Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Br)[CH3:10].[H-].[Na+].Cl>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:6]1[CH2:7][C:3]([O:2][CH3:1])=[CH:4][C:5]1=[O:8])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: COC1=CC(=O)NC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(OC)=CC1=O

Procedure:
4.27 g of 4-methoxy-3-pyrrolin-2-one and 8.30 g of bromoacetic acid ethyl ester were dissolved in 50 ml of dimethylformamide and mixed with 1.41 g of sodium hydride at 0° C., within 20 minutes, in 3 portions, with vigorous stirring and under argon. After 90 minutes of reaction time at 0° C., it was neutralized with dilute hydrochloric acid, and the solvent was evaporated off in a vacuum. The residue was taken up in 50 ml of ice water and twice extracted with 50 ml each of methylene chloride. The organic phase was dried over Na2SO4, and evaporated on the rotary evaporator under vacuum. The residue slowly thoroughly recrystallized at room temperature. 8.0 g of product having a melting point of 54° to 56° C. and a content according to GC of 90.8 percent was obtained.
Reaction SMILES: CN(C=O)C.C([O-])(O)=O.[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21](=O)[C:20](=[CH:23]N(C)C)[CH2:19][C:18](=[O:27])[N:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]=2[CH:34]=1.[NH:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=1)[C:36]([NH2:38])=[NH:37]>CCO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21]3[N:37]=[C:36]([NH:35][C:39]4[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=4)[N:38]=[CH:23][C:20]=3[CH2:19][C:18](=[O:27])[N:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]=2[CH:34]=1
Reactant: CN(C)C=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(c2ccccc2)C(=O)C3)cc1

Procedure:
In a manner similar to method I (DMF and NaHCO3 were used in place of EtOH and KCO3), 8-chloro-4-dimethylaminomethylene-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-i) and 4-guanidinobenzoic acid were converted to I-10 (61%): HRMS Calcd. for C25H17ClN4O3: 457.1067, Found 457.1076.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].CN.[CH:13]([N:16](C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:16][CH3:13])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CO
Product: CNc1ccc(C#N)cc1Cl

Procedure:
A solution of 3-chloro-4-fluorobenzonitrile (1.0 g), methylamine (16 mL of a 2 M solution in methanol) and diisopropylethylamine was reacted in the microwave at 120° C. for min. The mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 3-chloro-4-methylamino-benzonitrile. A suspension of 3-chloro-4-methylamino-benzonitrile (900 mg) in 2 M aqueous sodium hydroxide solution (30 mL) was heated at reflux for 3 h. After cooling to room temperature, the solution was acidified with 2 M aqueous hydrochloric acid and the resulting solid collected by filtration and air-dried to give 3-chloro-4-methylamino-benzoic acid. To a solution of 3-chloro-4-methylamino-benzoic acid (860 mg) in DMF (20 mL) was added carbonyl diimidazole (630 mg) and the reaction stirred at room temperature for 1 h. Then, methylamine hydrochloride (262 mg) and triethylamine (1.62 mL) were added and the reaction stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (3×40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-chloro-N-methyl-4-methylamino-benzamide.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][O:20][C:21]([CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)=[O:22]>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][C:21]([O:20][CH3:19])=[O:22])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: COC(=O)Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: COC(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
7-Aminocephalosporanic acid was reacted with 1-methoxycarbonylmethyl-1H-tetrazole-5-thiol in a conventional manner to give 7-amino-3-(1-methoxycarbonylmethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[S:5][CH:6]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>>[F:9][C:8]([F:11])([F:10])[C:7]([C:4]1[S:5][CH:6]=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(c1cc(Br)cs1)C(F)(F)F
Product: O=C(O)c1cccc(-c2csc(C(=O)C(F)(F)F)c2)c1
Yield: 46 %

