NMR (300 MHz, DMSO-d6) δ: 14.11 (s, 1H), 9.74 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.17 (t, J=8.1 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H).