Procedure:
This compound was synthesized from 1-(4-bromothiophen-2-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronic acid as described in example 88 step 3 (400 mg, yield 46%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.19 (br s, 1H), 8.85 (d, J=1.2 Hz, 1H), 8.50 (s, 1H), 8.29 (m, 1H), 8.10-8.08 (d, J=7.6 Hz, 1H), 7.96-7.94 (d, J=7.6 Hz, 1H), 7.62-7.59 (t, J=7.8 Hz, 1H). MS (ESI) m/z: Calculated for C13H7F3O3S: 300.01. found: 298.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: NCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Brc1cn2ccnc2c(NCc2ccncc2)n1
Temperature: 25 °C

Procedure:
A solution of 6,8-Dibromo-imidazo[1,2-a]pyrazine 3 (1.0 equiv.), 4-aminomethylpyridine (1.0 equiv.) and potassium carbonate (3.0 equiv.) is dissolved in 20 ml 3:1 acetonitrile: dimethylacetamide and is stirred at 100° C. for 16 hours. The mixture is cooled to RT and partitioned between ethyl acetate (EtOAc) and saturated NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-pyridin-4-ylmethyl-amine 4.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)([O:3]CC)=O.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH2:23][CH2:22][CH2:21][NH:24][C:1]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[O:3]
Reactant: NCCN
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Product: NCCNC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
A mixture of 2.85 g (10.3 mmol) of 6-(4-carboethoxymethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 13) and 9.3 g (155 mmol) of ethylenediamine is heated at 60° C. under N2 for 30 min. Volatile materials are removed in vacuo, and the residue is recrystallized from methanol-EtOAc to give 2.40 g of 6-[4-[2-aminoethylcarbamoylmethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid, m.p. 176°-177.5° C. Yield, 80%.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH:23]=O)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH2:23][N:36]3[CH2:35][CH2:34][CH:33]([C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:39])[F:40])=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1CN(C(=O)c2cccc3ccccc23)CC1c1ccsc1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Product: O=C(c1cccc2ccccc12)N1CC(CN2CCC(c3ccc(C(F)(F)F)cc3)CC2)C(c2ccsc2)C1

Procedure:
The title compound was prepared from 1-(1-naphthoyl)-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine (Example 82 and 4-(4-trifluoromethylphenyl)piperidine according to procedures described in Example 1, Step F. 1H NMR (CDCl3) δ7.34 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz); Mass Spectrum (CI) m/e=549 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14]([N:16]3[CH:20]=[CH:19]N=C3)=[O:15])=[N:10][C:9]=2[CH3:21])[CH:5]=[C:4]([CH3:22])[N:3]=1.NCC[C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>CN(C=O)C>[CH3:22][C:4]1[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:15])[NH:16][CH2:20][CH2:19][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:10][C:9]=2[CH3:21])[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)cc(C)n1
Reactant: CN(C)C(=O)CCN
Solvent: CN(C)C=O
Product: Cc1cc(-c2sc(NC(=O)NCCC(=O)N(C)C)nc2C)cc(C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide (Intermediate BA) (0.05 g, 0.16 mmol) in DMF (1.5 ml) under an inert atmosphere is added 3-amino-N,N-dimethyl-propionamide (Amine) (0.018 g, 0.16 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the resulting crude residue is dissolved in THF and passed through a plug of polymer supported isocyanate resin (0.5 g, pre-washed with THF). The solution is concentrated in vacuo and the crude residue is trituated with ether-ethyl acetate to afford the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[CH2:11][O:10]1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[CH3:23][N:24]([CH3:25])[CH2:11][CH:9]([OH:10])[CH2:8][O:7][C:6]1[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC
Reactant: CC(CCc1ccccc1OCC1CO1)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(CCc1ccccc1OCC(O)CN(C)C)Cc1ccccc1
Yield: 86 %

Procedure:
Following a procedure similar to that described in Example 1(b), 1.0 g of 2-[2-(3-methyl-4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran was treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 0.99 g (yield 86%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:22])[C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C:17]2=[O:21])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][CH2:8][CH2:7][CH2:6]1.C(OCC)C.[Cl-].[NH4+].[C:30]([Mg]Br)#[C:31][CH3:32]>C1COCC1>[F:1][CH:2]([F:22])[C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@:17]2([OH:21])[C:30]#[C:31][CH3:32])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][CH2:8][CH2:7][CH2:6]1
Reactant: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CCCC[C@@H]4[C@H]3[C@@H](C(F)F)C[C@@]21C
Reaction time: 16 h

Procedure:
A mixture of 11β-difluoromethylestr-4-en-17-one (XII, Example 14, 0.9 g) in propynyl magnesium bromide (0.5M, 10 ml) and THF is kept at 20°-25° for 16 hours. Diethyl ether and aqueous ammonium chloride are added and the diethyl ether phase is separated and washed with water and concentrated to a solid. The solid is purified by chromatography through silica gel using ethyl acetate/hexane (20/80) as the irrigant. The appropriate fractions are pooled and concentrated to give the title compound, IR (mull) 3400, 2237 and 1666 cm-1 ; MS (m/e) 348, 330, 315, 266 and 251; NMR (CDCl3) 0.87, 1.86 and 6.0 δ.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:15].C(=O)(O)[O-].[Na+].[C:21]([O:25][C:26](=O)[O:27]C(C)(C)C)([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:25][C:26](=[O:27])[N:7]([CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[C:3]([CH3:15])[CH:4]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1cc(CNCCC(C)C)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1Br
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(4-bromo-3-methyl-benzyl)-(3-methyl-butyl)-amine (I-2b: 13.7 g) was dissolved in 100 mL of ethyl acetate and treated with 200 mL of a saturated aqueous sodium bicarbonate solution and di-tert-butyl-carbonate (14.3 g, 65.5 mmol). The reaction mixture was stirred at 50° C. for 2 hours before cooling to room temperature and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (I-2c).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:24]=[O:25])C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([CH:24]=[O:25])=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a stirred solution of tert-butyl(4-chloropyridin-2-yl)carbamate (1.00 g, 4.37 mmol) in THF (30 mL) cooled to −78° C. was added n-butyllithium (2.55 M in hexane, 4.1 mL, 10.06 mmol) dropwise. After complete addition the solution was stirred at −78° C. for 1 h. DMF (1.591 mL, 20.55 mmol) was added dropwise and the resultant solution stirred at −78° C. for an additional 1 h. The reaction mixture was then quenched by addition of saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via neutral alumina gel chromatography (ethyl acetate/hexanes) to yield tert-butyl(4-chloro-3-formylpyridin-2-yl)carbamate (530 mg, 2.07 mmol, 27% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 10.55 (s, 1H), 8.52 (d, J=5.3 Hz, 1H), 7.06 (d, J=5.3 Hz, 1H), 1.56 (s, 9H); LCMS (ESI) m/e 255.2 [(M−H)−, calcd for C11H12ClN2O3 255.0]; LCMS retention time (Method C): tR=1.73 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8]1.[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8]1
Reactant: O=C1CCC(c2ccccn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1CC[C@H](c2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 3-(2-pyridyl)cyclopentan-1-one (3.17 g, 19.7 mmol) in MeOH (80 ml) was added portionwise NaBH4 (745 mg. 19.7 mmol) at 0° C., and stirred for 2 h at room temperature. The reaction mixture was poured into ice-water and then extracted with EtOAc. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/1→1/3) to yield trans-3-(2-pyridyl)cyclopentanol (965 mg, 30%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][CH:3]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:18][O:12][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(Nc1c(Cl)cccc1[N+](=O)[O-])C(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of N-(6-chloro-2-nitrophenyl)-2-methylalanine (X, EXAMPLE 14, 11.4 g), DMF (130 ml), potassium carbonate (18.2 g) and iodomethane (13.8 ml) is stirred at 20°-25° for 16 hr, diluted with water, extracted several times with ether. The ether phases are combined and are washed with water and saline, dried over magnesium sulfate and concentrated to give the title compound, IR (mineral oil) 3369, 2990, 2951, 1738, 1598, 1534, 1492, 1451, 1386, 1337, 1277, 1188, 1145, 1103 and 749 cm-1 ; NMR (CDCl3) 7.97, 7.55, 6.94, 6.89, 3.78 and 1.53 δ; MS (m/z) 272 and 213.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][C:11]([CH:13]=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:11]([CH3:13])[CH:10]=[N:9]2
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(=O)C=O
Solvent: CC#N
Product: Cc1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 61A (9.4 g, 50 mmol) in acetonitrile (100 mL) was treated with 40% aqueous pyruvic aldehyde (11.0 mL, 60 mmol) dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated and the residue was suspended in IPAc (100 mL) and filtered. The filtrate was washed with 20% brine, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with heptane:EtOH:MeOH (8:2:1) to provide the title compounds. MS 224 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.72 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.75-7.93 (m, 4H), 2.78 (s, 3H), 2.76 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 154.32, 153.73, 146.34, 145.83, 142.28, 141.17, 140.45, 139.34, 133.17, 132.15, 131.15, 130.75, 130.16, 129.71, 123.66, 122.38, 22.89.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][OH:25])[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[O:37]=[C:38]=[N:39][C:40](Cl)=[O:41].C(Cl)Cl.C[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[C:40](=[O:41])[NH:39][C:38](=[O:37])[O:25]5)[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NO)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@@H]2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)o1
Reaction time: 2.25 h

Procedure:
To a solution of 2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine, 55b, (0.072 g, 0.136 mmol) in THF (2 mL) at 0° C. was added N-(oxomethylene)carbamoyl chloride (0.014 mL, 0.176 mmol). A white solid formed immediately. The slurry was shaken and sonicated to make an even suspension/slurry. Then, —CH2Cl2 (1 mL)) was added to help solvate the slurry. After 135 min, the mixture was treated with NaOMe (2 mL, 25% w/v). After 2 min, the mixture was quenched with saturated NH4Cl and acidified with 1M HCl. The mixture was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Preparative HPLC provided the desired product (25 mg).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH2:21])[CH3:20]>O>[CH2:19]([NH:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][N:7]=1)[CH3:20]
Reactant: CCN
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Solvent: O
Product: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.289 mmol), water (1.2 mL) and ethylamine in water (70%, 1.2 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield the product (67 mg) as a white solid. 1H NMR δ ppm 8.62 (d, 1 H) 7.95 (dd, 1 H) 7.82 (d, 1 H) 7.64 (d, 1 H) 7.23 (t, 1 H) 7.07 (dd, 1 H) 6.57 (d, 1 H) 3.83 (s, 3 H) 3.33-3.40 (m, 2 H) 1.16 (t, 3 H); MS m/z (M+H) 286.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=O)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:41]1.NN.CCOC(C)=O>CN(C=O)C>[C:21]([C:20]1[CH:19]=[N:18][N:17]2[CH:24]=[C:25]([C:27]([NH:40][NH2:41])=[O:29])[CH:26]=[C:16]2[C:15]=1[NH:14][C@@H:11]1[CH2:12][CH2:13][C@@:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:32])[C:10]1([CH3:31])[CH3:30])(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C1(C)C
Yield: 106.4 %

Procedure:
A solution of 4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (3.0 g, 6.73 mmol), BOP (3.57 g, 8.08 mmol) and hydrazine (1.057 mL, 33.7 mmol) in DMF (25 mL) was stirred for 30 minutes, and then the reaction mixture was added 350 mL of EtOAc which was washed with 10% LiCl solution (2×100 mL), 100 mL of brine and dried over Na2SO4. Filtration and concentration gave the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (3.29 g, 99% yield). HPLC retention time=2.457 min., LC/MS (M+H)+=460.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 88.1 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.60 g, 8 mmol) and potassium phthalimide (2.22 g, 12 mmol) in N,N-dimethylformamide (30 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.95 g, 88.2%) as crystals.